WO2005121094A1 - Piperazine and piperidine derivatives as anti-hiv-agents - Google Patents

Abstract

This invention relates to a compound of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof, wherein R1 to R5 are defined in the description, and to processes for the preparation thereof, intermediates used in their preparation, compositions containing them and the uses of such derivatives. The compounds of the present invention inhibit the interaction of gp120 with CD4 and are 10 therefore of use in the treatment of HIV, a retroviral infection genetically related to HIV, or AIDS.

Description

PIPERAZINE AND PIPERIDINE DERIVATIVES AS ANTI-H V-AGENTS

This invention relates to six membered cyclic amine derivatives, to processes for their preparation, to compositions containing them and to their use. More particularly, the present invention relates to the use of six membered cyclic amine derivatives in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS). Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cofactors. It is recognised that for efficient entry into target cells, human immunodeficiency viruses require a chemokine receptor, such as CCR5 or CXCR-4, as well as the primary receptor CD4. The principal cofactor for the entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the β-chemokines RANTES, MIP-1α and MIP-1 β (Deng et al., 1996, Nature, 38, 661-666).

HIV attaches to the CD4 molecules on target cells through a region of its envelope protein, gp120. It is believed that the CD4 binding site on the gp120 of HIV interacts with the CD4 molecule on the target cell surface and undergoes conformational changes, which allow it to bind to further cell-surface receptors such as CCR5 or CXCR-4. This brings the viral envelope in closer proximity to the cell surface and allows i nteraction b etween g p41 o n the viral e nvelope a nd a f usion d omain on the host cell surface, subsequent fusion with the cell membrane and, ultimately, entry of the viral core into the cell.

Accordingly, compounds that inhibit the binding of gp120 with CD4, and hence prevent the entry of HIV-1 into a target cell, should be useful in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS). According to a first aspect of the present invention, there is provided a compound of formula (I)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:

R¹ is phenyl; napthyl; or a C-linked or N-linked, 5 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocycle wherein said heterocycle contains 1 to 4 nitrogen heteroatom(s), 1 or 2 nitrogen and 1 oxygen heteroatoms, or 1 or 2 nitrogen and 1 sulphur heteroatoms; wherein said phenyl, napthyl or heterocycle is optionally substituted by 1 to 3 atoms or groups selected from C C₆ alkyl,

C C₆ fluoroalkyl, C₃-C₇ cycloalkyl, phenyl, OH, C Cβ alkoxy, Cι-C₆ alkoxy C^C_B alkyl, OC C₆fluoroalkyl, C₀-C₂ alkylene NR⁶R⁷, halo, C₀-C₂ alkylene CN, C₀-C₂ alkylene C0₂R⁸, C₀-C₂ alkylene CONR⁶R⁷, Co-C₂ alkylene SR⁹, C₀-C₂ alkylene SOR⁹, C₀-C₂ alkylene S0₂R⁹, C₀-C₂ alkylene S0₂NR⁶R⁷, C₀-C₂ alkylene NR⁸COR⁹, C₀-C₂ alkylene NR⁸CONR⁶R⁷, C₀-C₂ alkylene NR⁸S0₂R⁹, C₀-C₂ alkylene R¹⁰, or, where R is a heterocycle, oxo; X is CH; or, where R¹ is phenyl; napthyl; or a C-linked heterocycle; may also be N;

R² and R³ are independently H, or Cι-C₆alkyl;

R⁴ is d-C₆ alkyl;

R⁵ is phenyl; naphthyl; or a C-linked, 6 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocycle wherein said heterocycle contains 1 to 4 nitrogen heteroatom(s), 1 or 2 nitrogen and 1 oxygen heteroatoms, or 1 or 2 nitrogen and 1 sulphur heteroatoms; wherein said phenyl, napthyl or heterocycle is optionally substituted by 1 to 3 atoms or groups selected from C C₆ alkyl,

Crd fluoroalkyl, C₃-C₇cycloalkyl, phenyl, OH, C C₆ alkoxy, C C₆ alkoxy

alkyl, OC Cβfluoroalkyl, C₀-C₂ alkylene NR⁶R⁷, halo, C₀-C₂ alkylene CN, C₀-C₂ alkylene C0₂R⁸, C₀-C₂ alkylene CONR⁶R⁷, Co-C₂ alkylene SR⁹, C₀-C₂ alkylene SOR⁹, C₀-C₂ alkylene S0₂R⁹, C₀-C₂ alkylene S0₂NR⁶R⁷, C₀-C₂ alkylene NR⁸C0R⁹, C₀-C₂ alkylene NR⁸CONR⁶R⁷, C₀-C₂ alkylene NR⁸S0₂R⁹, or C₀-C₂ alkylene R¹⁰, or, where R⁵ is a heterocycle, oxo;

R⁶ and R⁷ are independently H, C C₆ alkyl, C₃-C₇ cycloalkyl, phenyl or R¹⁰ , wherein said alkyl is optionally substituted by OH or C C₆ alkoxy; or when taken together with the nitrogen to which they are attached, R⁶ and R⁷ form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine, or thiomorpholine ring; wherein the said substituents are 1 or 2 groups selected from

alkyl or C₀-C_β alkylene NH₂;

R⁸ is H, Cι-C₆ alkyl or phenyl;

R⁹ is C Cβ alkyl or phenyl; and

R¹⁰ is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by 1 to 3 atoms or groups selected from C C₆ alkyl, C-|-C₆ alkoxy, cyano or halo. The term "alkyl" as a group or p art of a g roup i ncludes straight c hain a nd b ranched g roups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. The term "C₃.₇ cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "halo" means fluoro, chloro, bromo or iodo. In a further embodiment, X is N. In yet a further embodiment, X is CH. In yet a further embodiment, R¹ is a heterocycle selected from pyridyl, pyrimidinyl, isoquinolinyl, naphthridinyl, imidazopyrazinyl, benzisoxazolyl, furopyridinyl, quinazolinyl, pyrazolopyridinyl, oxazolopyridinyl, imidazopyridinyl, or dihydrofuropyndinyl; wherein said heterocycle is optionally substituted by 1 or 2 groups selected from C C alkyl, phenyl, C C₃aIkoxy, or CONR⁶R⁷. In yet a further embodiment, R¹ is isoquinolinyl, m ethyl pyridyl, phenylpyridyl or naphthridinyl. In yet a further embodiment, R² is CτC₄alkyl. In yet a further embodiment, R² is methyl. In yet a further embodiment, R³ is H. In yet a further embodiment, R⁴ is Cι-C₄alkyl. In yet a further embodiment, R⁴ is methyl. In yet a further embodiment, R⁵ is an optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or benzoxazolyl; wherein said substituents are 1 to 3 atoms or groups selected from C C₆ alkyl, C Cβ alkoxy, halo, CN, C0₂R⁸, CONR⁶R⁷, or R¹⁰. in yet a further embodiment, R⁵ is an optionally substituted phenyl or pyridyl, wherein said substituents are 1 to 3 groups selected from C C₆ alkoxy, C0₂R⁸, or CONR⁶R⁷. In yet a further embodiment, R⁶ is H or C C₄ alkyl. In yet a further embodiment, R⁷ is H, C C₄ alkyl or C₃-C₆ cycloalkyl, wherein said alkyl is optionally substituted by OH or C C₃ alkoxy. In yet a further embodiment, R⁸ is C_rC₄ alkyl. In yet a further embodiment, R⁹ is C C₄ alkyl. In yet a further embodiment, R¹⁰ is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted by 1 to 3 atoms or groups selected from C C₄ alkyl, C C₄ alkoxy, cyano or halo. In yet a further embodiment, there is provided a compound of formula (la)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R³, R⁴, R⁵ and X are as defined hereinabove with respect to a compound of formula (I), including all embodiments, and combinations of particular embodiments, thereof. In yet a further embodiment, there is provided a compound of formula (lb)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R³, R⁴ and R⁵ are as defined hereinabove with respect to a compound of formula (I), including all embodiments, and combinations of particular embodiments, thereof. In yet a further embodiment, there is provided a compound of formula (lc)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R⁴ and R⁵ are as defined hereinabove with respect to a compound of formula (I), including all embodiments, and combinations of particular embodiments, thereof. It is to be understood that the invention covers all combinations of particular embodiments of the invention as described hereinabove, consistent with the definition of compounds of formula (I). The compounds of the invention include compounds of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives i nclude complexes, p olymorphs, prodrugs and isotopically-labeled compounds, as well as salts, solvates and salt solvates thereof), and isomers thereof. In a further embodiment, the compounds of the invention are the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, in particular the compounds of formula (I). It is to be understood that in the aforementioned further embodiments of the invention there is included polymorphs and isomers of the compounds thereof. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate, bisulphate, borate, bromide, camsylate, carbonate, chloride, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrobromide, hydrochloride, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, sulphate, tartrate, tosylate and trifluoroacetate salts. Suitable b ase s alts a re formed f rom b ases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Complexes include clathrates, i.e. drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the pharmaceutical drug which contain two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms ("polymorphs") are encompassed within the scope of the invention. Polymorphism generally can occur as a response to changes i n temperature o r p ressure o r b oth, and can also result from variations in the crystallization process. Polymorphs can be distinguished by varjous physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs. Certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (C C₆)alkyl; (ii) where the compound of formula (I) contains an a lcohol f unctionality ( -OH), a n e ther thereof, for example, replacement of the hydrogen with (C CβJalkanoyloxymethyl; and (iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH₂ or - NHR where R ≠ H), an amide thereof, for example, replacement of one or both hydrogens with (C C₁₀)alkanoyl. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types in accordance with the invention may be found in the aforementioned references. Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include: (i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH): (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂); (v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and (vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH). In view of the definition of R⁴, compounds of formula (I) contain one or more asymmetric carbon atoms and therefore exist as two or more optical isomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically H PLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine.

Concentration of the eluate affords the enriched mixture. Stereoisomehc conglomerates m ay b e s eparated by e onventional t echniques k nown t o t hose skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New

York, 1994). The present invention also includes all pharmaceutically acceptable isotopically-Iabelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as

¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S. Certain isotopically-Iabelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹ C, ¹⁸F, ¹⁵0 and ¹³N, can be useful in

Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂0, d₆-acetone, d₆-DMSO. Preferred compounds of formula (I) include the compounds of Examples 1-42; and pharmaceutically acceptable salts, solvates or derivatives thereof. In the general processes, and schemes, that follow: X and R¹ to R¹⁰ are as previously defined unless otherwise s tated; Y i s h alo o r h ydroxy; Z i s a l eaving group, such as chloro, bromo, tosylate, mesylate or hydroxy; L is a leaving group, such as fluoro, chloro, bromo, iodo or mesylate; DMF is N,N- dimethylformamide; DMSO is dimethylsulphoxide; THF is tetrahydrofuran; WSCDI is 1-(3- dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride; DCC is N,N'-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1 -hydroxybenzotriazole hydrate; HBTU is 0-(1 H-benzotriazol-1- yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate; PyBOP® is benzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate; PyBrOP is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; Hunigs base is N-ethyldiisopropylamine; and Mukaiyama's reagent is 2-chloro-1- methylpyridinium iodide. Compounds of formula (I) may be prepared by any methods known for the preparation of compounds of analogous structure. Compounds of formula (I), and intermediates thereto, may be prepared according to the schemes that follow. It will be appreciated by those skilled in the art that certain of the procedures described in the schemes for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents. It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I). It will be still further appreciated by those skilled in the art that, as illustrated in the schemes that follow, it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups. The amino protecting groups boc, benzyloxycarbonyl, benzyl and acetyl are of particular use in the preparation of compounds of formula (I) and intermediates thereto.

