WO2006136917A1

WO2006136917A1 - Triazolylpiperidine derivatives and use thereof in therapy

Info

Publication number: WO2006136917A1
Application number: PCT/IB2006/001669
Authority: WO
Inventors: Christopher Gordon Barber; David Clive Blakemore
Original assignee: Pfizer Limited
Priority date: 2005-06-22
Filing date: 2006-06-12
Publication date: 2006-12-28

Abstract

The present invention provides compounds of formula (I) Wherein R1 , R2, R3 , R4 , Het and m are as defined in the description. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors.

Description

TRIAZOLYLPIPERIDINE DERIVATIVES AND USE THEREOF IN THERAPY

This invention relates to piperidine derivatives, to processes for their preparation, to compositions containing them and to their use.

More particularly, the present invention relates to the use of alpha-methyl piperidine derivatives in the treatment of a variety of disorders, including those in which the modulation of chemokine CCR5 receptors is implicated. Accordingly, the compounds of the invention are in particular useful in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), inflammatory diseases, autoimmune diseases and pain.

The name "chemokine", is a contraction of "chemotactic cytokines". The chemokines comprise a large family of proteins which have in common important structural features and which have the ability to attract leukocytes. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases.

The chemokine receptor CCR5 is of particular importance in the context of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP-1α and MIP-1 β, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).

Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.

HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Kaposi's sarcoma, and cancer of the lymph system. Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (AZT) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus. It is desirable to provide compounds for the treatment of HIV and other indications which have one or more of the following properties: are selective, have a rapid onset of action, are potent, are stable, are resistant to metabolism, or have other drug-like properties.

According to one 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 hydrogen or -COR⁷;

R² is halogen, nitro, cyano, CF₃, C_halky!, d.₄alkyloxy, C₁.₄3^yIoXy-C₁.₂alkyl, S(O)_n(C_1-4alkyl); R³ is hydrogen or C₁.₄ alkyl; R⁴ is C_1-4 alkyl; Het is a triazole of formula (i) or (ii)

(i) (ϋ)

R⁵ and R⁶ are independently hydrogen, C_1-4alkyl, C_3-6cycloalkyl, C_1-4alkyloxy or C^alkyloxy-C^alkyl; R⁷ is C_1-6alkyl; C₃.₆cycloalkyl; C_1-6alkyloxy; Cs-eCycloalkyl-C^alkyl; C^alkyloxy-C^alkyl; C_3-

₆cycloalkyloxy; phenyl; or heterocycle; wherein in each instance said alkyl, alkyloxy and cycloalkyl may be substituted by one or more halogen atoms; and wherein said phenyl and heterocycle may be substituted by 1 to 3 atoms or groups selected from oxo, acyl, halogen, C_1-4alkyl, C_1-4alkyloxy, S(O)_n(C₁^alkyl), nitro, cyano, and CF₃; m is 0, 1 or 2; n is 0, 1 or 2.

According to a further aspect of the present invention, there is provided a compound of formula (Ia) or (Ib):

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R¹, R², Het and m are as defined above, and the carbon atom marked with an asterisk '*' is an asymmetric carbon.

The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, n-hexyl. The term "alkyloxy" refers to a group -OR in which R is an alkyl as defined above.

The term "cycloalkyl" refers to a carbocyclic ring containing the specified number of carbon atoms. Examples of carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkyloxy" refers to a group -OR in which R is a cycloalkyl as defined above. The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "acyl" refers to a group -COR in which R is H or a C_1-4alkyl.

The term "heterocycle" refers to 4- to 12-membered saturated or partially unsaturated heterocyclic group in which one to three carbon atoms are replaced by heteroatoms selected from N, O and S, which group is monocyclic or polycyclic (e.g. bicyclic or tricyclic), and is optionally fused, bridged or spiranic. When the heterocycle contains one or more nitrogen atoms, N-oxides are included within the scope of the invention.

Examples of saturated or partially unsaturated heterocyclic groups include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyrane, tetrahydrothiopyrane, dioxane, diazepine, azabicycloheptane, azabicycloheptene, azabicyclooctane, oxaazabicyclooctane, azaadamantane, dihydroisoindole, octahydropyrrolopyrazine, tetrahydroisoxazolopyridine, tetrahydroim idazopyridine, tetrahydropyrazolopyridine.

In one embodiment, R¹ is hydrogen. In a further embodiment, R¹ is -COR⁷.

In one embodiment, R² is halogen. In a further embodiment, R² is fluorine.

In one embodiment, R³ is hydrogen. In one embodiment, Het is a triazole of formula (i). In a further embodiment, Het is a triazole of formula (ii).

In one embodiment, R⁵ is hydrogen or C_1-4alkyl. In a further embodiment, R⁵ is C^alkyl. In yet a further embodiment, R⁵ is methyl or ethyl.

In one embodiment, R⁶ is hydrogen, C^alkyl or C₃.₆cycloalkyl. In a further embodiment, R⁶ is C₁. ₄alkyl or C₃.₆cycloalkyl. In yet a further embodiment, R⁶ is methyl, ethyl, (iso)propyl or cyclopropyl.

In one embodiment, R⁷ is C^alkyl optionally substituted by one or more halogen atoms; C₃. ₆cycloalkyl optionally substituted by one or more halogen atoms; d^alkyloxy; C₃.₆cycloalkyl-C_1-2alkyl; C₁. ₄alkyloxy-C_1-4alkyl optionally substituted by one or more halogen atoms; or heterocycle optionally substituted by 1 to 3 atoms or groups selected from oxo, acyl and C^alkyl. In a further embodiment, R⁷ is C^alkyl optionally substituted by 1 to 3 fluorine atoms; C₃.₆cycloalkyl optionally substituted by 1 to 3 fluorine atoms; C^alkyloxy; Cs-ecycloalkyl-C^alkyl; C^alkyloxy-C^alkyl optionally substituted by 1 to 3 fluorine atoms; morpholine, piperidine or piperazine optionally substituted by C^alkyl or acetyl; tetrahydropyrane or tetrahydrothiopyrane optionally substituted by 1 or 2 oxo. In yet a further embodiment, R⁷ is methyl, 2,2,2-trifluoroethyl, (iso)propyl, methoxy, t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohehyl, 2,2-difluorocyclobutyl, 4,4-difluorocyclohexyl, 2,2,2-trifluoroethoxymethyl, cyclopropylm ethyl, morpholine, piperidine substituted by acetyl, piperazine substituted by methyl, tetrahydropyrane, or tetrahydrothiopyrane substituted by 1 or 2 oxo.

In another embodiment, R7 is Ci.₆alkyl; C₃.₆cycloalkyl; C₁.₆alkyloxy except tertiary alkyloxy; C₃.

C₃.₆cycloalkyloxy; phenyl; or heterocycle; wherein in each instance said alkyl, alkyloxy and cycloalkyl may be substituted by one or more halogen atoms; and wherein said phenyl and heterocycle may be substituted by 1 to 3 atoms or groups selected from oxo, acyl, halogen, C^alkyl, C^alkyloxy, S(O)_n(C₁.₄alkyl), nitro, cyano, and CF₃. In another embodiment, R⁷ is C_1-6alkyl optionally substituted by one or more halogen atoms; C₃.₆cycloalkyl optionally substituted by one or more halogen atoms; Ci-₆alkyloxy except tertiary alkyloxy; C₃.₆cycloalkyl-C_1-2alkyl; C₁.₄alkyloxy-C₁^alkyl optionally substituted by one or more halogen atoms; or heterocycle optionally substituted by 1 to 3 atoms or groups selected from oxo, acyl and C^alkyl. In a further embodiment, R⁷ is d^alkyl optionally substituted by 1 to 3 fluorine atoms; C₃.₆cycloalkyl optionally substituted by 1 to 3 fluorine atoms; C_1- ₄alkyloxy except tert-butyloxy; C₃.₆cycloalkyl-Ci_-2alkyl;

optionally substituted by 1 to 3 fluorine atoms; morpholine, piperidine or piperazine optionally substituted by C_1-2alkyl or acetyl; tetrahydropyrane or tetrahydrothiopyrane optionally substituted by 1 or 2 oxo. In yet a further embodiment, R⁷ is methyl, 2,2,2-trifluoroethyl, (iso)propyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohehyl, 2,2-difluorocyclobutyl, 4,4-difluorocyclohexyl, 2,2,2-trifluoroethoxymethyl, cyclopropylmethyl, morpholine, piperidine substituted by acetyl, piperazine substituted by methyl, tetrahydropyrane, or tetrahydrothiopyrane substituted by 1 or 2 oxo. The HIV potency in these four preceding embodiments (according to the tested examples herein) was sub 1μM.

In one embodiment, m is 0. In a further embodiment, m is 1. In one embodiment, R⁴ is methyl.

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 the compounds of formula (I) and (Ia) [collectively referred to hereafter as compounds of formula (I)].

The compounds of the invention include the compounds of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives include complexes, prodrugs, polymorphs and crystal habits thereof, and isotopes, as well as salts and solvates 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).

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

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

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

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

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass 5 transition')- The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in unsolvated and solvated forms. The term 0 '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.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris 5 (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry 0 independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may also exist in multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non- 5 stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O.

JO Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi- component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true

!5 crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'therm otropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COOTJa⁺, -COO K⁺, or -SO₃-Na⁺) or non-ionic (such as -N^'N⁺(CH₃)₃) polar

0 head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970), incorporated herein by reference. As indicated, so-called 'prodrugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Prodrugs 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), both incorporated herein by reference.

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), incorporated herein by reference.

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). The compounds of the invention have one or more asymmetric carbon atoms (that is the carbon atom attached to the NHR¹ group in formula (I)). The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line ( ), a zigzag line ( ~^^AΛ/ ), a solid wedge ( ~^^* ), or a dotted wedge ( ^""""""I ).The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included.

The compounds of the invention may also contain more than one asymmetric carbon atom, more particularly as shown by an asterisk in formulae (Ia) and (Ib). In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. In particular, in the following examples a single diastereoisomer is formed but its absolute configuration is not defined: examples 2-17,19-42, and 60-80. In these examples the bonds from the asymmetric carbon atoms are indicated by the use of a solid wedge and a solid line and indicate that a single diastereoisomer of undefined absolute configuration is present.

The use of a zigzag line to depict bonds from one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds from other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, diastereomers, 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, αf-lactate or /-lysine, or racemic, for example, dl- tartrate or cf/-arginine.

Cis/trans 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).

The present invention also includes all pharmaceutically acceptable isotopically-labelled 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 which predominates in nature.

Representative compounds of formula (I) include the compounds of Examples 35, 37, 39, 41, 42, 44, 45, 46, 47, 51 , 52, 56, 57, 58, 76, 79; and pharmaceutically acceptable salts, solvates or derivatives thereof.

In the general processes, and schemes, that follow: AcOH is acetic acid; DCC is N,N'- dicyclohexylcarbodiimide; DCM is dichloromethane; DIPEA is diisopropylethylamine; DMF is N,N- dimethylformamide; EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et₃N is triethylamine; EtOAc is ethyl acetate; EtOH is ethanol; HATU is 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBTU is O-Benzotriazol-1 yl-N,N,N',N'-tetramethyluronium-hexafluorophosphate;

HCI is hydrogen chloride; HOBT is 1-Hydroxybenzotriazole; MeI is methyl iodide; MeOH is methanol; THF is tetrahydrofuran; rt is room temperature.

The compounds of formula (I) may be prepared by any process used for preparing analogous compounds.

The compounds of formula (I) where R¹ is H may be prepared as depicted in Scheme 1 , wherein R², R⁴, Het and m are as defined above and PG¹ represents a suitable N-protecting group known to those skilled in the art, typically a CBz or Boc group.

