CN1863801A - Imidazopyridine substituted tropane derivatives with ccr5 receptor antagonist activity for the treatment of HIV and inflammation - Google Patents

Abstract

The present invention provides compounds of formula (I), wherein ^R1 and ^R2 are as defined in the specification. The compounds of the present invention are modulators, particularly antagonists, of the chemokine receptor CCR5. CCR5 receptor modulators are useful in treating a variety of inflammatory diseases and conditions, as well as infections with HIV and genetically related retroviruses.

Description

Imidazopyridine-substituted tropane derivatives with CCR5 receptor antagonist activity for the treatment of HIV and inflammation

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

More particularly, the present invention relates to the use of 8-azabicyclo[3.2.1]octane derivatives in the treatment of a variety of diseases including those involved in the regulation, especially antagonism, of the chemokine receptor CCR5 disease. Accordingly, the compounds of the present invention are useful in the treatment of HIV, such as HIV-1, and genetically related retroviral infections (and resulting acquired immunodeficiency syndrome, AIDS), as well as inflammatory diseases.

The term "chemokine" is an abbreviation for "chemotactic cytokine". Chemokines comprise a large family of proteins that share important structural features and the ability to attract leukocytes. Chemokines, as chemokines for leukocytes, play an essential role in attracting leukocytes to tissues in the body, a process necessary for both inflammation and the body's response to infection. Since chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents capable of modulating (preferably antagonizing) the activity of chemokines and their receptors are suitable for therapeutic treatment of said inflammatory and infectious diseases .

Chemokine receptor CCR5 is especially important for the treatment of inflammatory and infectious diseases. CCR5 is a receptor for chemokines, specifically macrophage inflammatory proteins (MIPs) named MIP-α and MIP-β, and proteins regulated by activation and expressed and secreted by normal T cells (RANTES). body.

The inventors have now discovered a class of compounds that are potent and selective modulators, especially antagonists, of the CCR5 receptor.

According to a first aspect of the present invention, there is provided a compound of formula (I) as shown below:

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

R ¹ is C ₁ -C ₆ alkyl; and

R ² is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, wherein the alkyl is optionally substituted by CF ₃ .

The term "alkyl" as a group or part of a group includes straight chain as well as branched chain groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term "C ₃ -C ₇ cycloalkyl" denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In one embodiment, R ¹ is C ₁ -C ₄ alkyl.

In another embodiment, R ¹ is methyl.

In another embodiment, R ² is C ₁ -C ₄ alkyl optionally substituted with CF ₃ .

In another embodiment, ^R2 is cyclopropyl or cyclobutyl.

In another embodiment, ^R2 is methyl, ethyl or isopropyl.

It is understood that the present invention covers all combinations of the above-mentioned embodiments of the present invention, as long as they meet the definition of the compound of formula (I).

The compounds of the present invention include compounds of formula (I) and their pharmaceutically acceptable salts, solvates or derivatives (the derivatives include complexes, prodrugs, isotope-labeled compounds, and their salts and solvates). In another embodiment, the compound of the present invention is a compound of formula (I) and pharmaceutically acceptable salts and solvates thereof, especially a compound of formula (I). It is understood that the above-mentioned compounds of the present invention include polymorphs and isomers thereof.

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

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, borate, bromide, camphorsulfonate, carbonate, chloride, lemon salt, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptanoate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoylbenz Hibenzate, hydrobromide, hydrochloride, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate Naphthoate, methosulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/phosphate Hydrogen salt/monohydrogen phosphate, sarcharate, stearate, succinate, sulfate, tartrate, tosylate and trifluoroacetate.

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

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The pharmaceutically acceptable salt of the compound of formula (I) can be prepared by one or more methods in the following three methods:

(i) reacting a compound of formula (I) with the desired acid;

(ii) removal of acid- or base-labile protecting groups from suitable precursors of compounds of formula (I), or ring-opening of suitable cyclic precursors (such as lactones or lactams) with the desired acid;

(iii) converting one salt of a compound of formula (I) into another salt by reaction with a suitable acid or using a suitable ion exchange column.

The above three methods are usually carried out in solution. The salt may precipitate out of solution and be collected by filtration or by evaporation of the solvent. The degree of ionization of the salt ranges from completely ionized to hardly ionized.

The compounds of the present invention can exist in both unsolvated and solvated forms. The term "solvate" as used herein is used to describe a complex molecule comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

The complexes include clathrates, that is, drug-host molecule inclusion complexes, which are different from the above-mentioned solvates in that the drug and host molecules in the inclusion complexes are stoichiometric or non-stoichiometric. Complexes also include complexes of drugs comprising two or more organic and/or inorganic components, wherein the components may be in stoichiometric or non-stoichiometric amounts. The resulting complex can be ionized, partially ionized or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64(8), 1269-1288 (August 1975), by Haleblian.

The compounds of the present invention have the ability to crystallize in more than one form, a characteristic known as polymorphism, and such polymorphs are fully encompassed within the scope of the present invention. Polymorphism typically occurs in response to changes in temperature or pressure, or both, and can also result from changes in the crystallization process. Polymorphs can be distinguished on the basis of various physical characteristics, which are typically distinguished by the compound's x-ray diffraction pattern, dissolution behavior, and melting point.

Certain derivatives of compounds of formula (I) which themselves have little or no pharmacological activity can be converted to compounds of formula (I) having the desired activity, for example by hydrolytic cleavage, when administered in vivo or on the surface of the body. Such derivatives are referred to as "prodrugs". Further information on the application of prodrugs can be found in the following literature: "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and W. Stella); and "Bioreversible Carriers in Drug Design", Pergamon Press , 1987 (ed. E.B. Roche, American Pharmaceutical Association).

For example, replacing the formula (I) with certain groups known to those skilled in the art as "prodrug groups", such as those disclosed in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985) Prodrugs of the invention can be prepared by appropriate functional groups present in the compounds.

Since the compound of formula (I) contains a secondary amino functional group (-NHR, where R≠H), examples of prodrugs of the present invention include its amides, produced eg by replacing a hydrogen atom with a (C ₁ -C ₁₀ )alkanoyl group.

Examples of other substituting groups of the above examples as well as examples of other prodrug types of the invention can be found in the above references.

Furthermore, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also within the scope of the present invention are metabolites of compounds of formula (I), ie compounds formed in vivo after administration of the drug. Some examples of metabolites of the invention include:

(i) When the compound of formula (I) contains a methyl group, its metabolite is a hydroxymethyl derivative (-CH ₃ →-CH ₂ OH);

(ii) when the compound of formula (I) contains a tertiary amino group, its metabolite is a secondary amino derivative (-NR ¹ R ² →-NHR ¹ or -NHR ² );

(iii) when the compound of formula (I) contains a secondary amino group, its metabolites are primary amino derivatives (-NHR ¹ →-NH ₂ );

(iv) When the compound of formula (I) contains a phenyl group, its metabolite is a phenol derivative (-Ph→-PhOH);

(v) When the compound of formula (I) contains an amido group, its metabolite is a carboxylic acid derivative (-CONH ₂ →COOH).

The compound of formula (I) may contain one or more other asymmetric carbon atoms, so there are two or more stereoisomers. The tropane ring of the compound of formula (I) can be substituted with imidazole in an endo- or exo-configuration, so geometric cis/trans (Z/E) isomers may be obtained. For example, tautomerism can occur when a compound contains a keto group. It follows that a single compound may exhibit more than one isomerism.

All stereoisomers of the compounds of formula (I) are included within the scope of the present invention, including all optical isomers, geometric isomers and tautomeric forms, as well as compounds exhibiting at least one isomerism, and mixtures of one or more of these forms. Also included within the scope of the invention are acid addition or base salts in which the counterion is optically active (e.g. D-lactate or L-lysine), or racemic (e.g. DL-tartrate or DL-lysine). - arginine).

Preference is given to imidazole substitution of the tropane ring in the endo configuration.

The endo/exo isomers can be separated using conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically active precursors, or resolution of racemates (or racemates of salts or derivatives), e.g. using chiral High pressure liquid chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (such as an alcohol); or, when the compound of formula (I) contains an acidic or basic group, the racemate The spinite reacts with acids or bases such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization and one or both of the diastereomers can be converted into the corresponding pure enantiomers using methods well known to those skilled in the art. Enantiomers.

Chromatography, usually HPLC, is performed on asymmetric resins with a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing 0 to 50%, usually 2 to 20%, isopropanol and 0 to 5% alkane An enantiomerically enriched form of a chiral compound of the invention (or a chiral precursor thereof) can be prepared with a base amine, typically 0.1% diethylamine. Concentration of the eluate afforded an enantiomeric enriched mixture.

Mixtures of stereoisomers can be separated using conventional techniques known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel (Wiley, New York, 1994).

The present invention also includes all pharmaceutically acceptable isotope-labeled compounds of formula (I), wherein one or more atoms are replaced with the same atomic number, but the atomic mass or mass number is different from the natural common atomic mass or mass number of atoms.

Examples of isotopes suitable for incorporation into compounds of the invention include isotopes of the following atoms: hydrogen atoms, such as ² H and ³ H; carbon atoms, such as ¹¹ C, ¹³ C, and ¹⁴ C; chlorine atoms, such as ³⁶ Cl; fluorine atoms, such as ¹⁸ F; iodine atom, ^{123 I} and ¹²⁵ I; nitrogen atom, such as ¹³ N and ¹⁵ N; oxygen atom, such as ¹⁵ O, ¹⁷ O and ¹⁸ O; phosphorus atom, such as ³² P;

Certain isotopically-labeled compounds of formula (I), for example those incorporating radioactive isotopes, are useful in tissue distribution studies of drugs and/or substrates. The radioactive isotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly suitable for this purpose in terms of ease of incorporation and existing detection means.