Scheme 1

In the case where X is CH, the piperidines of formula (VII) are either known compounds or may be prepared by conventional chemistry. In the case where X is N, the piperazines of formula (VII) may be prepared according to scheme 1a.

Scheme 1a

(IX) (VII)

Those skilled in the art will appreciate that a compound of formula (I), wherein X is N, may also be prepared according to the transformations described in schemes 1 and 1a, but carried out in a different order from that previously described, for example as shown in scheme 1 b Scheme 1b

With specific reference to schemes 1 ,1a and 1 b, the transformations depicted therein may be effected as follows:

(a),(d)&(e) Acid-amine coupling reactions Compounds of formulae ( I), ( II) o r ( IV) m ay be p repared by the reaction of the relevant acid chloride or acid bromide of formulae (VI) or (VIII), with the relevant amine of formulae (VII) or (IX) under conventional conditions. Conveniently, the reaction may be effected optionally using an acid acceptor such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; in the presence of a solvent, such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF); and at ambient temperature for 1-24 hours. The reactions may conveniently be carried out by reacting the relevant amine with 1.1 equivalents of the relevant acid chloride in dichloromethane at room temperature for 1 hour. In a further embodiment, compounds of formula (I), (II) or (IV) may be prepared by the reaction of t he relevant a cid of formulae (VI) o r (VIII), w ith t he relevant amine of formulae (VII) or (IX) under conventional conditions. Conveniently, the reaction may be effected using a reagent which activates the acid, such as WSCDI/DCC and HOBt/HOAt; an acid acceptor such as triethylamine or Λ/-ethyl-Λ/,Λ/- diisopropylamine; in the presence of a solvent, such as an haloalkane (e.g. dichloromethane), an ether (e.g. T HF) o r D MF; a nd a t a mbient temperature for 4-48 hours. The reactions may conveniently be carried out by reacting the relevant amine, 1.4 equivalents of WSCDI, 1.4 equivalents of HOBt, 2.2 equivalents of triethylamine a nd 1 .1 equivalents of the relevant carboxylic a cid i n dichloromethane at room temperature for 18 hours. In yet a further embodiment, compounds of formula (I), (II) or (IV) may be prepared by the reaction of the relevant acid of formulae (VI) or (VIII), with the relevant amine of formulae (VII) or (IX) using a reagent which activates the acid, such as HBTU, PyBOP, PyBrOP or Mukaiyama's reagent; an acid acceptor such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; in the presence of a solvent, such as an haloalkane (e.g. dichloromethane), an ether (e.g. THF) or DMF; and at ambient temperature for 4- 24 hours. The reactions may conveniently be carried out by reacting the relevant amine, 1.0 equivalents of the relevant carboxylic acid and 1.5 equivalents of HBTU in either dichloromethane or DMF at room temperature for 14 hours.

(b)&(c) Nucleophilic substitution Compounds of formulae (I) or (VII) may be prepared by the nucleophilic substitution of a compound of formulae (IV) or (IX), respectively, with a compound of formula R¹-L (V) under conventional conditions. Conveniently, the reaction may be effected using an alkali metal halide, such as caesium fluoride; optionally, an acid acceptor, such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; in the presence of a solvent such as DMSO, DMF or N-methylpyrrolidine; and at a temperature between 130°C and 180°C for 6-24 hours. The reactions may conveniently be carried out by reacting compounds of formula (IV) or (IX), R¹-L (V) and 1.0 equivalents of caesium fluoride and 1.2 equivalents of triethylamine in DMSO at 150°C for 24 hours. In a further embodiment, the reaction may conveniently be effected using a catalytic quantity of copper(ll)sulphate; optionally, an acid acceptor, such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; in the presence of a solvent such as DMSO, DMF or N-methylpyrrolidine; and at a temperature between 130°C and 180°C for 6-24 hours.

(f) Nucleophilic substitution i) When Z= Cl, Br, mesylate, tosylate: Compounds of formula (I) may be prepared by the nucleophilic substitution of a compound of formula (II) with an alcohol of formula (III) under conventional conditions. Conveniently, the reaction may be effected using an acid acceptor, such as triejhylamine, Λ/-ethyl-Λ/,Λ/-diisopropylamine or an alkali metal carbonate; in the presence of a solvent such as an haloalkane (e.g. dichloromethane), an ether (e.g. THF) or acetone; and at a temperature between ambient and reflux for 1-24 hours. The reactions may conveniently be carried out by reacting compounds of formulae (II) and (III) with 1.0 equivalents of caesium carbonate in acetone at reflux for 14 hours. ii) When Z= OH: Compounds of formula (I) may be prepared by the nucleophilic substitution of a compound of formula (II) with an alcohol of formula (III) under conventional conditions. Conveniently, the reaction may be effected in using triphenylphosphine or tri-o-tolylphosphine and either diethyl azodicarboxylate or di- isopropyl azodicarboxylate; in the presence of a a solvent such as an haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at a temperature between room temperature and reflux for 1 -24 h ours. T he reactions may conveniently be carried out by reacting compounds of formulae (II) and (III) with 1.2 equivalents of triphenylphosphine and 1.1 equivalents of di-isopropyl azodicarboxylate in THF at room temperature for 14 hours. Compounds of formula (VI) in reaction steps (a) and (d) may be prepared according to scheme 1c that follows.

Scheme 1c

<x) (XI) OT

wherein R is a lower alkyl such as C C₆ alkyl

(g) Nucleophilic substitution Nucleophilic substitution may be effected according to the conditions described in connection with step (f) hereinabove. (h) Ester hydrolysis Compounds of formula (VI) wherein Y is OH may be prepared by the hydrolysis of an ester of formula (XI) under conventional conditions. Conveniently, the reaction may be effected using aqueous alkali metal hydroxide solution or aqueous hydrochloric acid solution; in the presence of an optional co- solvent such as ethanol or dioxin; and at a temperature between 60 and 100°C for 1-18 hours. The reactions may conveniently be carried out by heating compounds of formula (XI) in aqueous 1 N sodium hydroxide solution and dioxan heated at 60 °C for 2 hours. Compounds of formulae (III), (V), (VIII), (IX) and (X) are either known compounds or may be prepared by conventional chemistry. According to another aspect, the invention provides the following processes for preparing compounds of formula (I). According to a first process (A), compounds of formula (I) may be prepared by coupling an acid of formula (VI)

with an amine of formula (VII), under conventional acid-amine coupling conditions.

Conveniently, acid amine coupling is effected under the conditions described hereinabove in connection with scheme 1 , step (d). According to a second process (B), compounds of formula (I) may be prepared by nucleophilic substitution of a compound of formula (II)

with an alcohol R⁵OH of formula (III) under conventional conditions. Conveniently, nucleophilic substitution is effected under the conditions described hereinabove in connection with scheme 1 , step (f). According to a third process (C), compounds of formula (I), wherein X is N, may be prepared by nucleophilic substitution of a piperazine of formula (IV)

with a compound R¹-L of formula (V) under conventional conditions. Conveniently, nucleophilic substitution is effected under the conditions described hereinabove in connection with scheme 1b, step (c). According to a fourth process (D), compounds of formula (I) may be prepared from other compounds of formula (I) by functional group interconversion under conventional conditions. For example, compounds of formula (I) which contain an ester group may be converted to corresponding compounds of formula (I) which contain a primary or secondary amide group by reacting the former with ammonia or a primary amine respectively. The compounds of the invention inhibit the interaction of gp120 with CD4 and are therefore of use in the treatment of HIV, a retroviral infection genetically related to HIV, and AIDS. Accordingly, in another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use as a medicament. In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS. In another aspect the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof for the manufacture of a medicament for the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS. In another aspect the invention provides a method of treatment of a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof. The compounds of the invention may be a dministered a s c rystalline o r a morphous p roducts. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their p reparation m ay b e found, for example, i n ' Remington's P harmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001 ). For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the d osage form, m ore typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet. Tablets a lso g enerally contain l ubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other possible ingredients include anti-oxidants, colourants, flavours, preservatives and taste- masking agents. Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H.

Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X). Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release f ormulations for the p urposes of the i nvention a re d escribed i n U S

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

(including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the compound.

Examples of such formulations include drug-coated stents and PGLA microspheres. The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10),

955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. M odified release formulations i nclude delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.

For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the compound, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative s olvents which m ay b e u sed instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglyco!ic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1μg to 10mg of the compound of the invention. The overall daily dose will typically be in the range 1μg to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, poiyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for m ost d osage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Inasmuch a s i t m ay desirable to administer a compound of the invention in combination with another therapeutic agent, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. For administration to human patients, having a weight of about 65 to 70kg, the total daily dose of a compound of the invention is typically in the range 1 to lOOOOmg, such as 10 to 1000mg, for example 25 to 500mg, depending, of course, on the mode of administration, the age, condition and weight of the patient, and will in any case be at the ultimate discretion of the physician. The total daily dose may be administered in single or divided doses. Accordingly in another aspect the invention provides a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers. The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives have the advantage that they are more selective, have a more rapid onset of action, are more potent, are better absorbed, are more stable, are more resistant to metabolism, have a reduced 'food effect', h ave a n i mproved s afety p rofile o r h ave o ther m ore d esirable p roperties ( e.g. w ith r espect to solubility or hygroscopicity) than the compounds of the prior art. The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives may be administered alone or as part of a combination therapy. Thus included within the scope of the present invention are embodiments comprising coadministration of, and compositions which contain, in addition to a compound of the invention, one or more additional therapeutic agents. Such multiple drug regimens, often referred to a s combination therapy, m ay b e u sed i n t he t reatment a nd prevention of infection by human immunodeficiency virus, HIV. The use of such combination therapy is especially p ertinent with respect to the treatment and prevention of infection and multiplication of the human immunodeficiency virus, HIV, and related pathogenic retroviruses within a patient in need of treatment or one at risk of becoming such a patient. The ability of such retroviral pathogens to evolve within a relatively short period of time into strains resistant to any monotherapy which has been administered to said patient is well known in the literature. A recommended treatment for HIV is a combination drug treatment called Highly Active Anti-Retroviral Therapy, or HAART. HAART combines three or more HIV drugs. Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ a compound of the invention in the form of monotherapy, but said methods and compositions may also be used in the form of combination therapy in which one or more compounds of the invention are coadministered in combination with one or more additional therapeutic agents such as those described in detail further herein. In a further embodiment of the invention, combinations of the present invention include treatment with a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, and one or more additional therapeutic agents selected from the following: HIV protease inhibitors (Pis), including but not limited to indinavir, ritonavir, saquinavir, nelfinavir, lopinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, AG1859 and TMC 114; non-nucleoside reverse transcriptase inhibitors (NNRTIs), including but not limited to: nevirapine; delavirdine; capravirine; efavirenz, rilpivirine; 5-{[3,5-diethyl-1-(2- hydroxyethyl)-1 /-/-pyrazol-4-yl]oxy}isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; 5-{[3-cyclopropyl-1 -(2-hydroxyethyl)-5-methyl-1 H-pyrazol-4-yl]oxy}isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; GW-8248; GW-5634 and TMC125; nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), i ncluding b ut n ot l imited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir dipivoxil, tenofovir, emtricitabine and alovudine; CCR5 antagonists, including but not limited to: maraviroc; methyl 1-e 7θO-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl- 4,5,6,7-tetrahydro-1 W-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof; methyl 3-enoO-{8-[(3S)-3-(acetamido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl- 4,5,6,7-tetrahydro-3r7-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof;

