NL1027301C2 - New tropane derivatives, useful to treat e.g. retrovirus infections, inflammatory diseases, multiple sclerosis, rheumatoid arthritis and graft rejection, are chemokine-5 receptor modulators - Google Patents

Abstract

Tropane derivatives (I) are new. Tropane derivatives of formula (I) and their salts, solvates and derivatives are new. [Image] R 1>1-6C alkyl; and R 2>1-6C alkyl or 3-7C cycloalkyl (alkyl is optionally substituted by CF 3). Independent claims are included for: (1) preparation of (I); and (2) intermediates of formulae (II), (IV), (VI), (VII), (XVI), (XVII), (XVIII), (XX) and (XXIII). [Image] ACTIVITY : Anti-HIV; Virucide; Antiinflammatory; Neuroprotective; Antiarthritic; Antirheumatic; Immunosuppressive; Gastrointestinal-Gen.; Cytostatic; Gynecological; Antidiabetic; Nephrotropic; Respiratory-Gen.; Cardiant; Antipsoriatic; Cerebroprotective; Vasotropic; Anorectic; CNS-Gen.; Antiarteriosclerotic; Dermatological; Analgesic; Tranquilizer; Antimicrobial; Hepatotropic; Antibacterial. MECHANISM OF ACTION : Chemokine-5 (CCR-5) receptor modulator. (I) were tested for its chemokine-5 receptor modulatory activity in chinese hamster ovary cells using intracellular calcium mobilization assay. The results showed that the median inhibitory concentration of tert-butyl-3-endo-[(3-nitro-4-pyridinyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate was 2.7 nM.

Description

r - *

5 TROPAN DERIVATIVES

The present invention relates to tropane derivatives, to methods for their preparation, to compositions containing tropane derivatives, and to the use thereof.

More specifically, the present invention relates to the use of 8-azabicyclo [3.2.1] octane derivatives in the treatment of a variety of conditions, including those in which the modulation, in particular antagonism, of chemokihe CCR5 receptors play a role. Be like that. compounds of the invention useful in the treatment of HIV, such as HIV-1, and genetically related retroviral infections (and the resulting immune deficiency syndrome, AIDS), and inflammatory diseases.

The name "chemokine" is an abbreviation for "chemotactic cytojcin". The chemokines form a large family of proteins that share important structural characteristics and that have the ability to attract leiiko cytes. As chemotactic factors for leukocytes, chemokines play an indispensable role in attracting leukocytes to different tissues of the body, a process that is essential for both inflammation and for the body's response to infection. Because chemokines and their receptors play a central role in the pathophysiology of inflammatory and infectious diseases, agents with a modulating, preferably antagonistic, activity on the activity of chemokines and their receptors are useful for the therapeutic treatment of such inflammatory and infectious diseases. .

The chemokine receptor CCR5 is of particular interest in the context of treatment of inflammatory and infectious diseases. CCR5 is a receptor for chemokines, in particular for the macrophage inflammatory proteins (MIP) that are designated as ΜΙΡ-Ια and MIP-Ιβ, and for a protein that is regulated upon activation and is normally expressed by T cells 5 and is excreted (regulated upon activation and normal T-cell expressed and sequenced, RANTES).

We have now found a group of compounds that are potent and selective modulators, in particular antagonists, of the CCR5 receptor.

According to a first aspect of the present invention, there is provided a compound of the formula (I) /

15 k “NsN

TT -T «0 Q.

20 li * 5s × ^ F

or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: R 1 represents (C 1 -C 6) alkyl; and R 2 represents (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl, wherein the alkyl is optionally substituted with. CF3.

The term "alkyl" as a group or part of a group includes both branched and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl,.

N-butyl, i-butyl, sec-butyl and t-butyl. The term "(C 3 -C 7) cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In one embodiment, R 1 represents (C 1 -C 4) alkyl.

In a further embodiment, R1 stands for methyl.

In a further embodiment, R 2 represents (C 1 -C 4) alkyl optionally substituted with CF 3.

10273 1 t 3

In a further embodiment, R2 represents cyclopropyl or cyclobutyl.

In a further embodiment, R2 represents methyl, ethyl or i-propyl.

It is further understood that the invention includes all combinations of embodiments of the invention as described above that are consistent with the definition of compounds of formula (I),

The compounds of the invention include compounds of the formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives include complexes, precursor drugs, and isotopically-labeled compounds, as well as salts and solvates thereof). In a further embodiment, the compounds of the invention are the compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, in particular the compounds of the formula (I).

It is understood that the aforementioned compounds of the invention also include polymorphs and isomers thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate, bisulfate, borate, bromide, camsylate, carbonate, chloride, citrate, edisylate, esylate, formate , fumarate, glucepatate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrobromide, hydrochloride, hydroiodide, iodide, isethionate, lactate, malate, raa-leaat, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, , succinate, sulfate, tartrate, tosylate and trifluoroacetate salts.

1027301 * 4

Suitable base salts are formed with bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, 5 meglumin, olamine, potassium, sodium, tromethamine, and zinc salts. For an overview of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formulation (I) can be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid; (Ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example a lactone or lactam, using the desired acid; or (iii) by converting one salt of the compound of formula (I) to another salt by reaction with a suitable acid by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The salt can precipitate from solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to virtually non-ionized.

The compounds of the invention can exist in both unsulvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention plus one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

1027301 $ 5

Complexes include clathrates, i.e., drug-host-inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the pharmaceutical drug that contain two or more organic and / or inorganic components, in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an overview of such complexes, see J Pharra Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

The compounds of the present invention may have the ability to crystallize in more than one form, a property known as polymorphism, and all such polymorphic forms ("polymorphs") are within the scope of the invention. generally occur in response to changes in temperature or pressure or both, and may also be due to variations in the crystallization process Polymorphs can be distinguished from each other by various physical properties, and usually the X-ray diffraction patterns, solubility behavior and melting point of the compound used to distinguish polymorphs from each other.

Certain derivatives of compounds of the formula (I) which themselves may have little or no pharmacological activity can, when administered in or on the body, be converted into compounds of the formula (I) with the desired activity, for example by means of hydrolytic cleavage. Such derivatives are referred to as "drug precursors". Further information regarding the use of drug precursors can be found in "Pro-drugs as Novel Delivery Systems", Vol. 35, ACS Symposium Series (T Higuchi and W Stella) and "Bio-reversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

10273Ü1

<I

6

Drug precursors in accordance with the invention can be produced, for example, by replacing suitable functionalities present in the compounds of formula (I) with certain groups known to those skilled in the art as "pro-groups" as described, for example, in "Design or Prodrugs "by H Bund-gaard (Elsevier, 1985).

Since the compounds of the formula (I) have a secondary amino functionality (-NHR where R * H), examples of drug precursors in accordance with the invention include amides thereof, for example produced by replacing hydrogen with (Cx-C10) alkanoyl.

Further examples of replacement groups in accordance with the previous examples and other examples of other drug precursors in accordance with the invention can be found in the aforementioned references.

In addition, certain compounds of the formula (I) may themselves act as drug precursors of other compounds of the formula (I).

Also included within the scope of the invention are metabolites of compounds of the formula (I), that is, compounds formed in vivo upon administration of the medicament. Some examples of metabolites in accordance with the invention are: (i) when the compound of formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH); (Ii) when the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NRXR2 -> -NHR1 or -NHR2); (iii) when the compound of formula (I) contains a secondary amino group, a primary amino derivative thereof (-NHR1 -> -NH2); 1027301 • »7 (iv) when the compound of formula (I) contains a phenyl group, a phenol derivative thereof (-Ph -> -

PhOH); and (v) when the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> -COOH).

Compounds of formula (I) may contain one or more other asymmetric carbon atoms and therefore exist as two or more stereoisomers. Imidazole substitution of the tropane ring in compounds of formula (I) may have either the endo or exo configuration, and therefore geometric cis / trans (or Z / E) isomers are possible. For example, if the compound contains a keto group, tautomeric isomerism ("tautomerism") may occur.

It follows that a single compound may exhibit more than one type of isomerism.

All stereoisomers of the compounds of the formula (I), including all optical isomers, geometric isomers and tautomeric forms, as well as compounds exhibiting more than one form of isomerism, and mixtures of one or more thereof are included within the scope of the present invention. Also acid addition or base salts whose counter ion is optically active, for example D-lactate or L-lysine, or racemically, for example DL-tartrate or DL-arginine are also within the scope of the present invention.

Imidazole substitution of the tropane ring in the endo configuration is preferred.

Endo / exo isomers can be separated from each other by conventional techniques well known in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis starting from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or of a derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or in the case where the compound of the formula (I) contains an acidic or basic group, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture can be separated by chromatography and / or fractional crystallization after which one or both of the diastereoisomers are converted to the corresponding pure enantiomer (s) well known to those skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography, usually HPLC, on an asymmetric mobile phase resin consisting of a hydrocarbon, typically heptane or hexane, with 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate yields the enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques known in the art - see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel (Wiley, New York, 1994).

The present invention also encompasses all pharmaceutically acceptable isotope-labeled compounds of the formula (I) in which one or more atoms have been replaced by 30 atoms with the same atomic number but with an atomic mass or mass number that is different from the atomic mass or mass number usually used in the nature is found.

Examples of isotopes suitable for incorporation into the compounds of the invention include 35 isotopes of hydrogen, such as 2 H and 3 H, carbon, such as nC, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 1027301 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 150, 170 and 180, phosphorus such as 32 P, and sulfur such as 35 S.

Certain isotope-labeled compounds of the formula (I), for example those containing a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of the simplicity with which they can be incorporated and the available detection means.

Substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic benefits that result from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, and may therefore be preferred in some cases.

Substitution with positron-emitting isotopes, such as UC, 18F, 150 and 13N, may be useful in Positron emission topography (PET) research for studying substrate receptor occupancy.

Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known in the art or by methods analogous to those described in the accompanying Examples and Preparations, using a suitable isotope-labeled reagent instead of the previously used un-labeled reagent.

Pharmaceutically acceptable solvates in accordance with the invention include those in which the crystallization solvent can be substituted isotope, e.g. D2O, de-acetone, de-DMSO.

Preferred compounds of the formula (I) include the compounds of Examples 1-8; and pharmaceutically acceptable salts, solvates or derivatives thereof.

In the general methods, and schemes that follow, the following applies: R 1 and R 2 are as defined in the foregoing unless otherwise specified; Z is OH, or a carboxylic acid activating group such as chloro or 1 H-imidazol-1-yl; EsGp is 1027301, an ester-forming group, such as C1-6 alkyl; Pg is an amino-protecting group, such as boe; ArLg is a leaving group suitable for aromatic nucleophilic substitution, such as those described in Jerry March, Advanced Organic Chemistry (4th edition), Wiley Interscience, 1992 ,. page 652 (incorporated herein by reference), e.g. F, Cl, Br, OMe or OEt; boe is t-butoxycarbonyl; DMF is N, N-dimethylformamide; DCM is dichloromethane: "THF is tetrahydrofuran; Lg is a leaving group suitable for aliphatic nucleophilic substitution, such as those described in Jerry March, ibid., Page 352 (incorporated herein by reference), including Cl, Br, I, and sulfonic acid esters (e.g., tosylate, mesylate, and triflate) ; WSCDI is 1- (3-dimethylaminopropyl-3-ethylcarbodilmide hydrochloride? DCC is Ν, Ν'-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1-hydroxybenzo triazole hydrate; HBTU is O-benzotriole is O-benzotriole -1-yl-Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate.