Substitution with heavier isotopes (e.g. deuterium, i.e. ² H) may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, so in some cases it may be preferable to use a heavier isotope. heavy isotopes.

Substitution with positron-emitting isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used in positron emission tomography (PET) studies to detect substrate acceptor occupancy.

Isotopically labeled reagents can generally be prepared using conventional methods known to those skilled in the art, or by methods similar to those described in the Examples and Preparations below, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent. Compounds of formula (I).

Pharmaceutically acceptable solvates of the invention include those wherein the solvent used for crystallization is isotopically substituted, eg _D2O , _d6 -acetone, _d6 -DMSO.

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

In the general preparations and schemes, the following conditions are followed: Unless otherwise specified, R and R are as defined ^above ; Z is OH or a carboxylic acid activating group such ^as chlorine or 1H-imidazol-1-yl; EsGp is an ester Forming group, such as C _1-6 alkyl; Pg is an amino protecting group, such as boc; ArLg is a leaving group suitable for aromatic nucleophilic substitution, such as "Advanced Organic Chemistry" by Jerry March (4th edition, Wiley Interscience, 1992, page 652, which is incorporated herein by reference), for example, has F, Cl, Br, OMe or OEt; boc is tert-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 disclosed in Jerry March (supra, p. 352, incorporated herein by reference), including Cl, Br , I, and sulfonates (such as tosylate, mesylate, and triflate); WSCDI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride; DCC is N,N-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1-hydroxybenzotriazole hydrate; HBTU is O-benzene Triazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate.

According to the first preparation method (A), the preparation of the compound of formula (I) is to make the compound of formula (II)

Reaction with compound of formula (III)

The coupling reaction is conveniently carried out under the conditions described in Scheme 1 step (i) hereinafter.

According to the second preparation method (B), the preparation of the compound of formula (I) is to make the compound of formula (XVI) under conventional carboxylic acid/amine coupling conditions

Reaction with a compound of formula (V).

The coupling reaction is conveniently carried out under the conditions described in step (i) of Scheme 1a hereinafter.

According to the third preparation method (C), the preparation of the compound of formula (I) is under conventional conditions, utilizing the amine of formula (XX),

Aldehydes of formula (XIX) are reductively aminated.

The reductive amination reaction is conveniently carried out under the conditions described in Scheme 1 step (g) hereinafter.

According to the fourth preparation (D), the compound of formula (I) is prepared by reductive amination of the nitrile of formula (XXI) using the amine of formula (XX) under conventional conditions.

The reductive amination reaction is conveniently carried out under the conditions described in Scheme 1 step (g) hereinafter.

According to the fifth preparation method (E), the preparation of the compound of formula (I) is under conventional alkylation conditions, utilizing the compound of formula (XXII),

Amines of formula (XX) are alkylated. The alkylation reaction is conveniently carried out in a suitable solvent such as an alkyl halide (e.g. DCM), alcohol (e.g. ethanol) or ether (e.g. THF); optionally in the presence of an amine (e.g. triethyl amine or N-ethyl-N,N-diisopropylamine) base; and the temperature is from ambient to elevated temperature (eg, reflux temperature).

According to another preparation (F), compounds of formula (I) are prepared by asymmetric reduction of enamides of formula (XXIII) under conventional reducing conditions.

This asymmetric reduction reaction is conveniently carried out under the following conditions: the presence of a transition metal (e.g. Rh, Ru, Pd, Pt, Ir or Ti) (e.g. 0.001-0.1 molar equivalents); a chiral ligand such as BINAP ( 2,2-bis(diphenylphosphino)-1,1'-binaphthyl), tol-BINAP (2,2-bis(diphenylphosphino)-1,1'-binaphthyl), Du-PHOS (1,2-bis(2,5-dimethyl Base (phospholano)) benzene) or Penn-Phos (P,P'-1,2-phenylene bis(endo-2,5-dimethyl-7-phosphabicyclo[2,2,1]heptane )) (for example 0.001-0.2 molar equivalents); hydrogen atom donors such as hydrogen molecules, phenylsilane, 2-propanol or ammonium formate; acetonitrile), esters (eg ethyl acetate), ethers (eg THF) or toluene; at temperatures ranging from 0°C to reflux; and optionally under elevated pressure.

According to another preparation method (G), the compound of formula (I) is prepared by reacting an amine of formula (II) or its metal salt (ie deprotonated form) with an ester of formula (XXIV) under conventional conditions.

R ¹ CO ₂ EsGp (XXIV) The above reaction can be conveniently carried out under the following conditions: there is an excess of a base such as an amine (for example triethylamine or N-ethyl-N,N-diisopropylamine); optionally in a suitable solvent such as an alkyl halide (eg DCM), ether (eg THF), ester (eg ethyl acetate) or toluene; with or without water present as a co-solvent. Alternatively, the reaction is carried out in the presence of an enzyme-catalyst in a suitable solvent such as an alkyl halide (eg DCM), ether (eg THF), ester (eg ethyl acetate) or toluene with or without the presence of water as a cosolvent.

A flow diagram is appended hereafter which further illustrates the general methods for preparing compounds of formula (I) and related intermediates.

Those skilled in the art will appreciate that certain procedures in the schemes illustrating the preparation of compounds of formula (I) and related intermediates may not apply to certain possible substituents.

Those skilled in the art can understand that it may be necessary or desirable to convert in an order different from that described in the flow chart, or modify one or more conversion reactions to obtain the desired compound of formula (I) .

Those skilled in the art can also understand that, as shown in the flow chart below, at any stage of compound synthesis of formula (I), it may be necessary or desirable to protect one or more sensitive groups in the molecule to avoid unwanted side effects. In particular, it is 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, "Protective Groups in Organic Synthesis" by Theodora W. Green and Peter G.M. Wuts, (3rd ed., John Wiley and Sons, 1999), especially Chapter 7, pp. 494-653 ("Protective Groups in Organic Synthesis" ), which is incorporated herein by reference, also describes methods for the removal of such groups.

Amino protecting groups boc, benzyloxycarbonyl, methoxycarbonyl, benzyl and acetyl are particularly suitable for the preparation of compounds of formula (I) and related intermediates.

Flowchart 1

Specifically with reference to flow chart 1, the conversion reaction described wherein can reach according to following steps:

(a) Substituting the leaving group on the nitropyridine of formula (XV) with an amine of formula (XIV), which is conveniently carried out under the following conditions: in the presence of an amine such as triethylamine or N-ethyl- N,N-diisopropylamine) or bases of alkali metal carbonates (such as sodium carbonate or potassium carbonate); in solvents such as alcohols (such as methanol or ethanol), nitriles (such as acetonitrile) or amides (such as DMF); and The temperature is from ambient to elevated temperature (eg, up to about 120°C).

(b) Reduction and in-situ cyclization of amino-nitropyridines of formula (XIII) can prepare imidazopyridines of formula (XII), and the reaction is conveniently carried out under the following conditions: there is a reducing agent (such as iron powder ) in the presence of a solvent such as a carboxylic acid (eg acetic acid) at a temperature ranging from ambient to up to about 120°C. The cyclization of the intermediate amino-aminopyridine is conveniently carried out by addition of acetic anhydride and at elevated temperature (eg about 140°C).

(c) The reduction of imidazopyridines of formula (XII) to imidazopiperidines of formula (XI) is conveniently carried out by catalytic hydrogenation over a suitable catalyst, for example a transition metal catalyst such as platinum (platinum oxide) or in the presence of 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 ambient to elevated temperatures (e.g. up to about 80 °C); pressure is elevated pressure, eg 150 to 500 kPa hydrogen (eg 400 kPa hydrogen).

(d) The imidazopiperidine of formula (XI) is protected by reaction with an alkyl chloroformate such as methyl chloroformate. The reaction is conveniently carried out with a base such as an amine (eg triethylamine or N-ethyl-N,N-diisopropylamine) in a solvent such as an alkyl halide (eg DCM) or an ether (eg THF) at room temperature.

(e) Another option for steps (c) and (d) is to use an alkyl chloroformate (such as methyl chloroformate) and an amine base (such as triethylamine or N-ethyl-N, N-di Isopropylamine) treatment of imidazopyridines of formula (XII) affords quaternized intermediates, which are reduced under conventional conditions. The quaternized intermediate can be prepared conveniently by adding methyl chloroformate to an imidazopyridine of formula (XII) at ambient temperature in the presence of a solvent such as an ether (eg THF) or an alkyl halide (eg DCM), followed by cooling It is reduced by adding an alkali metal halide (eg, lithium borohydride) at low temperature (eg, about -70°C). The intermediate produced is further reduced by catalytic hydrogenation in the presence of a suitable catalyst, for example a transition metal catalyst such as a palladium catalyst (for example palladium hydroxide or palladium on carbon) in the presence of an alcohol such as alcohol (such as methanol or ethanol) or Carboxylic acid (eg, acetic acid) in a solvent at a temperature from ambient to elevated temperature (eg, up to about 80°C).

(f) When the protecting group is an acetyl protecting group or the like, using a base such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) or an acid such as an inorganic acid (for example HCl) at an elevated temperature This protecting group can be conveniently removed by treatment at 60-100°C.