Scheme 1

a) R

the standard literature conditions, preferably in the presence of titanium tetraisopropoxide using a reducing agent (preferably sodium cyanoborohydride or alternatively sodium triacetoxyborohydride) in a suitable solvent such as EtOH or DCM/MeOH at rt. Separation of diastereoisomers can be carried out at this stage by, for example, flash chromatography on silica. b) Deprotection of the amine is carried out as follows:

^* Removal of the Boc group is carried out under acidic conditions e.g. HCI dissolved in ether/MeOH or EtOAc solution at 0⁰C to rt or trifluoroacetic acid in DCM.

* Removal of the CBz group is carried out by hydrogenolysis e.g. using a suitable catalyst (palladium hydroxide, palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as MeOH or EtOH or using ammonium formate and palladium hydroxide in a suitable solvent such as MeOH or EtOH under reflux.

The compounds of formula (I), where R¹ is COR⁷ may be prepared as depicted in Scheme 2, wherein R², R⁴, Het and m are as defined above and X represents Cl or OH.

Scheme 2

c) Amide or carbamate (I) is synthesised as follows:

* When X=CI, amine (I) is reacted with the acid chloride or chloroformate in the presence of a base such as Et₃N or DIPEA in a suitable solvent such as DCM or toluene at a temperature between O ⁰C and rt.

^* When X=OH, amine (I) is reacted with the acid in the presence of a coupling agent such as EDCI. HCI, HBTU, HATU, DCC or preferentially EDCI.Mel in a suitable solvent such as DCM or DMF. In the presence of EDCI. HCI or EDCI.Mel, HOBT is optionally added. In the case where the amine is present as a hydrochloride salt, a suitable base such as Et₃N or DIPEA is added. The reaction is typically carried out at rt. The compounds of formula (III) may be prepared according to Scheme 3, wherein R represents hydrogen or a C₁-C₄ alky! group (preferably methyl or ethyl), and R², R⁴, PG¹ and m are as defined above.

Scheme 3

d) Weinreb amide (Vl) is formed as follows:

* When R^a is an alkyl group, ester (V) is reacted with N,O-dimethylhydroxylamine hydrochloride and a Grignard reagent, preferentially iso-propylmagnesium bromide or choride, in a solvent such as THF at low temperature (typically around -10 ⁰C).

^* When R^a is a hydrogen, acid (V) (typically formed from ester (V), where R^a is alkyl, by hydrolysis under basic conditions such as with lithium hydroxide or sodium hydroxide in MeOH or THF/water) is reacted with N.O-dimethylhydroxylamine hydrochloride under standard amide coupling conditions. For example, the reaction may be carried out in the presence of a coupling agent such as EDCI. HCI, EDCI. MeI, HBTU, HATU, DCC and a base such as Et₃N or DIPEA in a suitable solvent such as DCM or DMF. In the presence of EDCI. HCI or EDCI. MeI, HOBT is also added. The reaction is typically carried out at rt. e) Alkyl ester (III) is formed by reaction of Weinreb amide (Vl) with an alkyl Grignard reagent such as methylmagnesium bromide or methylmagnesium chloride or with an alkyl lithium such as methyllithium at low temperature (typically -78 ⁰C) in a solvent such as THF or diethylether.

The compounds of formula (IV), where Het is triazole (ii), may be prepared as described in Scheme 4, wherein PG² represents a suitable N-protecting group, typically a CBz, Benzyl or Boc, preferably Benzyl; PG³ represents a suitable N-protecting group, typically a CBz, Benzyl or Boc, preferably Boc; R^a represents a C₁-C₄ alkyl group, preferably methyl or ethyl; and R⁵ and R⁶ are as defined above.

Scheme 4

f) An N-protected 4-piperidone, (VII), (e.g. 1 -benzyl-4-piperidone) is reacted with a protected hydrazine (e.g. terf-Butyl carbazate) in the presence of a mild acid such as acetic acid in a suitable solvent such as DCM at rt to give protected hydrazone (VIII). g) Reduction of (VIII) is carried out using a suitable reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of a mild acid such as AcOH in a solvent such as DCM at rt. h) Removal of the PG³ protecting group is carried out under standard conditions:

^* Removal of the Boc group may be carried out under conditions known to those skilled in the art such as acidic conditions e.g. HCI dissolved in ether/MeOH or EtOAc solution at O⁰C to rt or trifluoroacetic acid in

DCM.

* Removal of the CBz or benzyl group may be carried out by hydrogenolysis e.g. using a suitable catalyst (palladium hydroxide, palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as MeOH or EtOH or using ammonium formate and palladium hydroxide in a suitable solvent such as MeOH or EtOH under reflux. i) Triazole (IV) may be formed in two stages:

^* Reaction of piperidine hydrazine (X) with alkyl acetimidate hydrochloride (Xl) (e.g. ethyl acetimidate hydrochloride) in a solvent such as MeOH is carried out at rt. A suitable base (e.g. Et₃N) is required if the piperidine hydrazine is used as the hydrochloride salt. * The resulting product is used without purification and reacted with caution with anhydride (XII) at a temperature between 130 -200 ⁰C to give triazole (XIII). j) Removal of the PG² protecting group is carried out using standard conditions to give triazole (IV):

* Removal of the Boc group may be carried out under acidic conditions e.g. HCI dissolved in ether/MeOH or EtOAc solution at 0 ⁰C to rt or with trifluoroacetic acid in DCM. ^* Removal of the CBz or benzyl group is carried out by hydrogenolysis e.g. using a suitable catalyst (palladium hydroxide, palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as MeOH or EtOH or using ammonium formate and palladium hydroxide in a suitable solvent such as MeOH or EtOH under reflux. Triazole (XlII) can also be synthesised as shown in Scheme 5, wherein PG , R and R⁶ are as defined above.

Scheme 5

k) Amide (XIV) is reacted with dimethyl acetal (XV) in a suitable solvent such as toluene at reflux to generate acyl amidine (XVI).

I) Acyl amidine (XVI) is reacted with hydrazine (X) in the presence of a mild acid such as AcOH at 90⁰C to give triazole (XIII).

The compounds of formula (IV), where Het is triazole (i), may be prepared as described in Scheme 6, wherein X represents Cl or OH and PG², R⁵ and R⁶ are as defined above.

Scheme 6

(XVII) (XVIII)

m) Amide (XVIII) may be made by reaction of amine (XVII) with an acid chloride in a suitable solvent such as DCM or ether/water in the presence of a base such as Et₃N, DIPEA or sodium hydroxide at a temperature typically between 0 ⁰C and rt. Alternatively, the amide can be made by reaction of (XVII) with an acid in the presence of a suitable coupling agent such as EDCI. HCI, EDCI.Mel, HBTU, HATU or DCC in a suitable solvent such as DCM or DMF and optionally HOBT can also be added. A suitable base such as Et₃N or DIPEA is also added. The reaction is typically carried out at rt. n) Amide (XVIII) is converted to a vinyl halide such as the vinyl chloride with, for example, phosphorus pentachloride or phosphorus oxychloride in a solvent such as DCM at a temperature of 0 ⁰C to rt. The resulting vinyl halide is reacted with acyl hydrazide (R⁶C(=0)NHNH₂) in a suitable solvent such as tert- amyl alcohol at 0 ⁰C to rt and the resulting adduct is then ring-closed using acidic conditions such as 4- toluene sulphonic acid in toluene/dioxane at reflux to give triazole (XIX). o) Removal of the PG² protecting group can be carried out using standard methodology. For example, removal of a CBz or benzyl group is carried out by hydrogenolysis e.g. using a suitable catalyst (palladium hydroxide, palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as MeOH or EtOH or using ammonium formate and palladium hydroxide in a suitable solvent such as MeOH or EtOH under reflux.

The compounds of formula (I), where R¹ is COR⁷ may alternatively be prepared as shown in Scheme 7, wherein X represents Cl or OH, and R^a, R², R⁴, Het and m are as defined above.

Scheme 7

(XXIl)

p) Conversion of amine (XX) to amide (XXI) may be accomplished using standard amide formation conditions:

* When X=CI, amine (XX) is reacted with the acid chloride in the presence of a base such as Et₃N or DIPEA in a suitable solvent such as DCM or toluene at a temperature between O ⁰C and rt.

* When X=OH, amine (XX) is reacted with the acid in the presence of a coupling agent such as EDCI.HCI, EDCI.Mel, HBTU, HATU, DCC in a suitable solvent such as DCM or DMF. In the presence of EDCI.HCI or EDCI.Mel, HOBT is optionally added. In the case where the amine is present as a hydrochloride salt, a suitable base such as Et₃N or DIPEA is also used. The reaction is typically carried out at rt. q) Weinreb amide (XXII) may be formed by reaction of ester (XXI) with N,O-dimethylhydroxylamine hydrochloride and a Grignard reagent, preferentially iso-propylmagnesium bromide or choride, in a solvent such as THF at -10 ⁰C. r) Alkyl ester (XXIII) may be formed by reaction of Weinreb amide (XXII) with an alkyl Grignard reagent such as methylmagnesium bromide or methylmagnesium chloride or with an alkyllithium reagent such as methyllithium at -78 ⁰C in a solvent such as THF or diethylether. s) Reductive amination may be carried out in the presence of titanium tetraisopropoxide using a reducing agent (preferably sodium cyanoborohydride or alternatively sodium triacetoxyborohydride) in a suitable solvent such as EtOH or DCM/MeOH at rt. Separation of diastereoisomers can be carried out at this stage by, for example, flash chromatography on silica. The compounds of formula (I), where R is H may also be made as shown in Scheme 8, wherein PG³ represents a suitable N protecting group, typically allyl or benzyl, preferably allyl; L represents a suitable leaving group such as mesylate, tosylate, chloride or bromide, preferably mesylate; and R², R⁴, Het and m are as defined above.

Scheme 8

t) Ketone (XXIV) may be reduced using a suitable reducing agent such as sodium borohydride, lithium aluminium hydride, zinc borohydride, L-selectride, lithium tri-tert-butoxyaluminium hydride in a suitable solvent such as MeOH, EtOH, diethyl ether, THF at a temperature between -78 ⁰C and 0 ⁰C. The

IO resulting diastereoisomeric alcohols can be separated by flash chromatography on silica. u) The alcohol group of (XXV) is converted to a leaving group such as a mesylate, tosylate, chloride, bromide or iodide. For example, the mesylate may be formed using methane sulphonyl chloride in the presence of a suitable base such as Et₃N or DIPEA in a solvent such as DCM at a temperature between -78 ⁰C and 0 ⁰C and preferably around -40 ⁰C.

15 v) The leaving group is displaced using the 4-substituted piperidine (IV) using a suitable base such as potassium carbonate or cesium carbonate in a solvent such as acetonitrile at reflux. The reaction goes with stereochemical inversion at the reacting centre of (XXVI). w) The PG³ protecting groups are removed under standard conditions:

^* Removal of the benzyl groups may be carried out by hydrogenolysis e.g. using a suitable catalyst -0 (palladium hydroxide, palladium on carbon) under a hydrogen atmosphere in a suitable solvent such as

MeOH or EtOH or using ammonium formate and palladium hydroxide in a suitable solvent such as MeOH or EtOH under reflux.

* Removal of the allyl groups may be carried out using N,N'-dimethylbarbituric acid, tetrakis(triphenylphosphine)palladium in a solvent such as DCM at rt or using an acid such as

.5 methanesulphonic acid and palladium on carbon in a solvent such as water at reflux or using tris(triphenylphosphine)rhodium chloride in acetonitrile/water at reflux.

Further elaboration of (I) such as forming a carbamate or amide may be carried out as previously described. 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).