Λ/-{(1 S)-3-[3-endo-(5-isobUtyryl-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-1-yl)-8- azabicyclo[3.2.1]oct-8-yI]-1-(3-fIuorophenyl)propyl}acetamide or derivatives thereof; Sch D, ON04128, GW873140, AMD-887 and CMPD-167; other agents which inhibit the interaction of gp120 with CD4, including but not limited to BMS806, BMS-488043, 5-{(1S)-2-[(2R)-4-Benzoyl-2-methyl- piperazin-1-yl]-1-methyl-2-oxo-ethoxy}-4-methoxy-pyridine-2-carboxylic acid methylamide and 4-{(1 S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy}-3-methoxy-N-methyl- benzamide; other agents which inhibit the entry of HIV into a target cell, including but not limited to enfuviritide, T1249, PRO 542 , PRO 140 and TNX355; integrase inhibitors, including but not limited to L- 870,810; prenylation inhibitors such as statins (e.g. atorvastatin ); and RNaseH inhibitors.

There is also included within the scope the present invention, combinations of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents independently selected from the group consisting of proliferation inhibitors, e.g. hydroxyurea; immunomodulators, such as granulocyte macrophage colony stimulating growth factors (e.g. sargramostim), and various forms of interferon or interferon derivatives; other chemokine receptor agonists/antagonists, such as CXCR4 antagonists (e.g. AMD-070); agents which substantially inhibit, disrupt or decrease viral transcription or RNA replication such as inhibitors of tat (transcriptional trans activator) or nef (negative regulatory factor); agents which substantially inhibit, disrupt or decrease translation of one or more proteins expressed by the virus (including, but not limited to, down regulation of protein expression or antagonism of one or more proteins) other than reverse transcriptase, such as

Tat or Nef; agents which influence, in particular down regulate, CCR5 receptor expression; chemokines that induce CCR5 receptor internalisation such MIP-1α, MIP-1 β, RANTES and derivatives thereof; and other agents that inhibit viral infection or improve the condition or outcome of HIV-infected individuals through different mechanisms.

Agents which influence (in particular down regulate) CCR5 receptor expression include immunosupressants, such as calcineurin inhibitors (e.g. tacrolimus and cyclosporin A); steroids; agents which interfere with cytokine production or signalling, such as Janus Kinase (JAK) inhibitors (e.g. JAK-3 inhibitors, including 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1- yl}-3-oxo-propionitrile) and pharmaceutically a cceptable s alts, s olvates o r d erivatives t hereof; c ytokine antibodies (e.g. antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab); and agents which interfere with cell activation or cell cycling, such as rapamycin. There is also included within the scope the present invention, combinations of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus, among the agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. The i soforms of CYP450 that m ay b e b eneficially i nhibited i nclude, b ut a re n ot l imited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole.

It will be a ppreciated b y a p erson s killed i n t he a rt, t hat a c ombination d rug t reatment, a s d escribed herein above, may comprise two or more compounds having the same, or different, mechanism of action. Thus, by way of illustration only, a combination may comprise a compound of the invention and: one or more NRTIs; one or more NRTIs and a PI; one or more NRTIs and a CCR5 antagonist; one or more CCR5 antagonists; a PI; a PI and an NNRTI; an NNRTI; and so on. In addition to the requirement of therapeutic efficacy, which may necessitate the use of therapeutic agents in addition to the compounds of the invention, there may be additional rationales which compel or highly recommend the use of a combination of a compound of the invention and another therapeutic agent, such as in the treatment of diseases or conditions which directly result from or indirectly accompany the basic or underlying disease or condition. For example, it may be necessary or at least desirable to treat Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Human Papillomavirus (HPV), opportunistic infections (including bacterial and fungal infections), neoplasms, and other conditions which occur as the result of the immune-compromised state of the patient being treated. Other therapeutic agents may be used with the compounds of the invention, e.g., in order to provide immune stimulation or to treat pain and inflammation which accompany the initial and fundamental HIV infection. Accordingly, therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives also include agents having anti-hepatitis activity, in particular, agents having anti-HCV activity, i.e. agents which can inhibit a target such as, but not limited to, HCV metalloprotease, HCV serine protease, HCV polymerase (NS5B), HCV helicase, HCV NS4B protein, HCV NS5A protein, and TLR (Toll-Like Receptor) 7. Examples include, but are not limited to, interferons, pegylated interferons (e.g. peginterferon alfa-2a and peginterferon alfa-2b), lamivudine, ribavirin, and emtricitabine.Therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives further include antifungals such as fluconazole, itraconazole, and voriconazole; antibacterials such as azithromycin and cla thromycin; interferons, daunorubicin, doxorubicin, and paclitaxel for the treatment of AIDS related Kaposi's sarcoma; and cidofovir, fomivirsen, foscamet, ganciclovir and valcyte for the treatment of cytomegalovirus (CMV) retinitis. Further combinations for use according to the invention include combination of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof with a CCR1 antagonist, such as BX-471 ; a beta adrenoceptor agonist, such as salmeterol; a corticosteroid agonist, such fluticasone propionate; a LTD4 antagonist, such as montelukast; a muscarinic antagonist, such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 inhibitor, such as celecoxib, valdecoxib or rofecoxib; an alpha-2-delta ligand, such as gabapentin or pregabalin; a beta- interferon, such as REBIF; a TNF receptor modulator, such as a TNF-alpha inhibitor (e.g. adalimumab), a HMG CoA reductase inhibitor, such as a statin (e.g. atorvastatin); or an immunosuppressant, such as cyclosporin or a macrolide such as tacrolimus. In the above-described combinations, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and other therapeutic agent(s) may be administered, in terms of dosage forms, either separately or in conjunction with each other; and in terms of their time of administration, either simultaneously or sequentially. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s). Accordingly, in a further aspect the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more additional therapeutic agents. It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The invention is illustrated by the following Examples and Preparations in which the following further abbreviations may be used: h = hour min = minute

LRMS = low resolution mass spectrum APCI+ = atmospheric pressure chemical ionisation ES+ = electrospray ionisation

NMR = nuclear magnetic resonance Me = methyl

Example 1 4-((1 S)-2-r(2R)-4-(lsoquinolin-1 -yl)-2-methyl-piperazin-1 -yll-1 -methyl-2-oxo-ethoxy>-3-methoxy-benzoic acid methyl ester

A solution of 3-methoxy-4-{(1S)-1-methyl-2-[(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (0.5 g, 1.3 mmol), 1-chloroisoquinoline (0.22 g, 1.3 mmol), caesium fluoride (0.2 g, 1.3 mmol) and triethylamine (0.38 ml, 2.7 mmol) in DMSO (4 ml) were heated in a Reacti-vial ™ (Pierce Biotechnology) at 150°C for 18 hours. The reaction mixture was allowed to cool and partioned between ethyl acetate (50 ml) and water (15 ml). The aqueous phase was separated and extracted with ethyl acetate (30 ml). The combined organic extracts were dried (MgS0₄) and evaporated under reduced pressure to give an orange oil. The orange oil was purified by column chromatography on silica gel eluting with a gradient system changing from dichloromethane : methanol (99:1) to dichloromethane : methanol (95:5) to afford the title compound as a pale brown solid (0.21 g).

¹H NMR (400MHz, CDCI₃): δ : 8.13 (2H, m), 7.77 (1H, d), 7.67-7.48 (4H, m), 7.29 (1 H, t), 6.91 (1 H, d), 5.11 (1 H, m), 4.90-4.30 (1 H, m), 3.91 (3H, s), 3.90 (3H, s), 3.80-2.80 (3H, m), 1.71 (3H, d), 1.63+1.37 (3H, d) ppm.

LRMS (APCI+) : m/z [M+H]⁺ 465. Example 2

4-{(1S)-2-r(2R)-4-(lsoquinolin-1-yl)-2-methyl-piperazin-1-yll-1-methyl-2-oxo-ethoxy)-3-methoxy-N-methyl- benzamide

A mixture of 4-{(1 S)-2-[(2R)-4-(isoquinolin-1 -yl)-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy}-3- methoxy-benzoic acid methyl ester (0.09 g, 0.19 mmol) and 33% methylamine in ethanol (4 ml) were heated in a Reacti-vial ™ (Pierce Biotechnology) at 120°C for 18 hours. The reaction mixture was allowed to cool and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system changing from dichloromethane : methanol (99.5:0.5) to dichloromethane : methanol (96:4) to afford the title-compound as a colourless foam (0.064 g)-

¹H NMR (400MHz, CD₃OD): δ : 8.22 (1 H, d), 8.07 (1 H, dd), 7.84 (1 H, d), 7.70 (1 H, t), 7.61 (1H, t), 7.47 (1 H, s), 7.37 (2H, m), 6.93 (1 H, dd), 5.31 (1 H, m), 4.60-4.20 (1 H, m), 3.90 (3H, s), 3.80-3.40 (2H, m), 3.20-2.80 (2H, m), 2.89 (3H, s), 1.61 (3H, d), 1.49+1.30 (3H, d) ppm. LRMS (APCI+) : m/z [M+H]⁺ 463.

Example 3 4-{(1 S)-2-|^'(2R)-4-(lsoquinolin-1 -yl)-2-methyl-piperazin-1 -yll-1 -methyl-2-oxo-ethoxy>-3-methoxy- benzamide

A mixture of 4-{(1 S)-2-[(2R)-4-(isoquinolin-1 -yl)-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy}-3- methoxy-benzoic acid methyl ester (0.068 g, 0.15 mmol) and a saturated solution of ammonia in methanol (10 ml) were heated in a sealed metal vessel at 140°C for 18 hours. The reaction mixture was allowed to cool and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system changing from dichloromethane : methanol (99:1) to dichloromethane : methanol (95:5) to afford the title compound as a colourless foam (0.017 g). ¹H NMR (400MHz, CD₃OD): δ : 8.23 (1 H, d), 8.04 (1H, dd), 7.84 (1 H, d), 7.70 (1 H, t), 7.61 (1 H, t), 7.54 (1 H, s), 7.45 (1 H, m), 7.37 (1 H, m), 6.93 (1 H, dd), 5.31 (1 H, m), 4.60-4.20 (2H, m), 3.90 (3H, s), 3.80- 3.40 (2H, m), 3.20-2.80 (2H, m), 1.66 (3H, d), 1.65+1.40 (3H, d) ppm. LRMS (APCI+) : m/z [M+H]⁺ 449.