(g) Preparation of compounds of formula (VII) by reductive amination of amines of formula (VIII) with aldehydes of formula (IX). The reaction conveniently employs an alkali metal hydride reducing agent such as sodium triacetoxyborohydride, cyanide in the presence of an acid such as an organic acid (e.g. acetic acid) in a solvent such as an ether (e.g. THF) or an alkyl halide (e.g. DCM). Sodium borohydride or sodium borohydride at ambient temperature.

(h) When the protection of step (d) is provided by a methoxycarbonyl group, by using a base such as an alkali metal hydroxide (eg sodium hydroxide or potassium hydroxide) in a solution such as an aqueous alcohol (eg H ₂ O/propan-2 -alcohol) at elevated temperature (eg 100°C) for removal of the methoxycarbonyl group.

(i) Acid/amine coupling reactions can be conveniently carried out as follows: using an amine of formula (VI) and an acid chloride of formula (V); an excess of an acid acceptor such as triethylamine or N-ethyl-N,N- Diisopropylamine; solvents such as alkyl halides (eg DCM) or ethers (eg THF); at ambient temperature.

Alternatively, the acid/amine coupling reaction can be carried out using an acid of formula (V) activated by a reagent such as WSCDI or DCC and HOBT or HOAt; an excess of an acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine; solvents such as alkyl halides (eg DCM) or ethers (eg THF); and ambient temperature.

(j) when the protecting group is a boc protecting group, in the presence of an acid such as a mineral acid (e.g. anhydrous HCl) or trifluoroacetic acid in a suitable solvent such as an ester (e.g. ethyl acetate), an alkyl halide (e.g. DCM) or The protecting group is conveniently removed in ether such as THF at 0°C to ambient temperature.

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

Those skilled in the art will appreciate that one or more transformation reactions may be carried out in a different sequence than that described in Scheme 1, or may be modified in order to provide the desired compound of formula (I).

In a variant of Scheme 1, steps (h) to (k) are performed in a different order to prepare compounds of formula (I), as shown in Scheme 1a below.

Flowchart 1a

Compounds of formula (XX) have structures similar to compounds of formula (I) or related intermediates and can be prepared in a similar manner.

Compounds of formula (III), (V), (IX), (XV), (XIX), (XXI), (XXII) and (XXIII) are known compounds or can be prepared using conventional chemical methods; for example , see WO 01/90106 (especially pages 5-19), which is incorporated herein by reference.

Compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives are useful because of their pharmacological activity in animals, including humans. More specifically, they are useful in the treatment of disorders involving modulation of the CCR5 receptor. Disease types of particular interest include HIV, HIV genetically related retroviral infections, AIDS, and inflammatory diseases.

The compounds of the present invention are useful in the treatment of respiratory diseases including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.

Other treatable diseases are those initiated, invaded or associated in any other way by T cells transported in different organs. It is contemplated that the compounds of the present invention are useful in the treatment of such diseases, especially (but not limited to) disorders for which the relationship with CCR5 or CCR5 chemokines has been established, more particularly (but not limited to): multiple sclerosis; joint arthritis, such as rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; and graft rejection, especially but not limited to solid organ transplants such as heart, Lung, liver, kidney and pancreas transplants (such as kidney and lung allografts). Other diseases for which a similar relationship to CCR5 or CCR5 chemokines has been established include, but are not limited to: inflammatory bowel disease, including Crohn's disease and ulcerative colitis; endometriosis; type 1 diabetes; Glomerular disease (eg, glomerulonephritis); fibrosis, eg, of the liver, lung, and kidney; chronic pancreatitis; inflammatory lung disease; encephalitis, eg, HIV encephalitis; chronic heart failure; ischemic heart disease ; Psoriasis; Stroke; Obesity; Central nervous system (CNS) disorders such as AIDS-related dementia 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 (such as peripheral neuropathic pain); and pain caused by surgery, infection, injury, or other Stress response to traumatic injury.

Infectious diseases involving modulation of the CCR5 receptor include acute and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections; bubonic, septicemic, and pneumonic plague; poxvirus infections such as smallpox; toxoplasma infections; mycobacterial infections; trypanosome infections such as Chagas disease; pneumonia; and cryptosporidiosis.

For a recent review of possible applications of chemokine and chemokine receptor blockers, see "The chemokine/chemokinereceptor family: potential and progress for therapeutic intervention" by Cascieri, M.A. and Springer, M.S., Curr. Opin. Chem. Biol., 4(4), 420-7 (August 2000).

Accordingly, another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use as a medicament.

Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of diseases involving modulation of CCR5 receptors.

Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of HIV, HIV genetically related retrovirus infection, AIDS or inflammatory diseases.

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

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

Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for the treatment of inflammatory bowel disease; endometriosis; type I diabetes; nephropathy; fibrosis; Chronic pancreatitis; inflammatory lung disease; encephalitis; chronic heart failure; ischemic heart disease; psoriasis; stroke; obesity; central nervous system (CNS) disease; anemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; cancer; pain; and stress responses resulting from surgery, infection, injury, or other traumatic injury.

Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of HBV, HCV, plague, poxvirus infection, toxoplasmosis, mycobacterial infection, Worm infection, pneumonia, or cryptosporidiosis.

Another aspect of the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof in the preparation of a medicament for treating diseases involving the regulation of CCR5 receptors.

Another aspect of the present invention provides a method for treating a disease in a mammal, wherein the disease involves modulation of the CCR5 receptor, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof treatment of the mammal.

The compounds of the invention may be administered as crystalline or amorphous products. For example, they can be obtained in the form of solid plugs, powders or films by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying. Microwave or radio frequency drying can be applied for this purpose.

The compounds of the present invention may be administered alone, or in combination with one or more compounds of the present invention or in combination with one or more other drugs (or any combination thereof). Generally, these compounds are administered in formulations containing one or more pharmaceutically acceptable excipients. The term "excipient" is used to describe any ingredient other than a compound of the invention. The choice of excipient will depend largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation are described, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

The compounds of the present invention can be administered orally. Oral administration can involve swallowing, whereby the compound enters the gastrointestinal tract, or buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid preparations such as tablets, capsules containing granules, liquids or powders, lozenges (including those filled with liquids), chewables, multiparticulates and nanoparticles, gels, solid solutions, liposomes, Films (including mucoadhesives), pellets (ovules), sprays, and liquid formulations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillings for soft or hard capsules, and generally contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils and one or more emulsifiers and / or suspending agent. Liquid formulations can also be prepared by reconstituting solids (for example from sachets).

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

For tablets, depending on the dosage, the drug may comprise from 0.1% to 80% by weight of the dosage form, more usually from 1% to 60% by weight, for example from 5% to 50% by weight. Tablets often contain disintegrants in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, Crystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 0.1% to 25% by weight of the dosage form, more usually from 0.5% to 20% by weight, for example from 1% to 15% by weight.

Binders are often used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous lactose, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, Starch, Calcium Carbonate and Dicalcium Phosphate Dihydrate.

Tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80; and glidants, such as silicon dioxide and talc. When present, the surfactants comprise from 0.2% to 5% by weight of the tablet; the glidants comprise from 0.2% to 1% by weight of the tablet.

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

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder by weight, about 0% to about 85% diluent by weight, about 1% to about 10% disintegrant, and about 0.25% to about 10% lubricant by weight.

Tablet blends can be compressed directly or by roller compression. Alternatively, the tablet blend or a portion of the blend may be wet, dry or melt granulated, melt congealed or extruded prior to tabletting. The final formulation may comprise one or more layers, which may be coated or uncoated; it may even be encapsulated.

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

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

Modified release formulations suitable for the purposes of the present invention are described in US Patent 6,106,864. Other suitable drug release technologies, such as high energy dispersions and osmotic and coated particles, are described in Verma et al., "Pharmaceutical Technology On-line", 25(2), 1-14 (2001). The use of chewing gums to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and cartridges.

Parenteral formulations are usually aqueous solutions which may contain excipients such as salts, carbohydrates and slowing agents (preferably at a pH of 3 to 9), although for some uses it is more appropriate to formulate them as sterile non-aqueous solutions, Alternatively, it may be formulated in dry form for use with a suitable vehicle, such as sterile pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example by freeze-drying, is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the invention for use in the preparation of parenteral solutions can be increased using appropriate formulation techniques, such as the addition of solubilizing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may be formulated as solid, semi-solid or thixotropic liquids for administration as implanted depots providing modified release of the compounds. Examples of such formulations include drug-coated stents and PGLA microspheres.

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

Other means of topical administration include drug delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (eg, Powderject ^™ , Bioject ^™ , etc.) injections .

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

The compounds of the invention may also be administered intranasally or by inhalation, usually in dry powder form from a dry powder inhaler (used alone in a dry mixture, for example, with lactose, or as mixed component granules, for example, with phospholipids such as phosphatidylcholine mixture), or as a vapor from a pressurized container, pump, nebulizer, nebulizer (preferably one that uses electrohydrodynamics to produce a fine mist), or a nebuliser Sol spray application, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal administration, the powder may contain bioadhesives such as chitosan or cyclodextrin.

