WO2007065256A1 - Novel spiropiperidine compounds and methods for the modulation of chemokine receptor activity - Google Patents

Abstract

The present invention relates to spiropiperidine compounds of formula (I) wherein W, X, Y, Z, R1, R2 and R3 are as defined herein, and pharmaceutically acceptable salts, hydrates and solvates thereof. These spiropiperidine compounds are useful for the modulation of CCR5 chemokine receptor activity, particularly in the prevention or treatment of inflammatory diseases, immunoregulatory diseases, organ transplantation reactions and infectious diseases such as HIV infections.

Description

NOVEL SPIROPIPERIDINE COMPOUNDS AND METHODS FOR THE MODULATION OF CHEMOKINE RECEPTOR ACTIVITY

FIELD OF THE INVENTION

The present invention relates to novel spiropiperidine compounds and a method of modulating chemokine receptor activity using these compounds. The present invention is also directed to novel spiropiperidine compounds which are useful in the prevention or treatment of diseases associated with the modulation of CCR5 chemokine receptor activity. The present invention is further directed to a method of blocking cellular entry of HIV in a subject and to compositions using these compounds.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and they also play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Chemokines are small 70 to 80 amino acid proteins with well-characterized three-dimensional structures, usually stabilized by two disulfide bridges. They are divided into four families on the basis of pattern of conserved cysteine residues. Chemokine receptors have been designated such as, CCRl, CCR2 , CCR2A, CCR2B, CCR3 , CCR4 , CCR5 , CCR6 , CCR7 , CCR8 , CCR9 , CCRlO, CXCRl, CXCR2, CXCR3 , and CXCR4 and therefore agents which modulate these receptors may be useful in the prevention and treatment of diseases as mentioned above .

One of them, the C-C chemokines family, includes potent chemoattractants of monocytes and lymphocytes such as RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin, MIP-Ia and MlP-lβ (Macrophage Inflammatory Proteins) and human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and MCP-3) . More specifically, C-C chemokine receptor 5 (CCR5) , a β- chemokine receptor with a seven- transmembrane-protein structure, was found to serve as a coreceptor for non- syncytium- inducing or macrophage-tropic HIV-I (R5 viruses) . It was also established that CCR5 is the principal chemokine receptor required for the entry of HIV into the cell during primary infection. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. It would therefore be useful to provide novel compounds which are modulators of chemokine receptor activity.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel compounds represented by formula (I) :

(D or pharmaceutically acceptable salts, hydrates or solvates thereof,

wherein z IS

R₁ is chosen from NR₈R₉,

(ID ;III)

(IV) ^(V)

R₂ is chosen from optionally substituted Ci-I₀ alkyl, optionally substituted C₂ I₀ alkenyl (e.g. C_{2 6} alkenyl) , optionally substituted C_{2 10} alkynyl (e.g. C₂_₆ alkynyl) , optionally substituted C_6-12 aryl or optionally substituted 3 to 10 membered heterocycle;

R₃ is chosen from H, optionally substituted C_{1 10} alkyl or optionally substituted C₆.₁₂ aryl;

R₄, R₅, R' ₅ and R" ₅ are each independently chosen from H, optionally substituted Ci_-I0 alkyl, optionally substituted C_2-I0 alkenyl (e.g. C_{2 6} alkenyl), optionally substituted C_{2 I0} alkynyl (e.g. C₂_₆ alkynyl), optionally substituted C_{6 12} aryl, optionally substituted 3 to 10 membered heterocycle, optionally substituted C_6-12 aralkyl (e.g. C_7-12 aralkyl) or optionally substituted heteroaralkyl (e.g., wherein the heteroaryl potion has 3 to 10 members and the alkyl portion has 1 to 6 carbon atoms) ; R₆ and R"₆ are each independently H, optionally substituted C_1-I0 alkyl (e.g. C_{1 4} alkyl) , optionally substituted C_2-10 alkenyl (e.g. C₂.₄ alkenyl) , or optionally substituted C_2-I0 alkynyl (e.g. C_{2 4} alkynyl);

R₇ is H, optionally substituted C_{1 10} alkyl, optionally substituted C_2-I₀ alkenyl, optionally substituted C_2-I₀ alkynyl, optionally substituted C_{6 12} aryl, optionally substituted 3 to 10 membered heterocycle, optionally substituted C_{6 12} aralkyl (e.g. C_7-12 aralkyl) or optionally substituted heteroaralkyl (e.g., wherein the heteroaryl potion has 3 to 10 members and the alkyl portion has 1 to 6 carbon atoms) , or R"₆ and R₇ can also be taken together to form an optionally substituted 3 to 10 membered heterocycle; and

R₈ and R₉ are each independently chosen from H or optionally substituted C_1-10 alkyl.

In another aspect, there is provided a method of modulating chemokine receptor activity in a subject comprising administering to the subject an effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there is provided a method for prevention or treatment of certain inflammatory diseases, immunoregulatory diseases, organ transplantation reactions and in the prevention and treatment of infectious diseases such as HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there is provided a method for the prevention or treatment of diseases associated with the modulation of CCR5 chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there is provided a method for blocking cellular entry of HIV in a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or composition of the invention to block HIV from cellular entry in said subject.

In still another aspect, there is provided a method for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent.

In another aspect, there is provided a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.

In another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the prevention or treatment of diseases associated with the modulation of chemokme receptor activity.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, compounds of the present invention comprise those wherein the following embodiments are present, either independently or m combination In one embodiment, the present invention provides novel compounds represented by formula I.

(D or pharmaceutically acceptable salts, hydrates or solvates thereof wherein W, X, Y, Z, R₁, R₂ and R₃ are defined above.