Examples 4-7 were prepared by the method described above for Example 1 , using the corresponding piperazine of formula (IV) and the corresponding compound of formula (V).

LRMS was by APCI+ and data quoted are for [M+H]⁺.

Examples 8, 10, 12 were prepared by the method described above for Example 2, from, respectively, Examples 4, 5 and 6. Examples 9, 11 , 13 were prepared by the method described above for Example 3, from, respectively, Examples 4, 5 and 6. Example 14 was prepared by the method described above for Example 2, from Example 15. Example 15 was prepared by the method described above for Example 1 , u sing t he corresponding piperazine of formula (IV) and the corresponding compound of formula (V).

LRMS was by APCI+ and data quoted are for [M+H]⁺.

Example 16 2-Chloro-5-f(1 S)-2-f(2R)-4-isoquinolin-1-yl-2-methylpiperazin-1-vn-1-methyl-2-oxoethoxy)quinoline

A solution of (2S)-2-[(2-chloroquinolin-5-yl)oxy]propanoic acid (Preparation 13) (0.3 g, 1.2 mmol), 1- [(3R)-3-methylpiperazin-1-yl]isoquinoline (0.27 g, 1.2 mmol), 0-benzotriazole-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.54 g, 1.4 mmol) and triethylamine (0.83 mL, 6 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL), washed with aqueous sodium hydroxide solution (1N, 2 X 5 mL), dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient system changing from pentane:ethyl acetate, 66:33 to pentane:ethyl acetate 15:85 to afford the title compound as a white solid, 0.35 g. LRMS (APCI⁺): m/z [M+H]⁺ 461 ¹H NMR (400MHz, CDCI₃): δ: 8.60 (1 H, m), 8.15-8.05 (2H, m), 7.75 (1 H, m), 7.60 (3H, m), 7.50 (1 H, m), 7.40 (1 H, m), 7.30 (1 H, m), 6.90 (1 H, m), 5.15 (1 H, m), 5.00-2.60 (7H, m), 1.80 (3H, d), 1.65+1.40 (3H together, d) ppm. Example 17

5-{(1S)-2-r(2R)-4-lsoquinolin-1-yl-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxy)-N-methylquinolin-2- amine

A solution of 2-chloro-5-{(1S)-2-[(2R)-4-isoquinolin-1-yl-2-methylpiperazin-1-yl]-1-methyl-2- oxoethoxy}quinoline (0.1 g, 0.22 mmol), methylamine hydrochloride (0.15 g, 2.2 mmol), tetraethylammonium fluoride (0.057 g, 0.44 mmol) and triethylamine (0.3 mL, 2.2 mmol) in DMSO (1 mL) was heated in a Reacti-vial™ at 130 °C for 48 hours. The cooled reaction mixture was purified on a FractionLynx autopurification system to afford the title compound as a yellow solid, 0.032 g. LRMS (APCI⁺): m/z [M+H]⁺ 456

¹H NMR (400MHz, CDCI₃): δ: 10.3 (1 H, br s), 9.00-7.30 (7H, m), 6.90 (1 H, m), 6.70 (1 H, m), 5.30 (1 H, m), 5.00-3.20 (7H, m), 3.10 (3H, s), 1.80 (3H, d), 1.50+1.30 (3H together, d) ppm.

Example 18

2-r(5-((1 S)-2-r(2R)-4-lsoquinolin-1 -yl-2-methylpiperazin-1 -yll-1 -methyl-2-oxoethoxy)quinolin-2- vDaminolethanol

The title compound was prepared from 2-chloro-5-{(1S)-2-[(2R)-4-isoquinolin-1-yl-2-methylpiperazin-1- yl]-1-methyI-2-oxoethoxy}quinoline and ethanolamine, according to the method decribed above in

Example 17, as a pale brown solid.

LRMS (APCI⁺): m/z [M+H]⁺ 486

¹H NMR (400MHz, CDCI₃): δ: 8.30 (1 H, m), 8.15-8.05 (2H, m), 7.75 (1 H, m), 7.60 (1 H, m), 7.50 (1 H, m),

7.40 (1 H, m), 7.30 (2H, m), 6.60 (2H, m), 6.00 (1 H, br s), 5.15 (2H, m), 5.00-2.60 (11 H, m), 1.80-1.40

(6H, m) ppm. Examples 19-34 were prepared by the method described above for Example 16, using the corresponding piperazine or piperidine of formula (VII) and the corresponding carboxylic acid of formula (VI).

LRMS was by APCI+ and data quoted are for [M+H]⁺.

Example 35

4-Methoxy-N-methyl-5-((1 S)-1 -methyl-2-r(2R)-2-methyl-4-(1 H-pyrrolor3,2-clpyridin-4-yl)piperazin-1 -yll-2- oxoethoxy)pyridine-2-carboxamide

A solution of (S)-2-(4-methoxy-6-methylcarbamoyl-pyridin-3-yloxy)-propionic acid hydrochloride (0.06 g, 0.2 mmol), 4-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrrolo[3,2-c]pyridine (0.045 g, 0.2 mmol), O- benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.118 g, 0.3 mmol) and triethylamine

(0.087 mL, 0.6 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a gradient system changing from ethyl acetate:methanol 95:5 to ethyl acetate:methanol:concentrated aqueous ammonia 90:10:1 to afford the title compound as a yellow solid, 0.021 g. LRMS (APCI⁺): m/z [M+H]⁺ 453

¹H NMR (400MHz, CDCI₃): δ: 8.05 (1 H, m), 7.85 (1 H, m), 7.75 (2H, m), 7.00 (1 H, m), 6.65 (1H, m), 5.15 (1 H, m), 4.90-3.10 (7H, m), 3.95 (3H, s), 3.00 (3H, s), 1.60 (3H, m), 1.30 (3H, m) ppm.

Example 36 4-Methoxy-N-methyl-5-{(1 S)-1 -methyl-2-r(2R)-2-methyl-4-(1 H-pyrrolor3,2-clpyridin-4-yl)piperazin-1 -yll-2- oxoethoxy|pyridine-2-carboxamide

A solution of (2S)-2-({1-[(methylamino)carbonyl]isoquinolin-5-yl}oxy)propanoic acid (0.065 g, 0.2 mmol),

4-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrrolo[3,2-c]pyridine (0.27 g, 1 .2 m mol), 0 -benzotriazoIe-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.099 g, 0.25 mmol) and triethylamine (0.145 mL, 1 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL), washed with water (2 X 5 mL), 10 % w/v aqueous potassium carbonate solution (2 X 5 mL), dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient system changing from ethyl acetate:methanol 98:2 to ethyl acetate:methanol 90:10 to afford the title compound as a yellow solid, 0.024 g. LRMS (APCI⁺): m/z [M+H]⁺ 473 ¹H NMR (400MHz, CDCI₃): δ: 9.15 (1 H, m), 8.45 (1 H, m), 8.25 (1 H, m), 8.10 (1 H, m), 7.85 (1 H, m), 7.50 (1 H, m), 7.05 (2H, m), 6.85 (1 H, m), 6.40 (1 H, m), 5.20-2.80 (7H, m), 3.05 (3H, s), 1.75 (3H d), 1.20 (3H, m) ppm.

Example 37 Methyl 5- 1 S)-2-IT2R)-4-(1.2-benzisoxazol-3-yl)-2-methylpiperazin-1 -yll-1 -methyl-2- oxoethoxy)isoquinoline-1-carboxylate

A solution of 5-{(1 S)-2-[(2R)-4-(1 ,2-benzisoxazol-3-yl)-2-methylpiperazin-1-ylj-1-methyI-2-oxoethoxy}-1- chloroisoquinoline (0.095 g, 0.2 mmol), dichloro(1 ,1-bis(diphenyIphosphino)ferrocene)paIladium(ll) (0.017 g, 0.02 mmol) and triethylamine (0.03 mL, 0.2 mmol) in methanol (3 mL) was heated under a carbon monoxide atmosphere (689 kPa) at 100 °C for three hours. The reaction mixture was allowed to cool to room temperature, filtered through Arbocel^® and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient system changing from pentane:ethyl acetate, 50:50 to ethyl acetate to afford the title compound as a pale brown solid, 0.045 g. LRMS (APCI⁺): m/z [M+H]⁺ 475

¹H NMR (400MHz, CDCI₃): δ: 9.05 (1 H, d), 8.45 (1 H, m), 8.25 (1 H, m), 8.15 (1 H, m), 7.60-7.40 (4H, m), 7.20 (1 H, m), 7.05 (1 H, m), 5.20 (1 H, m), 5.00-2.80 (7H, m), 3.70 (3H, s), 1.85 (3H d), 1.50+1.20 (3H together, d) ppm.

Example 38

5-((1 S)-2-r(2R)-4-(1 ,2-Benzisoxazol-3-yl)-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxy)-N- methylisoquinoline-1 -carboxamide

The title compound was prepared from methyl 5-{(1S)-2-[(2R)-4-(1 ,2-benzisoxazol-3-yl)-2- methylpiperazin-1-yl]-1-methyl-2-oxoethoxy}isoquinoline-1-carboxylate, according to the method described above in Example 2, as a white solid.

LRMS (APCI⁺): m/z [M+H]⁺ 474

¹H NMR (400MHz, CDCI₃): δ: 9.15 (1 H, d), 8.45 (1H, m), 8.25 (1 H, m), 8.10 (1 H, m), 7.60-7.40 (4H, m), 7.20 (1 H, m), 7.05 (1 H, m), 5.20 (1 H, m), 5.00-2.80 (7H, m), 3.05 (3H, s), 1.80 (3H d), 1.50+1.20 (3H together, d) ppm.

Example 39

4-{(1S)-2-r(2R)-4-(2,3-Dihvdrofuror3,2-clPyridin-4-yl)-2-methylpiperazin-1-vπ-1-methyl-2-oxoethoxy)-3- methoxy-N-methylbenzamide

A solution of 4-{(1S)-2-[(2R)-4-furo[3,2-c]pyridin-4-yl-2-methylpiperazin-1-yl]-1-methyl-2-oxoethoxy}-3- methoxy-N-methylbenzamide (0.055 g, 0.12 mmol) a nd 1 0 % w/w P d o n carbon (wet, D egussa type E101 ) (0.01 g) in ethanol (2 mL) was hydrogenated (275 kPa H₂) at 50 °C for 18 hours. The reaction mixture was filtered through Arbocel^®, washing through with ethanol (5 mL). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia 98:2:0.5 to afford the title compound as a white solid, 0.021 g. LRMS (APCI⁺): m/z [M+H]⁺ 455

¹H NMR (400MHz, CD₃OD): δ: 7.85 (1 H, m), 7.45 (1 H, m), 7.35 (1H, m), 6.90 (1 H, m), 6.40 (1 H, m), 5.25 (1 H, m), 4.80-2.70 (11 H, m), 3.90 (3H, s), 2.90 (3H, s), 1.60 (3H, m), 1.40+1.20 (3H together, d) ppm.