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives are useful because they have pharmacological activity in animals, including humans. More particularly, they are useful in the treatment of a disorder in which the modulation, in particular antagonism, of CCR5 receptors is implicated. Disease states of particular interest include HIV, retroviral infections genetically related to HIV and AIDS.

Other disease states of interest include inflammatory diseases, autoimmune diseases and pain. The compounds of this invention may be used for treatment of respiratory disorders, including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, sarcoidosis; farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia.

Other conditions that may be treated are those triggered, affected or are in any other way correlated with T-cell trafficking in different organs. It is expected that the compounds of this invention may be useful for the treatment of such conditions and in particular, but not limited to, conditions for which a correlation with CCR5 or CCR5 chemokines has been established, and more particularly, but not limited to, the following: multiple sclerosis; Behcet's disease, Sjogren's syndrome or systemic sclerosis; arthritis, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; and graft rejection, in particular, but not limited to, solid organ transplants, such as heart, lung, liver, kidney and pancreas transplants (e.g. kidney and lung allografts), and graft versus host rejection; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; inflammatory lung conditions ; endometriosis; renal diseases, such as glomerular disease (e.g. glomerulonephritis); fibrosis, such as liver, pulmonary and renal fibrosis; encephalitis, such as HIV encephalitis; chronic heart failure; myocardial infarction; ischaemic heart disease; hypertension; stroke; obesity; restenosis; atherosclerotic plaque; psoriasis; atopic dermatitis; CNS diseases, such as AIDS related dementias and Alzheimer's disease; anaemia;chronic pancreatitis; type I diabetes; Hashimoto's thyroiditis; cancer, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma , breast cancer and multiple myeloma; pain, such as nociceptive pain and neuropathic pain (e.g. peripheral neuropathic pain); and stress response resulting from surgery, infection, injury or other traumatic insult.

Infectious diseases where modulation of the CCR5 receptor is implicated include acute and chronic hepatitis B Virus (HBV) and hepatitis C Virus (HCV) infection; bubonic, septicemic, and pneumonic plague; pox virus infection, such as smallpox; toxoplasmosis infection; mycobacterium infection; trypanosomal infection such as Chagas' Disease; pneumonia; and cytosporidiosis.

For a review of possible applications of chemokines and chemokine receptor blockers see Riberio and Horuk, "The Clinical Potential of Chemokine Receptor Antagonists", Pharmacology and Therapeutics 107 (2005) p44-58.

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 the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

In another aspect the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

In another aspect the invention provides a method of treatment of a disorder in which the modulation of CCR5 receptors is implicated which comprises administering to a patient in need thereof (e.g a human patient or an animal patient) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof.

The compounds of the invention are useful in the treatment of the diseases, disorders or conditions mentioned above. Diseases of particular interest include HIV, retroviral infections genetically related to HIV, and AIDS.

Other diseases of interest include inflammatory diseases, autoimmune diseases and pain. Other diseases of interest include rheumatoid arthritis, fibrosis, graft rejection and pain.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

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

Edition (Mack Publishing Company, 1995), incorporated herein by reference.

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

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) 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, Λ± (6), 981 -986, by Liang and

Chen (2001), incorporated herein by reference.

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight

% of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to

1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.

Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.

The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosaαe Forms: Tablets, Vol. 1 , by H.

Lieberman and L. Lachman (Marcel Dekker, New York, 1980), incorporated herein by reference. Consumable oral films for human or veterinary use are typically pliable water-soluble or water- swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (I) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

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 formulations for the purposes of the invention are described in US Patent

No. 6,106,864, incorporated herein by reference. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et a/ (2001), incorporated herein by reference. The use of chewing gum to achieve controlled release is described in WO 00/35298, incorporated herein by reference. 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, intrasternal, intracranial, intramuscular, intrasynovial 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 formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(αf/-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically, (intra)dermally, or transdermal^ to the skin or mucosa. 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), incorporated herein by reference.

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. Modified release formulations include 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, 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, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

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

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-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 1μg 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 formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

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

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, 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 "puff¹ containing from 1μg to 10mg of the compound of the invention. The overall daily dose will typically be in the range 1 μg 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, gels, 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, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

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 most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148, incorporated herein by reference. Inasmuch as it may desirable to administer a combination of active compounds, 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 in accordance with 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) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

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 10,000mg, such as 10 to 1 ,000mg, 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 comprising 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', have an improved safety profile or have other more desirable properties (e.g. with respect 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 co-administration 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 as combination therapy, may be used in the treatment and prevention of any of the diseases or conditions mediated by or associated with CCR5 chemokine receptor modulation, particularly infection by human immunodeficiency virus, HIV. The use of such combination therapy is especially pertinent 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 co-administered in combination with one or more additional therapeutic agents such as those described in detail further herein.

The therapeutic agents that may be used in combination with the compounds of the present invention include, but are not limited to, those useful as HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), CCR5 antagonists, agents which inhibit the interaction of gp120 with CD4, other agents which inhibit the entry of HIV into a target cell (such as fusion inhibitors), inhibitors of HIV integrase, RNaseH inhibitors, prenylation inhibitors, maturation inhibitors which act by interfering with production of the HIV capsid protein, compounds useful as anti-infectives, and others as described below. It will be appreciated by a person skilled in the art, that a combination drug treatment, as described 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 Pl; one or more NRTIs and another CCR5 antagonist; a Pl; a Pl and an NNRTI; an NNRTi; and so on. Examples of PIs include, but are not limited to, amprenavir (141W94), CGP-73547, CGP-61755,

DMP-450 (mozenavir), nelfinavir, ritonavir, saquinavir (invirase), lopinavir, TMC-126, atazanavir, palinavir, GS-3333, KN 1-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX-478, indinavir, tipranavir, TMC-114, DPC-681 , DPC-684, fosamprenavir calcium (Lexiva), benzenesulfonamide derivatives disclosed in WO 03/053435, R-944, Ro-03-34649, VX-385, GS-224338, OPT-TL3, PL-100, PPL-100, SM-309515, AG-148, DG-35- VIII, DMP-850, GW-5950X, KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003, Vb- 19038, A-77003, BMS-182193, BMS-186318, SM-309515, JE-2147, GS-9005.

Examples of NRTIs include, but are not limited to, abacavir, GS-840, lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine, didanosine, stavudine, zidovudine, tenofovir disoproxil fumarate, amdoxovir (DAPD), SPD-754, SPD-756, racivir, reverset (DPC-817), MIV-210 (FLG), beta-L-Fd4C (ACH- 126443), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340, emtricitabine (FTC).

Examples of NNRTIs include, but are not limited to, efavirenz, HBY-097, nevirapine, TMC-120 (dapivirine), TMC-125, etravirine, delavirdine, DPC-083, DPC-961, capravirine, rilpivirine, 5-{[3,5-Diethyl- 1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; GW-678248, GW-695634, MIV-150, calanolide, and tricyclic pyrimidinone derivatives as disclosed in WO 03/062238.

Examples of CCR5 antagonists include, but are not limited to, TAK-779, SC-351125, ancriviroc (formerly known as SCH-C), vicroviroc (formerly known as SCH-D), maraviroc, PRO-140, apliviroc (formerly known as GW-873140, Ono-4128, AK-602), AMD-887 CMPD-167, methyl 1-endo{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-eπdo-{8-[(3S)-3-(acetamido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl- 4,5₎6,7-tetrahydro-3/-/-imidazo[4,5-c|pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, ethyl 1-eπc/o-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8- azabicyclo[3.2.1 ]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, and Λ/-{(1 S)-3-[3-eπαfo-(5-lsobutyryl-2- methyl-4₎5_I6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3- fluorophenyl)propyl}acetamide) or pharmaceutically acceptable salts, solvates or derivatives thereof.

Examples of entry and fusion inhibitors include, but are not limited to, BMS-806, 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-{(iS)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1-yl]-1-methyl-2-oxo-ethoxy}-3- methoxy-N-methyl-benzamide, enfuvirtide (T-20), sifuvirtide, SP-01A, T1249, PRO 542, AMD-3100, Soluble CD4, compounds disclosed in JP 2003171381 , and compounds disclosed in JP 2003119137.

Examples of inhibitors of HIV integrase include, but are not limited to, L-000870810 GW-810781 , 1,5-naphthyridine-3-carboxamide derivatives disclosed in WO 03/062204, compounds disclosed in WO 03/047564, compounds disclosed in WO 03/049690, and 5-hydroxypyrimidine-4-carboxamide derivatives disclosed in WO 03/035076, MK-0518, and GS-9137 (JTK-303).

Examples of prenylation inhibitors include, but are not limited to, HMG CoA reductase inhibitors, such as statins (e.g. atorvastatin).

Examples of maturation inhibitors include 3-O-(3',3'-dimethylsuccinyl)betulic acid (otherwise known as PA-457) and alphaHG A.

Anti-infectives that may be used in combination with the compounds of the present invention include antibacterials and antifungals. Examples of antibacterials include, but are not limited to, atovaquone, azithromycin, clarithromycin, trimethoprim, trovafloxacin, pyrimethamine, daunorubicin, clindamycin with primaquine, fluconazole, pastill, ornidyl, eflornithine pentamidine, rifabutin, spiramycin, intraconazole-R51211 , trimetrexate, daunorubicin, recombinant human erythropoietin, recombinant human growth hormone, megestrol acetate, testerone, and total enteral nutrition. Examples of antifungals include, but are not limited to, anidulafungin, C31G, caspofungin, DB-289, fluconazaole, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole.

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 AD-439, AD-519, alpha interferon, AS-101 , bropirimine, acemannan, CL246,738, EL10, FP-21399, gamma interferon, granulocyte macrophage colony stimulating factor (e.g. sargramostim), IL-2, immune globulin intravenous, IMREG-1 , IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon, methionine-enkephalin, MTP-PE, remune, rCD4, recombinant soluble human CD4, interferon alfa-2, SK&F106528, soluble T4 thymopentin, tumor necrosis factor (TNF), tucaresol, recombinant human interferon beta, interferon alfa n-3.

- Tachykinin receptor modulators (e.g. NK1 antagonists) and various forms of interferon or interferon derivatives.

- Other chemokine receptor agonists/antagonists such as CXCR4 antagonists (e.g AMD070 and AMD3100) or CD4 antagonists (e.g. TNX-355).

- 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; examples of such agents include, but are not limited to, 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-pyrrolo[2,3- d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile) and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies (e.g. antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab);

- Agents which interfere with cell activation or cell cycling, such as rapamycin. 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 CCR5 chemokine receptor modulated disease or condition. For example, where the basic CCR5 chemokine receptor modulated disease or condition is HIV infection and multiplication it may be necessary or at least desirable to treat Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Human Papillomavirus (HPV), 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 useful in the treatment of hepatitis, such as interferons, pegylated interferons (e.g. peginterferon alfa-2a and peginterferon alfa-2b), long-acting interferons (e.g. album in-interferon alfa), lamivudine, ribavirin, emtricitabine, viramidine, celgosivir, valopicitabine, HCV-086, HCV-796, EMZ702, BILN2061, IDN6566, NM283, SCH 6 and VX-950; serine inhibitors as disclosed in WO 05/007681; arylthiourea derivatives as disclosed in WO 05/007601 , purine nucleoside analogues as disclosed in WO 05/009418, imidazole derivatives as disclosed in WO 05/012288, aza-peptide-based macrocyclic derivatives as disclosed in WO 05/010029. - Agents useful in the treatment of AIDS related Kaposi's sarcoma, such as interferons, daunorubicin, doxorubicin, paclitaxel, metal lo-matrix proteases, A-007, bevacizumab, BMS-275291 , halofuginone, interleukin-12, rituximab, porfimer sodium, rebimastat, COL-3.