According to a first method (A), compounds of the formula (I) can be prepared by a compound of the formula (II)

i Mev_N

Reacting with a compound of the formula (III) 35 1027301 *> 5 11 "V R '^ 2.

under conventional carboxylic acid / amine coupling conditions. Conveniently, the coupling is performed under the conditions described below in connection with scheme 1, step (i). .

According to a second method (B), compounds of the formula (I) can be prepared by a compound of the formula (XVI). reacting with a compound of the formula (V).

(V) 30 'under conventional carboxylic acid / amine coupling conditions. Conveniently the coupling is performed under the conditions described below in connection with scheme la, step (i).

According to a third method (C), compounds of the formula (I) can be prepared by reacting a compound of the formula (XIX) 1027301 (XIX) with an amine having the formula (XX) 15 Ra (XX) 20 under conventional conditions. Conveniently, reductive amination is performed under the conditions described below in connection with scheme 1, step (g).

According to a fourth method (D), compounds of the formula (I) can be prepared by reacting a compound of the formula (XXI) PO00> 35 with an amine of the formula (XX) under conventional conditions. Conveniently, reduction 1027301 * 13: amination is carried out under the conditions described below in connection with scheme 1, step (g).

According to a fifth method (E), compounds of the formula (I) can be prepared by alkylating an amine of the formula (XX) with a compound of the formula (XXII). ≤ s / L9 (XXI!) under conventional alkylation conditions. Conveniently, alkylation is carried out in one. suitable solvent, such as a haloalkane (e.g., DCM), an alcohol (e.g., ethanol) or an ether (e.g., THF); optionally in the presence of a base such as an amine (e.g., triethylamine or N-ethyl-N, N-diisopropylamine); and at room or higher temperature (e.g. reflux).

According to another method. (F), compounds of the formula (I) can be prepared by asymmetric reduction of an enamide of the formula (XXIII).

30 H

RVNV ^ N for 8 H X B (xxiii) 0 ill ° .35 under conventional reduction conditions. Asymmetric reduction is conveniently performed in the presence of 1027301% 14 of a transition metal such as Rh, Ru, Pd, Pt, Ir or Ti (e.g. present in an amount of 0.001-0.1 mol-eq.); a chiral ligand such as BINAP (2,2-bis (diphenylphosphino) -1,1V binaphthyl), tol-BINAP (2,2-bis (di-p-tolylphosphino) -5 1,1'-binaphthyl), Du- PHOS (1,2-bis (2,5-dimethylphospholano) benzene) or Penn-Phos (P, P * -1,2-phenylenebis (endo-2,5-dimethyl-7-phosphabicyclo [2,2,1] heptane) (e.g. present in an amount of 0.001-0.2 mol-eq.); a hydrogen donor such as molecular hydrogen, phenylsilane, 2-propanol or ammonium formate; in a solvent such as an alcohol (e.g. methanol, ethanol or 2-propanol), a nitrile (e.g., acetonitrile), an ester (e.g., ethyl acetate), an ether (e.g., THF), or toluene, at a temperature of from 0 ° C to reflux temperature. and optionally at elevated pressure.

According to another method (G), compounds of the formula (I) can be prepared from the amine of the formula (II), or a metal salt thereof (ie a deprotated form), by reaction with an ester with the formula (XXIV) R 1 CO 2 EsGp (XXIV) under conventional conditions. Conveniently the reaction is carried out in the presence of an excess of a base such as an amine ((e.g. triethylamine or N-ethyl-ethyl, Ν-diisopropylamine); an optional catalyst; in a suitable solvent such as a haloalkane (e.g. DCM), an ether (e.g., THF), an ester (e.g., ethyl acetate), or toluene, with or without water present as a co-solvent, Alternatively, the reaction may be carried out in the presence of an ezyme catalyst; suitable solvent such as a haloalkane (e.g., DCM), an ether (e.g., THF), an ester (e.g., ethyl acetate), or toluene, with or without water present as a co-solvent.

1027301 15.

Schemes following general processes for the preparation of compounds of formula (I) / and intermediates therefor.

Those skilled in the art will understand that some of the processes described in the schemes for the preparation of compounds of formula (I) or intermediates therefor may not be applicable to some of the possible substituents.

The person skilled in the art will further understand that it may be necessary or desirable to carry out the conversions described in the diagrams in a different order than the one described, or to modify one or more of the conversions, in order to obtain the desired compound of the formula (I).

It will further be understood by those skilled in the art that, as illustrated in the following schemes, it may be necessary or desirable to protect one or more sensitive groups in the molecule at any stage of the synthesis of compounds of the formula (I). thus preventing unwanted side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) can be used in a conventional manner. See, for example, the one described in "Protective Groups in Organic Synthesis" by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular Chapter 7, pp. 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.

The amino protecting groups boe, benzyloxycarbonyl, methoxycarbonyl, benzyl and acetyl are particularly useful in the preparation of compounds of formula (I) and intermediates thereof.

1027301 * 16

Scheme 1 5 '' λ W W, (iVY) ,, M) irV ^ s /.

(a) N ^ J (XV) / \ 10 / (c) / \ (d) om Mee 'Me.

h (Meco) ao y = \ y = \ 15 Pa ») pai) * pg“ Vv Λ ^: 1: η ί ^ Ο-ρ »Λ Vv

20% I% V

too). (h) m. 1 (V)

25 "V *. ^ 2 RV

/ νΧ / '- Λ ΠΓ- Η ίΛΤ \ W ° w * Ρβ'T ^ 1 ^ w- Ρβ jC ril ^ (v ·) rii LJl 30 LJL ·> ^ ö) ^ NesH j? Me 0 R "^ z (lil)

i h r \ T \ _ / VN ^ O

35 "γΝγ-s / N ^ w -r2 w ° a * £ ;; ·.

Ν ', / Τ 1027301 «· 17

With specific reference to scheme 1, the conversions shown therein can be performed as follows. (a) Substitution of a leaving group on a nitro-pyridine of the formula (XV) with an amine of the formula (XIV) is conveniently carried out in the presence of a base such as an amine (e.g. triethylamine or N -ethyl-Ν, Ν-diisopropylamine) or an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate); in a solvent, such as an alcohol (e.g. methanol or ethanol), a nitrile (e.g. acetonitrile) or an amide (e.g. DMF); and at room temperature or a higher temperature (e.g. up to about 120 ° C).

(b) an imidazopyridine of the formula (XII) can be prepared by reduction and in-situ cyclization of an amino-nitropyridine of the formula (XIII). The reduction is conveniently carried out in the presence of a reducer, such as iron powder; a solvent such as a carboxylic acid (e.g. acetic acid); and at from about room temperature to about 120 ° C. Cyclization of the intermediate amino-aminopyridine is conveniently carried out by adding an acetic anhydride and at elevated temperature (e.g., about 140 ° C).

(c) Reduction of an imidazopyridine of the formula (XII) to an imidazopiperidine of the formula (XI) is conveniently carried out by catalytic hydrogenation in the presence of a suitable catalyst, such as a transition metal catalyst, for example a platinum (e.g. platinum oxide) or a palladium (e.g., palladium hydroxide or palladium on carbon) catalyst; in a solvent such as an alcohol (e.g., methanol or ethanol) or a carboxylic acid (e.g., acetic acid); at room temperature or elevated temperature (e.g. up to 80 ° C; and at elevated pressure such as from 150 to 500 kPa hydrogen (e.g., 400 kPa hydrogen).

(d) The imidazopiperidine of the formula (XI) can be protected by reaction with an alkyl 1027301 * 18 chloroformate (e.g., methyl chloroformate). The reaction is conveniently carried out in a solvent such as a haloalkane (e.g., DCM) or an ether (e.g., THF) using a base such as an amine (e.g., triethylamine or N-ethyl-N, N-5 diisopropylamine) at room temperature.

(e) In an alternative to steps (cj and (d), an imidazopyridine of formula (XII) is treated with an alkyl chloroformate (e.g., methyl chloroformate) and an amine base (e.g., triethylamine or N-ethyl). -N, N-diisopropylamine), which yields a quaternary intermediate, which is reduced under conventional conditions, methyl chloroformate is conveniently added to an imidazopyridine of the formula (XII) in the presence of a solvent, such as an ether (e.g. THF ) or a haloalkane (e.g. DCM) and at room temperature yielding a quaternary intermediate, which is then reduced by adding an alkali metal halide, such as lithium borohydride, at a reduced temperature (e.g. about -70 ° C). Intermediate 20 is further reduced by catalytic hydrogenation in the presence of a suitable catalyst, such as a transition metal catalyst, e.g., a palladium (e.g., palladium hydroxide) ide or palladium on carbon) catalyst; in a solvent such as an alcohol (e.g., methanol or ethanol) or a carboxylic acid (e.g., acetic acid); at room temperature or elevated temperature (e.g. up to 80 ° C).

(f) When the protecting group is an acetyl or comparable group, its removal is carried out manually by treatment with a base such as an alkali metal hydroxide (e.g. sodium or potassium hydroxide) or an acid, such as an inorganic acid (e.g. HCl) and at elevated temperature, such as from 60-100 ° C. (g) Compounds of the formula (VII) are prepared by reductive amination of an aldehyde of the formula (IX) with an amine of the formula (VIII). Conveniently the reaction is carried out in the presence of f 0 2 7 3 U t

* I

19 an acid such as an organic acid (e.g. acetic acid); in a solvent such as an ether (e.g., THF) or a haloalkane (e.g., DCM); using an alkali metal hydride as a reducer, such as sodium triacetoxy borohydride, sodium cyanoborohydride or sodium borohydride; and at room temperature.

(h) When protection in step (d) is obtained by means of a methoxycarbonyl group, the removal thereof is conveniently carried out by treatment with a base, such as an alkali metal hydroxide (e.g. sodium or potassium hydroxide) in a solvent, such as an aqueous alcohol (e.g., H 2 O / propan-2-ol) at. an elevated temperature (e.g. 100 ° C).

(i) The acid / amine coupling is conveniently carried out with the aid of an amine of the formula (VI) and an acid chloride of the formula (V); an excess of an acid acceptor, such as triethylamine or N-ethyl-N, N-diisopropylamine; a solvent such as a haloalkane (e.g., DCM) or an ether (e.g., THF); and at room temperature. Alternatively, the acid / amine coupling can be carried out using an acid of the formula (V) activated by reagents such as WSCDI or DCC and HOBt or HOAt; an excess of an acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine; a solvent, such as a haloalkane (e.g., DCM) or an ether (e.g., THF); and at room temperature.

(j) When the protecting group is a boc group, its removal is conveniently carried out in the presence of an acid, such as an inorganic acid (e.g.

Anhydrous HCl) or trifluoroacetic acid; in a suitable solvent such as an ester (e.g., ethyl acetate), haloalkane (e.g., DCM) or ether (e.g., THF); and from 0 ° C to room temperature.

(k) The acid / amine coupling is conveniently carried out using an amine of the formula (II) and an acid or acid chloride of the formula (III), under the conditions described in step (i) above.

1027301 * * 20

Those skilled in the art will appreciate that one or more of the conversions described in scheme 1 can be performed. in an order different from the described order, or may be modified, to obtain the desired compound of the formula (I).