Example 40

3-Methoxy-N-methyl-4-l(1 S)-1 -methyl-2-r(2R)-2-methyl-4-π ,3loxazolor4.5-clpyridin-4-ylpiperazin-1 -yll-2- oxoethoxy)benzamide

A solution of __ 4-{(1S)-2-[(2R)-4-(3-amino-4-hydroxypyridin-2-yl)-2-methylpiperazin-1-yl]-1-methyl-2- oxoethoxy}-3-methoxy-N-methylbenzamide (0.007 g, 0.16 mmol) in diethoxymethyl acetate (5 mL) was heated at 120 °C for four hours. The cool reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was separated, dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 90:10 to afford the title compound as a white solid, 0.0035 g.

LRMS (APCI⁺): m/z [M+Hf 454

¹H NMR (400MHz, CDCI₃): δ: 8.05 (1 H, m), 7.90 (1 H, m), 7.45 (2H, m), 7.15 (1 H, m), 6.90 (2H, m), 6.00

(1 H, m), 5.10 (1 H, m), 5.00-3.10 (7H, m), 3.90 (3H, s), 3.00 (3H, d), 1.60 (3H, m), 1.30 (3H, m) ppm. Example 41

4-((1S)-2-r(2R)-4-(1 H-lmidazof4,5-clpyridin-4-yl)-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxy>-3- methoxybenzoic acid

A solution of 4-{(1S)-2-[(2R)-4-(3,4-diaminopyridin-2-yl)-2-methylpiperazin-1-yl]-1-methyl-2-oxoethoxy}-3- methoxy-N-methylbenzamide (0.177 g, 0.4 mmol) in diethoxymethyl acetate (10 mL) was heated at 110 °C for four hours. The cool reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was separated, dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system changing from ethyl acetate:methanol 95:5 to 80:20 to afford the title compound as a white solid, 0.077 g. LRMS (ESI^"): m/z [M-H]⁺ 438 ¹H NMR (400MHz, CDCI₃): δ: 7.95 (2H, m), 7.65 (1 H, m), 7.60 (1 H, m), 7.35 (1H, s), 6.90 (2H, m), 5.10 (2H, m), 5.00-2.80 (7H, m), 3.90 (3H, s), 1.65 (3H, m), 1.30 (3H, m) ppm.

Example 42

4-((1 S)-2-r(2R)-4-(1 H-lmidazor4,5-clpyridin-4-yl)-2-methylpiperazin-1-vπ-1-methyl-2-oxoethoxy)-3- methoxy-N-methylbenzamide

The title compound was prepared from 4-{(1S)-2-[(2R)-4-(1 H-imidazo[4,5-c]pyridin-4-yl)-2- methylpiperazin-1-yl]-1-methyI-2-oxoethoxy}-3-methoxybenzoic acid and methylamine hydrochloride, according to the method described above in Example 16, as a light brown solid. LRMS (APCI⁺): m/z [M-H]⁺ 453

¹H NMR (400MHz, CDCI₃): δ: 7.95 (2H, m), 7.45 (1 H, m), 7.35 (1 H, m), 7.15 (1 H, m), 6.90 (2H, m), 6.10 (1 H, m), 5.20-3.10 (8H, m), 3.90 (3H, s), 3.00 (3H, d), 1.65 (3H, m), 1.30-1.10 (3H, m) ppm. Preparation 1

3-Methoxy-4-f(1S)-1-methoxycarbonyl-ethoxy1-benzoic acid methyl ester

Diisopropyl azodicarboxylate (4mL, 20mmol) in tetrahydrofuran (15mL) was added dropwise to an ice- cooled solution of m ethyl vanillate (3.64g, 20mmol), (R)-methyl lactate (2.08g, 20mmol) and triphenyl phosphine (5.24g, 20mmol) in tetrahydrofuran (30mL) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50mL) and hexane (50mL). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. P urification of the residue by column chromatography on silica gel, eluting with hexane:ethyl acetate, 85:15 to 75:25 afforded the title compound in 71 % yield, 3.8g LRMS (ES⁺): m/z [M+H]⁺ 269

Preparation 2

4-[(1 S)-1-Carboxy-ethoxy1-3-methoxy-benzoic acid methyl ester

Lithium hydroxide monohydrate (4.2g, lOOmmol) was added portionwise to a solution of 3-Methoxy-4- [(1S)-1-methoxycarbonyl-ethoxy]-benzoic acid methyl ester (32g, 120mmol) in methanol (150mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified with 2M hydrochloric acid to pH4 and was then extracted with ethyl acetate (3x150mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to afford the title compound in 91 % yield, 23g. LRMS (ES⁺): m/z [M+H]⁺ 255

Preparation 3

(3R)-4-r(2S)-2-(2-Methoxy-4-methoxycarbonyl-phenoxy)-propionyll-3-methyl-piperazine-1-carboxylic acid tert-butyl ester

Triethylamine (16.5 ml, 118 mmol) was added to a solution of 4-[(1 S)-1-carboxy-ethoxy]-3-methoxy- benzoic acid methyl ester (30.0 g, 118 mmol), (3R)-3-methyl-piperazine-1 -carboxylic acid tert-butyl ester (23.6g, 118 mmol) and 3-(diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (35.3 g, 118 mmol) in THF (400 ml). The mixture was stirred for 18 hours then diluted with ethyl acetate (800 ml) and washed sequentially with water (300 ml), 10 % citric acid solution (300 ml), water (300 ml), 10% sodium carbonate solution (300 ml) and water (200 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichIoromethane:methanol, 99:1 to 93:7 afforded the title compound as a colourless foam, 31.1 g. LRMS (ES⁺): m/z [M+H]⁺ 438

Preparation 4

3-Methoxy-4-{(1 S)-1 -methyl-2-r(2R)-2-methyl-piperazin-1 -yll-2-oxo-ethoxy)-benzoic acid methyl ester

HCI gas was bubbled into a cold (-5°C) solution of (3R)-4-[(2S)-2-(2-methoxy-4-methoxycarbonyl- phenoxy)-propionylj-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.3 mmol) in dichloromethane (20 ml) until saturated. After 30 minutes the solution was evaporated under reduced pressure to afford the title compound as a yellow solid, 0.9 g. LRMS (ES⁺): m/z [M+H]⁺ 337

Preparation 5

Methyl 5-(benzyloxy)isoquinoline-1 -carboxylate

A solution of 5-(benzyloxy)-1-chloroisoquinoline (WO9920608) (1.75 g, 6.5 mmol), dichloro(1 ,1- bis(diphenylphosphino)ferrocene)palladium(ll) (0.53 g, 0.65 mmol) and triethylamine (1.81 mL, 13 mmol) in methanol (30 mL) was h eated u nder a carbon m onoxide atmosphere ( 689 k Pa) at 1 00 ° C for s ix hours. The reaction mixture was allowed to cool to room temperature, filtered through Arbocel^® and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 80:20 to afford the title compound as a pale yellow solid, 1.64 g. LRMS (APCI⁺): m/z [M+H]⁺ 294 Preparation 6 5-(Benzyloxy)-N-methylisoquinoline-1 -carboxamide

A solution of methyl 5-(benzyloxy)isoquinoline-1-carboxylate (1.64 g, 5.6 mmol) in ethanol (10 mL) and a solution of methylamine in ethanol (33% w/w in ethanol) (15.6 mL) were heated in a sealed metal vessel at 90 °C for four hours. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient system changing from pentane:ethyl acetate, 80:20 to ethyl acetate to afford the title compound as a white solid, 1.36 g. LRMS (APCI⁺): m/z [M+H]⁺ 293

Preparation 7

5-Hvdroxy-N-methylisoquinoline-1 -carboxamide

A suspension of 5-(benzyloxy)-N-methylisoquinoline-1 -carboxamide (0.92 g, 3.2 mmol) and 10 % palladium hydroxide on carbon (0.23 g) in ethanol (30 mL) was heated to 70 °C and ammonium formate (0.3 g, 4.8 mmol) added portionwise. The reaction mixture was stirred at 70 °C for two hours, allowed to cool to room temperature and filtered through Arbocel^®. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography o n s ilica g el, e luting with p entane:ethyl acetate, 80:20 to afford the title compound as a white solid, 0.58 g. LRMS (ES): m/z [M+H]⁺ 203

Preparation 8

Methyl 2-({1-r(methylamino)carbonyllisoquinolin-5-yl)oxy)propanoate

A suspension of 5-hydroxy-N-methyIisoquinoline-1-carboxamide (0.23 g, 1.1 mmol), methyl 2- bromopropanoate (0.14 mL, 1.2 mmol) and caesium carbonate (0.74 g, 2.2 mmol) in acetone (30 mL) was stirred at room temperature for two hours. Additional methyl 2-bromopropanoate (0.07 mL, 10.6 mmol) was then added and stirring continued for a further hour. The reaction mixture was evaporated under reduced pressure and the residue partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was separated, dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 40:60 to afford the title compound as a white solid, 0.285 g. LRMS (ES): m/z [M+H]⁺ 289

Preparation 9

2-((1 -f(Methylamino)carbonyllisoquinolin-5-ylloxy)propanoic acid hvdrochloride

A solution of methyl 2-({1-[(methylamino)carbonyl]isoquinolin-5-yl}oxy)propanoate (0.285 g, 1.0 mmol) and aqueous sodium hydroxide solution (1N, 1.5 mL, 1.5 mmol) in 1 ,4-dioxan (10 mL) was heated at 60 °C for three hours. - The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was dissolved in water (10 mL) and washed with dichloromethane (5 mL). The aqueous layer was acidified to pH2 by the addition of concentrated aqueous hydrochloric acid and then evaporated under reduced pressure. The residue was slurried with isopropyl alcohol (10 mL), filtered and the filtrate evaporated under reduced pressure to afford the title compound as a pale yellow powder, 0.33 g. LRMS (ES): m/z [M+H]⁺ 275

Preparation 10

Methyl (2S)-2-(quinolin-5-yloxy)propanoate

A solution of di-/so-propyl azodicarboxylate (2.95 mL, 15.2 mmol) in tetrahydrofuran (40 mL) was cooled to 5 °C and triphenylphosphine (4.34 g, 16.6 mmol) added portionwise to give a pale yellow solution. (R)- methyl lactate (1.32 mL, 13.8 mmol) and 5-hydroxyquinoline (2.0 g, 13.8 mmol) were then added and the solution stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was separated and washed with water (20 mL), 10% w/v aqueous potassium carbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried (MgS0₄) and concentrated under reduced pressure, the residue was triturated with pentane:ethyl acetate (4:1 v/v, 30 mL) and the p recipitated triphenylphosphine oxide removed b y f iltration. T he f iltrate was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a gradient system changing from pentane:ethyl acetate, 80:20 to pentane:ethyl acetate 20:80 to afford the title compound as a colourless oil, 2.77 g. LRMS (APCI⁺): m/z [M+H]⁺ 232