- Agents useful in the treatment of cytomegalovirus (CMV), such as fomivirsen, oxetanocin G, cidofovir, cytomegalovirus immune globin, foscarnet sodium, lsis 2922, valacyclovir, valganciclovir, ganciclovir. - Agents useful in the treatment of herpes simplex virus (HSV), such as acyclovir, penciclovir, famciclovir,

ME-609.

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).

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 isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole.

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.

The invention is illustrated by the following Preparations and Examples in which the following further abbreviations may be used:

0.88 ammonia = concentrated ammonium hydroxide solution APCI = atmospheric pressure chemical ionisation DMSO = dimethyl sulphoxide ES = electrospray ionisation HRMS = high resolution mass spectrum

LCMS = liquid chromatography-mass spectroscopy;

LRMS = low resolution mass spectrum

MS = mass spectrum

NMR = nuclear magnetic resonance eq. = equivalent h = hour min = minute m.p. = melting point Preparation 1: Ethyl PSl-S-rfcvclobutylcarbonvOaminoi-S-phenylpropanoate

Cyclobutane carboxylic acid chloride (1OmL, 87.4mmol) was added dropwise to an ice-cooled solution of ethyl (3S)-3-amino-3-phenylpropanoate (2Og, 87.4mmol) and Et₃N (30.5mL, 219mmol) in DCM 5 (30OmL). Once addition was complete, the reaction was stirred at rt for 18h. The mixture was diluted with water (20OmL) and the layers separated. The organic solution was washed with water (2x200mL), dried (MgSO₄) and evaporated under reduced pressure to afford the title compound as a crystalline solid, 21.5g.

LRMS : m/z APCI 276 [MH]⁺ 0

Preparation 2: Ethyl (3SI-3-IΪ terf-butoxycarbonyl)aminol-3-phenylpropanoate

Et₃N (53.4mL, 383mmol) and di-tert-butyl dicarbonate (75.95g, 348mmol) were added to an ice- cooled solution of ethyl (3S)-3-amino-3-phenylpropanoate (8Og, 348mmol) in THF (50OmL) and the 5 mixture stirred at rt for 18h. The mixture was diluted with EtOAc (50OmL), then washed with water (50OmL), 10% citric acid solution (3x500mL), water (50OmL) and brine (50OmL). The organic solution was dried (MgSO₄) and evaporated under reduced pressure to afford the title compound as a white solid in quantitative yield.

LRMS : m/z APCI 294 [MH]⁺ 0

Preparation 3: tert-Butyl U1 S)-3-fmethoxy(methyl)amino1-3-oxo-1-phenylpropyl}carbamate

iso-Propylmagnesium chloride (250 ml of a 2N solution in diethyl ether, 500 mmol) was added dropwise to a solution of the ester from preparation 2 (47.74g, 160mmol) and N,O-dimethylhydroxylamine !5 hydrochloride (24.19g, 248mmol) in THF (50OmL) at -10⁰C under nitrogen, so as to maintain the temperature below -5°C during the addition. The mixture was stirred for 1.5h and then left at 4°C for 18h. Additional iso-propylmagnesium chloride (6OmL, 120mmol) and N,O-dimethylhydroxylamine hydrochloride (7.8Og, 80mmoi) were added and the reaction stirred for a further 2h at 0°C. The reaction was quenched by the careful addition of saturated ammonium chloride solution (200ml), followed by water (20OmL). The layers were separated, the aqueous phase extracted with EtOAc (50OmL), and the organic solutions washed with water (25OmL) and brine (25OmL), dried (MgSO₄) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using EtOAc:pentane (5:95) to afford the title compound as a golden oil, 26.8g. LRMS : m/z APCI 309 [MH]⁺

Preparation 4; te/t-Butyl {(1 S)-1 -(3-f luorophenyl)-3-rmethoxy(methyl)amino1-3- oxopropyPcarbamate

iso-Propylmagnesium chloride (242.1 mL of a 2N solution in diethyl ether, 484.2 mmol) was added dropwise to a stirred solution of methyl (3S)-3-[(terf-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoate (EP 1013276 preparation 30) (24g, 80.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (23.6g, 242.2 mmol) in THF (24OmL) at -10⁰C under nitrogen. The temperature was maintained below -5°C during the addition. The mixture was stirred for 1.5h and then left at 4°C for 18h. The mixture was cooled to -10⁰C and saturated ammonium chloride solution (6OmL) was added. After stirring for 15 min, dilute hydrochloric acid (15OmL of a 2N solution) was added and the mixture was extracted with EtOAc (3 x 10OmL). The combined organic fractions were washed with brine, dried (MgSO₄) and the solvent removed under reduced pressure to give the desired compound as a yellow oil, 28g. LRMS : m/z APCI 327 [MH]⁺

Preparation 5: N-U1 Sl-S-rMethoxyfmethvOaminoi-S-oxo-i-phenylpropyllcvclobutanecarboxamide

lsopropyl magnesium chloride (31OmL, 2M in THF, 620mmol) was added dropwise to an ice-cooled solution of the ester from preparation 1 (21.5g, 78mmol) and N,O-dimethylhydroxylamine hydrochloride

(30.5g, 310mmol) in THF (40OmL), so as to maintain the internal temperature below 4⁰C. Once addition was complete, the mixture was stirred at 0⁰C for an hour. The reaction was quenched by the addition of ammonium chloride solution (40OmL) and the mixture extracted with EtOAc (30OmL). The organic extracts were dried (MgSO₄) and evaporated under reduced pressure to afford the title compound as a crystalline solid, 21.4g.

LRMS : m/z APCI 291 [MH]⁺ ,

Preparation 6: tert-Butyl r(1S)-3-oxo-1-phenylbutvncarbamate

Methylmagnesium bromide (3M in ether, 90.7mL, 272.1 mmol) was added dropwise to a stirred solution of the amide from preparation 3 (27.97g, 90.7mmol) in THF (250 ml_) at -78°C under nitrogen. 5 The mixture was stirred at this temperature for 6h and then left at 4°C for 16h. The mixture was cooled to -78°C and saturated ammonium chloride solution (10OmL) was added dropwise. The mixture was then allowed to warm to rt and water (50OmL) was added. The mixture was extracted with EtOAc (3 x 40OmL) and the combined organic fractions were washed with water (50OmL) and brine (50OmL), dried (MgSO₄) and the solvent removed under reduced pressure to give the title compound as a solid, 21.58g. 0 LRMS : m/z ES 264 [MH]⁺

Preparation 7: ferf-Butyl r(1S)-1-(3-fluorophenyl)-3-oxobutvπcarbamate

Methylmagnesium chloride (80.7mL of a 3N solution in THF, 242.1 mmol) was added dropwise to a 5 stirred solution of the amide from preparation 4 (26.3g, 80.7mmol) in THF (250 mL) at -78°C under nitrogen. The mixture was stirred at this temperature for 2h and then left at 4°C for 16h. The mixture was cooled to -78°C and saturated ammonium chloride solution (15m L) was added dropwise. The mixture was allowed to warm to rt and dilute hydrochloric acid (8OmL of a 2N solution) was added. The mixture was extracted with EtOAc (3 x 10OmL) and the combined organic fractions were washed with brine, dried 0 (MgSO₄) and the solvent removed under reduced pressure to give the title compound as a white solid,

21.8g.

LRMS : m/z APCI 282 [MH]⁺

Preparation 8: /V-rdSl-S-Oxo-i-phenylbutyllcyclobutanecarboxamide

The title compound was obtained as a white foam in quantitative yield, from the compound of preparation 5, following the procedure described in preparation 7. LRMS : m/z APCI 246 [MH]⁺ paration 9: ΛM1-Benzvlpiperidin-4-vh-2-methvlpropanamide

lsobutyryl chloride (27,5mL, 262mmol) was added dropwise over 15 min to an ice-cooled solution of 4-amino-1-benzylpiperidine (45.Og, 236mmol) and sodium hydroxide (11.4g, 285mmol) in ether (12OmL) and water (66ml_) and once addition was complete, the mixture was stirred at rt for 18h. The resulting precipitate was filtered off and dried in vacuo to afford the title compound as a white solid,

58.76g.

LRMS : m/z APCI 261 [MH]⁺

Preparation 10: A/-π-Benzylpiperidin-4-yl)acetamide

The title compound was obtained as a white solid, from 4-amino-1-benzylpiperidine and acetyl chloride, following the procedure described in preparation 9. m. p. 131.1 to 132.5°C

Preparation 11: te/f-Butyl 2-f1-benzylρiperidin-4-ylidene)hvdrazinecarboxvlate

te/t-Butyl carbazate (27.88g, 211mmol) and glacial acetic acid (26mL) were added to solution of 1- benzyl-4-piperidone (40g, 211mmol) in DCM (40OmL) and the mixture stirred at rt for 18h. The mixture was carefully neutralised by the addition of saturated sodium bicarbonate solution, and the layers separated. The organic phase was washed with further saturated sodium bicarbonate solution (20OmL), water (20OmL) and brine (20OmL). The solution was dried (MgSO₄) and evaporated under reduced pressure to provide the title compound in quantitative yield.

LRMS : m/z APCI 304 [MH]⁺

Preparation 12: ferf-Butvl 2-(1-benzvlpiperidin-4-vl)hvdrazinecarboxvlate

Sodium borohydride (23.95g, 633mmol) was added portionwise to an ice-cooled solution of the compound from preparation 11 (64.02g, 211mmol) in DCM (50OmL) and acetic acid (285mL). The mixture was allowed to warm to rt and stirred for 24h. The mixture was re-cooled in an ice-bath, carefully quenched with water, and the mixture concentrated under reduced pressure to remove the organic solvent. The solution was diluted with DCM (20OmL) and basified using solid sodium hydroxide. The layers were separated, the aqueous phase extracted with DCM (2x200ml_) and the combined organic solutions washed with water (30OmL), dried (MgSO₄) and evaporated under reduced pressure to afford the crude title compound, 63.Og. LRMS : m/z APCI 306 [MH]⁺

Preparation 13: 1-Benzyl-4-hvdrazinopiperidine dihvdrochloride

HCI gas was bubbled through an ice-cooled solution of the compound from preparation 12 (63.Og, 206mmol) in MeOH (50OmL), and once saturated the solution was stirred at rt for 72h. The solution was re-saturated with HCI gas periodically, and the mixture allowed to stir at rt for a further 36h. The solution was evaporated under reduced pressure to afford the crude title compound as a white solid. LRMS : m/z APCI 206 [MH]⁺

Preparation 14: 1-Benzyl-4-(3-isopropyi-5-methyl-4/f-1.2.4-triazol-4-yl)piperidine

Phosphorous pentachloride (59.8g, 287mmol) was added portionwise over 20 min to an ice-cooled solution of the compound from preparation 9 (57.8g, 220mmol) in DCM (50OmL), the solution was allowed to warm to rt and stirred for 2h. The solution was re-cooled in an ice-bath, a slurry of acetic hydrazide (48.94g, 661mmol) in tert-amyl alcohol (30OmL) added and the mixture allowed to stir at rt for 16h. The solution was concentrated under reduced pressure and the residue re-suspended in toluene (25OmL) and dioxan (25OmL) and 4-toluenesulphonic acid (1.4g, 7.36mmol) added. The mixture was heated under reflux for 5h, then allowed to cool. The mixture was concentrated under reduced pressure, the residue partitioned between water (40OmL) and DCM (40OmL) and the layers separated. The aqueous layer was washed with DCM (10OmL) then basified to pH 8 using solid potassium hydroxide. The aqueous solution was extracted with DCM (1 L in total), the organic extracts dried (MgSO₄) and evaporated under reduced pressure. The residual oil was crystallised from diethyl ether to afford the title compound as a white solid, 10.4g.

The ethereal solution was concentrated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of EtOAc:MeOH (100:0 to 80:20) to afford additional compound, 28.6g.