In a variation on scheme 1, the compounds of formula (I) can be prepared by carrying out steps (h) to (k) in a different order, as illustrated in the following scheme la.

10

Schedule la iy h.

IC - '.

15 pb ^

(VID

"I *" A -V-

RT / H *

- '0 (XVII)

Jv (XVIII) 25 '<h) j • · - Ua

10 '- 0 - 1 p8 M · yNH

30. Y Yr ^ CX xx

Compounds of the formula (XX) have a structure that is analogous to that of compounds of the formula (I), or intermediates thereof, and can be prepared by analogous methods.

1027301 * 9 21

Compounds of the formulas (III), (V), (IX), (XV), (XIX), (XXI), (XXII) and (XXIII) are either known compounds or can be prepared by conventional chemical. methods; see for example WO 01/90106 (in particular pp. 5-19), incorporated herein by reference.

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

The compounds of the present invention can be used to treat. respiratory disorders, including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary diseases, cystic fibrosis, asthma, emphysema, rhinitis, and chronic sinusitis. "

Other conditions that could be treated are those that are induced, affected, or op. otherwise related to. T cell distribution in different organs. It is expected that the compounds of the present invention may be useful for the treatment of such disorders and in particular, among others, disorders in which a relationship with CCR5 or CCR5 chemokines has been established, and more particularly including the following; multiple sclerosis; arthritis such as rheumatoid arthritis, spondyloarthropathies, gout, osteoarthritis, systemic lupus erythematosus and juvenile arthritis; and transplant rejection, in particular inter alia organ transplants such as heart, lung, liver, kidney and pancreatic grafts (e.g., kidney and lung allografts). 'Other conditions for which a similar correlation with C.CR5 or CCR5 chemokines has been established include: inflammatory bowel diseases, 1 027 3 µl * * 22 including Crohn's disease and ulcerative colitis; and dometriosis; type I diabetes; kidney diseases, such as glomerular disease (e.g. glomerulonephritis); fibrosis, such as liver, lung and renal fibrosis; chronic pancreatitis; in-5 flare-pulmonary disease; encephalitis, such as HIV encephalitis; chronic heart failure; ischemic heart disease; psoriasis; heart attack; being overweight; CNS diseases, such as AIDS-related dementias and Alzheimer's disease; anemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; cancer, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma and breast cancer; pain, such as nociceptive pain and neuropathic pain (e.g. peripheral neuropathic pain); and stress response due to surgery, infection, injury or other traumatic seizure.

Infectious diseases where modulation of the CCR5 recombinant plays a role include acute and chronic infection with hepatitis B Virus (HBV) and hepatitis C Virus (HCV); bubonic, septicemic and pulmonary plague; infection with a smallpox virus; toxoplasmosis infection ,; mycobacterium infection; tyrpanosomal infection such as Chagas disease; pneumonia; and cytosporidiosis.

For a recent overview of possible uses of chemokines and chemokine receptor blockers, see Cascieri, M.A., and Springer, M.S., "The chemokine / chemokine receptor family: potential and progress for therapeutic intervention," Curr. On in. Chem. Biol, 4 (4), 420-7 (August 2000).

Accordingly, in another aspect, the present 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 condition in which the modulation of CCR5 receptors plays a role.

1027301 * 1 23

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of HIV, a genetically HIV-related retroviral infection, AIDS, or an inflammatory disease.

In another aspect the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of a respiratory disorder include adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis.

In another aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of multiple sclerosis, rheumatoid arthritis or graft rejection.

In another aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of inflammatory bowel disease; endometriosis; type I diabetes; kidney diseases; fibrosis; chronic pancreatitis; inflammatory lung disease; encephalitis; chronic heart failure; ischemic heart disease; psoriasis; heart attack; being overweight; CNS diseases; anemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; cancer, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma and breast anchor; pain; or stress response due to surgery, infection, injury or other traumatic seizure.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of HBV, HCV, plague, smallpox virus, toxoplasmosis, mycobacterium, trypanosoma, pneumonia , or cytosporidiosis.

1027301 • # 24

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

In another aspect, the invention provides a method for the treatment of a mammalian condition in which the modulation of CCR5 receptors plays a role, comprising treating the mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or derivative thereof.

The compounds of the invention can be administered as crystalline or amorphous products. They can be obtained, for example, in the form of solid granulates, powders, or films, by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporation. Microwave or radio wave drying can be used for this purpose.

They may be taken individually, or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or in a combination thereof). In general, they will be administered as a formulation with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe ingredients other than the compound (s) of the invention. The choice of excipients will largely depend on factors such as the method of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be obvious to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 1027301.

25 den in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention can be administered orally. Oral administration may include ingestion, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, wherein the compound is taken directly into the blood stream from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules with solid particles, liquids, or powders, pastilles (including liquid-filled), chewable tablets, multi- and nano-solid particles, gels, solid solution, li posomes, films; (including mucoadhesive), ovules, spays, and liquid formulations.

Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillings in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol. col, methylcellulose, or a suitable oil, and one or more emulsifiers and or suspending agents. Liquid formulations can also be prepared by reconstitution or a solid, for example, from a sachet.

The compounds of the invention can also be used in fast-dissolving, fast-disintegrating dosage forms as described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For tablet dosage forms, the drug may be from the dosage form from 0.1 wt% to 80 wt%, more usually from 1 wt% to 60 wt%, such as 5 wt% to 50 wt%. In addition to the drug, tablets generally contain a disintegrant.

Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, 1027301 26.

crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl groups, starch * pregelatinized starch and sodium alginate. In general, the disintegrant will comprise from 0.1 wt% to 25 wt%, more usually from 0.5 wt% to 20 wt%, such as 1 wt% to 15 wt%, of the dosage form.

Binders are generally used to provide cohesive properties to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, calcium carbonate and dibasic calcium phosphate dihydrate.

Tablets may optionally also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. If present, surfactants may comprise from 0.2 wt% to 5 wt% of the tablet, and lubricants may comprise from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include antioxidants, colorants, flavorings, preservatives and taste masking agents.

A typical exemplary tablet contains up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt%, 1027301 * 27 diluent, from about 1 wt% to about 10 wt % disintegrant, and from about 0.25 wt% to about. about 10 wt% lubricant.

Tablet mixtures can be compressed into tablets directly or with the aid of a roller. Tablet mixtures can be granulated wet, dry or melted, solidified from melt, or extruded prior to tableting. The final formulation may contain one or more layers and may or may not be covered; it may also be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms; Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include those for delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified-release formulations for the purposes of the invention are described in U.S. Patent No. 6,106,864. A further description of other suitable release technologies, such as high energy dispersions and osmotic and coated particles can be found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to effect controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly into the blood stream, into muscles, or into an internal organ. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle (including micro 1027301)

I

28 needle injectors, needle-free injectors and infusion techniques.

Parenteral formulations are usually aqueous solutions that may contain excipients such as salts, carbohydrates and buffers (preferably for a pH between 3 and 9), but for some applications they may be better formulated as a sterile non-aqueous solution or as a dried form which can 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 means of lyophilization, can be easily achieved with the aid of standard pharmaceutical techniques which are well known to those skilled in the art.

The solubility of compounds of the invention used for the preparation of parenteral solutions can be increased by the use of suitable formulation techniques, such as the addition of solubility-enhancing agents.

Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include those for delayed, sustained, pulsed, controlled, targeted and programmed release. Compounds of the invention can therefore be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot. modified release of the compound. Examples of such formulations include drug-covered stents and PGLA microspheres.

The compounds of the invention may also be applied topically to the skin or mucous membranes, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, moldings, foams, films, skin patches, waffles, implants, sponges, fibers, bandages and microemulsions. . Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be added - see, e.g., J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other methods of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and micro needle or needle free (eg Pöwderject ", Bioject * 1, etc.) injection.

Formulations for topical administration can be formulated for immediate and / or modified release. Modified-release formulations include those for delayed, sustained, pulsed, controlled, targeted, and programmed release.

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either individually, or as a mixture, for example in a dry lactose mixture, or as a multi-component particles, for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics for producing a fine mist), or nebulizer, whether or not using a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound of the invention, which may include, for example, ethanol (optionally aqueous ethanol) or a suitable other means for dispersing, solubilizing, or extending the 1027301

"I

Release of the agent, the propellant (s) as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or an oligamic acid.

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

Capsules (for example, made from gelatin or HPMC), blisters and cartridges for use in an inhaler or inhaler can be formulated with a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and an excipient such as 1 -leucine, mannitol, or magnesium stearate. The lactose can 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 formulation as a solution for use in an atomizer using electro-hydrodynamics to produce a fine mist can contain from 1 pg to 20 mg of the compound per atomization and the atomized volume can vary from 1 μΐ to 100 μΐ. A typical formulation may include a compound of the invention, propylene glycol, sterile water, ethanol, and sodium chloride. contain. Other solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

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

10273U1 • m 31

Formulations for inhaled / intranasal administration can be formulated for immediate and / or modified release, using, for example, poly (DL-lactic-co-glycolic acid) (PGLA). Modified-release formulations include those for 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 that delivers a metered amount. Devices in accordance with the invention are typically designed to administer a metered dose or "puff" containing from 1 pg to 10 mg of the compound of the invention. The overall daily dose will typically be between 1 pg to 200 mg, which can be administered as a single dose or, more commonly, as partial doses during the day.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. A traditional suppository base is cocoa butter, but various alternatives may be used if appropriate.

Formulations for rectal / vaginal administration can be formulated for immediate and / or modified delivery. Modified release formulations include those for delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention may also be administered directly into the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ocular and / or aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, waffles, lenses and particle or vesicular systems , such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, 1027301

* · I

Polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gel gum, may be added together with a preservative such as benzalcium chloride. Such formulations can also be delivered by iontophoresis.

Formulations for ocular / aural administration can be formulated for immediate and / or modified delivery. Modified release formulations include those for delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in the aforementioned methods of administration.

Drug-cyclodextrin complexes, for example, have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an excipient, i.e., as a carrier, diluent, or solubilizer. The cyclodextrins most commonly used for these purposes are alpha, beta, and gamma cyclodextrins, examples of which can be found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.

To the extent that it is desirable to administer a compound of the invention in combination with another therapeutic agent, for example for the treatment of a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical preparations, of which at least one compound of the invention contains, are suitably prepared.

combined in the form of a kit suitable for co-administration of the compounds.

The kit of the invention in this case contains two or more separate pharmaceutically acceptable preparations, at least one of which contains a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and means for separately containing these preparations, such as a container, compartmentalized bottle, or compartmentalized foil package. An example of such a kit is the known blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is suitable in particular for administering different dosage forms, for example orally and parenterally, for administering the individual preparations at different dosing intervals, or for titrating the different preparations against each other. To support compliance, the kit typically contains directions for administration and may include a so-called memory aid.

For administration to human patients, weighing about 65 to 70 kg, the total daily dose of a compound of the invention is typically in the order of 1 to 10000 mg, e.g. 10 to 1000 mg, e.g. 25 to 500 mg, of course depending on the method of administration, the age, condition and weight of the patient, and in any case will ultimately be based on the judgment of the treating physician. The total daily dose can be administered in single or subdivided 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.