Pressurized containers, pumps, sprayers, nebulizers or mist-makers containing solutions or suspensions of compounds of the invention comprising, for example, ethanol (optionally aqueous ethanol) or other suitable solvents for dispersing, solubilizing or prolonging the release of the compounds. a displacing agent; a propellant as a solvent; and optionally a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

The drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) prior to use as a dry powder or suspension formulation. This can be accomplished by any suitable comminuting method, such as a helical jet mill, a fluidized bed jet mill, supercritical fluid treatment to form nanoparticles, high pressure homogenization or spray drying.

Capsules (for example made of gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated as a powder mix containing the compound of the invention, a suitable powder base such as lactose or starch) and performance modifiers (such as +/- leucine, mannitol or magnesium stearate). Lactose can be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers employing electrohydrodynamic fine mist generation contain 1 μg to 20 mg of the compound of the invention per spray, with a spray volume of 1 μl to 100 μl. A typical formulation may contain a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycols.

Suitable flavoring agents such as menthol and levomenthol or sweetening agents such as saccharin or sodium saccharin may be added to formulations of the invention for inhaled/intranasal administration.

Formulations for inhalation/intranasal administration may be formulated as immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by the valve delivering the metered dose. Dosage units of the invention are generally designed to administer a metered dose or "shot" containing 1 μg to 10 mg of a compound of the invention. The total daily dosage is usually 1 μg to 200 mg, which may be administered in a single dose, or more often as divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, eg, in the form of suppositories, pessaries or enemas. Cocoa butter is the conventional suppository base, but various other alternative bases may be used as appropriate.

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

Compounds of the invention may also be administered directly to the eye or ear, typically as drops of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular or otic administration include ointments, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable implants (e.g., silicones), wafers, Lenses and microparticle or vesicle systems, such as nonionic surfactant niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum (gelan gum), which can be used together with preservatives such as benzalkonium chloride. Such formulations can also utilize iontophoresis for transport.

Formulations for ophthalmic/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted or programmed release.

In order to improve the solubility, dissolution rate, taste-masking, bioavailability and/or stability of the compounds of the present invention for any of the aforementioned modes of administration, they may be combined with soluble macromolecular entities (such as cyclodextrins and their suitable derivatives or polymers containing polyethylene glycol) combinations.

For example, drug-cyclodextrin complexes have been found to be generally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as co-additives, ie as carriers, diluents or co-solvents. Most commonly used for this purpose are α-, β- and γ-cyclodextrins, examples of which can be found in International Patent Applications WO 91/11172, WO 94/02518 and WO 98/55148.

Since it may be desirable to administer a compound of the invention in combination with other therapeutic agents, for example for the treatment of a particular disease or condition, it is convenient to combine two or more pharmaceutical compositions (at least one of which contains a compound of the invention) into Kit forms suitable for co-administration of the compositions are also within the scope of the invention.

Therefore, the kit of the present invention comprises two or more separate pharmaceutical compositions, at least one of which contains the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate or derivative thereof, and comprises Means for containing the compositions separately, such as containers, divided vials or compartmentalized foil packs. An example of such a kit is the blister pack commonly used for packaging tablets, capsules and the like.

The kits of the invention are particularly suitable for administration of different dosage forms, for example, oral and parenteral dosage forms; for administration of separate compositions at different dosing intervals; or for escalation of individual doses of the separate compositions. To help with compliance, kits often include medication directions and may offer so-called "memory aids."

If administered to a patient with a body weight of about 65 to 70 kg, the total daily dose of the compound of the invention will generally be from 1 to 10,000 mg, such as 10 to 1,000 mg, such as 25 to 500 mg, depending of course on the mode of administration, age, condition of the patient and weight, and in any event the final decision will be made by the doctor. The total daily dose can be administered in single or divided doses.

Therefore, another aspect of the present invention provides a pharmaceutical composition as defined below, which contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and one or more pharmaceutically acceptable excipients excipients, diluents or carriers.

Compared with the compounds in the prior art, the compound of formula (I) and its pharmaceutically acceptable salts, solvates and derivatives have the following advantages: higher selectivity, faster onset of action, stronger, better absorption, Are more stable, more metabolizable, have reduced "food impact", have improved safety, or have other more desirable properties (such as solubility or hygroscopicity).

In particular the compounds of the invention have reduced inhibitory activity on the HERG potassium channel. It has been established that the prolongation of myocardial action potential duration (QT prolongation) is due to effects on HERG potassium channels (Expert Opinion of Pharmacotherapy, 2, pp. 947-973, 2000). QT prolongation is known to have the potential to produce the fatal arrhythmia of torsades de pointes (TdP). By providing compounds exhibiting further reduced inhibitory activity on HERG potassium channels with comparable or improved pharmacokinetics, the present invention provides compounds that are therapeutically effective CCR5 antagonists with further cardiac safety improve.

Compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives may be administered alone or as part of a combination therapy. Accordingly, contemplated within the scope of this invention are embodiments in which, in addition to a compound of the invention, one or more other therapeutic agents are co-administered, as well as compositions further comprising said one or more other therapeutic agents . This multi-drug regimen, commonly referred to as combination therapy, is useful in the treatment and prophylaxis of any disease or condition involving or associated with modulation of the CCR5 chemokine receptor, in particular caused by the human immunodeficiency virus (HIV) infection. The use of such combination therapy for the treatment and prevention of infection and proliferation of human immunodeficiency virus (HIV) and related pathogenic retroviruses is particularly appropriate in patients in need of treatment or in patients at risk of disease. It has long been well known in the literature that such retroviral pathogens can evolve within a relatively short period of time into strains that are resistant to any monotherapy that has been administered to the patient. The recommended therapy for HIV is a combination drug therapy called "highly active antiretroviral therapy" or HAART. HAART combines three or more HIV medicines. Therefore, the treatment methods and pharmaceutical compositions of the present invention can use the compounds of the present invention in the form of monotherapy, but can also use the methods and compositions in the form of combination therapy, wherein one or more of the compounds of the present invention The compounds of are co-administered in combination with one or more other therapeutic agents, such as those detailed below.

In another embodiment of the present invention, the combination of the present invention includes treatment with a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more other therapeutic agents, wherein The other therapeutic agents mentioned above are selected from: HIV protease inhibitors (PIs), including but not limited to indinavir, ritonavir, saquinavir, nelfinavir, lopinavir, amprenavir, Atazanavir, tipranavir, AG1859 and TMC114; non-nucleoside reverse transcriptase inhibitors (NNRTIs), including but not limited to nevirapine, delavirdine, capravirine, efavirenz, 5- {[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile or a pharmaceutically acceptable salt, solvate or derivative thereof, 5-{[3-cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-4-yl]oxy}isophthalonitrile or its pharmaceutically acceptable salt, solvent Compounds or derivatives, GW-8248, GW-5634 and TMC125; nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), including but not limited to zidovudine, didanosine, zalcitabine, Tavudine, lamivudine, abacavir, adefovir dipivoxil, tenofovir, emtricitabine and alovudine; other CCR5 antagonists, including but not limited to N-{ (1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1] Oct-8-yl]-1-phenylpropyl}-4,4-difluorocyclohexanecarboxamide or its pharmaceutically acceptable salt, solvate or derivative, 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-carboxylic acid methyl ester or pharmaceutically acceptable salts, solvates or derivatives thereof, 3-endo-{8-[(3S)- 3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7 -Methyl tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, 1-endo-{8-[(3S)-3- (Acetamido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-5-carboxylic acid ethyl ester or its pharmaceutically acceptable salts, solvates or derivatives, Sch D, ONO4128, GW873140, AMD-887 and CMPD-167; inhibit Agents that interact with gp120 and CD4, including but not limited to BMS806, BMS-488043, 5-{(1S)-2-[(2R)-4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy}-4-methoxy-pyridine-2-carboxylic acid carboxamide, and 4-{(1S)-2[(2R)-4-benzoyl- 2-Methyl-piperazin-1-yl]-1-methyl-2-oxo-ethoxy}-3-methoxy-N-methyl-benzamide; other substances that inhibit HIV entry into target cells Agents, including but not limited to enfuviritide, T1249, PRO 542, and PRO 140; integrase inhibitors, including but not limited to L-870, 810; and RNaseH inhibitors.

Combinations of compounds of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof with one or more other therapeutic agents are also included within the scope of the present invention. The other therapeutic agents are independently selected from From: Proliferation inhibitors, such as hydroxyurea; Immunomodulators, such as granulocyte-macrophage colony-stimulating growth factor (e.g., sargragrastim), tachykinin receptor modulators (e.g., NK1 antagonists), and various forms of interferon or interferon derivatives; other chemokine receptor agonists/antagonists, such as CXCR4 antagonists (such as AMD-070); agents that substantially inhibit, disrupt or reduce viral transcription or RNA replication, such as tat ( transactivator) or nef (negative regulator) inhibitor; essentially inhibits, disrupts or reduces translation of one or more proteins expressed by the virus other than reverse transcriptase (including but not limited to one or Agents that downregulate or antagonize protein expression of more than one protein), such as Tat or Nef; agents that affect (especially downregulate) CCR5 receptor expression; chemokines that induce CCR5 receptor internalization, such as MIP-1α, MIP - lβ, RANTES and derivatives thereof; and other agents that inhibit viral infection or ameliorate the condition or outcome of HIV-infected individuals via different mechanisms.

Agents that affect (especially downregulate) CCR5 receptor expression include: immunosuppressants such as calcineurin inhibitors such as tacrolimus and cyclosporine A; steroids; agents that interfere with cytokine production or signaling Agents, such as Janus kinase (JAK) inhibitors, such as JAK-3 inhibitors, including 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies, for example inhibiting interleukin-2 ( IL-2) receptor antibodies, including basiliximab and daclizumab; and agents that interfere with cell activation or cell cycle, such as rapamycin.