LRMS : m/z APCI 299 [MH]⁺ Preparation 15: i-Benzyl-4-(3,5-dimethyl-4tf-1,2,4-triazol-4-yl)piperidine

The title compound was obtained as a white solid in 52% yield from the compound from preparation 10 and acetic hydrazide, following the procedure described in preparation 14, except the product was 5 isolated after trituration with ether. LRMS : m/z TSP 271.3 [MH]⁺

Preparation 16: N-U1 £)-1 -(Dimethylamino)ethylidenelcyclopropanecarboxamide

0 A mixture of cyclopropanecarboxamide (511mg, 6mmol) and N,N-dimethylacetamide dimethylacetal (1.6g, 12mmol) in toluene (1OmL) was heated at 120⁰C for 6h. The cooled solution was concentrated under reduced pressure and the residue was purified by column chromatography using a Biotage® silica gel cartridge and an elution gradient of DCM:MeOH (98:2 to 95:5) to afford the title compound in quantitative yield. 5 LRMS : m/z APC1 155 [MH]⁺

Preparation 17: 1 -Benzyl-4-(5-isopropyl-3-methyl-1 H-I ,2,4-triazoH -vDpiperidine

A mixture of the compound from preparation 13 (5.Og, 17.97mmol), ethyl acetimidate hydrochloride 0 (2.22g, 17.97mmol) and triethylamine (7.56mL, 53.91 mmol) in MeOH (10OmL) was stirred at rt for 2h.

The solution was concentrated under reduced pressure and the residue treated with isobutyric anhydride

(55m L) and the mixture heated to 200°C for 2h. The cooled mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (15OmL) and 1 N sodium hydroxide solution (15OmL) and the layers separated. The organic phase was washed with 1N sodium hydroxide solution (10OmL),

!5 water (10OmL) and brine (10OmL), then dried (MgSO₄) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia

(98:2:0.2) to afford the title compound, 1.45g.

LRMS : m/z APCI 299 [MH]⁺ Preparation 18: 1-Benzvl-4-f5-ethvl-3-methyl-1H-1,2,4-triazol-1-vl)piperidine

The title compound was obtained as a dark brown oil in 36% yield, from the compound from preparation 13 and propionic anhydride, following a similar procedure to that described in preparation 17. LRMS : m/z APCI 285 [MH]⁺

Preparation 19: 1 -Benzyl-4-(5-cvclopropyl-3-methyl-1 H-1 ,2,4-triazol-1 -vDpiperidine

A mixture of the compounds from preparations 16 (924mg, 6mmol) and 13 (1.35g, 6.6mmol) in AcOH (15ml_) was heated at 90⁰C for 3h. The cooled mixture was concentrated under reduced pressure and the residue azeotroped with toluene (2x). The resulting oil was dissolved in EtOAc, the solution washed with 10% potassium carbonate solution, dried (MgSO₄) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of DCM:MeOH (100:0 to 90:10) to afford the title compound, 1.14g.

LRMS : m/z APCI 297 [MH]⁺

Preparation 20: 1-Benzyl-4-(3-ethyl-5-methyl-1 H-1,2,4-triazol-1 -vDpiperidine

A mixture of the hydrazine hydrochloride from preparation 13 (1.12g, 4.03mmol), ethyl propionimidate hydrochloride (J. Org. Chem. 1989; 54(6); 1256) and Et₃N (1.7mL, 12.1mmol) in MeOH (4OmL) was stirred at rt for 18h. The mixture was concentrated under reduced pressure, the residue dissolved in acetic anhydride (15mL) and the solution heated at 140° for 5 minutes. The cooled solution was partitioned between 1 N sodium hydroxide solution and EtOAc, and the pH of the mixture adjusted to 14 using solid sodium hydroxide. The layers were separated, and the organic phase evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using EtOAc:MeOH (100:0 to 90:10) to afford the title compound as a clear oil, 270mg.

LRMS : m/z APCI 285 [MH]⁺ Preparation 21 : 1-Benzyl-4-(3,5-diethyl-1 H- 1.2.4-triazol-1-yl)piperidine

The title compound was obtained as a clear oil in 49% yield, from the compound of preparation 13, ethyl propionomidate and propionic anhydride, following the procedure described in preparation 20. LRMS : m/z APCI 299 [MH]⁺

Preparation 22: 4-(3-lsopropyl-5-methyl-4tf-1.2.4-triazol-4-yl)piperidine

A mixture of the compound from preparation 14 (28.61 g, 96mmol), ammonium formate (6Og, 96mmol) and palladium hydroxide (3g) in EtOH (30OmL) was stirred at 60⁰C for 4h. The cooled mixture was filtered through Arbocel® and the filtrate evaporated under reduced pressure. The crude product was filtered through silica gel, eluting with DCM:MeOH:0.88 ammonia (80:20:2) to afford a clear gum. This was triturated with tert-butyl methyl ether to afford the title compound as a white solid.

LRMS : m/z ES 209 [MH]⁺

Preparation 23: 4-(3,5-Dimethyl-4tf-1 ,2,4-triazol-4-yl)piperidine

Palladium hydroxide (4.5g) and ammonium formate (35g, 0.55mol) were added to an ice-cooled solution of the compound from preparation 15 (3Og, 0.11mol) in EtOH (25OmL) and the mixture heated under reflux for 2h. Additional ammonium formate (35g, 0.55mol) was added, the mixture stirred for a further 2h at reflux, and then a further 48h at rt. Additional ammonium formate (1Og, 1.10mol) and palladium hydroxide (500mg) were added and the mixture heated at reflux for a further 2h. The cooled mixture was filtered through Celite®, washing through with EtOH (20OmL). The filtrate was concentrated under reduced pressure and the residue triturated with ether to afford the title compound as a white solid, 16g.

LRMS : m/z TSP 181.2 [MH]⁺ Preparation 24: 4-(5-lsopropyi-3-methvi-1 H-Λ .2.4-triazoH -yl)piperidine

A mixture of the compound from preparation 17 (1.73g, 5.80mmol), ammonium formate (2.2g,

34.86mmol) and palladium hydroxide (300mg) in EtOH (5OmL) was stirred at 60⁰C for 3h. The cooled mixture was filtered through Arbocel® and the filtrate evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with DCM:MeOH:0.88 ammonia

(93:7:0.7) to afford a white solid, 544mg.

LRMS : m/z APCI 209 [MHf

Preparation 25: 4-f5-Ethyl-3-methyl-1 H-Λ .2.4-triazol-1 -vDpiperidine

The title compound was obtained from the compound from preparation 18 in 56% yield, following the procedure described in preparation 24.

LRMS : m/z APC1 195 [MH]⁺

Preparation 26: 4-(5-Cyclopropyl-3-methyl-1 H-Λ ,2,4-triazoH-vQpiperidine

The title compound was obtained from the compound from preparation 19 as a white solid in 91% yield, following a similar procedure to that described in preparation 24, except the product was not purified by column chromatography. LRMS : m/z ES 207 [MH]⁺

Preparation 27: 4-(3-Ethyl-5-methyl-1W-1,2,4-triazol-1 -vDpiperidine hydrochloride

A mixture of the compound from preparation 20 (270mg, 0.95mmoi), ammonium formate (631 mg, lOmmol) and palladium hydroxide (27mg) in EtOH (2OmL) was stirred at 8O⁰C for 30 min. The cooled mixture was filtered through Arbocel® and the filtrate concentrated under reduced pressure. The residue was suspended in 2N hydrochloric acid and stirred at 8O⁰C for an hour. The cooled solution was evaporated under reduced pressure to afford the title compound as a white solid. LRMS : m/z ES 195 [MH]⁺

Preparation 28: 4-(3.5-Diethyl-1A-H,2.4-triazol-1-yl)piperidine hydrochloride

The title compound was obtained as a white solid from the compound from preparation 21 , following the procedure described in preparation 27. LRMS : m/z APCI 209 [MH]⁺

Preparation 29: (2,2,2-Trifluoroethoxy)acetic acid

A solution of 2,2,2-trifluoroethanol (1Og, 87mmol) in THF (25mL) was added carefully to a cooled (- 15°C) solution of sodium hydride (2.88g, 80% dispersion in mineral oil, 96mmol) in THF (25mL), and the solution then stirred for an hour at -15°C. The solution was concentrated under reduced pressure, the residue suspended in DMSO (25OmL), chloroacetic acid sodium salt (11.64g, 100mmol) added and the reaction stirred at rt for 18h. The reaction was diluted with water (75OmL), and extracted with EtOAc (2x). The aqueous solution was acidified with 2N hydrochloric acid and extracted with EtOAc (2x). These combined organic extracts were washed with brine, dried (MgSO₄) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using DCM:MeOH (90:10) to afford the title compound as a colourless oil, 8.94g.

LRMS : m/z UK 332536

Preparation 30: Tetrahvdro-2/f thiopyran-4-carboxylic acid

A solution of tetrahydro-2H-thiopyran-4-carbonitrile (HeIv. Chim. Acta. 80; 5; 1997; 1528) (8g, 63mmol) in a minimum volume of MeOH was added to a solution of sodium hydroxide (25.16g, 629mmol) in water (109mL) and EtOH (55mL) and the reaction heated under reflux for 5h. The solution was cooled to 0⁰C, then acidifed using concentrated hydrochloric acid. The solution was concentrated under reduced pressure to remove the EtOH, and the aqueous solution extracted with DCM (3x200mL). The organic extracts were evaporated under reduced pressure to afford the title compound as a yellow solid, 6.65g.

¹H-NMR (DMSO d₆ 400MHz): δ 1.62 (m, 2H), 2.10 (m, 2H), 2.34 (m, 1 H), 2.60 (m, 4H). Preparation 31: Methyl tetrahvdro-2W-thiopyran-4-carboxylate

Trimethylsilyl diazomethane (2M in hexane, 45.4ml., 90.8mmol) was added dropwise to a solution of the acid from preparation 30 (6.65g, 45mmol) in toluene (20OmL) and MeOH (67ml_). Once addition was complete, the reaction was quenched by the addition of AcOH (sufficient to cause de-colourisation of the solution). The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel using DCM:Me0H (98:2 to 95:5) to afford the title compound as a white solid, 6.95g.

¹H-NMR (CDCI₃, 400MHz): δ 1.85 (m, 2H), 2.20 (m, 2H), 2.40 (m, 2H, 2.66 (m, 4H), 3.66 (s, 3H).

Preparation 32: Methyl tetrahvdro-2AY-thiopyran-4-carboxylate 1,1 -dioxide

Sodium periodate (18.55g, 86.7mmol) and water (14mL) were added to a solution of the ester from preparation 31 (6.95g, 43mmol) in MeOH (14OmL) and the reaction stirred at rt for 30 min. The mixture was concentrated under reduced pressure and the residue pre-adsorbed onto silica gel. This was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (100:0:0 to 95:5:0.5) as eluent to afford the title compound as a white solid, 1.87g.

¹H-NMR (CDCI₃, 400MHz): δ 2.40 (m, 4H), 2.66 (m, 1 H), 2.98 (m, 2H), 3.17 (m, 2H), 3.75 (s, 3H)

Preparation 33: Tetrahydro-2tf-thiopyran-4-carboxyHc acid 1.1-dioxide

Water (2mL) and lithium hydroxide solution (1M, 25.5mL, 25.5mmol) were added to a solution of the ester from preparation 32 (2.99g, 17mmol) in MeOH (6OmL) and the reaction stirred at rt for 18h. The reaction was concentrated under reduced pressure, 1M hydrochloric acid (25.5mL) and water (1OmL) were added, and the mixture stirred for an hour. The solution was concentrated under reduced pressure and the residue triturated with isopropanol/pentane. The resulting precipitate was filtered off, the filtrate dried (MgSO₄) and evaporated under reduced pressure to afford the title compound.