Preparation 11

Methyl (2S)-2-[(1 -oxidoquinolin-5-yl)oxylpropanoate

m-Chloroperbenzoic acid (3.58 g, 10.4 mmol) was added to a solution of methyl (2S)-2-(quinolin-5- yloxy)propanoate (2.0 g, 8.7 mmol) in dichloromethane (20 mL) and the solution stirred at room temperature for 18 hours. The reaction mixture was washed with water (20 mL), aqueous sodium hydroxide solution (1 N, 20 mL), dried (MgS0 ) and concentrated under reduced pressure to afford the title compound as an orange oil which was used directly without further purification, 2.61 g. LRMS (ES⁺): m/z [M+H]⁺ 248

Preparation 12 Methyl (2S)-2-r(2-chloroquinolin-5-yl)oxylpropanoate

Methyl (2S)-2-[(1-oxidoquinolin-5-yl)oxy]propanoate (2.6 g, 10.5 mmol) and phosphorous oxychloride

(2.94 mL, 31.5 mmol) in dichloromethane (50 mL) were heated under reflux for three hours. The reaction mixture was allowed to cool and carefully treated with water (20 mL). The organic layer was separated, dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 80:20 to afford the title compound as a pale yellow oil, 0.98 g. LRMS (ES⁺): m/z [M+H]⁺ 266

Preparation 13 (2S)-2-|-(2-Chloroquinolin-5-yl)oxylpropanoic acid

A solution of methyl (2S)-2-[(2-chloroquinolin-5-yl)oxy]propanoate (0.98 g, 3.7 mmol) and aqueous sodium hydroxide solution (1 N, 4.4 mL, 4.4 mmol) in 1 ,4-dioxan (15 mL) was heated at 60 °C for three hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was d issolved i n water (10 mL) and acidified to pH 4-5 by the addition of acetic acid. The aqueous phase was extracted with ethyl acetate (2 X 20 mL), the combined organic extracts dried (MgS0₄) and evaporated under reduced pressure to afford the title compound as a pale yellow powder, 0.84 g. LRMS (ES): m/z [M+H]* 252

Preparation 14

Methyl (2S)-2-({1-r(methylamino)carbonyriisoquinolin-5-yl)oxy)propanoate

The title compound was prepared from 5-hydroxy-N-methylisoquinoline-1 -carboxamide and (R)-methyl lactate, according to the method described above in Preparation 10, as a pale yellow oil. LRMS (ES): m/z [M+H]⁺ 289 Preparation 15 (2S)-2-({H(Methylamino)carbonvπisoquinolin-5-ylK>xy)propanoic acid

The title compound was prepared from methyl (2S)-2-({1-[(methylamino)carbonyl]isoquinolin-5- yl}oxy)propanoate, according to the method described above in Preparation 13, as a yellow powder. LRMS (ES): m/z [M+H]⁺ 275

Preparation 16 4-Hvdroxy-3-methoxy-N-methyl-benzamide

To a mechanically stirred suspension of vanillic acid (84 g, 0.5 mol) in dry THF (300 mL) was added portion-wise carbonyldiimidazole (97 g, 0.6 mol). Gaseous evolution was observed and the mixture became homogeneous after approx 5 minutes. After further stirring for 30 minutes an off-white precipitate form and stirring was maintained for a further 3 hours under nitrogen. After this time LCMS analysis indicated that the vanillic acid had been consumed and a solution of 2 M methylamine in THF (1000 mL, 2 mol) was added in one portion and the mixture stirred for a further 16 hours to generate a tan precipitate. The precipitate was filtered, washed with THF (2 x 250 mL) followed by ether (300 mL) and dried under vacuum to afford the N-methylammonium salt of the title compound (87g, 82%). LRMS (ESI+): m/z [M+H]⁺ 182.

A portion of the ammonium salt (1.06 g, 5 mmol) was refluxed in ethyl acetate under a stream of nitrogen for 2 hours. The reaction was evaporated to give an oily solid, which was triturated with ethyl acetate to afford the title compound as a tan solid (750 mg) LRMS (ESI+): m/z [M+H]⁺ 182. Preparation 17 (2S)-2-(2-Methoxy-4-methylcarbamoyl-phenoxy)-propionic acid

To a stirred mixture of triphenylphosphine (42 g, 0.16 mol), 4-hydroxy-3-methoxy-N-methyl-benzamide (20 g, 0.11 mol) and (R)-methyl lactate (12 g, 0.12 mol) in dry THF (300 mL) at -5 °C was added dropwise a solution of di-/so-propyl azodicarboxylate (32 mL, O.16 mmol) in dry THF (100 mL) over 30 minutes. The solution was allowed to warm to room temperature and stirred for 2 hours. After this time tic analysis indicated that the starting phenol had been consumed. The crude reaction mixture was evaporated under reduced pressure to give a viscous oil. To a stirred solution of this oil in methanol (150 mL) was added lithium hydroxide monohydrate (5.4 g, 0.13 mol) and the mixture stirred for 48 hours. After this time LCMS analysis indicated that the intermediate methyl ester had been consumed. The crude reaction mixture was evaporated and partitioned between ether (500 mL) and water (150 mL). The aqueous phase was separated and washed with ether (2 x 300 mL) and ethyl acetate (2 x 300 mL). The aqueous phase was then acidified to pH 2 using concentrated aqueous hydrochloric acid resulting in the formation of a white precipitate. This precipitate was filtered off, washed with water (2 x 100 mL) and recrystallised from ethanol water (1 :1 by volume, 80 mL per 20 g) to afford the title compound as a white solid (21 g, 75%). LRMS (ESI+): m/z [M+H]⁺ 254

Preparation 18

5-Benzyloxy-4-methoxy-pyridine-2-carboxylic acid methylamide

5-Benzyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (24.7 g, 90.4 mmol) (Tetrahedron Letters, 38, 1297 (1997)) was dissolved in a solution of methylamine in ethanol (3M, 82 mL) and the mixture heated in a sealed metal vessel at 50 °C for 18 hours. The cool reaction mixture was evaporated under reduced pressure to dryness and the residue purified by column chromatography on silica gel, eluting with dichIoromethane:methanol, 97:3 to afford the title compound as a white solid, 21.9 g. LRMS (APCI⁺): m/z [MH]⁺ 273 Preparation 19

5-Hvdroxy-4-methoxy-pyridine-2-carboxylic acid methylamide

A solution of 5-benzyloxy-4-methoxy-pyridine-2-carboxylic acid methylamide (10.8 g, 39.7 mmol) and 10 % w/w Pd on carbon (0.1 g) in methanol (100 mL) was hydrogenated (138 kPa H₂) at room temperature for five hours. The reaction mixture was filtered through Arbocel^®, washing through with methanol (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound as a white solid, 7.2 g. LRMS (APCI⁺): m/z [M+H]⁺ 183

Preparation 20

(S)-2-(4-Methoxy-6-methylcarbamoyl-pyridin-3-yloxy)-propionic acid methyl ester

5-Hydroxy-4-methoxy-pyridine-2-carboxylic acid methylamide (13.1 g, 72 mmol), (R)-methyl lactate (8.23 g, 79 mmol) and triphenylphosphine (30.1 g, 15 mmol) were dissolved in THF (150 mL) and the mixture cooled to 0 °C under a nitrogen atmosphere. A solution of di-/so-propyl azodicarboxylate (21.2 mL, 108 mmol) in THF (50 mL) was then added dropwise over one hour, the reaction mixture allowed to warm to room temperature and stirred for an additional 18 hours. The reaction mixture was evaporated to dryness and the residue used directly in the following step.

Preparation 21 (S)-2-(4-Methoxy-6-methylcarbamoyl-pyridin-3-yloxy)-propionic acid hvdrochloride

(S)-2-(4-Methoxy-6-methylcarbamoyl-pyridin-3-yloxy)-propionic acid methyl ester (crude product from

Preparation 20) (assumed to be 72 mmol), was dissolved in methanol (150 mL), lithium hydroxide (3.93 g, 94 mmol) added portionwise and the mixture stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water (300 mL) and a 1 :1 v/v mixture o f e thyl a cetate a nd d iethyl e ther ( 300 m L). T he a queous I ayer was separated and washed sequentially with ethyl acetate (2 X 200 mL), diethyl ether (2 X 200 mL) and finally a 1 :1 v/v mixture of ethyl acetate and diethyl ether (300 mL). The aqueous layer was acidified to pH1 by addition of concentrated hydrochloric acid (-30 mL) and then evaporated to dryness. The residue was re-dissolved in acetonitrile (200 mL) and water (200 mL) and then evaporated under reduced pressure until the volume of solvent had reduced to -100 mL. On standing at room temperature a white solid started to precipitate (the title compound), acetonitrile (100 mL) was added and the mixture stirred and sonicated to complete the precipitation. The resulting white solid was filtered off, washed with a little acetonitrile and dried under vacuum to give the title compound as a white solid, 25.87 g. LRMS (APCI⁺): m/z [M+H]⁺ 255

Preparation 22 1-[(3R)-3-Methylpiperazin-1-vπisoquinoline

A solution of (2R)-2-methylpiperazine (9.83 g, 98 mmol) and 1-chloroisoquinoline (16.0 g, 98 mmol) in diisopropylethylamine (34 mL) and n-butanol (150 mL) was heated at 100 °C for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and washed with water (2 X 100 mL). The organic layer was separated and the combined aqueous layers saturated with sodium chloride and extracted with ethyl acetate (200 mL). The combined organic layers were dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system changing from ethyl acetate:methanol 98:2 to ethyl acetate:methanol:concentrated aqueous ammonia 90:10:1 to afford the title compound as a yellow oil, 9.0 g. LRMS (ES): m/z [M+H]⁺ 228

Preparation 23

8-f(3R)-3-Methylpiperazin-1 -yllimidazofl ,2-alpyrazine

A solution of (2R)-2-methylpiperazine (0.2 g, 1.95 mmol), 8-chloroimidazo[1 ,2-a]pyrazine (0.2 g, 1.3 mmol) and diisopropylethylamine (0.45 mL, 2.6 mmol) in n-butanol (10 mL) was heated at 100 °C for three hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:concentrated aqueous ammonia, 95:5:0.5 to afford the title compound as a pale orange solid, 0.16 g. LRMS (ES): m/z [M+H]⁺ 218

Preparation 24

3-[(3R)-3-Methylpiperazin-1 -yll-1 ,2-benzisoxazole

A solution of (2R)-2-methylpiperazine (0.13 g, 1.3 mmol), 3-chIoro-1 ,2-benzisoxazole (0.2 g, 1.3 mmol) and triethylamine (0.36 mL, 2.6 mmol) in ethoxyethanol (8 mL) was heated at reflux for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (2 X 10 mL). The organic layer was dried (MgS0₄) and evaporated under reduced pressure to afford the title compound as a brown oil, 0.14 g. LRMS (APCI⁺): m/z [M+H]⁺ 218

Preparations 25-29 were prepared by the same method as Preparation 23 from (2R)-2-methylpiperazine and the corresponding chloro-heterocycle.