10273-10 * 34

The compounds of the formula (I) and the pharmaceutically acceptable salts, solvates or derivatives thereof have the advantage that they are more selective, have a fast onset of action, are more powerful, are better absorbed, are more resistant to metabolism, a lesser "food effect" have a better safety profile or have other more desirable properties (e.g. with regard to solubility or hygroscopicity) than the compounds of the prior art.

In particular, the compounds of the invention have a lower inhibitory activity on the HERG potassium channel. Prolongation of the duration of the cardiac action potential (QT prolongation) has been identified as being the consequence of action on the HERG potassium channel (Expert Opinion of Pharmacotherapy, g, pp947-973, 2000). It is known that QT prolongation is potentially responsible for producing fatal cardiac arrhythmias of Torsades de Pointes (TdP). By providing compounds that exhibit a further reduced inhibitory activity on the HERG potassium channel, with comparable or improved pharmacokinetics, the invention provides compounds that are therapeutically effective CCR5 antagonists with further improved cardiac safety.

The compounds of the formula (I) and the pharmaceutically acceptable salts, solvates and derivatives thereof can be administered alone or as part of a combination therapy. Thus, within the scope of the invention, embodiments include co-administration of one or more other therapeutic agents, and compositions comprising one or more other therapeutic agents in addition to a compound of the invention. Such multiple drug regimens, often referred to as combination therapy, can be used in the treatment and prevention of diseases or conditions mediated by or associated with CCR5 chemokine receptor modulation, in particular infection by human immunodeficiency virus, HIV. The use of such a combination therapy is particularly applicable to the treatment and prevention of infection and propagation of human immunodeficiency virus, HIV, and related pathogenic retroviruses in a patient in need of treatment or someone in need of it risk becoming such a patient. The ability of such retroviral pathogens to evolve in a relatively short time to strains that are resistant to any monotherapy administered to the patient is well known in the literature. A recommended treatment for HIV is a combined drug treatment called highly active anti-retroviral therapy (Highly Active Anti-Retroviral Therapy, or HAART). HAART combines three or more HIV-15 drugs. The treatment methods and pharmaceutical compositions of the present invention can therefore use a compound of the invention in the form of a monotherapy, but these methods and compositions can also be used in the form of combination therapy wherein one or more compounds of the invention may be administered in combination with one or more other therapeutic agents such as those described in more detail below.

In a further embodiment of the invention, combinations of the present invention include treatment with a compound of formula (I), or a pharmaceutically acceptable salt> solvate or derivative thereof, and one or more other therapeutic agents selected from the the following: H1V protease inhibitors (PIs), such as indinavir, ritonavir, saquinavir, nelfina-vir, lopinavir, amprenavir, atazanavir, tipranavir, AG 1859 and TMC 114, among others. non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as: nevirapin; delavirdine; capravirine; efavirenz; 5 - {[3,5-35 Diethyl-1- (2-hydroxyethyl) -li-pyrazol-4-yl] oxy} isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; 5 - {[3-Cyclopropyl-1-1027301 • * 36 (2-hydroxyethyl) -5-methyl-11-pyrazol-4-yl] oxy} isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; GW-8248; GW-5634 and TMC125; nucleoside / nucleotide reverse transcriptase seraners (NRTIs), such as zidovudine, didanosine, zalcacabine, stavudine, lamivudine, abacavir, adefovir dipivoxil, tenofovir, emtricitabine and alovudine; other CCR5 antagonists, such as, inter alia: N - {(IS) -3- [3- (3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl) -exo-8-10 azabicyclo [3.2.1] oct-8-yl] -1-phenylpropyl} -4,4-difluorocyclohexanecarboxamide or pharmaceutically acceptable salts, solvates or derivatives thereof, 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'-imidazo [4,5 -c] pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3-endo- (8 - [(3S) -3- (acetamido) -3- (3-fluorophenyl) propyl] -8- azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-20 tetrahydro-3.ff-imidazo [4,5-c] pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, ethyl 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'-imidazo [4,5-c} pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof,

Sch D, NO04128, GW873140, AMO-887 and CMPO-167; agents that inhibit the interaction of gp120 with CD4, such as, among others, BMS806, BMS-488043, 5 - {(IS) -2 - [- (2R) -4-Benzoyl-2-methyl-piperazin-1-yl] - 1-methyl-2-oxo-ethoxy] -4-methoxy-pyridine-2-carboxylic acid methylamide and 4 - ((1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl) ] -1-methyl-2-oxo-ethoxy} - 3-methoxy-N-methyl-benzamide: other agents that inhibit the entry of HIV into a target cell, such as, for example, enfuviritide, T1249, PRO 542 and PRO 140 integrase inhibitors, such as L-870,810 and RNaseH inhibitors, among others.

1027301 * 37

Also included within the scope of the invention are combinations of a compound of formula (I) or a formula. maceutically acceptable salt, solvate or derivative thereof, together with one or more. other therapeutic agents, independently selected from the group consisting of proliferation inhibitors, e.g., hydroxyurea; immunomodulators, such as granulocyte macrophage colony stimulating growth factors (e.g., sargramostim), 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., AMD-070); agents that substantially inhibit, interrupt or reduce viral transcription or RNA replication such as tat (transcriptional trans-activator) or nef (negative regulatory factor) inhibitors; agents that significantly inhibit, interrupt or reduce the translation of one or more virus-expressed proteins other than reverse transcriptase, such as Tat or Nef (such as downregulation or protein expression or antagonism of one or more proteins); agents that influence, and in particular downregulate, expression of the CCR5 receptor; chemokines that induce CCR5 receptor internalization, such as MIP-lci, MIP-β, RANTES and derivatives thereof; and other agents that inhibit viral infection or improve the disease image or course in HIV infected individuals through various mechanisms.

Agents that influence (in particular down-regulate) expression of the CCR5 receptor include immunosupressants, such as calcineurin inhibitors (e.g., tacolimus and cyclosporin A); steroids; agents that interfere with cytokine production or signaling, such as Janus Kinase (JAK) inhibitors (e.g., JAK-3 inhibitors, such as 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, such as basiliximab 1027301

* P

38 and daclizumab); and agents that interfere with cell activation or with the cell cycle, such as rapamycin.

Also within the scope of the present invention are combinations of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more other therapeutic agents that speed up the rate of metabolism of the compound of the compound. reduce the invention to lead to increased exposure in patients. Increasing exposure in such a manner is known as boosting. This has the advantage of increasing the effectiveness of the compound of the invention or lowering the dose needed to achieve the same effectiveness as an un boosted dose. The metabolization of the compounds of the invention includes oxidative processes performed by P450 (CYP450) enzymes, in particular CYP3A4 and conjugation by UDP-glucuronosyltransferase and sulfating enzymes. Thus, the means that can be used to increase a patient's exposure to a compound of the present invention include those that can act as inhibitors of at least one cytochrome P450 (CYP450) enzymes isoform. The isoforms of CYP450 that can be favorably inhibited include CYP1 A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that can be used to inhibit CYP3A4 include ritonavir, saquinavir or ketoconazole.

Those skilled in the art will recognize that treatment with a combination of drugs, as described above, may comprise two or more compounds with the same or with different mechanisms of action. A combination may therefore contain, by way of example, a compound of the invention and: one or more NRTs; one or more NRTIs and a PI; one or more NRTIs and another CCR5-35 antagonist? a PI? a PI and an NNRTI; an NNRTI; and so on .

1027301 * # 39

In addition to the requirement of therapeutic effectiveness, which may necessitate the use of therapeutic agents in addition to the compounds of the invention, there may be other reasons that the use of a combination of a compound of the invention and another therapeutic agent is necessary or desirable such as in the treatment of diseases or conditions that are a direct consequence of or indirectly associated with the underlying CCR5 chemokine receptor modulated disease or condition. For example, when the underlying CCR5 chemokine receptor modulated disease or condition consists of H1V infection and proliferation, it may be necessary or at least desirable to prevent Hepatitis C virus (HCV), Hepatitis B virus (HBV) infection, Human Papillomavirus (HPV), opportunistic infections (including bacterial and fungal infections), neo-plasmas, and other conditions that result from the immunocompromised state of the treated patient being treated. Other therapeutic agents can be used with the compounds of the invention, e.g., to provide immune stimulation or to treat pain and inflammation that accompany the initial and fundamental HIV infection.

Accordingly, therapeutic agents that can be used in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and derivatives also include: interferons, pegylated interferons (e.g., peginterferon alfa-2a, and peginterferon alfa 2b), lamivudine, ribavirin and emtricitabine for the treatment of hepatitis; antifungal agents such as fluconazole, phosphluconazole, itraconazole, and voriconconole; antibacterial agents such as azithromycin and clarithromycin; interferons, daunorubicin, doxorubicin, and paclitaxel for the treatment of AIDS-related Ka-35 posi's sarcoma; and cidofovir, fomivirsen, foscarnet, gan-ciclovir, and valcyte for the treatment of cytomegalovirus (CMVj retinitis.

1027301 m Λ 40

Other combinations for use according to the invention include combination of a compound with the form. mule (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 as fluticasone propionate; a LTD4 antagonist, such as montelukast; a musarin-like antagonist / such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 inhibitor / such as ce-lecoxib / 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), an HMG-CoA reductase inhibitor, such as a statin (e.g. atorvastatin); or an immune system suppressor such as cyclosporin or a macrolide such as tacrolimus.

In the combinations described above, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and other therapeutic agent (s) can be administered, in terms of dosage forms, either individually or in conjunction with each other ; and in terms of their time of or administration, either simultaneously or sequentially. The administration of the one agent can thus take place prior to, simultaneously with, or following the administration of the other agent (s).

Accordingly, in another aspect, the invention provides a pharmaceutical composition containing a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more other therapeutic agents.

It is to be understood that all references made herein to treatment include curative, palliative and prophylactic treatment.

The invention is illustrated with reference to the following Examples and Preparations, in which further the. the following abbreviations can be used: 1027301 41 h = hour min = minute LRMS = high-resolution mass spectrum HRMS = high-resolution mass spectrum 5 APCI + = chemical ionization at atmospheric pressure ESI + = electrospray ionization NMR = nuclear magnetic resonance tic thin-layer chromatography Me * methyl 10

Example 1 N - ((IS) -3- [3-endo- (5-Acetyl-2-methyl-4,5,6,7-tetrahydro-10-imidazo [4,5-c] pyridin-1-yl ) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide

Me Μβ H ^ 20 · k / ΝγΜθ F · '^

To a stirred solution of the amine N - {(15) -3-25 [3-endo- (2-Methyl-4f5,6,7-tetrahydro-1] i-imidazO [4,5- c] pyridin-1-yl) ) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide (94 mg, 0.21 mmol) in dichloromethane (5 mL), at room temperature, became acetyl chloride (18 μΐ, 0.26 mmol) added, followed by N, N-30 diisopropylethylamine (45 μΐ, 0.26 mmol). After 15 hours, the reaction mixture was diluted with dichloromethane (5 ml) and water (5 ml) and then passed over a phase separation pattern. The organic component was concentrated by passing a stream of nitrogen over the solution and the resulting mixture was purified using a Mega Bond Elutplas ™ Si cartridge (10g, Varian) with elution. with dichloromethane / methanol: concentrated aqueous ammonia 1-027301 42 (95: 5: 0.5, by volume) to give the title compound as a white foam (80 mg, 79%).

LRMS (electrospray): m / z [M + Na +] 504, [MH * +] -4.82.