Also included within the scope of the present invention is the combination of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof with one or more other therapeutic agents that reduce the concentration of the present invention. The rate of metabolism of the compound, thereby increasing the patient's exposure to the drug. Increasing drug exposure in this way is called boosting. Boosting has the benefit of increasing the potency of a compound of the invention or reducing the dose required to achieve the same potency as a non-boosting dose. The metabolism of the compound of the present invention includes: the oxidation process by P450 (CYP450) enzymes, especially CYP3A4, and the binding reaction by UDP glucuronosyltransferase and sulphating enzyme. Thus, among agents that can be used to increase a patient's exposure to the compounds of the present invention include those capable of acting as inhibitors of at least one cytochrome P450 (CYP450) enzyme isoform. CYP450 isoforms that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Suitable agents that may be used to inhibit CYP3A4 include, but are not limited to, ritonavir, saquinavir, or ketoconazole.

Those skilled in the art will understand that the above-mentioned combination drug therapy may include two or more compounds with the same or different mechanism of action. Thus, by way of illustration only, combinations may include compounds of the invention in combination with: one or more NRTIs; one or more NRTIs and a PI; one or more NRTIs with other CCR5 antagonists ; PI; PI and NNRTI; NNRTI; and so on.

In addition to the requirement of therapeutic efficacy (which necessitates the use of therapeutic agents other than the compounds of the present invention), there are other reasons that compel or strongly recommend the use of compounds of the present invention in combination with other therapeutic agents, for example in the treatment of essential or latent CCR5 A disease or condition directly caused by or indirectly associated with a chemokine receptor modulated disease or condition. For example, when the underlying CCR5 chemokine receptor modulated disease or condition is HIV infection and proliferation, it is necessary or at least desirable to treat hepatitis C virus (HCV), hepatitis B virus (HBV), human papillomavirus (HPV), opportunistic infections (including bacterial and fungal infections), neoplasms and other conditions resulting from the immunodeficiency status of the treated patients. Other therapeutic agents may be used with the compounds of the invention, for example, to provide immune stimulation or to treat pain and inflammation associated with incipient and fundamental HIV infection.

Accordingly, therapeutic agents for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof also include: interferons, pegylated interferons (such as pegylated Alcoholated interferon alfa-2a and pegylated interferon alfa-2b), lamivudine, ribavirin, and emtricitabine; antifungal agents such as fluconazole, phosfluconazole, itracon azoles and voriconazole; antibacterial agents such as azithromycin and clarithromycin; interferons, daunorubicin, doxorubicin, and paclitaxel for the treatment of AIDS-associated Kaposi's sarcoma; and treatment of cytomegalovirus (CMV) Retinitis cidofovir, cidofovir, foscarnet, ganciclovir, and valganciclovir.

Other combinations suitable for use in the present invention include combinations of compounds of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof with the following agents: CCR1 antagonists (such as BX-471); beta adrenoceptor agonists, such as salmeterol; corticosteroid agonists such as fluticasone propionate; LTD4 antagonists such as montelukast; muscarinic antagonists such as tiotropium; PDE4 inhibitors such as cilomilast or roflumilast COX-2 inhibitors such as celecoxib, valdecoxib, or rofecoxib; alpha-2-delta ligands such as gabapentin or pregabalin; beta-interferons such as REBIF; TNF receptor modulators such as TNF-α inhibitors (eg, adalimumab), HMG CoA reductase inhibitors such as statins, such as atorvastatin; or immunosuppressants, such as cyclosporin or macrolides such as Cromus.

In the above combination, in terms of dosage form, the compound of formula (I) or its pharmaceutically acceptable salt, solvate or derivative and other therapeutic agents can be administered separately or in combination with each other; in terms of administration time, they can be administered simultaneously or sequentially apply. Thus, one component medicament may be administered before, simultaneously with, or after the other component medicament.

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

It is understood that references to treatment herein include curative, palliative or prophylactic treatment.

The invention is further illustrated by the following examples and formulations, wherein the following abbreviations are used:

h = hour;

min=minute;

LRMS = low resolution mass spectrum;

HRMS = high resolution mass spectrometry;

APCI+ = atmospheric pressure chemical ionization;

ESI+ = electric spray ionization method;

NMR = nuclear magnetic resonance;

tlc = thin layer chromatography;

Me = methyl group.

Example 1

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

Acetyl chloride (18 μl, 0.26 mmol) was added to the amine N-{(1S)-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 (94mg, 0.21mmol ) in dichloromethane (5 ml) followed by the addition of N,N-diisopropylethylamine (45 μl, 0.26 mmol). After 15 hours, the reaction mixture was diluted with dichloromethane (5ml) and water (5ml) and passed through a phase separation cartridge. A stream of nitrogen was passed through the solution to concentrate the organic components, and the resulting mixture was purified using a Mega Bond Elut ^flash Si column (10 g, Varian) with dichloromethane:methanol:concentrated ammonia (95:5:0.5 by volume). Elution afforded the title compound (80 mg, 79%) as a white foam.

LRMS (electrospray method): m/z [M+Na ⁺ ] 504, [MH ⁺ ] 482

Found C, 63.35; H, 7.32; N, 13.59. _{Calcd for C27H36N5FO2.0.5CH2Cl2} C, 63.03; _{H ,} 7.12; _N , 13.36.

[α] _D -21.7°(2.12mg/ml MeOH solution)

Example 2-3

These examples were prepared according to the method described in Example 1 above, using N-{(1S)-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 and corresponding A compound of formula (V). LRMS all adopt the electric spray ionization method.

Example 2

LRMS：m/z[MH⁺]522实测值C，67.01；H，7.74；N，12.94.C₃₀H₄₀FN₅O₂.0.1 H₂O计算值C，66.77；H，7.84；N，1 2.93％.[α]_D-20.9°(2.04 mg/ml MeOH溶液)

LRMS: m/z [MH ⁺ ] 522 found C, 67.01; H, 7.74; N, 12.94. Calcd for C 30 H ₄₀ FN ₅ O ₂ .0.1 H ₂ O C, 66.77; H, 7.84; N, ₁ 2.93%.[α] _D -20.9°(2.04 mg/ml MeOH solution)

Example 3

LRMS: m/z _[ MH ⁺ ] 508 found C, 66.53; H, 7.59; N, 13.23. Calcd for C 29 H ₃₈ FN ₅ O ₂ .0.1 H ₂ O C, 66.26; H, 7.67; N, 13.32 %.[α] _D -20.5°(2.38 mg/ml MeOH solution)

Example 4

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

Triethylamine (7.0ml, 50.0mmol) was added to N-{(1S)-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 (19.9g, 45.3mmol) In a stirred solution in tetrahydrofuran (500ml), isobutyryl chloride (5.3ml, 50.mmol) was then added dropwise. 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 about 300ml and ethyl acetate (200ml) was added. _The reaction mixture was washed with 10% aqueous _K2CO3 (200 ml; weight/volume). The aqueous phase was separated and extracted with ethyl acetate (100ml). The organic fractions were combined, washed with brine (100ml), dried ( _MgSO4 ) and concentrated until a mobile oil was obtained which was just beginning to foam. The residue was dissolved in ethyl acetate (100ml) and heated to 90°C. Water (0.5ml) was added to the hot solution and the mixture was allowed to cool slowly to room temperature. The precipitate was collected by filtration, washed with ethyl acetate (50 ml), and dried under reduced pressure to obtain the title compound (20.9 g, 90%) as a white solid.

LRMS: m/z [MH ⁺ ] 510

¹ H NMR (400MHz, CD ₃ OD): δ: 7.29-7.35 (1H, m), 7.1 2-7.14 (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(1H , m), 2.77-2.84and 2.69-2.75(2H, 2×m), 2.39-2.51(2H, m), 2.36 and 2.35(3H, 2×s), 2.20-2.30(2H, m), 2.03- 2.13(2H, m), 1.95(3H, s), 1.84-1.90(2H, m), 1.55-1.65(4H, m), 1.08-1.11 and 1.04-1.06(6H, 2×m). Rotamers body.

Found C, 66.94; H, 7.92; N, 13.47. C ₂₉ H ₄₀ FN ₅ O ₂ .0.5 H ₂ O.

Calculated for C, 67.16; H, 7.97; N, 13.50.

[α] _D -23.4°(1.64mg/ml MeOH solution)

Example 5-7

These examples were prepared according to the method described in Example 1 above, using N-{(1S)-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 and corresponding A compound of formula (V). Except that the atmospheric pressure chemical ionization method is used in Example 6, all other LRMS adopt the electric aerosol method.