LRMS was by APCI+ and data quoted are for [M+H]⁺.

Preparation 30 tert-Butyl 4-isoouinolin-1 -yl-3,6-dihvdropyridine-1 (2H)-carboxylate

A solution of 1-bromoisoquinoline (0.35 g, 1.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (US 2004/0186103) (0.5 g, 1.68 mmol), dichloro(1 ,1-bis(diphenylphosphino)ferrocene)palladium(ll) (0.065 g, 0.05 mol equiv.) and potassium carbonate (0.66 g, 5.0 mmol) in 1 ,2-dimethoxyethane (10 mL) was heated at 80 °C for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was purified' by column chromatography on silica gel eluting with ethyl acetate:pentane 50:50 to afford the title compound as a pale yellow oil, 0.14 g. LRMS (APCI⁺): m/z [M+H]⁺ 311 Preparation 31 tert-Butyl 4-isoquinolin-1-ylpiperidine-1-carboxylate

A solution of tert-butyl 4-isoquinolin-1-yl-3,6-dihydropyridine-1(2H)-carboxylate (0.14 g, 0.45 mmol) and 10 % w/w Pd on carbon (0.03 g) in ethanol (5 mL) was hydrogenated (550 kPa H₂) at room temperature for four hours. The reaction mixture was filtered through Arbocel^®, washing through with ethanol (10 mL). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system changing from ethyl acetate:pentane 20:80 to ethyl acetate:pentane 33:66 to afford the title compound as a colourless oil, 0.017 g. LRMS (APCI⁺): m/z [M+H]⁺ 313

Preparation 32 1-Piperidin-4-ylisoquinoline hvdrochloride

tert-Butyl 4-isoquinolin-1-ylpiperidine-1-carboxylate (0.017 g, 0.05 mmol) was added to a solution of HCI in dioxan (4N, 1 mL) and the mixture stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure to afford the title compound as a yellow solid, 0.013 g. LRMS (APCI⁺): m/z [M+H]⁺ 213

Preparation 33

Methyl (2S)-2-(f4-methoxy-6-(1 H-pyrazol-5-yl)pyridin-3-ylloxy)propanoate

2-Methoxy-4-(2H-pyrazol-3-yl)-phenol (WO05/016344, preparation 34) (0.2 g, 1.05 mmol), (R)-methyl lactate (0.11 mL, 1.15 mmol) and triphenylphosphine (0.28 g, 1.05 mmol) were dissolved in THF (6 mL) and the mixture cooled to 0 °C under a nitrogen atmosphere. Di-/so-propyl azodicarboxylate (0.23 mL, 1.15 mmol) was then added and the reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (40 mL) and washed sequentially with water (10 mL), aqueous hydrochloric acid (1 N, 10 mL) and finally saturated aqueous sodium hydrogencarbonate solution (10 mL). The organic layer was dried (MgS0₄), evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system changing from diethyl etherdichloromethane 70:30 to diethyl etherdichloromethane 85:15 to afford the title compound as a colourless oil, 0.22 g. LRMS (APCI⁺): m/z [M+H]⁺ 277

Preparation 34 (2S)-2-([4-Methoxy-6-(1 H-pyrazol-5-yl)pyridin-3-vnoxy)propanoic acid

Methyl (2S)-2-{[4-methoxy-6-(1 H-pyrazol-5-yl)pyridin-3-yl]oxy}propanoate (0.36 g, 1.3 mmol), was dissolved in methanol (10 mL), lithium hydroxide (0.065 g, 1.6 mmol) added and the mixture stirred at 50 °C for 18 hours. The cool reaction mixture was evaporated to dryness and the residue partitioned between water (15 mL) and diethyl ether (30 mL). the aqueous layer was separated and washed with ethyl acetate (30 mL). The aqueous layer was then acidified to pH4 by the addition of aqueous hydrochloric acid (2N) and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were dried (MgS0₄) and evaporated under reduced pressure to afford the title compound as a pale yellow solid, 0.18 g. LRMS (APCI⁺): m/z [M+H]⁺ 263

Preparation 35 tert-Butyl (3R)-4-((2S)-2-{2-methoxy-4-r(methylamino)carbonvn-phenoxy)propanoyl)-3-methylpiperazine-

1-carboxylate

The title compound was prepared from tert-butyl (3R)-3-methylpiperazine-1-carboxylate and (2S)-2-(2- methoxy-4-methylcarbamoyl-phenoxy)-propionic acid (WO05/016344, preparation 5), according to the method described above in Preparation 3, as a white solid. LRMS (APCf ): m/z [M+H]⁺ 436

Preparation 36

3-Methoxy-N-methyl-4-((1S)-1-methyl-2-r(2R)-2-methylpiperazin-1-yll-2-oxoethoxy)benzamide hydrochloride

The title compound was prepared from tert-butyl (3R)-4-((2S)-2-{2-methoxy-4-[(methylamino)- carbonyl]phenoxy}propanoyl)-3-methylpiperazine-1-carboxylate, according to the method described above in Preparation 4, as a white solid. LRMS (APCI⁺): m/z [M+H]⁺ 336

Preparation 37

4-((1S)-2-f(2R)-4-(4-Hvdroxy-3-nitropyridin-2-yl)-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxy)-3- methoxy-N-methylbenzamide

A solution of 3-methoxy-N-methyl-4-{(1S)-1-methyl-2-[(2R)-2-methylpiperazin-1-yl]-2- oxoethoxy}benzamide hydrochloride (0.35 g, 1.03 mmol), 2-chloro-3-nitropyridin-4-ol (US 2003/0225131 ) (0.15 g, 0.86 mmol) and triethylamine (0.4 mL, 3.09 mmol) in n-butanol (10 mL) was heated at 120 °C for two hours. The cool reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol 90:10 to afford the title compound as a yellow oil, 0.28 g. LRMS (APCI⁺): m/z [M+H]⁺ 474 Preparation 38

4-((1S)-2-r(2R)-4-(3-Amino-4-hvdroxypyridin-2-yl)-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxyV3- methoxy-N-methylbenzamide

A suspension of 4-{(1 S)-2-[(2R)-4-(4-hydroxy-3-nitropyridin-2-yl)-2-methyIpiperazin-1 -yl]-1 -methyl-2- oxoethoxy}-3-methoxy-N-methylbenzamide (0.28 g, 0.59 mmol), ammonium formate (0.18 g, 2.93 mmol) and 20 % palladium hydroxide on carbon (0.07 g) in ethanol (10 mL) was heated under reflux for four hours. The cool reaction mixture was filtered through Arbocel^® and evaporated under reduced pressure. The r esidue w as p urified b y c olumn c hromatography o n s ilica g el e luting w ith ethyl acetate:methanol 80:20 to. afford the title compound as a white solid, 0.1 g. LRMS (ESI⁺): m/z [M+H]⁺ 444

Preparation 39 N-Benzyl-4-chloro-3-nitropyridin-2-amine

A solution of 2,4-dichloro-3-nitropyridine (US 2003/0225131 ) (1.0 g, 5.18 mmol), benzylamine (0.56 g, 5.18 mmol) and triethylamine (2.17 mL, 15.54 mmol) in n-butanol (50 mL) was heated at 80 °C for three hours. The cool reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, dried (MgS0₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 85:15 to afford the title compound as a yellow solid, 0.624 g. LRMS (APCI⁺): m/z [M+H]⁺ 264 Preparation 40

4-((1S)-2-{(2R)-4-r4-(Benzylamino)-3-nitropyridin-2-yll-2-methylpiperazin-1-yll-1-methyl-2-oxoethoxy)-3- methoxy-N-methylbenzamide

The title compound was prepared from 3-methoxy-N-methyl-4-{(1S)-1-methyl-2-[(2R)-2-methylpiperazin- 1-yl]-2-oxoethoxy}benzamide hydrochloride and N-benzyl-4-chloro-3-nitropyridin-2-amine, according to the method described above in Preparation 37, as a yellow oil. LRMS (APCQ: m/z [M-H]⁺ 561

Preparation 41

4-((1S)-2-r(2R)-4-(3,4-Diaminopyridin-2-yl)-2-methylpiperazin-1-vn-1-methyl-2-oxoethoxyV3-methoxy-N- methylbenzamide

The title compound was prepared from 4-((1S)-2-{(2R)-4-[4-(benzylamino)-3-nitropyridin-2-yl]-2- methylpiperazin-1-yl}-1-methyl-2-oxoethoxy)-3-methoxy-N-methylbenzamide, according to the method described above in Preparation 38, a light red gum. LRMS (APCI⁺): m/z [M+H]⁺ 443

Preparation 42 4-Amino-3-methylpyridine N-oxide

A suspension of 3-methyl-4-nitropyridine N-oxide (2.0 g, 13 mmol) and palladium hydroxide on carbon (0.4 g) in ethanol (30 mL) was heated to 60 °C. Ammonium formate (3.3 g, 52 mmol) was then added portionwise a nd the m ixture h eated at 60 ° C for three h ours. The cool reaction mixture was filtered through Arbocel^® and the filtrate evaporated under reduced pressure to afford the title compound as a colourless oil, 1.81 g.