Found C, 63.35; H, 7.32; N, 13.59. C 27 H 36 N 5 FO 2 * 0.5 CH 2 Cl 2 requires C, 63.03; H, 1.12} N, 13.36.

(a) D -21.7 ° (2.12 mg / ml in MeOH).

Examples 2-3

These examples were prepared according to the procedure described above for Example 1 with N - ((1S) -3- [3-endo (2-Methyl-4,5,6,7-tetrahydro> -lii-imidazo [4 5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide and the corresponding compound of formula (V) .All LRMS was electrospray ionization.

Example 2

Me '

20 μ) = N

O X N> 0

F

LRMS: m / z [MH +] 522.

Found C, 67.01; H, 7.74; N, 12.94. C 30 H 40 FN 5 O 2 · 0.1 H 2 O requires C, 66.77; H, 7.84; N, 12.93%.

(a) D -20.9 ° (2.04 mg / ml in MeOH).

30

Example 3

Me '35 ^γ ^ Ι F ° 1027301 43 LRMS: m / z [ΜΗ] 508.

Found C, 66.53; H, 7.59; N, 13.23. C 29 H 38 FN 5 O 2 * 0.1 H 2 O requires C, 66.26; H, 7.67; N, 13.32%.

[Α] D -20.5 ° (2.38mg / ml in MeOH).

Example 4 N - {(1 S) -3- [3-endo- (5-Isobutyl-2-methyl-4,5r6,7-tetrahydro-1-imidazo [4,5-c] pyridin-1-yl) - 8-10 azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide

Me 15. '' UI · '· ΙΓ y-v N') Ir V® 20

To a stirred solution of aiftine N - {(IS) -3- [3-endo- (2-Methyl-4,5,6,7-tetrahydro-1'-imidazo [4,5-c] pyridin-1-yl) ) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-25 fluorophenyl) propyl) acetamide (19.9 g, 45.3 mol) in tetrahydrofuran (500 ml) became triethylamine ( 7.0 ml, 50.0 mmol) added, followed by dropwise addition of isobutyryl chloride (5.3 ml, 50 mmol). After 1 hour a second portion of isobutyryl chloride (0.5 ml, 5.0 mmol) was added dropwise. After 0.5 hours, the reaction mixture was concentrated to approximately 300 ml and ethyl acetate (200 ml) was added. The reaction mixture was washed with 10% aq. K 2 CO 3 solution (200 ml; w / v). The aqueous phase was separated and extracted with ethyl acetate (100 ml). The organic components were combined, washed with brine (100 ml), dried (MgSO 4) and concentrated until a movable oil was obtained that just started to form a foam 1027301 44 *. The residue was dissolved in ethyl acetate (100 ml) and heated to 90 ° C. Water (0.5 ml) was added to the hot surface and the mixture was slowly cooled to room temperature. The precipitate was collected by filtration, washed with ethyl acetate (50 ml) and dried. under reduced pressure to give the title compound as a white solid (20.9 g, 90%).

LRMS: m / z [MH +] 510.

* H NMR. (400 MHz, CD3 OD): δ: 7.29-7.35 (1H, m), 7.12-7.14 (1H, m), 7.05-7.07 (1H, m), 6, 92-6.97 (1H, m), 5.13-5.17 (1H, m), 4.52-4.63 (1H, m), 4.43-4.44 (2H, m), 3.78-3.89 (2H, m), 3.31-3.40 (2H, m), 2.90-3.06. (1 H, m), 2.77-2.84 and 2.69-2.75 (2 H, 2 x m), 2.39-2.51 (2 H, ra), 2.36 and 2.35 (3 H (2xs), 2.20-2.30 (2H, m), 2.03-2.13 (2H, m), 1.95 (3H, 15 s), 1.84-1.90 (2H, m), 1.55-1.65 (4 H, m) +. 1.08-1.11 and · 1.04-1.06 (6H, 2 x m). Rotamers.

Found C, 66.94; H, 7.92; N, 13.47. G29H40 FN502 · 0.5 H2O. requires C, 67> 16; H, 7.97; N, 13.50.

[a] D -23.4 ° (1.64 mg / ml in MeOH).

20

Examples 5-7.

These examples were prepared according to the process described above for Example 1 with N - {(1 S) -3- [3-endo- (2-Methyl-4,5,6,7-tetrahydro-1-yl) -imidazo 14.5-25 c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl) -1- (3-fluorophenyl) propyl} acetamide and the corresponding compound of formula (V). All LRMS was electrospray, except for Example 6, where chemical ionization at atmospheric pressure was used.

30 • Example 5

Me

VU

35 A r 1 Q C VMe

F

10273U

* 45 LRMS: m / z 4 96 [MH +].

Found C, 67.47; H ,. 7.75; N, 14.06. C28 H3 FN5 O2 · 0.15 H2 O requires C, 67.49; H, 7.75; N, 14.05%.

[A] D -21.5.5 (2.00 mg / ml in MeOH) (NMR data follows in the table).

Example 6

Me 10 κι h Wn

Me / <\> N JL

JT. Pi

F

LRMS 532 [M + Na +], 510 [MH +].

Found C, 6.69; H, 7.97; N, 13.06. C 29 H 18 FN 5 O 2 · 0.1 H 2 O requires e, 66.0.1; H, 8.02; N, 13.27%.

[A] D -25.5 ° (2.14 mg / ml in MeOH).

Example 7 25 '

Me VUjsAv.

° Jl. ^ N> | p ^ Me 30 ° LRMS (electrospray) 546 [M + Na +], 524 [ΜΗ *].

Found C, 65.50; H, 7.93; N, 12.45. C30 H42 FN5 O2 O.15 H2 O. 35 requires C, 65.43; H, 8.24; N, 12.72%.

[a] D -28.2 ° (2.06 mg / ml in MeOH).

1027301 • k 46

Example 5 NMR.

N - {(IS) -3- [3-endo- (2-Methyl-5-propionyl-4,5,6,7-tetrahydro-1-imidazo [4,5-c] pyridin-1-yl) -8- Azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide * H NMR (400 MHz, CD3 OD): 6: 7.31 ^ 7.37 (1H, m), 7 / 14-7.16 (1H, d), 7.06-7.10 (1H, m), 6.94-6, 99. (1H, m), 5.14-5.21 (1H, m), 4.56-4.63 (1 H, m), 4.40 and 4.45 (2 H, 2 x s), 3.81-3, 89 (1 H, m), 3.75-3, 80 (1H, m), 3.33-3.41 (2H, m), 2.78-2.86 (1H, m), 2.70-2.76 (1H, m), 2.40- 2.54 (4H, m), 2.37 and 2.38 (3H, 2 x sj, 2.23-2.30 (2H, m), 2.07-2.14 (2H, m), 1 98 (3H, s), 1.86-1.93 (2H, mj, 1.57-1.67 (4H, m), 1.07-1.17 (3H, m). Rotamers.

15

Example 8 N - {(15) -3- [3-endo- (2-Methyl-5- (3,3,3, trifluoropropionyl) -4.5, 6,7-tetrahydro-10-imidazo [4,5- c] pyrldin-1-yl) -8-20 azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide

Me

25

vl °

30 F

To a stirred solution of 3,3,3-trifluoropropionic acid (15 μΐ, 1.71 mmol) in dichloromethane (2 ml) was added O-benzotriazol-1-yl-W / W / W '/ N'-tetramethyluronium hexafluorophosphate "(65 mg, 1.71 mmol), triethylamine (47 μΐ, 3.41 mmol) added, followed by the amine N - {(IS) -3- [3-endo- (2-Methyl-4,5, 6,7-tetrahydro-1027301 47 '· 1H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclot3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide (50 mg, 1.14 mmol). The reaction mixture was heated to 30 ° C for 15 hours, concentrated by passing a stream of nitrogen over the surface, and purified by preparative HPLC (Phenomenex C-15 x 10). cm 10pm column, 20 ml / min flow rate, detection at 225 nm, mobile phase gradient 95: 5 to 5:95 A: B, (A: 0.1% diethylamine in H 2 O, B: MeCN)) whatever the title compound as a gum (20 mg).

LRMS (electrospray) 550 [MH +].

HRMS (electrospray). Found 550.2800. C 28 H 36 N 5 F 4 O 2 (MH +), requires 550; 2800.

Example 9 N - {(1 S) -3- [3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1'-imidazole 4,5c] pyridin-1-yl) - 8-Azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide-fumarate 20

Me. .

Me H

Vv ^ SrYi r 25 Γ \.

O

To a solution of N - {(1 S) -3- [3-endo (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-lff-imidazo [4,5-c] pyridine) 1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide (300 mg, 0.59 mmol) in tetrahydrofuran (2 ml) at reflux temperature a solution of fumaric acid (68 mg, 0.59 mmol) in hot ethanol (2 ml) was added dropwise. After 48 hours, tetrahydrofuran (2 ml) was added and after 48 hours the crystals were collected by filtration, washed with tetrahydrofuran (2 ml) and dried in air to remove the title feather binding as a white powder (110 mg, 30%).

Found C, 62.04; H, 7.26; N, 10.70. C 33 H 44 FN 5 ≤ 0.75 H 2 O requires C, 62.00; H, 7.17; N, 10.96. . "

Example 10 N - {(15) -3- [3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo [4,5-c] pyridin-1-yl) ) -8-10 azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide 15 Me

Me. H

SA -SA 0

20 F

N - {(1 S) -3- [3-endo- (2-MethylT4,5,6,7-tetrahydro-1F-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2. 1] oct-8-yl] -25 1- (3-fluorophenyl) propyl) acetamide (264.4 g, 0.60 mol) was added to propan-2-ol (2.67 L), followed by potassium carbonate (92.7 g, 0.67 mol) and the resulting mixture was cooled to 15 ° C. iso-Butyryl chloride (97.8 g, 0.91 mol) was then added in 10 minutes, keeping the temperature below 25 ° C and after stirring for 10 minutes, the reaction was complete. Then potassium carbonate (267.2 g) in water (2.40 L) was added and the resulting two phases were separated. The aqueous layer was then extracted with ethyl acetate (2.67 L) and the combined organic fractions were washed with saturated aqueous sodium chloride (1.32 L) and water (800 ml), and then concentrated in vacuo. The residue was diluted 1027301 49 * with ethyl acetate (1.07 L) and again concentrated in vacuo. This re-dilution and concentration step was repeated and the resulting residue was treated with ethyl acetate until a total volume of 1.07 1 was reached. This was cooled to 0-5 ° C, stirred for 2 hours, filtered, and washed with cold ethyl acetate (2 x 130 mL). The solid product was then dried in a vacuum oven at 50 ° C to give the title compound (269.8 g, 0.53 mol, 88.0%).

10

Example 11 N - {(1 S) -3- [3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1-imidazo [4,5-c] pyridin-1-yl ) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3- 15. fluorophenyl) propyl} acetamide-fumarate

Me

20 T

° J [^ πΟγ-Απ

25 * O

N - {(IS) -3- [3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c) pyridin-1-yl) - 8-Azabicyclo [3.2.1] oct-8-yl) -1- (3-30 fluorophenyl) propyl J. acetamide (554.0 g, 1.08 mol) was added to propan-2-ol. (13.85 L) followed by fumaric acid (126.2 g, 1.09 mol) and the resulting mixture was heated to reflux for 20 minutes and stirred. This solution was then clarified by filtration at this temperature, before being concentrated in vacuo to a solvent volume or 4 ml / g based on the initial amount of N - {(1 S) - 1027301 • ► 50 3- [3 -endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-11β-imidazo [4,5-c) pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8 -yl) 1- (3-fluorophenyl) propyl} acetamide. This was cooled to 0-5 ° C, stirred for 2 hours, filtered and washed with cold propane-2-ol (2 x 550 ml). The solid product was then dried in a vacuum oven at 50 ° C to give the title compound (495.9 g, 0.79 mol, 72.9%).