Example 5

LRMS：m/z 496[MH⁺]实测值C，67.47；H，7.75；N，14.06.C₂₈H₃₈FN₅O₂.0.15 H₂O  计算值C，67.49；H，7.75；N，14.05％.[α]_D-21.5°(2.00mg/ml MeOH溶液)NMR数据如下

LRMS: m/ _z 496 [MH ⁺ ] found C, 67.47; H, 7.75 _; N, 14.06. Calcd for _{C28H38FN5O2.0.15H2O} C, _67.49 ; H, _7.75 ; N, 14.05 %.[α] _D -21.5° (2.00mg/ml MeOH solution) NMR data are as follows

Example 6

LRMS 532[M+Na⁺]，510[MH⁺]实测值C，65.69；H，7.97；N，13.06.C₂₉H₄₀FN₅O₂.0.1 H₂O计算值C，66.01；H，8.02；N，13.27％.[α]_D-25.5°(2.14mg/ml MeOH溶液)

LRMS 532 [M+Na ⁺ ], 510 [MH ⁺ _{] Found C, 65.69; H, 7.97; N, 13.06. Calcd for C 29 H 40 FN 5} O ₂ .0.1 H ₂ O C, 66.01; H, 8.02 ; N, 13.27%.[α] _D -25.5° (2.14mg/ml MeOH solution)

Example 7

LRMS(电雾法)546[M+Na⁺]，524[MH⁺]实测值C，65.50；H，7.93；N，12.45.C₃₀H₄₂FN₅O₂.0.15H₂O计算值C，65.43；H，8.24；N，12.72％.[α]_D-28.2°(2.06mg/ml MeOH溶液)

LRMS (electrospray method) 546[M+Na ⁺ ], 524[MH ⁺ ] measured value C, 65.50; H, 7.93; N, 12.45. C ₃₀ H ₄₂ FN ₅ O ₂ .0.15H ₂ O calculated value C, 65.43; H, 8.24; N, 12.72%.[α] _D -28.2° (2.06mg/ml MeOH solution)

The NMR data of embodiment 5

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

¹ H NMR (400MHz, CD ₃ OD): δ: 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(1H, m), 4.40 and 4.45(2H, 2×s), 3.81-3.89(1H, 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×s), 2.23-2.30 (2H, m ), 2.07-2.14 (2H, m), 1.98 (3H, s), 1.86-1.93 (2H, m), 1.57-1.67 (4H, m), 1.07-1.17 (3H, m). Rotamers.

Example 8

N-{(1S)-3-[3-endo-(2-methyl-5-(3,3,3-trifluoro-propionyl)-4,5,6,7-tetrahydro-1H-imidazole And[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide

O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (65 mg, 1.71 mmol) and triethylamine (47 μl, 3.41 mmol) were added to 3, To a stirred solution of 3,3-trifluoropropionic acid (15 μl, 1.71 mmol) in dichloromethane (2 ml), the amine N-{(1S)-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 (50 mg, 1.14 mmol). The reaction mixture was heated at 30° C. for 15 hours, concentrated by passing a stream of nitrogen into the solution, and purified by preparative HPLC [Phenomenex C ₁₈ 15×10 cm, 10 micron column, 20 ml/min flow rate, 225 nm detection wavelength, mobile phase gradient 95:5 to 5:95 A:B (A: 0.1% diethylamine in water; B: MeCN)], the title compound was obtained as a gum (20 mg).

LRMS (electrospray method): 550 [MH ⁺ ]

HRMS (charged spray method). The measured value is 550.2800. Calcd _{. for C28H36N5F4O2} (MH ⁺ ) _{, 550.2800} .

Example 9

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide. Fumarate

N-{(1S)-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 (300mg, 0.59mmol) in tetrahydrofuran To the solution in (2ml) was added dropwise a solution of fumaric acid (68mg, 0.59mmol) in hot ethanol (2ml). After 48 hours, tetrahydrofuran (2ml) was added, and after another 48 hours, the crystals were collected by filtration, washed with tetrahydrofuran (2ml), and air-dried to obtain the title compound (110mg, 30%) as a white powder.

Found C, 62.04; H, 7.26; N, 10.70. C ₃₃ H ₄₄ FN ₅ O ₆ .0.75H ₂ O

Calculated for C, 62.00; H, 7.17; N, 10.96.

Example 10

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

N-{(1S)-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 (264.4g, 0.60mol) was added to propan-2-ol (2.67L), Potassium carbonate (92.7 g, 0.67 mol) was then added and the resulting product was cooled to 15°C. Isobutyryl chloride (97.8 g, 0.91 mol) was then added over 10 minutes, maintaining the temperature below 25°C, and the reaction was complete after 10 minutes of stirring. Potassium carbonate (267.2 g) in water (2.40 L) was then added and the resulting two phases were separated. The aqueous layer was extracted with ethyl acetate (2.67 L), and the combined organic phases were washed with saturated aqueous sodium chloride (1.32 L) and water (800 mL), then concentrated in vacuo. The residue was diluted with ethyl acetate (1.07 L) and concentrated again in vacuo. The re-dilution and concentration steps described above were repeated and the resulting residue was treated with ethyl acetate until the total volume reached 1.07 L. Cool to 0-5°C, stir for 2 hours, filter and wash with ice-cold ethyl acetate (2 x 130ml). The solid product was then dried in a vacuum oven at 50°C to obtain the title compound (269.8 g, 0.53 mol, 88.0%).

Example 11

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide. Fumarate

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide (554.0g, 1.08mol) was added to propane-2- Alcohol (13.85 L), then fumaric acid (126.2 g, 1.09 mol) was added and the resulting product was warmed to reflux and stirred for 20 minutes. At this temperature, the solution was clarified by filtration and then concentrated in vacuo until N-{(1S)-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 The calculated solvent volume is 4ml/g. Allow to cool to 0-5°C, stir for 2 hours, filter and wash with ice-cold propan-2-ol (2 x 550ml). The solid product was then dried in a vacuum oven at 50°C to afford the title compound (495.9 g, 0.79 mol, 72.9%).

Example 12

According to the above-mentioned method for preparing the fumarate of Example 9, prepare N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl} (D)-tartrate salt of acetamide using N-{(1S)-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 with D-tartaric acid. PXRD peak data are provided below.

Preparation Example 1

8-Benzyl-8-azabicyclo[3.2.1]octan-3-one

A solution of 2,5-dimethoxytetrahydrofuran (50 g, 378 mmol) in hydrochloric acid (0.025 N, 160 ml) was cooled at 0°C for 16 hours. Benzylamine hydrochloride (65g, 453mmol), oxymalonic acid (55g, 377mmol) and aqueous sodium acetate (300ml, 0.69M) were added, and the reaction was stirred at room temperature for 1 hour. The mixture was heated at 50°C for an additional 90 minutes, then cooled in an ice bath and basified to pH 12 using 2N sodium hydroxide solution. The layers were separated and the aqueous phase was washed with ethyl acetate (3 x 300ml). The combined organic extracts were washed with water, dried ( _MgSO4 ), filtered and evaporated under reduced pressure. The residual brown oil was distilled under reduced pressure (126°/3 mmHg) to give the title compound (37.81 g) as an off-white solid.

LRMS: m/z 216.3 (MH ⁺ ).

Preparation example 2

tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

At room temperature and a hydrogen pressure of 269kPa, 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (15.0g, 69.7mmol), di-tert-butyl dicarbonate (18.2g , 83.4 mmol) and palladium hydroxide on charcoal (20% w/w, 3.0 g) in ethyl acetate (165 mL) was stirred for 4 hours. The mixture was filtered through Arbocel ^(R) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of hexane:ether (100:0 to 50:50) to give the title compound (16.2 g) as a colorless oil which crystallized on standing.

¹ H NMR (400MHz, 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, m), 4.35-4.58 (2H, m) ppm.

Preparation example 3

3-(Benzylamino)-endo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester

At room temperature, tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0g, 44.4mmol), benzylamine (4.85ml, 49.7mmol) and triacetoxy A solution of sodium borohydride (14.11 g, 66.6 mmol) in a mixture of glacial acetic acid:dichloromethane (1:9 v/v, 290 mL) was stirred for 16 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (200ml), washed with saturated aqueous sodium carbonate solution (50ml) and water (50ml). The organic solution was dried ( _MgSO4 ), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:conc. ammonia (98:2:0.25) as eluent to give the title compound (7.00 g) as a white solid.

¹ H NMR (400MHz, CDCl ₃ ): δ: 1.42-1.48 (11H, m), 1.52-1.61 (2H, m), 1.85-2.19 (5H, m), 2.95-3.03 (1H, m), 3.74 ( 2H, s), 4.03-4.23 (2H, m), 7.20-7.26 (1H, m), 7.26-7.32 (4H, m) ppm.

Preparation Example 4

tert-butyl 3-endo-amino-8-azabicyclo[3.2.1]octane-8-carboxylate

Make 3-(benzylamino)-endo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7.00g, 22.1mmol), ammonium formate (7.00g, 111mmol) and hydrogen A mixture of palladium oxide on carbon (20% w/w, 0.7 g) in ethanol (200 ml) was heated at 50° C. until gas evolution ceased. The cooled mixture was filtered through Arbocel ^(R) and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:conc. ammonia (98:2:0.25 to 95:5:0.5) to give the title compound (4.70 g) as a colorless oil.

LRMS: m/z 227.2 (MH ⁺ )

Preparation Example 5

3-Endo-[(3-nitro-4-pyridyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

3-Amino-endo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.0g, 13.2mmol), 4-ethoxy-3-nitropyridine.hydrochloride (2.7g, 13.2mmol) and N-ethyl-N,N-diisopropylamine (1.89g, 14.6mmol) were dissolved in 1-methyl-2-pyrrolidone (5ml) and heated at 120°C for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (150ml), washed with water (3 x 50ml), saturated aqueous sodium bicarbonate (50ml) and brine (30ml). The organic layer was dried ( _MgSO4 ) and the solvent was removed by evaporation under reduced pressure. The 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 ⁺ )

Preparation example 6

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

3-endo-[(3-nitro-4-pyridyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.40g, 12.6mmol) and iron powder (2.11g, 37.8mmol) was dissolved in glacial acetic acid (50ml) and the mixture was heated at 60°C for 2 hours. Acetic anhydride (8ml) was then added, the mixture was heated at 140°C for 18 hours, the cooled reaction mixture was filtered through a pad of Arbocel ^(R) and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (200ml) and water (200ml) and the mixture was adjusted to pH 9 using 2N aqueous sodium hydroxide solution. The mixture was filtered again through a pad of Arbocel ^(R) and the organic phase was separated. The aqueous layer was extracted with dichloromethane (100ml) and the combined organic extracts were dried ( _MgSO4 ). The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and dried ( _MgSO4 ) to give the title compound as a white solid (3.27g).