LRMS : m/z 178 [M]⁺ Example 1 : terf-Butvl U1 S)-3-f4-(3-isQDrQDvl-5-methvl-4H-1 ,2.4-triazol-4-vl)piperidin-1 -vll-1 - phenylbutyltearbamate

A solution of the ketone from preparation 6 (2.11g, 8.02mmol), the amine from preparation 22 (3.34g, 16.04mmol) and titanium tetraisopropoxide (12mL, 40.65mmol) in DCM (95m!_) was stirred at rt under nitrogen for 18h. Sodium cyanoborohydride (756mg, 12.03mmol) in MeOH (2OmL) was added and the mixture was stirred for a further 24h. Saturated sodium hydrogen carbonate solution was added and the mixture stirred for 15min, then filtered through Celite®, washing through with EtOAc. The filtrate was separated, the organic phase washed with saturated sodium bicarbonate solution (10OmL), water (10OmL) and brine (2x10OmL) and dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (97.5:2.5:0.25) to afford the title compound as a mixture of diastereomers as a gum, 2.25g.

LRMS : m/z ES 456 [MH]⁺

Examples 2 and 3: fe/f-Butyl {(1S)-3-r4-(3-isopropyl-5-methyl-4Af-1,2,4-triazol-4-yl)piperidin-1 -yll-1 - phenylbutvDcarbamate

A solution of the ketone from preparation 6 (5.Og, 19mmol), the amine from preparation 22 (7.9g, 38mmol) and titanium tetraisopropoxide (10OmL, 78mmol) in DCM (10OmL) was stirred at rt under nitrogen for 18h. Sodium cyanoborohydride (2.4g, 38mmol) and MeOH (5OmL) were added and the mixture was stirred for a further 24h. Saturated sodium hydrogen carbonate solution was added to the mixture and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residual aqueous solution was extracted with EtOAc. The combined organic extracts were evaporated under reduced pressure and the residue purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (99:1 :0.1) to afford diastereoisomer 1 (example 2) as a white foam, 327m g.

¹H-NMR (CD₃OD, 400MHz): δ 1.01 (d, 3H), 1.30-1.46 (m, 15H), 1.61-1.70 (m, 1 H), 1.82-2.01 (m, 3H), 2.16-2.39 (m, 3H), 2.58 (s, 3H), 2.62 (m, 1H), 2.75 (m, 1H), 2.82 (m, 1H), 2.97 (m, 1H), 3.20 (m, 1H), 4.01-4.12 (m, 1 H), 4.80 (m, 1 H), 7.21 (m, 1 H), 7.32 (m, 4H).

Further elution provided the second diastereoisomer (example 3) as a white foam, 1.5Og. Η-NMR (CD₃OD, 400MHZ): δ 1.03 (d, 3H), 1.38 (d, 6H)₁ 1.41 (s, 9H), 1.60 (m, 1 H), 1.84-2.02 (m,

3H), 2.20-2.32 (m, 2H), 2.40 (m, 1 H), 2.50-2.66 (m, 5H), 2.80 (m, 1 H), 3.01 (m, 1H), 3.25 (m, 1 H), 4.07 (m, 1 H), 4.86 (m, 1 H), 7.22 (m, 1 H), 7.32 (m, 4H).

Examples 4 and 5: te/t-Butyl f(1S)-1-(3-fluorophenyl)-3-r4-(3-isopropyl-5-methyl-4/f1,2,4-triazol-4- yl)piperidin-1-vπbutyl}carbamate

Titanium tetraisopropoxide (5.5mL, 18.5 mmol) was added to a stirred solution of the ketone from preparation 7 (1.04g, 3.69 mmol) and the amine from preparation 22 (1.0g, 4.8 mmol) in EtOH (2OmL) at rt under nitrogen. The mixture was stirred for 16h. Sodium cyanoborohydride (0.35g, 5.54 mmol) was added to the mixture which was stirred for a further 72h. Saturated sodium hydrogen carbonate solution (15mL) was added followed by EtOAc (5OmL). The mixture was stirred for 30 min and then filtered through Celite®. The resulting solution was washed with brine, dried (MgSO₄) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (99:1 :0.1 to 95:5:0.5) as eluent. The product was purified again using acetonitrile:water:0.88 ammonia (98:2:1) as eluent to give the compound of example 4 (diastereoisomer 1) as a white solid, 297mg.

¹H-NMR (CD₃OD, 400MHz): δ 1.04 (d, 3H), 1.42 (s, 9H), 1.86 (d, 6H), 1.61 (m, 1H), 1.85-2.02 (m, 3H), 2.19-2.33 (m, 2H), 2.40 (m, 1H), 2.58 (s, 3H), 2.51-2.68 (m, 2H), 2.78 (m, 1 H), 3.01 (m, 1H), 3.26 (m, 1H), 4.09 (m, 1H), 4.70 (m, 1H), 6.96 (m, 1H), 7.08 (m, 1H), 7.15 (d, 1H), 7.33 (m, 1H). Further elution provided the second diastereoisomer (example 5) as a white solid, 119mg.

¹H-NMR (CD₃OD, 400MHz): δ 1.01 (d, 3H), 1.35 (d, 6H), 1.44 (s, 9H), 1.63 (m, 1 H), 1.81-1.98 (m, 3H), 2.13-2.40 (m, 3H), 2.56 (s, 3H), 2.67 (m, 1H), 2.72-2.87 (m, 2H), 2.96 (m, 1 H), 3.27 (m, 1 H), 4.07 (m, 1 H), 4.84 (m, 1 H), 6.95 (m, 1 H), 7.05 (m, 1 H), 7.12 (d, 1H), 7.33 (m, 1H).

Examples 6 and 7: tert-Bulyl K1S)-3-f4-f5-ethyl-3-methyl-1/f-1.2.4-triazol-1-yl)piperidin-1-vπ-1- phenylbutyllcarbamate

Titanium tetraisopropoxide (4.8ml_, 16.04mmol) was added to a solution of the ketone from preparation 6 (840mg, 3.21 mmol) and the amine from preparation 25 (810mg, 4.17mmol) in EtOH (15ml_) and the reaction was stirred at rt under nitrogen for 16h. Sodium cyanoborohydride (300mg, 4.81 mmol) was added and the mixture was stirred for a further 24h. Saturated sodium hydrogen carbonate solution (2OmL) and EtOAc (15OmL) were added to the reaction and the resulting mixture was filtered through Celite®. The filtrate was washed with brine, and the organic phase dried (MgSO₄) and concentrated under reduced pressure. The residue purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (98:2:0.2 to 95:5:0.5) to afford diastereoisomer 1 (example 6) as a white solid, 433mg. ¹H-NMR (CD₃OD, 400MHz): δ 0.96 (d, 3H), 1.28 (t, 3H), 1.44 (S₁ ^' 9H), 1.62 (m, 1 H), 1.83-1.91 (m,

2H), 1.99-2.20 (m, 1 H), 2.15-2.26 (m, 1 H), 2.25 (s, 3H), 2.27-2.37 (m, 2H), 2.67-2.78 (m, 2H), 2.74-2.80 (m, 3H), 2.94 (m, 1 H), 4.11 (m, 1 H), 4.79 (m, 1 H), 7.19-7.35 (m, 5H).

Further elution provided the second diastereoisomer (example 7) as a white solid, 240mg.

¹H-NMR (CD₃OD, 400MHz): δ 1.02 (d, 3H), 1.28 (t, 3H), 1.40 (s, 9H), 1.57 (m, 1H), 1.81-1.91 (m, 2H), 1.96 (m, 1 H), 2.13-2.26 (m, 2H), 2.27 (s, 3H), 2.32-2.42 (m, 1 H), 2.51-2.65 (m, 2H), 2.71-2.81 (m, 3H), 2.98 (m, 1 H), 4.11 (m, 1 H), 4.66 (m, 1H), 7.18-7.35 (m, 5H).

Examples 8 and 9: te/t-Butyl fM S)-3-r4-(5-ethyl-3-methyl-1H-1.2,4-triazol-1-vhpiperidin-1-vn-1-(3- fluorophenvDbutvπcarbamate

The title compounds were prepared from the ketone from preparation 7 and the amine from preparation 25, following the procedure described in examples 6 and 7.

Diastereoisomer 1 (example 8) was obtained as a white solid, 310mg (21%). ¹H-NMR (CD₃OD, 400MHz): δ 0.97 (d, 3H), 1.28 (t, 3H), 1.44 (s, 9H), 1.62 (m, 1 H), 1.83-1.92 (m, 2H), 2.03 (m, 1 H), 2.22 (m, 1 H), 2.26 (s, 3H), 2.28-2.36 (m, 2H), 2.55-2.68 (m, 2H), 2.73-2.81 (m, 3H), 2.95 (m, 1H), 4.12 (m, 1H), 4.83 (m, 1H), 6.95 (m, 1H), 7.03 (m, 1 H), 7.11 (d, 1H), 7.33 (m, 1H).

Further elution provided the second diastereoisomer (example 9) as a white solid, 310mg (21%). ¹H-NMR (CD₃OD, 400MHz): δ 1.02 (d, 3H), 1.28 (t, 3H), 1.41 (s, 9H), 1.57 (m, 1H), 1.81-2.00 (m, 3H), 2.13-2.26 (m, 2H), 2.27 (s, 3H), 2.36 (m, 1 H), 2.53-2.65 (m, 2H), 2.73 (m, 1 H), 2.77 (q, 2H), 2.93- 3.01 (m, 1 H), 4.12 (m, 1 H), 4.68 (m, 1 H), 6.94 (m, 1 H), 7.08 (m, 1 H), 7.15 (d, 1 H), 7.33 (m, 1H).

Examples 10 and 11: tert-Butyl fπ S)-3-r4-(5-isopropyl-3-methyl-1 W-1,2.4-triazol-1-yl)piperidin-1-yll- 1 -phenylbutylTcarbamate

The title compounds were prepared from the ketone from preparation 6 and the amine from preparation 24, following a similar procedure to that described in examples 6 and 7, except DCM:MeOH:0.88 ammonia (98.75:1.75:0.125 to 95:5:0.5) was used as the column eluent.

Diastereoisomer 1 (example 10), was obtained in 38% yield (1.96g).

¹H-NMR (CDCI₃, 400MHz): δ 0.98 (d, 3H), 1.28 (d, 6H), 1.42 (s, 9H), 1.62 (m, 1 H), 1.83 (m, 2H), 2.03 (m, 1H), 2.20-2.39 (m, 6H), 2.62 (m, 2H), 2.78 (m, 1 H), 2.97 (m, 1 H), 3.21 (m, 1 H), 4.18 (m, 1 H), 4.80 (m, 1H), 7.21 (m, 1H), 7.30 (m, 4H).

Further elution provided the second diastereoisomer (example 11) in 21% yield (1.06g).

¹H-NMR (CDCI₃, 400MHz): δ 1.01 (d, 3H), 1.30 (d, 6H), 1.42 (s, 9H), 1.59 (m, 1H), 1.84 (m, 2H), 1.98 (m, 1H), 2.19-2.31 (m, 5H), 2.39 (m, 1H), 2.55-2.63 (m, 2H), 2.78 (m, 1H), 2.99 (m, 1H), 3.20 (m, 1 H), 4.18 (m, 1H), 4.63 (m, 1H), 7.21 (m, 1 H), 7.33 (m, 4H).

Examples 12 and 13: fe/t-Butyl f(1S)-3-r4-(5-cvclopropyl-3-methyl-1W-1,2,4-triazol-1-yl)piperidin-1- yll-1 -phenylbutylTcarbamate

The title compounds were prepared from the ketone from preparation 6 and the amine from preparation 26, following a similar procedure to that described in examples 6 and 7, except DCM was used as the reaction solvent, and DCM:MeOH:0.88 ammonia (98:2:0.2) was used as the column eluent.