Example 12

The (D) tartrate salt of N - {(IS) -3- [3-endo (5-10 isobutyryl-2-methyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c ) pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl) -1- (3-fluorophenyl) propyl) acetamide was prepared according to the method described above for the fumarate salt of Example 9 with N- { (1S) -3- [3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1 -ff-imidazo [4,5-c] pyridin-1-yl) -8- azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide and D-tartaric acid. The PXRD peak data is provided later.

Preparation 1 8-Benzyl-8-azabicyclo [3.2.1] octane-3-one A solution of 2,5-dimethoxy tetrahydrofuran (50 g, 378 mmol) in hydrochloric acid (0.025 N, 160 ml) was added for 16 hours cooled to 0 ° C. Benzylamine hydrochloride (65 g, 453 mmol), ketomonic acid (55 g, 377 mmol) and an aqueous solution of sodium acetate (300 ml, 0.69 M) were added and the reaction mixture was stirred at room temperature for 1 hour, The mixture was heated to 50 ° C for 90 minutes, then cooled in an ice bath and leached to pH 12 with 2 N sodium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The remaining brown oil was distilled under reduced pressure 1027301 • 9 51 (126 ° C / 3 mm Hg) to give the title compound as an off-white solid (37.81 g).

LRMS: m / z 216.3 (MH +).

Preparation 2 tert-Butyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carbonylate 10%

A mixture of 8-benzyl-8-azabicyclo [3.2.1] octane-3-one (15.0 g, 69.7 mmole), di-tfc-butyl dicarbonate (18.2 g).

83.4 mmol) and 20% w / w palladium hydroxide on carbon (3.0 g) in ethyl acetate (165 ml) was stirred at room temperature under an atmosphere of hydrogen at 269 kPa for 4 hours. the mixture was filtered over Arbocel® and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of hexane: ether (100: 0 to 50: 50) which the title compound delivered as a colorless oil that crystallized while standing (16.2 g). * H-NMR (400 MHz, CDCl 3): δ: 1.48 (9H, s), 1.60-1.68 (2H, m), 2.00-2.11 (2H, m), 2, 26-2.34 (2H, m), 2.48-2.82 (2H, 25 m), 4.35-4.58 (2H, mj ppm).

Preparation 3 tert-Butyl-3- (benzylamino) -ehdo-8-azabicyclo [3.2.1loctane-8-carboxylate 30 ° 35 °

A solution of. tert-butyl-3-oxo-8-azabicyclo- [3.2.1] octane-8-carboxylate (10.0 g, 44.4 mmol), benzyla-1 0 2 7 3 U 1 52 mine (4.85 ml) (49.7 mmol) and sodium triacetoxyborohydride (14.11 g, 66.6 mmol) were stirred for 16 hours at room temperature in a mixture of glacial acetic acid: dichloromethane (1: 9 v / v, 290 ml). The solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate.

(200 ml), then washed with saturated aqueous sodium carbonate solution (50 ml) and water (50 ml). The organic solution was. dried (MgSO 4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an eluent of dichloromethane: methanol: concentrated aqueous ammonia (98: 2: 0.25) to give the title compound as a white solid (7.00 g) · 1 H-NMR (400 MHz, CDCl3): δ: 1.42-1.48 (11H, m), 1.52-1.61 (2H, m), 1.85-2.19 (5H, m), 2 , 95-3.03 (1 H, m), 3.74 (2 H, s), 4.03-4.23 (2 H, m), 7.20-7.26 (1 H, m), 7.26 -7.32 (4 H, m) ppm.

Preparation 4 fcert-Butyl-3-endo-amino-8-azabicyclo [3.2.1] octane-8-carboxylate

: -rhT

25 "V

O

A mixture of tert-butyl 3- (benzylamino) -endo-8-azabicyclo [3.2.1] octane-8-carboxylate (7.00 g, 22.1 mmol), ammonium formate (7.00 g, 111 mmol) ) and 20% w / w palladium hydroxide. on carbon (0.70 g) in ethanol (200 ml) was heated to 50 ° C until gas was stopped. The cooled mixture was filtered over Arbocel® and the filtrate was evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: concentrated aqueous ammonia (98: 2: 1027301 * 9 '', 53, 0.25 to 95: 5: 0.5) yielding the title compound as a colorless oil (4.70 g).

LRMS: m / z 227.2 (MH +).

Preparation 5 tert-Butyl-3-endo - [(3-nitro-4-pyridinyl) amino] -8-azabicyclo [3.2.1] octane-8-carboxylate! "··" i

° "SO

itV

Me O

Tert-Butyl-3-amino-ehdo-8-azabicyclo [3.2.1] octane-8-carboxylate (3.0 g, 13.2 in mol), 4-ethoxy-3-nitropyridine hydrochloride (2.7 g, 13.2 nmmol) and N-ethyl-N, N-diisopropylamine (1.89 g, 14.6 mmol) were dissolved in 1-20 methyl-2-pyrrolidinone (5 ml) and heated to 120 ° C for 18 hours.

The cooled reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (3 x 50 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml) and brine (30 ml). The organic layer was dried (MgSO 4) and the solvent was removed by evaporation under reduced pressure. This residue was triturated with diethyl ether and filtered to give the title compound as a yellow solid (1.5 g).

LRMS: m / z 349 (MH +).

30 - ""

Preparation 6 1-endo- (8-Acetyl-8-azabicyclo [3.2.1] oct-3-yl) -2-methyl-1H-imidazo [4,5-c] pyridine.

·. ·: I

. . · I 35

• "I

1027301 "·" i * ». · 54 "* -? ~ JC" k /

T

Ο tert-Butyl-S-eni [(3-nitro-4-pyridinyl) amino] -β-10 azabicyclo [3.2.1] octane-8-carboxylate (4.40 g, 12.6 mmol) and iron powder ( 2.11 g, 37.8 mmol) were dissolved in ice-acetic acid (50 ml) and the mixture was heated to 60 ° C for 2 hours. Acetic anhydride (8 ml) was then added and the mixture was heated to 140 ° C for 18 hours. The cooled reaction mixture was filtered over a layer of Arbocel® eri solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (200 ml) and water (200 ml) and the mixture was adjusted to pH 9 with 2 N aqueous sodium hydroxide solution. The mixture was filtered again over a layer of Arbocel® and the organic phase was separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic extracts were dried (MgSO 4). Solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and dried (Mg-SO 4) to give the title compound as a white solid (3.27 g).

LRMS: m / z 285 (MH +).

Preparation 7 1-endo (8-acetyl-8-azabicyclo [3.2.1] oct-3-yl) -5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [ 4,5-c] pyridine 35 55273 * 55. .

èJ

Benzyl bromide (lf78 g, 10.4 mmol) was added to a solution of 1-endo- (8-acetyl-8-azabicyclo [3.2.1] octr · 3-yl) -2-methyl-lff-imidazo [4,5-c] pyridine (2/47 g, 8/7 mmol) in ethanol (20 ml) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then cooled to -70 ° C and sodium borohydride (0.33 g, 8.7 mmol) was added portionwise in ten minutes. After one hour at -70 ° C, the reaction mixture was allowed to warm to -40 ° C / and then cooled again to -70 ° C and more sodium borohydride (0/33 g, 8.7 mmol) was added. After an additional hour at -70 ° C, water (10 ml) was added and the reaction was allowed to warm to room temperature. The ethanol was evaporated under reduced pressure and the aqueous residue was extracted with dichloromethane (3 x 25 ml). The combined organic extracts were dried (MgSO 4) and solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: methanol: diethylamine (100: 0: 2, pp volume basis, changing to 98: 2: 2 then to 95: 5: 2 ). Product-containing fractions were evaporated to provide the title compound as a white foam (2.23 g).

LRMS: m / z 37.9 (MH +).

Preparation 8 1-endo- (8-Azabicyclo [3 - 2.11 oct-3-yl) -5-benzyl-2-methyl-4,5 / 6,7-tetrahydro-1H-imidazo [4,5-c] pyridine 102730 * 565: 1-endo- (8-Acetyi-8-azabicyclo [3.2.1] oct-3-yl) -5-benzyl-2-methyl-4, 5,6,7-tetrahydro-1-imidazo [4,5-c] pyridine (2.23 g, 5.89 mmol) was dissolved in 6 N aqueous hydrochloric acid (30 mL) and heated under reflux for 18 hours. The cooled reaction mixture was adjusted to pH 10 by adding 2 N aqueous sodium hydroxide solution and extracted with dichloromethane (2 x 50 ml). The combined organic extracts were dried (MgSO *) and solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography.

20 on silica gel eluting with a solvent gradient of! dichloromethane: methanol: diethylamine (100: 0: 0.5, by volume, changing to 93: 7: 1). Product-containing fractions were evaporated to give the title compound as a white foam (1.47 g).

LRMS (electrospray): m / z [M + H] + 337.

Preparation 9 tert-Butyl- (IS) -1- (3-fluorophenyl) -3-oxopropyl carbamate 3 °; Me

Media ^ 0 ^ 0

Me HNv ^ s ^ O

II

1027301 + Λ '' · '57' Λ

Diisobutylaluminum hydride (1 Μ in dichloromethane, 39 ml # 39 mmol) was cooled to -78 ° C and added dropwise to a solution of methyl (3S) -3 - [(tert-butoxycarbonyl) amino) -3- (3-fluorophenyl propanoate (WO

5,0039125, p60, preparation 12) (5.4 g, 18.2 mmol) in dichloromethane (100 ml) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes, after which methanol (50 ml, pre-cooled to -78 ° C) was added. The reaction mixture was stirred for 30 minutes, after which 2 N hydrochloric acid (250 ml) was added. The biphasic mixture was allowed to warm to room temperature, the layers were separated, and the Organic layer was dried. (MgSO *), filtered and evaporated under reduced pressure. the title compound yielded as a clear, colorless oil, 4.8 g.

LRMS: m / z 268.1 (MH +).

Preparation 10 tert-Butyl- (15) -3- [3-endo- (5-benzyl-2-methyl-4,5,6,7-20 tetrahydro-1-imidazo [4,5-c] pyridin-1-one) -yl) -8-azabicyclor 3.2.2] oct-8-yl -1- (3-fluorophenyl) propyl carbamate

Me O

":

Acetic acid (0.39 g, 6.4 mmol) was added to a stirred solution of 1-endo (8-azabicyclo [3.2.1] oct-3-yl) -5-benzyl-2-methyl-4 5,6,7-tetrahydro-1-imidazo (4,5-pyridine (2.16 g, 6.4 mmol) and tert-butyl (15) -1- (3-35 fluorophenyl) -3-oxopropyl carbamate ( 2.06 g, 7.7 mmol) dissolved in dichloromethane (25 ml) under nitrogen at room temperature, then sodium triacetoxyborohydride 1027301 * 6'58 (1r-63 g, 7.7 immol) was added and the reaction mixture was at room temperature for 2 hours The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 ml) and dichloromethane (50 ml).