LRMS: m/z 285 (MH ⁺ ).

Preparation Example 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

Benzyl bromide (1.78 g, 10.4 mmol) was added to 1-endo-(8-acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-imidazo[ 4,5-c]pyridine (2.47g, 8.7mmol) was dissolved in ethanol (20ml) 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 dropwise over ten minutes. After 1 hour at -70°C, the reaction mixture was allowed to warm to -40°C, then cooled again to -70°C and sodium borohydride (0.33 g, 8.7 mmol) was added again. After another 1 hour at -70°C, water (10 ml) was added and the reaction mixture was allowed to warm to room temperature. Ethanol was evaporated under reduced pressure and the aqueous residue was extracted with dichloromethane (3 x 25ml). The combined organic extracts were dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a solvent gradient of ethyl acetate:methanol:diethylamine (by volume, 100:0:2 shifted to 98:2:2, then to 95:5: 2) Elution. Fractions containing product were evaporated to give the title compound (2.23g) as a white foam.

LRMS: m/z 379 (MH ⁺ )

Preparation example 8

1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4 , 5-c]pyridine

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 (2.23g, 5.89mmol) was dissolved in 6N aqueous hydrochloric acid (30ml), and heated under reflux for 18 hours. The cooled reaction mixture was adjusted to pH 10 by addition of 2N aqueous sodium hydroxide solution and extracted with dichloromethane (2 x 50ml). The combined organic extracts 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:diethylamine (100:0:0.5 changing to 93:7:1 by volume). Fractions containing product were evaporated to give the title compound (1.47g) as a white foam.

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

Preparation Example 9

tert-Butyl 1-(S)-1-(3-fluorophenyl)-3-oxopropylcarbamate

Diisobutylaluminum hydride (1M dichloromethane solution, 39ml, 39mmol) was cooled to -78°C, and then added dropwise to (3S)-3-[(tert-butoxycarbonyl)amino]-3- A solution of methyl (3-fluorophenyl)propionate (WO0039125, p. 60, Preparation 12) (5.4 g, 18.2 mmol) in dichloromethane (100 ml). The reaction was allowed to stir at -78°C for 30 minutes, then methanol (50ml, precooled to -78°C) was added. The reaction was allowed to stir for 30 minutes before 2N hydrochloric acid (250ml) was added. The biphasic mixture was allowed to warm to room temperature, the layers were separated, the organic layer was dried ( _MgSO4 ), filtered and evaporated under reduced pressure to afford the title compound (4.8g) as a clear colorless oil.

LRMS: m/z 268.1 (MH ⁺ )

Preparation Example 10

(1S)-3-[3-endo-(5-benzyl-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)propylcarbamate tert-butyl ester

At room temperature under nitrogen, acetic acid (0.39 g, 6.4 mmol) was added to 1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4 , 5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (2.16g, 6.4mmol) and (1S)-1-(3-fluorophenyl)-3-oxopropyl Into a stirred solution of tert-butyl carbamate (2.06 g, 7.7 mmol) was dissolved in dichloromethane (25 mL). Sodium triacetoxyborohydride (1.63 g, 7.7 mmol) was then added and the reaction was left at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50ml) and dichloromethane (50ml). The organic phase was removed and the aqueous phase was washed with dichloromethane (50ml). 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:conc. ammonia (99:1:0.1 changing to 96:4:0.4 by volume). Fractions containing product were evaporated to give the title compound (2.56g) as a white foam.

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

Preparation Example 11

(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-aza tert-butyl bicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

(1S)-3-[3-endo-(5-benzyl-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)propylcarbamate tert-butyl ester (2.55g, 4.34mmol), ammonium formate (2.73g, 43.4 mmol) and palladium hydroxide on carbon (20% w/w, 0.25 g) in ethanol (35 ml) was heated to 60°C. After 1 hour additional ammonium formate (0.63 g, 10.1 mmol) was added and heating was continued at 60 °C for an additional 2 hours. The cooled reaction mixture was then filtered through Arbocel ^(R) and the filtrate evaporated under reduced pressure. The residue was partitioned between dichloromethane (100ml) and saturated aqueous sodium bicarbonate (50ml), the organic phase was separated and washed with water (30ml). The organic layer was 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:conc. ammonia (99:1:0.1 to 93:7:1 by volume) to afford a white foam The title compound (1.50 g).

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

Preparation Example 12

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

Methyl chloroformate (0.167 g, 1.76 mmol) was added to (1S)-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)propylcarbamate tert-butyl (0.80 g, 1.60 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 1.5 hours, then washed with saturated aqueous sodium bicarbonate (10 mL). The organic phase was separated and the aqueous phase was extracted again with dichloromethane (2 x 10ml). The combined dichloromethane extracts were dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure. Purification of the residue by flash column chromatography on silica gel, eluting with a solvent mixture of dichloromethane:methanol:concentrated ammonia (99:1:0.1 converted to 93:7:1), afforded the title compound as a white foam ( 0.84g).

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

Preparation Example 13

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

At 0°C, pass hydrogen chloride gas into 1-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propyl}-8-aza Bicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylic acid methyl ester (0.83 g, 1.50 mmol) in dichloromethane (15 ml) until the solution was saturated. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was suspended in dichloromethane (10ml). This operation was repeated three times to obtain the title compound (0.82 g) as a white solid.

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

Preparation Example 14

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-carboxylic acid methyl ester

Under nitrogen at room temperature, acetyl chloride (0.062 g, 0.79 mmol) was added to 1-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-aza Bicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylic acid methyl ester. Hydrochloride (0.409g, 0.72mmol) and triethylamine (0.33g, 3.25mmol) were dissolved in dichloromethane (10ml) and the reaction mixture was stirred for 2 hours. The solution was then washed with water (10ml), 1N sodium hydroxide solution (10ml) and brine (10ml). The organic phase was separated, dried ( _MgSO4 ) and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol:conc. ammonia (99:1:0.1 changing to 97:3:0.3 by volume). Fractions containing product were evaporated to give the title compound as a white foam (0.24g).

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

Preparation Example 15

N-{(1S)-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

To 1-endo-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl} -Methyl 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate (13.27g, 26.7mmol) in propan-2-ol (80ml ) was added 2M aqueous sodium hydroxide solution (120ml) and the mixture was heated at reflux for 48 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (2 x 200ml). The combined organic fractions were washed with brine (150ml), dried ( _MgSO4 ) and concentrated under reduced pressure. The crude product mixture was purified by flash column chromatography eluting with dichloromethane:methanol:conc. ammonia (90:10:1 then shifted to 80:201 by volume) to afford the title as a white foam Compound (8.54 g, 73%).

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

Preparation Example 16

N-{(1S)-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

The 1-endo-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl} -Methyl 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate. (L)-tartrate (WO03/084954, Example 46 ) (898 g, 1.39 mol) was added to dichloromethane (4.5 L) and water (4.5 L). Aqueous sodium hydroxide solution (10M, 450ml) was then added and the resulting mixture was stirred for 15 minutes. The two phases were separated and the aqueous layer was extracted with additional dichloromethane (2.25 L). The combined organic phases were then concentrated and the resulting oil was dissolved in propan-2-ol (4.5 L). Aqueous sodium hydroxide (2M, 6.93 L, 13.9 mol) was then added and the biphasic mixture was heated at reflux for 65 hours. After cooling to room temperature, the phases were separated and the aqueous layer was extracted with ethyl acetate (4.5 L). 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, additional ethyl acetate (4.5 L) was added and the resulting slurry was stirred at 0-5°C for 1 hour, filtered and washed with ice-cold ethyl acetate (2 x 450ml). The solid product was then dried in a vacuum oven at 40°C to yield the title compound (547.2 g, 1.24 mol, 89.8%). The LRMS data of the title compound were the same as those of the title compound of Preparation 15.

biological data

The ability of compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate the activity of chemokine receptors is demonstrated by methods known in the art, for example by using J.Leukoc.Biol. , 60, 147-52 (1996) for CCR5 binding assays; and/or using intracellular calcium mobilization assays as described by the same author. Cell lines expressing the receptor of interest include those that express the receptor naturally, such as PM-1, or IL-2 stimulated peripheral blood lymphocytes (PBL), or cells engineered to express recombinant receptors, such as CHO, 300.19, L1.2 or HEK-293.

The compound of Example 4 had _IC50 values of 7.5 nM (MIP-1α), 7.3 nM (MIP-1β) and 6.7 nM (RANTES) when tested using the CCR5 binding assay of Combadiere et al. (supra).

The compound of Example 5 had _IC50 values of 2.7 nM (MIP-1α), 2.4 nM (MIP-1β) and 1.9 nM (RANTES) when tested using the CCR5 binding assay of Combadiere et al.