LRMS (APCI⁺): m/z [M+H]⁺ 125

Preparation 43

1 H-Pyrazolor4,3-clpyridine N-oxide

A solution of 4-amino-3-methylpyridine N-oxide (1.0 g, 8 mmol) in glacial acetic acid (3 mL) and water (30 mL) was warmed to 95 °C. An aqueous solution of sodium nitrite (1.67 g, 24 mmol) in water (20 mL) was then added dropwise and the mixture heated at 95 °C for 18 hours. The cool reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system changing from ethyl acetate:methanol 95:5 to ethyl acetate:methanol:concentrated aqueous ammonia 90:10:1 to afford the title compound as a yellow solid, 0.44 g. LRMS (APCI⁺): m/z [M+H]⁺ 136

Preparation 44 4-Chloro-1 H-pyrazolor4,3-clpyridine

A solution of 1 H-pyrazolo[4,3-c]pyridine N-oxide (0.4 g, 3 mmol) in phosphorous oxychloride (10 mL) was heated at 110 °C for 18 hours. The cool reaction mixture was evaporated under reduced pressure and the residue carefully dissolved in water (30 mL). The solution was basified with 10 % w/v aqueous potassium carbonate solution and extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were dried (MgS0₄) and evaporated under reduced pressure to give the title compound as a yellow solid, 0.1 g. LRMS (APCI⁺): m/z [M+H]⁺ 154 Preparation 45

4-r(3R)-3-Methylpiperazin-1 -yll-1 H-pyrazolor4₁3-clpyridine

The title compound was prepared from 4-chloro-1 H-pyrazolo[4,3-c]pyridine and (2R)-2-methylpiperazine, according to the method described above in Preparation 23, as a yellow solid. LRMS (APCI⁺): m/z [M+H]⁺ 218

Biological Data The ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate gp120 activity, in particular inhibit the interaction of gp120 with CD4, is demonstrated using a gp160 induced cell-cell fusion assay to determine the IC₅₀ values of compounds against HIV-1 fusion. The gp160 induced cell-cell fusion assay uses a HeLa P4 cell line and a CHO- Tat10 cell line. The HeLa P4 cell line expresses CCR5 and CD4 and has been fransfected with HIV-1 LTR-β- Galactosidase. The media for this cell line is Dulbecco modified eagle's medium(D-MEM) (without L- glutamine) containing 10% foetal calf serum (FCS), 2mM L-glutamine penicillin/streptomycin (Pen/Strep; 100U/mL penicillin + 10mg/mL streptomycin), and 1 μg/ml puromycin. The CHO cell line is a Tat (transcriptional trans activator)-expressing clone from a CHO JRR17.1 cell line that has been fransfected with pTat puro plasmid. The media for this cell line is rich medium for mammalian cell culture originally developed at Roswell Park Memorial Institute RPMI1640 (without L- glutamine containing 10% FCS, 2mM L-glutamine, 0.5 mg/ml Hygromycin B and 12μg/ml puromycin. The CHO JRR17.1 line expresses gp160 (JRFL) and is a clone that has been selected for its ability to fuse with a CCR5/CD4 expressing cell line. Upon cell fusion, Tat present in the CHO cell is able to transactivate the HIV-1 long terminal repeat (LTR) present in the HeLa cell leading to the expression of the β-Galactosidase enzyme. This expression is then measured using a Fluor Ace™ β-Galactosidase reporter assay kit (Bio-Rad cat no. 170-3150). This kit is a quantitative fluorescent assay that determines the level of expression of β - galactosidase using 4-methylumbelliferul-galactopyranoside (MUG) as substrate. β-Galactosidase hydrolyses the fluorogenic substrate resulting in release of the fluorescent molecule 4- methylumbelliferone (4MU). Fluorescence of 4-methylumbelliferone is then measured on a fluorometer using an excitation wavelength of 360nm and emission wavelength of 460nm. Compounds that inhibit fusion will give rise to a reduced signal and, following solubilisation in an appropriate solvent and dilution in culture medium, a dose-response curve for each compound can be used to calculate IC₅₀ values. All the Examples of the invention have IC₅₀ values, according to the above method, of less than 1μM. IC₅₀ values, according to the above method, for the compounds of Examples 1 , 6 ,11 and 18 are 1.5nM, 139nM ,535nM and 40pM respectively. The ability of compounds of formula (I) to inhibit the interaction of gp120 with CD4 is further demonstrated using an enzyme linked immunosorbent assay (ELISA). Maxisorp plates (Nunc) are coated with 2μg/well of anti-gp120 antibody (D7324). 100μl of gp120 (dilution pre-determined by titration) is added to each well and incubated for 90 minutes at room temperature. The sample is removed and the wells are washed with PBS (phosphate buffered saline) + 0.01% TWEEN® (polyethylene glycol sorbitan monolaurate). 50μl/weil of compound is added followed by 50μl (0.1 μg) of soluble CD4 conjugated to horseradish peroxidase (Autogen Bioclear). The plate is incubated for 90 minutes at room temperature before the wells are washed again. The substrate OPD (o-phenylenediamine, S igma) i s added at a concentration of 0.5mg/ml and the plate incubated in the dark at room temperature for 3 minutes before 3M HCI is added to stop the reaction. Compounds that inhibit the interaction of gp120 with soluble CD4 will give rise to a reduced absorbance at 492nm. IC₅₀ values for the compounds of Examples 1 , 2, 3, 7, 12 and 25 are 0.5, 0.2, 0.3, 10.7, 2.8 and 0.02μM respectively.

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:

R¹ is phenyl; napthyl; or a C-linked or N-linked, 5 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocycle wherein said heterocycle contains 1 to 4 nitrogen heteroatom(s), 1 or 2 nitrogen and 1 oxygen heteroatoms, or 1 or 2 nitrogen and 1 sulphur heteroatoms; wherein said phenyl, napthyl or heterocycle is optionally substituted by 1 to 3 atoms or groups selected from C C₆ alkyl, CrCs fluoroalkyl, C₃-C₇ cycloalkyl, phenyl, OH, C C₆ alkoxy, C C₆ alkoxy Cι-C₆ alkyl, OC C₆fluoroalkyl, C₀-C₂ alkylene NR⁶R⁷, halo, C₀-C₂ alkylene CN, C₀-C₂ alkylene C0₂R⁸, C₀-C₂ alkylene CONR⁶R⁷, C₀-C₂ alkylene SR⁹, C₀-C₂ alkylene SOR⁹, C₀-C₂ alkylene S0₂R⁹, C₀-C₂ alkylene S0₂NR⁶R⁷,

C₀-C₂ alkylene NR^aCOR⁹, C₀-C₂ alkylene NR⁸CONR⁶R⁷, C₀-C₂ alkylene NR⁸S0₂R⁹, C₀-C₂ alkylene R¹⁰, or, where R¹ is a heterocycle, oxo;

X is CH; or, where R¹ is phenyl; napthyl; or a C-linked heterocycle; may also be N;

R² and R³ are independently H, or C C₆alkyl;

R⁴ is C C₆ alkyl;

R⁵ is phenyl; naphthyl; or a C-linked, 6 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocycle wherein said heterocycle contains 1 to 4 nitrogen heteroatom(s), 1 or 2 nitrogen and 1 oxygen heteroatoms, or 1 or 2 nitrogen and 1 sulphur heteroatoms; wherein said phenyl, napthyl or heterocycle is optionally substituted by 1 to 3 atoms or groups selected from C^Ce alkyl, C C₆ fluoroalkyl, C₃-C₇ cycloalkyl, phenyl, OH, C C₆ alkoxy, C C₆ alkoxy Cι-C₆ alkyl, OCrC₆fluoroalkyl, C₀-C₂ alkylene NR⁶R⁷, halo, C₀-C₂ alkylene CN, C₀-C₂ alkylene C0₂R⁸, C₀-C₂ alkylene CONR⁶R⁷, C₀-C₂ alkylene SR⁹, C₀-C₂ alkylene SOR⁹, C₀-C₂ alkylene S0₂R⁹, C₀-C₂ alkylene S0₂NR⁶R⁷, C₀-C₂ alkylene NR⁸COR⁹, C₀-C₂ alkylene NR⁸CONR⁶R⁷, C₀-C₂ alkylene NR⁸S0₂R⁹, or C₀-C₂ alkylene R¹⁰, or, where R⁵ is a heterocycle, oxo;

R⁶ and R⁷ are independently H, Ci-Cg alkyl, C₃-C₇ cycloalkyl, phenyl or R¹⁰ , wherein said alkyl is optionally substituted by OH or C C₆ alkoxy; or when taken together with the nitrogen to which they are attached, R⁶ and R⁷ form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine, or thiomorpholine ring; wherein the said substituents are 1 or 2 groups selected from C₁-C₆ alkyl or C₀-C₆ alkylene NH₂;

R⁸ is H, C Ce alkyl or phenyl;

R⁹ is C Ce alkyl or phenyl; and

R^1Q is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by 1 to 3 atoms or groups selected from C Ce alkyl, C C₆ alkoxy, cyano or halo.

2. A compound as claimed in claim 1 wherein X is N.

3. A compound as claimed in claim 1 or 2 wherein R¹ is a heterocycle selected from pyridyl, pyrimidinyl, isoquinolinyl, naphthridinyl, imidazopyrazinyl, benzisoxazolyl, furopyridinyl, quinazolinyl, pyrazolopyridinyl, oxazolopyridinyl, imidazopyridinyl, or dihydrofuropyridinyl; wherein said heterocycle is optionally substituted by 1 or 2 groups selected from C₁-C₄alkyl, phenyl, C^Csalkoxy, or CONR⁶R⁷.

4. A compound as claimed in any preceding claim wherein R¹ is isoquinolinyl, methylpyridyl, phenylpyridyl or naphthridinyl.

5. A compound as claimed in any preceding claim wherein R² is CτC alkyl.

6. A compound as claimed in any preceding claim wherein R² is methyl.

7. A compound as claimed in any preceding claim wherein R³ is H.

8. A compound as claimed in any preceding claim wherein R⁴ is Cι-C alkyl.

9. A compound as claimed in any preceding claim wherein R⁴ is methyl.

10. A compound as claimed in any preceding claim wherein R⁵ is an optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or benzoxazolyl; wherein s aid s ubstituents a re 1 to 3 atoms o r g roups s elected f rom C C₆ alkyl, C C₆ alkoxy, halo, CN, C0₂R⁸, CONR^δR⁷, or R¹⁰.

11. A compound as claimed in any preceding claim wherein R⁵ is an optionally substituted phenyl or pyridyl, wherein said substituents are 1 to 3 groups selected from C C₆ alkoxy, C0₂R⁸, or CONR⁶R⁷.

12. A compound as claimed in any preceding claim wherein R⁶ is H or C C₄ alkyl.

13. A compound as claimed in any preceding claim wherein R⁷ is H, C C₄ alkyl or C₃-C₆ cycloalkyl, wherein said alkyl is optionally substituted by OH or C C₃ alkoxy.

14. A compound as claimed in any preceding claim wherein R⁸ is C C₄ alkyl.

15. A compound as claimed in any preceding claim wherein R⁹ is C C₄ alkyl.

16. A compound as claimed in any preceding claim wherein R¹⁰ is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted by 1 to 3 atoms or groups selected from C C₄ alkyl, CrC₄ alkoxy, cyano or halo.

17. A compound as claimed in any preceding claim of formula (la)

(la) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R³, R⁴, R⁵ and X are as defined in any of claims 1 to 16.

18. A compound as claimed in claim 17 of formula (lb)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R³, R⁴and R⁵ are as defined in any of claims 1 to 16.

19. A compound as claimed in claim 18 of formula (lc)

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², R⁴ and R⁵ are as defined in any of claims 1 to 16.

20. A pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to a ny p receding claim, together with o ne o r more pharmaceutically acceptable excipients, diluents or carriers.

21. A pharmaceutical composition according to claim 20 including one or more additional therapeutic agents.

22. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 19 for use as a medicament.

23. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 19 for use in the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS.

24. The use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof as claimed in any one of claims 1 to 19 for the manufacture of a medicament for the treatment of a HIV, a retroviral infection genetically related to HIV, or AIDS.

25. A method of treatment of a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 19.

26. A compound of formula (II)

wherein R¹, R², R³ and R⁴ are as defined in any of claims 1 to 16 and Z is a leaving group.