The organic phase was removed and the aqueous phase was washed with dichloromethane (50 ml). The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol: concentrated ammonia (99 1: 0.1, by volume, changing to 96: 4: 0.4). Product-containing fractions were evaporated, yielding the title compound as. a white foam (2.56 g).

LRMS (electrospray: m / z [M + H] + 588.

Preparation 11 tert-Butyl- (15) -3- [3-endo- (2-methyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-rl-yl) -8 -azabicyclo [3.2.1] oct-8-yl] -20 1- (3-fluorophenyl) propyl carbamate ~.

Me O

30

A mixture of tert-butyl (1 S) -3- [3-endo (5-benzyl-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo [4,5-c] pyridine-1) -yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl carbamate (2.55 g, 4.34 mmol), ammonium formate (2.73 g, 43 , 4 mmol) and 20% w / w palladium hydroxide on carbon (0.25 g) in ethanol (35 ml) was heated to 60 ° C. After one hour more ammonia formate (0.63 g, 10.1 1027301 59 mmol) was added and the mixture was heated to 60 ° C for another two hours. The cooled reaction mixture was then filtered over Arbocel * and the filtrate was evaporated under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and saturated aqueous sodium hydrogen carbonate solution (50 µl), the organic phase was separated and washed with water (30 ml). The organic layer was dried (MgSC> 4) and solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol: concentrated ammonia (99: 1: 0.1 changing to 93: 7: 1) to give the title compound as a white foam ( 1.50 g).

LRMS (electrospray): m / z [M + H] + 498.

Preparation 12

Methyl 1-endo- (8 - {(3S) -3- [(tert-butoxycarbonyl) amino] -3- (3-fluorophenyl) propyl} -8-azabicyclo [3.2.1] oct-3-yl) - 2-20 methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carbonate

25 S

30 Me O

Methyl chloroformate (0.167 g, 1.76 mmol) was added to a solution of tert-butyl (1 S) -3- [3-endo (2-methyl-4,5,6,7-tetrahydro-1fl). -imidazo (4,5-c] pyridin-1-yl) -8-azabicyclo [3,2,1] oct-8-yl] -1- (3-102730 *.

60 fluorophenyl) propyl carbamate (0.80 g, 1.60 mmol) in dichloromethane (10 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and then washed with saturated aqueous sodium hydrogen carbonate solution (10 ml). The organic phase was removed and the aqueous layer was extracted with more dichloromethane (2 x 10 ml). The combined dichloromethane extracts. were dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent mixture of dichloromethane: methanol: concentrated ammonia (99: 1: 0.1 changing to 93: 7: 1) to give the title compound as a white foam (0.84 g).

LRMS (electrospray): m / z [M + H] + 556.

"· I

Preparation 13

Methyl 1-endo {8 - [(3S) -3-amino-3- (3-fluorophenyl) propyl] -1-8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5, 6,7-tetrahydro-11-20 imidazo [4,5-c] pyridine-5-carbonate-trihydrochloride 30

Hydrochloric acid gas was bubbled through a solution of methyl 1-endo (8- {(3S) -3- [(tert-butoxycarbonyl) amino] -3- (3-fluorophenyl) propyl} -8-azabicyclo [3.2. .1] oct-3-yl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-5-carbonate (0.83 g, 1.50 mmol) in dichloromethane (15 ml) at 0 ° C until the solution was saturated.

1027301%, then the opportunity to warm to room temperature and stirred for one hour. Solvent was evaporated under reduced pressure and the residue was suspended in dichloromethane (10 ml). This process was repeated three times, yielding the title compound as one. white solid (0.82 g).

LRMS (electrospray): m / z [M + H] + 456.

Preparation 14 Methyl 1-endo- {8-Γ (35) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2- methyl 4,5,6,7-tetrahydro-11-imidazo [4,5-c] pyridine-5-carbonate

Acetyl chloride (0.062 g, 0.9 mmol) was added to a solution of methyl 1-endo {8 - [(3S) -3-amino-3- (3-fluorophenylpropyl] -8-azabicyclo [3.2.1] oct-3-yl] -2-methyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridine-5-carbonate trihydrochloride (0.409 g, 0.72 mmol) and triethylamine (0.33 g, 3.25 mmol), dissolved in dichloromethane (10 ml) under nitrogen at room temperature, and the reaction mixture was stirred for 2 hours. The solution was then washed with water (10 ml), 1N sodium hydroxide solution ( 10 ml) and brine (10 ml) The organic phase was separated, dried (MgSO 1) and solvent was removed under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol : concentrated ammonia (99: 1: 0.1, by volume, changing to 97: 3: 0.3) Product-containing fractions 1027301 • 62 were evaporated, yielding the title compound as a white plate µm (0.24 g).

LRMS (electrospray): m / z [M + H] + 498.

5 Preparation 15.

N - {(IS) -3- [3-endo- (2-Methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [ 3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide

15 J

To a stirred solution of Methyl 1-endo {8-20 [(3S) -3- (acetyiamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-11-imidazo [4,5-c] pyridine-5-carboxylate (13.27 g, 26.7 mmol) in propan-2-ol (80 ml 2 M aqueous sodium hydroxide solution (120 ml) was added and the mixture was heated to reflux for 48 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic components were washed with brine (150 ml), dried (MgSOf) and concentrated under reduced pressure. The crude product mixture was purified by flash column chromatography eluting with dichloromethane: methanol: concentrated ammonia (90: 10: 1 then 80: 20: 1, by volume) to give the title compound as a white foam (8.54 g , 73%).

LRMS (chemical ionization at atmospheric pressure): m / z [MH +] 440.

1027301 63 • 0

Preparation 16 N- {(IS) -3- [3-endo- (2-Methyl-4,5,6,7-tetrahydro-1-imidazo [4,5-c] pyridin-1-yl) -8- azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide 5-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-1H-imidazo [4,5-c] pyridine-5 carbonate (L) tartrate (WO 03/084954, Example 46) (898 g, 1.39 mol) was added to dichloromethane (4.5 L) and water (4.5 L). Then aqueous sodium hydroxide (10 M, 450 ml) was added and the result was stirred for 15 minutes. The two phases were separated and the aqueous layer was extracted with more dichloromethane (2.25 L). The combined organic phases were then concentrated and the resulting oil was dissolved in propan-2-ol (4.5 L). Then aqueous sodium hydroxide (2 M, 6.93 L, 13.9 mol) was added and the biphasic mixture was heated to reflux for 65 hours. After cooling to room temperature, the phases were separated and the watt layer became low. extracted with ethyl acetate (4.5. 1). The combined organic phases were then washed with saturated aqueous sodium chloride (4.5 L) and concentrated in vacuo. The residue was diluted with ethyl acetate (9 L) and concentrated again in vacuo. Finally, more ethyl acetate (4.5 L) was added and the resulting slurry was stirred for 1 hour at 0-5 ° C, filtered and washed with cold ethyl acetate (2 x 450 ml).

1027301 64.

The solid product was then dried in a vacuum oven at 40 ° C to give the title compound (547.2 g, 1.24 mol, 89.8%). The LRMS data for the title compound was identical to that of the title compound of Prepa-5 raat.

Biological information

The ability of the compounds of formula (I) and the pharmaceutically acceptable salts, solvates and derivatives thereof, to modulate chemokine receptor activity has been demonstrated according to methodology known in the art, such as using the CCR5 assay binding according to Combadiere et al., J. Leukoc. Biol, 60, 147-52 (1996) described methods; and or using the intracellular calcium mobilization assays as described by these same authors. Cell lines that express the receptor in question include those that naturally express the receptor, such as PM-1, or IL-2-stimulated peripheral blood lymphocytes (PBL), or a cell designed to produce a recombinant receptor. such as CHO, 300.19, L1.2 or HEK-293.

The compound of Example 4, when tested using the CCR5 binding assay according to Comba-25 et al. (Ibid.) IC 50 values of 7.5 nM (ΜΙΡ-Ια), 7.3 nM (ΜΙΡ -Ιβ) and 6.7 nM (RANTES).

The compound of Example 5 showed, when tested using the CCR5 binding assay according to Combadiere et al. IC 50 values of 2.7 nM (ΜΙΡ-Ια), 2.4 nM (MIP-30 1β) and 1, 9 nM (RANTES).

All examples were found, when tested using the assay for intracellular calcium mobilization according to Combadiere et al. (Ibid.) Potent antagonists with IC 50 values of less than 100 nM (MIP-ip).

The pharmacological activity of the compounds of formula (I) and the pharmaceutically acceptable salts, solvates and derivatives thereof has been further demonstrated with the aid of a gpl60-induced cell-cell fusion assay to assess the IC50 values. determining compounds against HIV-1 fusion. The gp150-induced cell-cell fusion assay uses a HeLa P4 cell line and a CHO-Tat10 cell line.

The HeLa P4 cell line expresses CCR4 and CD4 and is transfected with HIV-1 LTR-β-galactosidase. The medium for this cell line is Dulbecco's modified Eagle's medium (D-MEM) (without: -glutamine) with 10% fetal calf serum (FCS), 2 mM L-glutamine penicillin-10 ne / stpretomycin (Pen / Strep; 100 U / ml) penicillin + 10 mg / ml streptomycin), and 1 pg / ml puromycin.

The CHO cell line is. a Tat (transcriptional trans-activator) expressing clone from a CHO-JRR17.1 cell line transfected with pTat-puro-15 plasmid. The medium for this cell line is rich medium for mammalian cell culture originally developed at the Roswell Park Memorial Institute RPMI1640 (without L-glutamine) with 10% FCS, 2 mM L-glutamine, 0.5 mg / ml Hygromycin B and 12 pg / ml of puromycin. The CHO-JRR17.1 cell line 20 expresses gpl60 (JRFL) and is a clone selected for its ability to fuse with a CCR5 / CD4-expressing cell line.

After cell fusion, the Tat present in the CHO cell line is able to transactivate the long-term repeat sequence (LTR) of HIV-1 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 with which the expression level of β-galactosidase can be determined using 4-methylumbelliferyl-galactopyranoside (MUG) as a substrate. β-Galactosidase hydrolyses the fluorogenic substrate resulting in the release of the fluorescent molecule 4-35 methylumbelliferone (4MU). The fluorescence of 4-methylumbelliferone is then measured on a fluorescent 1027301

* I

66 meters at an excitation wavelength of 360 nm and an emission wavelength of 460 nm.

Compounds that inhibit fusion will lead to a reduced signal and after solubilization in an appropriate solvent and dilution in culture medium, a dose-response curve can be used for each compound to calculate IC50 values.

All compounds of the Examples of the invention have IC 50 values, according to the above method, of less than 10 nM. The compounds of Examples 1 and 5 have an IC 50 value of 130 and 120 pM, respectively.

Powder X-ray diffraction (PXRD) data All PXRD patterns were measured on a Bruker D500

Powder diffractometer in the 2-theta angle range of 2-55 ° with a step size of 0.02 °. The sample was rotated under irradiation with copper K-alpha X-rays (Wavelength = 1.5046 Angstroms) filtered through a graphite mono-chromator (λ = 0.15405 nm) with the X-ray tube operating at 40 kV / mA. The diffractometer was calibrated with a standard quartz sample before and after measurement of each sample.