Diastereoisomer 1 (example 12) was obtained as a white solid, 350mg (26.5%).

¹H-NMR (CD₃OD, 400MHz): δ 0.98 (m, 5H), 1.10 (m, 2H), 1.42 (s, 9H), 1.60-1.66 (m, 1 H), 1.96 (m, 2H), 2.02-2.10 (m, 2H), 2.20-2.40 (m, 6H), 2.60-2.68 (m, 2H), 2.80 (m, 1H), 2.98 (m, 1H), 4.38 (m, 1 H), 4.80 (m, 1H), 7.22 (m, 1H), 7.30 (m, 4H).

Further elution provided the second diastereoisomer (example 13) as a white solid, 186mg (14%).

¹H-NMR (CD₃OD, 400MHz): δ 0.98 (m, 2H), 1.01-1.13 (m, 5H), 1.28-1.43 (m, 9H), 1.56-1.60 (m, 1 H), 1.90-2.00 (m, 3H), 2.04 (m, 1H), 2.19-2.30 (m, 5H), 2.40 (m, 1 H), 2.57-2.66 (m, 2H), 2.78 (m, 1 H), 3.00 (m, 1 H), 4.38 (m, 1 H), 4.64 (m, 1 H), 7.20 (m, 1 H), 7.32 (m, 4H). Examples 14 and 15: te/f-Butvl 1(1 Sϊ-3-r4-r3-ethvl-5-methvl-1 H-1.2.4-triazoH -vl)piperidin-1 -vli-1 -

PhenylbutvDcarbamate

The title compounds were obtained from the compounds of preparations 6 and 27, following a similar procedure to that described in examples 6 and 7, except 10 eq. titanium isopropoxide and 2 equivalents of Et₃N were used in the reaction.

Diastereoisomer 1 (example 14) was obtained as a clear oil, 110mg (26.5%).

¹H-NMR (CDCI₃, 400MHz): δ 0.82 (d, 3H), 1.25 (t, 3H), 1.40 (m, 9H), 1.58 (m, 1 H), 1.83-1.97 (m, 4H), 2.05-2.38 (m, 3H), 2.40 (s, 3H), 2.57 (m, 1H), 2.61-2.78 (m, 3H), 3.00 (m, 1 H), 3.94 (m, 1 H), 4.97 (m, 1 H), 7.19-7.38 (m, 5H), 7.60 (br s, 1 H).

Further elution provided the second diastereoisomer (example 15) as a clear oil, 74mg (18%).

¹H-NMR (CDCI₃, 400MHz): δ 0.80-1.00 (m, 3H), 1.20-1.58 (m, 13H), 1.81-2.00 (m, 4H), 2.19-2.38 (m, 3H), 2.41 (s, 3H), 2.57-2.79 (m, 4H), 3.01 (m, 1 H), 3.90 (m, 1 H), 4.65 (m, 1 H), 6.37 (m, 1 H), 7.20-7.37 (m, 5H).

Examples 16 and 17: tert-Butyl U1 S)-3-r4-(3,5-diethyl-1Af-1,2,4-triazol-1-vnpiperidin-1-vn-1- phenylbutyljcarbamate

The title compounds were obtained from the compounds of preparations 6 and 28, following a similar procedure to that described in examples 6 and 7, except 10 eq. titanium isopropoxide and 2 equivalents of Et₃N were used in the reaction.

Diastereoisomer 1 (example 16) was obtained as a clear oil, 151mg (36%).

¹H-NMR (CDCI₃, 400MHz): δ 0.82 (d, 3H), 1.31 (m, 6H), 1.42 (m, 9H), 1.59 (m, 1 H), 1.86 (m, 2H), 2.02-2.42 (m, 4H), 2.56 (m, 1 H), 2.60-2.78 (m, 6H), 3.00 (m, 1 H), 3.90 (m, 1H), 4.97 (m, 1 H), 7.19-7.37 (m, 5H), 7.62 (br s, 1H).

Further elution provided the second diastereoisomer (example 17) as a clear oil, 160mg (38%).

¹H-NMR (CDCI₃, 400MHz): δ 0.96 (d, 3H), 1.22-1.47 (m, 13H), 1.76-1.98 (m, 4H), 2.19-2.38 (m, 3H), 2.57 (m, 1 H), 2.62-2.78 (m, 6H), 3.01 (m, 1 H), 3.90 (m, 1 H), 4.65 (m, 1H), 6.37 (m, 1 H), 7.20-7.37 (m, 5H). Example 18: (1 S^-3-F4-f 3-lsopropvl-5-methvl-4H-1 ,2,4-triazol-4-vQpiperidin-1 -vli-1 -ohenvlbutan-1 - amine dihvdrochloride

HCI gas was bubbled through a solution of the compound from example 1 (2.69g, 5.9mmol) in EtOAc (5OmL), until saturation was achieved. The solution was stirred at rt for 45 min, evaporated under reduced pressure, and the product dried in vacuo to afford the title compound as a mixture of diastereomers as a solid.

LRMS : m/z ES 354 [MH]⁺

Examples 19 to 34

A solution of the protected amines (1 eq.) in MeOH (4.5-12mLmmol^"1) and 2N ethereal hydrochloric acid (60-150 eq) was stirred at rt for 16h. The mixture was evaporated under reduced pressure to afford the title compounds as white solids.

Examp e number o precursor in parenthesis NMR spectra were run at 400 MHz in CD₃OD A = the reaction was performed in DCM

B = isolated as the free base, after treatment with 1 N sodium hydroxide

Examples 35 to 42

Et₃N (6 eq.) was added to a stirred suspension of the appropriate amine (1 eq) in DCM (12.6mLmmol^"1) at rt and the mixture was stirred for 10 min. The appropriate acid (1.5 eq.) and HATU (1.5 eq.) were added and the mixture stirred at rt for 16h. Saturated sodium hydrogen carbonate solution was added and the layers separated. The organic layer was washed with brine, dried (MgSO₄) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia as eluent. The product was treated with 2N ethereal hydrochloric acid to provide the title compounds as white solids.

-.Λαi nμic i iui i iuci vji μi cυui sυi ii i μcu ci m icaia

NMR spectra were run at 400 MHz in CD₃OD

A = isolated as the free base 2,2-Difluorocyclobutanecarboxylic acid was obtained as described in J. Org. Chem. (1987), 52(9), 1872- 1874. 4,4-Difluorocyclohexanecarboxylic acid was obtained as described in WO 9727185, preparation 9(a).

Examples 43 to 50

The appropriate acid chloride (1.2 eq) was added to a solution of the amine hydrochloride from example 18 (1 eq.) and Et₃N (3.5eq.) in DMF (9.5mLmmor¹), and the reaction stirred at rt for 18h. The mixture was concentrated under reduced pressure, the residue partitioned between DCM and 10% sodium bicarbonate solution and this mixture shaken for 30 min. The layers were separated, the aqueous solution extracted with DCM and the combined organic extracts evaporated under reduced pressure to afford the title compounds as a mixture of diastereomers.

Examples 51 to 59

A solution of HOBT hydrate (1.2 eq. of 0.126M in DMF), followed by a solution of ECDI hydrochloride (1.2 eq. of 0.126M in DMF) and DIPEA (4.5 eq.) were added to the appropriate acid (1.1 eq.). A solution of the amine from example 18 (1^"eq.) in DMF (9mLmmol^"1) was added and the reaction stirred at rt for 18h. The mixture was concentrated under reduced pressure, the residue partitioned between DCM and 10% sodium bicarbonate solution and this mixture shaken for 30 min. The layers were separated, the aqueous solution extracted with DCM and the combined organic extracts evaporated under reduced pressure to afford the title compounds as a mixture of diastereomers.

A = tetrahydro-2H-pyran-4-carboxylic acid -described in WO 00/39125, preparation 17.

B = 2-(2,2,2-trifiuoroethoxy)acetic acid from preparation 29

C = tetrahydro-2H-thiopyran-4-carboxylic acid 1 ,1 -dioxide from preparation 33

D = tetrahydro-2H-thiopyran-4-carboxylic acid 1 -oxide-described in Arkiv foer Kemi

(1966), 26(6), 73-7 [CAN 66:18629]

Examples 60 to 63

Et₃N (6 eq.) was added to a solution of the appropriate amine (1 eq.), the appropriate acid (1.1 eq.), EDCI HCI (1.2 eq.) and HOBT (1.2eq.) in DCM (12-15mLmmol^"1) and the reaction stirred at rt for 16h. The mixture was partitioned between sodium bicarbonate solution and DCM and the layers separated. The organic phase was washed with water and brine, dried (MgSO₄) and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia to afford the title compounds.

xamp e number of precursor in parenthesis ** NMR spectra were run at 400 MHz in CD₃OD

Examples 64 to 68

DIPEA (4.5 eq.) was added to a solution of the appropriate amine (1 eq.), the appropriate acid (1.05 eq.), EDCI HCI (1.2 eq.) and HOBT hydrate (1.2eq.) in DMF (28-3Om Lm m of¹) and the mixture stirred at rt for 16h. The mixture was concentrated under reduced pressure and the residue partitioned between sodium bicarbonate solution and DCM and the layers separated. The organic phase was dried (MgSO₄) and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia as eluent to afford the title compounds.

xample number of precursor in parenthesis NMR spectra were run at 400 MHz in CDCI₃ except ex. 66 (CD₃OD)

Examples 68 to 75

A mixture of the appropriate amine (1eq.), the appropriate acid (1.2 eq), HATU (1.2eq.) and Et₃N (5eq.) in DCM (4ml_) was stirred at rt for 18h. The reaction was quenched by the addition of saturated sodium carbonate solution, and the layers separated. The organic layer was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:EtOAc:DCM:MeOH (100:0:0:0 to 0:100:0:0 to 0:0:100:0 to 0:0:90:10). The product was dissolved in DCM, the solution treated with ethereal hydrochloric acid (2N), and evaporated under reduced pressure to afford the title compounds.

Example 76: 4,4-Dif \uoro-N-U 1 S)-3-r4-(5-isopropyl-3-methvi-1 H-Λ ,2,4-triazol-1 -yl)piperidin-1 -yll-1 - phenylbutvDcvclohexanecarboxamide

EDCI HCI (880mg, 2.94mmol) and HOBT hydrate (2mg, 0.12mmol) were added to a solution of the amine from example 27 (870mg, 2.45mmol) in DCM (25mL). 4,4-Difluorocyclohexanecarboxylic acid (450mg, 2.69mmol) was added and the mixture stirred at rt for 16h. Saturated sodium bicarbonate solution (3OmL) was added, the layers separated and the aqueous phase extracted with DCM (2OmL). The combined organic solutions were washed with water (5OmL) and brine, then dried (MgSO₄) and evaporated under reduced pressure. The residue was azeotroped with ether and the crude product purified by column chromatography on silica gel using ether:MeOH:0.88 ammonia (98:2:0.2) as eluent to afford the title compound as a white solid, 830mg. 'H-NMR (CD₃OD, 400MHz): δ 0.96 (d, 3H), 1.30 (d, 6H), 1.63 (m, 1H), 1.71-2.04 (m, 8H), 2.03-2.20 (m, 4H), 2.22 (m, 1H), 2.27 (s, 3H), 2.35 (m, 1H), 2.47 (m, 1H), 2.60-2.74 (m, 2H), 2.81 (m, 1 H), 3.01 (m, 1H), 3.22 (m, 1H), 4.21 (m, 1H), 5.09 (t, 1H), 7.22 (m, 1H), 7.26-7.35 (m, 4H).