Compounds of all examples were potent antagonists with _IC50 values below 100 nM (MIP-1β) when tested using the intracellular calcium mobilization assay of Combadiere et al., supra.

The pharmacological activity of the compound of formula (I) and its pharmaceutically acceptable salts, solvates and derivatives is further confirmed by gp160-induced cell-cell fusion assay (for testing the IC ₅₀ value of the compound against HIV-1 fusion). The gp160-induced cell-cell fusion assay used the HeLa P4 cell line and the CHO-Tat10 cell line.

The HeLa P4 cell line expresses CCR5 and CD4 and has been transfected with the HIV-1 LTR-β-galactosidase gene. The medium for culturing this cell line is Dulbecco's modified eagle's medium (D-MEM) (without L-glutamine), which contains 10% fetal calf serum (FCS), 2 mM L-glutamine penicillin/streptavidin (Pen/Strep); 100 U/ml penicillin + 10 mg/ml streptomycin) and 1 μg/ml puromycin.

The CHO cell line is a Tat (transactivator of transcription) expressing clone derived from the CHO JRR17.1 cell line that has been transfected with the pTat puro plasmid. The medium for culturing this cell line was rich medium RPMI1640 (without L-glutamine) originally developed by Roswell Park Memorial Institute for mammalian cell culture, which contains 10% FCS, 2mM L-glutamine, 0.5mg/ml hygromycin B and 12μg/ml puromycin. The CHO JRR177.1 cell line expresses gp160(JRFL) and is a clone selected for its ability to fuse with CCR5/CD4 expressing cell lines.

Once the cells are confluent, Tat present in CHO cells can transactivate the HIV-1 long terminal repeat (LTR) present in HeLa cells, resulting in the expression of β-galactosidase. Expression was then determined using the Fluor Ace ^™ β-Galactosidase Reporter Assay Kit (Bio-Rad, Cat# 170-3150). The kit is a quantitative fluorescence analysis method using 4-methylumbelliferyl galactopyranoside (MUG) as a substrate to measure the expression of β-galactosidase. β-galactosidase hydrolyzes the fluorescent substrate and releases the fluorescent molecule 4-methylumbelliferone (4MU). Then measure the fluorescence intensity of 4-methylumbelliferone on a fluorimeter, the excitation wavelength is 360nm, and the emission wavelength is 460nm.

Compounds that inhibit cell fusion cause a decrease in signal, and dose-response curves for each compound are used to calculate _IC50 values following solubilization in an appropriate solvent and dilution in media.

According to the method described above, the IC ₅₀ values of all the example compounds of the present invention are lower than 10 nM. The IC ₅₀ values of the compounds of Example 1 and Example 5 were 130 and 120 pM, respectively.

Powder X-ray Diffraction (PXRD) Data

All PXRD patterns were collected by a Bruker D5000 powder diffractometer with a 2-theta angle range of 2-55° and a step size of 0.02°. The sample was rotated while irradiating the sample with copper K-α1 X-rays (wavelength = 1.5046 Angstroms) filtered through a graphite monochromator (λ = 0.15405 nm) equipped with X-rays operating at 40kV/40mA Tube. Calibrate the diffractometer with standard quartz samples before and after data collection for each batch of samples.

The main peaks (2-theta angle units are °) of the PXRD patterns of Examples 10, 11 and 12 are described in the table below.

Table 1: N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c PXRD peak data of ]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) 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

Table 2: N-{(1S)-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.PXRD peak data of fumarate Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) 6.7 38.6 19.1 18.2 25.0 12.9 10.0 34.1 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

Table 3: N-{(1S)-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. PXRD peak of (D)-tartrate data Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) 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

For N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide. PXRD pattern simulation of fumarate (including 2 -θ angle, d-spacing and relative intensity) were calculated from the single crystal structure of the compound using the "Reflex Powder Diffraction" module (version 2.2) of Accelrys Materials Studio ^TM . The relevant simulation parameters are:

Wavelength = 1.540562 Angstroms (Cu Kα)

Polarization factor = 0.5

Pseudo-Voigt plot (U=0.01, V=-0.001, W=0.002)

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide. The main peak of the simulated PXRD pattern of fumarate ( 2-θ angle unit is °) is shown in Table 4.

Table 4: N-{(1S)-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. Simulated PXRD peak of fumarate data Angle (°2-θ) strength(%) Angle (°2-θ) strength(%) 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 (DSC) Data

All DSC were acquired by a Perkin Elmer PYRIS Diamond DSC equipped with an autosampler and nitrogen gas flow. The sample was placed in a 50 μl aluminum pan with a hole and a lid, and heated from 10°C to 300°C at a rate of 20°C/min.

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

Sample weight: 3.016mg

Endothermic peak: 118°C-melting

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-1- Base)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide. Fumarate

Sample weight: 2.905mg

Endothermic peak: 219°C-melting

Endothermic event occurs at 228°C

Exothermic event occurs at 246°C

N-{(1S)-3-[3-endo-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide.(D)-tartrate

Sample weight: 2.979mg

Endothermic peak: 217°C-melting

Claims (19)

1. formula (I) compound or its pharmaceutically useful salt, solvate or derivative,

Wherein:

R ¹Be C ₁-C ₆Alkyl; And

R ²Be C ₁-C ₆Alkyl or C ₃-C ₇Cycloalkyl, wherein this alkyl is optional by CF ₃Replace.

2. as the desired compound of claim 1, wherein R ¹Be C ₁-C ₄Alkyl.

3. as claim 1 or 2 desired compound, wherein R ¹It is methyl.

4. as each desired compound, wherein R in the claim 1 to 3 ²Be optional by CF ₃The C that replaces ₁-C ₄Alkyl.

5. as each desired compound, wherein R in the above-mentioned claim ²Be methyl, ethyl or sec.-propyl.

6. as each desired compound, wherein R in the claim 1 to 3 ²Be cyclopropyl or cyclobutyl.

7. as the desired compound of claim 1, it is selected from:

In N-{ (1S)-3-[3-to-(5-ethanoyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(5-tetramethylene carbonyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(5-cyclopropane carbonyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(2-methyl-5-propionyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(5-butyryl radicals-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(2-methyl-5-(2,2-dimethyl-propionyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

In N-{ (1S)-3-[3-to-(2-methyl-5-(3,3,3-three fluoro-propionyls)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;

And their pharmaceutically useful salt, solvate or derivative.

8. pharmaceutical composition contains in the aforesaid right requirement each formula (I) compound or its pharmaceutically useful salt, solvate or derivative and one or more pharmaceutically useful vehicle, diluent or carrier.

9. the pharmaceutical composition of claim 8 contains one or more other therapeutical agent.

10. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 are used as medicine.

11. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 are used for the treatment of and relate to the disease of regulating the CCR5 acceptor.

12. the compound of claim 11, wherein this disease be the human immunodeficiency virus infection, with retroviral infection, acquired immune deficiency syndrome (AIDS) or the inflammatory diseases of human immunodeficiency virus's genetic correlation.

13. the compound of claim 11, wherein this disease is multiple sclerosis, rheumatoid arthritis or transplant rejection.

14. the compound of claim 11, wherein this disease is an inflammatory bowel; Endometriosis; Type i diabetes; Ephrosis; Fibrosis; Chronic pancreatitis; Inflammatory lung disease; Encephalitis; Chronic heart failure; Ischemic heart disease; Psoriasis; Apoplexy; Obesity; Central nervous system disease; Anemia; Restenosis; Atherosclerotic plaque; Atopic dermatitis; Chronic pancreatitis; Cancer; Pain; Or by the stress reaction of performing the operation, infect, damaging or other traumatic injury produced.

15. the compound of claim 11, wherein this disease is hepatitis b virus infected, infection with hepatitis C virus, the plague, poxvirus infection, toxoplasmosis, mycobacterial infections, trypanosome infection, pneumonia or cryptosporidiosis.

16. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative are used for the treatment of purposes in the medicine that wherein relates to the disease of regulating the CCR5 acceptor in preparation in the claim 1 to 7.

17. treatment suffers from the mammiferous method that wherein relates to the disease of regulating the CCR5 acceptor, this method comprises each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 of this administration significant quantity.

18. each formula (I) compound or the method for its pharmaceutically useful salt, solvate or derivative in the preparation claim 1 to 7, this method comprises the following steps:

(A) under the carboxylic acid/amine coupling condition of routine, make formula (II) compound

React with formula (III) compound

(B) under the carboxylic acid/amine coupling condition of routine, make formula (XVI) compound

React with the formula V compound

(C) under normal condition, utilize the amine of formula (XX),

Make the aldehyde of formula (XIX) be reduced amination,

(D) under normal condition, utilize the amine of formula (XX), make the nitrile of formula (XXI) be reduced amination,

(E) under conventional alkylation conditions, utilize formula (XXII) compound,

The amine that makes formula (XX) is by alkylation;

(F) under the conventional reduction condition, the alkene acid amides that makes formula (XXIII) is by asymmetric reduction,

Perhaps

(G) under normal condition, the amine of formula (II) or its metal-salt (being the deprotonation type) react with the ester of formula (XXIV),

R ¹CO ₂EsGP (XXIV)

R wherein ¹And R ²Define as claim 1 Chinese style (I) compound, Lg is the leaving group that is suitable for the aliphatics nucleophilic substitution, and EsGp is that ester forms group.

19. formula (II), (IV), (VI), (VII), (XVI), (XVII), (XVIII), (XX) or compound (XXIII).