The main peaks (in degrees 2-theta) of the PXRD patterns for samples 10, 11 and 12 are weather data in the following tables: 1027301 •> 67

Table 1: The PXRD peak data for N- {(IS) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydra-lff-imidazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide.

Angle Intensity Angle Intensity Angle Intensity (° 2-theta) te (%) (° 2-theta) te (%) (° 2-theta) te (%) 8.1 __90.5__17.0__49.6__24.1 35 , 8 9.0__20.9__17.8__80.7__24.8__29.5 9.8__12.8__18.3__67.4__25.4__38.0 10.7 __89.1__18.6__43.6__25.6__34.6 11.3 __39.8__18.9__48.3__26.2 43.0 12.3 __100.0 19.9__39.2__27.0__21.3 13.1 __24.2__20.5__48.3__27.9__28.6 14.1 __67.3__21.0__43.8__28.9__25.5 14.5 __19.4__21.5__50.4__29.4__24 , 6 15.8 __55.4__22.5__51.4__30.0__21.7 16.3 __49.9__23.1__46.1__35.9__18.9

16.6 48.5 23.3 54.9 I

5,127,301. 68

Table 2: The PXRD peak data for N - {(IS) -3- (3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide fumarate.

Angle Intensity Angle Intensity Angle Intensity (° 2-theta) counts (%) (° 2-theta) counts (%) (° 2-theta) counts (%) 6.7__38.6__19.1__18.2__25.0__12 , 9 10.0 __34J .__ 19.6__77.8__25.5__10.1 10.2 17.7__20.1__10.2__26.7__17.6 10.4 __36.2__20.6__65.2__28.3__24.1 10.9__16.2__20.8__23.4__28.6__13, 6 12.8__13.1__21.1__42.3__29.0__10.1 13.6 __10.1__22.2__20.2__29.7__19.0 16.7 100.0 22.6__24.1__30.0__12.8 17.0 16.1__22.9__37.0__31.0__11, 0 17.6 32.0__23.4__12.3__33.0__15.2 18.2 31.1 24.8__14.3__34.6__13.2 18.4 77.8 || 5 1027301 • * * 69

Table 3: The PXRD peak data for N - {(1 S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-liimimazazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide (D-tartrate).

Angle Intensity Angle Intensity Angle Intensity (° 2-theta) (%) (° 2-theta) (%) (° 2-theta) te (%) ____ theta) ____ 5, 0_12.5_16.6_42.4_28, 0_21.2_ 6.9_59.6 17.1 100.0 29.1_25.7 9.0_17.1 18.0 65.1 29.7_21.6 9.2_10.9 18.5 50.0 30.9 17, 2 10.0 14.6 19.0 27.1 32.1 21.0 10.4 17.3 19.5 23.9 __ 11.0 15.1_20.0_31.5 ___ 12.4 14.5 20.8 30.6 ___ 13.6 12.5 21.2_42.2 ____ 14.4 _13.7_21.4_39.0 ___ 14.8 10.1 22.5 41.6 ___ 16.4 [41.3 | 25.0 | 15.8 | 5 (

A PXRD pattern simulation for N - {(1 S) -3- [3-endo (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-11-imidazo [4,5-c] pyridine) 1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide fumarate with 2-theta angles, 10 d-spacings and relative intensities was calculated based on of its crystal structure using the "Reflex Powder Diffraction" module or Accelrys Materials Studio ™ [version 2.2]. The simulation parameters used were: Wavelength = 1.540562 A (Cu-Κα),

Polarization Factor = 0.5

Pseudo-Voigt Profile (ü = 0.01, V = -0.001, W = 0.002).

The main peaks (in degrees 2-theta) of the simulated PXRD pattern for N - {(IS) -3- [3-endo- (5-isobutyryl-2-methyl-4,5, 6,7-) tetrahydrimiimidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-2727U * * 70 fluorophenyl) propyl} acetamide- fumarate are shown in Table 4.

Table 4: Simulated PXRD peak data for N - {(IS) -3- [3-5 endo- (5-isobutyryl-2-methyl-4,5 / 6,7-tetrahydro-lff-imidazo [4,5- c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide fumarate.

Angle Intensity Angle Intensity (<> 2-theta) quality (%) (° 2-theta) quality (%) 6.7__59.4__19.6 98.3 10.0 __64.5__20.6__56.8 10.5 __67.7__21, 1__45.1 11.0 __28.8__22.2__13.8 12.8__12.7__22.5 16.1 13.6 __17.0__22.9__39.1 16.7 __93.8__23.4 10.0 17.0 __19.6__26.8 11.2 17.7 __32, 3 28.3__15.5 18.2__30.0__28.6__10.8 18.5__100.0__29.7__14.1 19.1 15.4 30.0 11.6 Differential-Scanning Calorimetry Qeqevens

All DSC data was measured on a Perkin Elmer PYRIS Diamond DSC with autosampler, with a nitrogen gas stream. Samples were placed in 50 μΐ aluminum containers with holes and lids and heated at a speed of 20 ° C for 15 min "1 from 10 to 300 ° C.

N - {(1 S) -3- [3-endo- (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-lifimidazo [4,5-c] pyridin-1-yl) - 8-azabicyclo [3.2.1] oct-8-yl] -1- (3-20 fluorophenyl) propyl) acetamide

Sample size 3.016 mg.

Endothermic peak at 118 ° C - melt.

0> 727301 •> 71 N - {(IS) -3- [3-endo (5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-lff-imidazo [4,5-c] pyridine) 1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-5 fluorophenyl) propyl} acetamide fumarate

Sample size 2.905 mg.

Endothermic peak at 219 ° C - melt.

Endothermic effect at 228 ° C.

Exothermic effect at 246 ° C.

N- {(IS) -3- [3-endo- (5-isobutyryl-2-methyl-4, 5, 6,7-tetrahydro-1'-imidazo [4,5-c] pyridin-1-yl) ) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-15 fluorophenyl) propyl} acetamide tartrate

Sample size 2,979 mg.

Endothermic peak at 217 ° C - melt.

1027301

Claims (18)

A compound of formula (I) · ·. Me ^ υ 10 κ Yï v -X. ». .o ···· “.. or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: R 1 represents (C 1 -C 6) alkyl; and R2 represents {C1 -C6) alkyl or (C3 -C7) cycloalkyl, wherein the alkyl is optionally substituted with CF3. 2. A compound according to claim 1, wherein R 1 represents (C 1 -C 4) alkyl. A compound according to claim 1 or 2, wherein R 1 represents methyl. A compound according to any of claims 1 to 3, wherein R 2 is (C 1 -C 4) alkyl, optionally substituted with CF 3. 5 N - {(IS) -3- [3-endo- (5-Acetyl-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide; N - {(IS) -3- [3-endo- (5-Cyclobutanecarbonyl-2-methyl-4f5,6,7-tetrahydro-lifimidazo [4,5-c] pyridin-1-yl) -8- Azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide; N - {(IS) -3- [3-endo- (5-Cyclopropanecarbonyl-2-methyl-4,5,6 / 7-tetrahydro-1-imidazo [4,5-c] pyridin-1-yl) - 8-azabicyclo [3.2.1] oct-8-yl] -1- (3-15 fluorophenyl) propyl) acetamide; N - {(1 S) -3- (3-endo- (5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-1-yl) - 8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide; N - {(1 S) -3- [3-endo- (2-Methyl-5-propionyl-4,6,6,7-tetrahydro-1 H-imidazo [4,5-c] pyridin-1-yl) -8 -azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide; N - {(IS) -3- [3-endo- (5-Butyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl} acetamide; N - {(IS) -3- [3-endo- (2-Methyl-5- (2,2-dimethyl-propionyl) - 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-30 fluorophenyl) propyl) acetamide; N - {(1 S) -3- [3-endo- (2-Methyl-5- (3,3,3-trifluoropropionyl) -4,5,6,7-tetrahydro-1-iraidazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl] -1- (3-fluorophenyl) propyl) acetamide; And pharmaceutically acceptable salts, solvates or derivatives thereof. 1027301 X 5. A compound according to any one of the preceding claims, wherein R 2 is methyl, ethyl or i-propyl. 1027301 t 5 - CONCLUSIONS A compound according to any of claims 1 to 3, wherein R 2 represents cyclopropyl or cyclobutyl. The compound of claim 1 selected from: A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any one of the preceding claims, together with one or more pharmaceutically acceptable excipients, diluents or carriers. The pharmaceutical composition according to claim 8, further comprising one or more other therapeutic agents. 10 10 Jl JL pcvi),::; 15 with a compound of formula (V) (V) 20 under conventional carboxylic acid / amine coupling conditions; (C) Reductive amination of an aldehyde of the formula (XIX) in an amine of the formula (XX). ^; R 1, (XX) 5 ΗΝ "" Χ /> - under conventional conditions; (D) Reductive amination of a nitrile of the formula (XXI) Y y cN <xx 0 with an amine of the formula (XX) under conventional conditions; (E) alkylation of a compound of the formula (XX) or a salt thereof with a compound of the formula 25 (XXII) H 30 ° 35 under conventional conditions; 1027301 I (m) asymmetric reduction of an enamine of the formula (XXIII) 5 L \ MV \ 10 (L JL ^> F under conventional conditions; (G) reacting the amine of the formula (II) , or a metal salt thereof (ie a deprotonated form) with an ester of the formula (XXIV) 20 R’CC ^ EsGp (XXJV). i under conventional conditions; wherein R1 and R2 are as defined in claim 1 for a compound of the formula (I) / Lg represents a leaving group suitable for aliphatic nucleophilic substitution, and EsGp represents an ester-forming group. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any one of claims 1 to 7, for use as a medicament. 15 A compound of the formula (I) or a pharmaceutically acceptable salt,. solvate or derivative thereof, according to any of claims 1 to 7, for the treatment of a condition in which the modulation of CCR5 receptors plays a role. A compound according to claim 11, wherein the condition is HIV, an infection with an H1V-related retrovirus, AIDS, or an inflammatory disease. 25 The compound of claim 11, wherein the condition is multiple sclerosis, rheumatoid arthritis, or transplant rejection. The compound of claim 11, wherein the condition is inflammatory bowel disease; endometriosis; type I diabetes; kidney diseases; fibrosis; chronic pancreatitis; inflammatory lung disease; encephalitis; chronic heart failure; ischemic heart disease; psoriasis; 35 heart attack; being overweight; CNS diseases; anemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; cancer, such as non-Hodgkin's 1027301. Lymphoma, Kaposi's sarcoma, melanoma and breast anchor; pain; or stress response due to surgery, infection, injury or other traumatic seizure. 15 CCR5 receptors play a role. The compound of claim 11, wherein the disorder is HBV, HCV, plague, pox virus, toxoplasmosis, mycobacterium, trypanosoma, pneumonia, or cytosporidiosis. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any of claims 1 to 7, for the manufacture of a medicament for the treatment of a condition in which the modulation of A method for preparing a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any of claims 20. to 7, comprising: (A) reacting a compound ( II) $ k Me'NjsS; N 25 'λ, nn ^ r 2 UL ° w with a compound of formula (III) O 35 - 1. Z (III) 1027301 * under conventional carboxylic acid / amine coupling conditions; (B) reacting a compound of the formula (XVI) κ Μθν ^ ν; A compound of the formula (II), (IV), (VI), (VII), (XVI), (XVII), (XVIII), (XX) or (XXIII). 1027301