Example 77: ΛA-ff 1 S)-3-\4-( S-Cvclopropyl-S-methyl-i H-I .2.4-triazol-1 -yl)piperidin-1 -yll-1 - phenylbutylM^-difluorocyclohexanecarboxamide

A mixture of the amine from example 29 (50mg, 0.14mmol), 4,4-difluorocyclohexanecarboxylic acid (34mg, 0.21 mmol), HATU (64mg, 0.17mmol) and Et₃N (39μL, 0.28mmol) in DCM (5ml_) was stirred at it for 18h. The mixture was partitioned between saturated sodium carbonate solution (1OmL) and DCM (1OmL) and the layers separated. The organic layer was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of DCM:MeOH:0.88 ammonia (98:2:0.2). The product was further purified using an lsolute SCX-2 ion exchange cartridge eluting with MeOH, followed by 2M methanolic ammonia to afford the title compound as an oil, 40mg.

¹H-NMR (CD₃OD, 400MHz): δ 0.98 (m, 5H), 1.08 (m, 2H), 1.63 (m, 1H), 1.76-2.19 (m, 13H), 2.21 (s, 3H), 2.24 (m, 1 H), 2.37-2.50 (m, 2H), 2.68 (m, 2H), 2.82 (m, 1 H), 3.02 (m, 1 H), 4.40 (m, 1 H), 5.07 (t, 1 H), 7.22 (m, 1H), 7.33 (m, 4H).

Example 78: N-UΛ S)-3-r4-(5-Cvclopropyl-3-methyl-1 H-Λ ,2,4-triazol-1 -yl)piperidin-1 -ylM - phenylbutylM^-difluorocyclohexanecarboxamide

The title compound was obtained in 71% yield from the compound of preparation 30, following the procedure described in example 77. ¹H-NMR (CD₃OD, 400MHz): δ 0.98 (m, 2H), 1.01 (d, 3H), 1.10 (m, 2H), 1.62-2.12 (m, 13H), 2.21

(m, 5H), 2.36-2.42 (m, 2H), 2.60 (m, 2H), 2.78 (m, 1 H), 3.01 (m, 1 H), 4.39 (m, 1 H), 5.01 (m, 1 H), 7.21 (m, 1 H), 7.37 (m, 4H). Example 79j N-UI S)-3-r4-(3-lsopropyl-5-methyl-4H-1 ,2.4-triazol-4-vnpiperidin-1 -yli-1 ■ phenylbutyltevclobutanecarboxamide

Titanium tetraisopropoxide (0.6ml_, 2.05mmol) was added to a stirred solution of the ketone from

5 preparation 8 (100mg, 0.41mmol) and the amine from preparation 22 (120mg, 0.53mmol) in DCM (1OmL) at rt under nitrogen and the mixture stirred for 16h. Sodium cyanoborohydride (39mg, 0.62mmol) and

MeOH (2mL) were added and the mixture stirred for 2h. Saturated sodium hydrogen carbonate solution

(3mL) and EtOAc (15mL) were added and the mixture stirred for 10 min. The resulting precipitate was filtered off through Celite® and the filtrate concentrated under reduced pressure. The crude product was 0 purified by column chromatography on silica gel using DCM:MeOH:0.88 ammonia (99:1:0.1 to 95:5:0.5) to afford the title compound, 40mg.

¹H-NMR (CD₃OD, 400MHz): δ 1.02 (t, 3H), 1.35 (d, 6H), 1.70 (m, 1H), 1.83-2.40 (m, 12H), 2.50- 2.60 (m, 4H), 2.70-2.85 (m, 2H), 2.91, 3.03 (2xm, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 4.06 (m, 1H)₁ 5.04-5.15 (m, 1H), 7.21 (m, 1 H), 7.34 (m, 4H). 5

Example 80: N-UI S)-3-r4-(3,5-Dimethyl-4AM .2,4-triazol-4-yl)piperidin-1 -yli-1 - phenylbutyllcyclobutanecarboxamide

The title compound was obtained in 12% yield from the ketone from preparation 8 and the amine 0 from preparation 23, following the procedure described in example 79.

¹H-NMR (CD₃OD, 400MHz): δ 1.02 (t, 3H), 1.69 (m, 1 H), 1.87-2.33 (m, 12H), 2.52 (s, 6H), 2.73 (m, 1 H), 2.82 (d, 1 H), 2.90 (d, 1 H), 3.02 (d, 1 H), 3.14 (m, 1 H), 4.01 (m, 1 H), 5.07 (m, 1H), 7.22 (m, 1 H), 7.29-7.33 (m, 4H).

^}-5 Biological Data

The ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate chemokine receptor activity is demonstrated by methodology known in the art, such as by using the assay for CCR5 binding following procedures disclosed in Combadiere et al., J. Leukoc. Biol., 60, 147-52 (1996); and/or by using the intracellular calcium mobilisation assays as 0 described by the same authors, and/or inhibiting cell fusion following procedures disclosed in Bradley et al., J Biomol Screen 9, 516-24 (2004). Cell lines expressing the receptor of interest include those naturally expressing the receptor, such as PM-1, or IL-2 stimulated peripheral blood lymphocytes (PBL), or a cell engineered to express a recombinant receptor, such as CHO, 300.19, L1.2 or HEK-293.

The pharmacological activity of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives is further 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 transfected 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 1μg/ml puromycin.

The CHO cell line is a Tat (transcriptional trans activator)-expressing clone from a CHO JRR17.1 cell line that has been transfected with pTat puro plasmid. The media for this cell line is rich medium for mammalian cell culture originally developed at Roswell Park Memorial Institute RPMH 640 (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-methylumbelliferyl-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 solubilization in an appropriate solvent and dilution in culture medium, a dose-response curve for each compound can be used to calculate IC₅₀ values.

The compounds of the invention have an IC₅₀ in the above cell fusion assay, of less than 100 μM, in particular less than 10 μM, more particularly less than 1 μM, or as useful as intermediates (e.g. wherein

R¹ is H or tert-butyloxycarbonyl) in the formation of such HIV compounds. By way of illustration, the compounds from examples 35, 38, 44, 46, 48, 54, 57, 59, 65, 76 and 80 have an IC₅₀ of 4.3nM, 62.OnM,

3.11nM, 0.137nM, 315nM, 85.3nM, 6.1 nM, 28.7nM, 1 ,40OnM, 3.1nM and 37.5nM, respectively. In general, the compounds tested (excluding the intermediates of R¹ is H and tert-butyloxycarbonyl) displayed acceptable metabolic stability in our liver microsome invitro assay.

Claims

1. A compound of formula (I):

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

R¹ is hydrogen or -COR⁷;

R² is halogen, nitro, cyano, CF₃, d^alkyl, Ci-₄alkyloxy, C^alkyloxy-d^alkyl, S(O)_n(C₁.₄alkyl);

R³ is hydrogen or C_1-4 alkyl;

R⁴ is C_1-4 alkyl;

Het is a triazole of formula (i) or (ii)

(0 ⁽«⁾

R⁵ and R⁶ are independently hydrogen,

R⁷ is C_1-6alkyl; C₃.₆cycloalkyl; Ci.₆alkyloxy; Cs-ecycloalkyl-d-aalkyl; d.₄alkyloxy-C_1-4alkyl; C₃. ₆cycloalkyloxy; phenyl; 4- to 12-membered saturated or partially unsaturated heterocyclic group in which one to three carbon atoms are replaced by heteroatoms selected from N, O and S, which group is monocyclic or polycyclic and is optionally fused, bridged or spiranic; wherein in each instance said alkyl, alkyloxy and cycloalkyl may be substituted by one or more halogen atoms; and wherein said phenyl and heterocycle may be substituted by 1 to 3 atoms or groups selected from oxo, acyl, halogen, C_1-4alkyl, Ci. ₄alkyloxy, S(O)_n(C₁ ^alkyl), nitro, cyano and CF₃; m is 0, 1 or 2; n is 0, 1 or 2.

2. A compound according to claim 1 , wherein R¹ is hydrogen.

3. A compound according to claim 1 , wherein R¹ is -COR⁷.

4. A compound according to any one of claims 1 to 3, wherein R² is halogen.

5. A compound according to one of claims 1 to 4, wherein R³ is hydrogen.

6. A compound according to one of claims 1 to 5, wherein Het is a triazole of formula (i).

7. A compound according to one of claims 1 to 5, wherein Het is a triazole of formula (ii).

8. A compound according to claim 6 or 7, wherein R⁵ is hydrogen or C^alkyl.

5 9. A compound according to claim 6 or 7, wherein R⁶ is hydrogen, C_1-4alkyl or C₃.₆cycloalkyl.

10. A compound according to one of claims 1 to 9 wherein R⁴ is methyl.

11. A compound according to one of claims 1 to 10, wherein R⁷ is C_1-6alkyl optionally substituted by 10 one or more halogen atoms; C₃.₆cycloalkyl optionally substituted by one or more halogen atoms; C₁.

₆alkyloxy; C₃.₆cycloalkyl-C_1-2alkyl; C_Malkyloxy-C₁.₄alkyl optionally substituted by one or more halogen atoms; or heterocycle optionally substituted by 1 to 3 atoms or groups selected from oxo, acyl and C_1- ₄alkyl.

15 12. A compound according to one of claims 1 to 11 , wherein R⁷ is C_halky! optionally substituted by one or more halogen atoms; C₃.₆cycloalkyl optionally substituted by one or more halogen atoms; C_1- ₆alkyloxy except a tertiary alkyloxy; C₃.₆cycloalkyl-C_1-2alkyl; C_1-4alkyloxy-C₁^alkyl optionally substituted by one or more halogen atoms; or heterocycle optionally substituted by 1 to 3 atoms or groups selected from oxo, acyl and d^alkyl.

20

13. A compound according to one of claims 1 to 12, wherein R⁷ is C^alkyl optionally substituted by 1 to 3 fluorine atoms; C₃.₆cycloalkyl optionally substituted by 1 to 3 fluorine atoms; C_1-4alkyloxy except tert- butyloxy; C₃.₆cycloalkyl-C_1-2alkyl; d^alkyloxy-C^alkyl optionally substituted by 1 to 3 fluorine atoms; morpholine, piperidine or piperazine optionally substituted by C^alkyl or acetyl; tetrahydropyrane or

25 tetrahydrothiopyrane optionally substituted by 1 or 2 oxo.

14. A compound according to one of claims 1 to 13, wherein m is 0 or 1.

15. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically 30 acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, together with one or more pharmaceutically acceptable excipients, diluents or carriers

16. A pharmaceutical composition according to claim 15 comprising one or more additional therapeutic agents. 5

17. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, or a pharmaceutical composition according to claim 12 or 13, for use as a medicament.

W 18. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16, for use in the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

19. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16, for use in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, an inflammatory disease, an autoimmune disease or pain.

20. The use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, or of a pharmaceutical composition according to claim 15 or 16, in the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

21. Use according to claim 20 wherein the disorder is HIV, a retroviral infection genetically related to HIV, AIDS, an inflammatory disease, an autoimmune disease or pain.

22. A method of treating a disorder in which the modulation of CCR5 receptors is implicated which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16.

23. A method according to claim 22 wherein the disorder is HIV, a retroviral infection genetically related to HIV, AIDS, or an inflammatory disease.

21. A process of making a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivativ /ee tthheerreeooff wwhhiicchh ccoommpprriisseess:: a) deprotecting a compound of formula:

in which R², R⁴, m and Het are as defined in claim 1 , and PG¹ is a protecting group; or b) reacting the compound obtained in step a) with a compound of formula R⁷COX, in which R⁷ is as defined in claim 1 and X is Cl or OH; and c) optionally converting the compound obtained in step a) or in step b) to a pharmaceutically acceptable salt, solvate or derivative thereof.