In one embodiment, the present invention provides novel compounds represented by formula (Ia) :

:ia) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄, R'₅ and R"₅ are defined above. In one embodiment, the present invention provides novel compounds represented by formula (Ib) :

or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄, R'₅ and R"₅ are defined above.

In one embodiment, the present invention provides novel compounds represented by formula (Ic) :

(Ic) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃ and R₄ are defined above .

In one embodiment, the present invention provides novel compounds represented by formula (Id) :

(Id) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄, R₅, R'₅ and R"₅ are defined above.

In one embodiment, the present invention provides novel compounds represented by formula (Ie) :

(Ie) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄, R₅, R'₅ and R"₅ are defined above. In one embodiment, the present invention provides novel compounds represented by formula (If) :

(if) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄, R'₅ and R"₅ are defined above.

In one embodiment, the present invention provides novel compounds represented by formula (Ig) :

⁽ig) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄ and R'₅ are defined above. In one embodiment, the present invention provides novel compounds represented by formula (Ih) :

(Ih) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein R₁, R₂, R₃, R₄ and R'₅ are defined above.

In one embodiment, the compounds of the present invention are in the (S) -enantiomer as represented by formula (Ii) :

(Ii) or pharmaceutically acceptable salts, hydrates or solvates thereof wherein W, X, Y, Z, R₁, R₂ and R₃ are defined above.

In one embodiment , the compounds of the present invention are in the form of the R isomer. In one embodiment, the compounds of the present invention are in the form of the S isomer. In a further embodiment, R₁ is chosen from:

(ID (in)

(IV) ^<V)

Wherein, R₇ is cyclohexyl, cyclopentyl or cyclobutyl unsubstituted or substituted by one or more substituents independently chosen from halogen, nitro, nitroso, SO₃Rf, SO₂Rf, PO₃R₆₅R₆₆, CONRgRh, C_1-6 alkyl, C_{7 18} aralkyl, C_6-12 aryl, C_1-6 alkyloxy, C_6-12 aryloxy, C(O)C₁-_S alkyl, C(O)C₆_₁₂ aryl, C(O)C₇-₁₂ aralkyl, C(O)NHRf, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl, oxo, oxime, NRgRh, C(O)ORf, cyano, azido, amidino and guanido;

wherein Rf, R₆₅, R₆₆, Rg and Rh in each case are independently H, C_{1 6} alkyl, C_{2 6} alkenyl, C₂_₆ alkynyl, C₆ i₂ aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, or C₇_₁₈ aralkyl.

In a further embodiment, R₁ is:

O

N R₇

R₆

(II)

wherein R₆ is as defined above and R₇ is chosen from optionally substituted C_1-10 alkyl .

In further embodiment, R₁ is:

(II)

wherein:

R₇ is cyclopropyl;

R₇ is 4 , 4-difluorocyclohexyl ;

R₇ is isopropyl .

In a further embodiment, R₁ is:

(IV)

wherein R₆ is as defined above and R₇ is optionally substituted C_1-10 alkyl. In further embodiments , R₁ is :

(IV)

wherein R₇ is tert-butyl . In a further embodiment, R₂ is chosen from optionally substituted C_6-I2 aryl or optionally substituted 3 to 10 membered heterocycle.

In a further embodiment R₂ is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from halogen, nitro, nitroso, SO₃R₆₂/ PO₃R₆₅R₆₆, CONR₆₃R₆₄, C_1-6 alkyl, C_{2 6} alkenyl, C₂-₆ alkynyl, C₇_₁₂ aralkyl, C_{6 12} aryl, C_{1 6} alkyloxy, C_{2 6} alkenyloxy, C₂_₆ alkynyloxy, C_{6 12} aryloxy, C (O) C_1-6 alkyl, C (0) C₂.₆ alkenyl, C (O) C₂.₆ alkynyl , C(O)C_{6 12} aryl, C(O)C_7-12 aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl , hydroxyl, NR₆₃R₆₄, C(O)OR₆₂, cyano, azido, amidino and guanido,- wherein R₆₂, R₆₅, R₆₆, R₆₃ and R₆₄ are each independently chosen from H, C_{1 12} alkyl, C_2-12 alkenyl, C_{2 12} alkynyl, C₆. ₁₂ aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, C_7-I8 aralkyl,

or R₆₅ and R₆₆ are taken together with the oxygen atoms to form a 5 to 10 member heterocycle,

or R₆₃ and R₆₄ are taken together with the nitrogen atom to form a 3 to 10 member heterocycle.

R₂ is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from a halogen, C_{1 6} alkyl, C_1-6 alkyloxy, CF₃, COOH, COOC₁-_S alkyl, cyano, NH₂, nitro, NH(Ci_-6 alkyl) , N(C_x-6 alkyl)₂ and a 3-8 member heterocycle .

R₄ is C₁-I₂ alkyl, C₆_₁₂ aryl, C_7-I₂ aralkyl, 3 to 10 membered heterocycle or optionally substituted which are unsubstituted or substituted by one or more substituents chosen from a halogen, C_1-6 alkyl, C_{x 6} alkyloxy, CF₃, COOH, COOC₁^ alkyl, cyano, NH₂, nitro, NH(C_{1 6} alkyl), N(C_{1 6} alkyl) ₂ and a 3-8 member heterocycle.

R₄ is phenyl or benzyl which are unsubstituted or substituted by one or more substituents chosen from halogen, nitro, CONR₆₃R₆₄, Ci_-6 alkyl, C_{2 6} alkenyl, C_{1 6} alkyloxy, C_{2 6} alkenyloxy, C_{2 6} alkynyloxy, C_{6 12} aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl , hydroxyl, NR₆₃R₆₄, C(O)OR₆₂, cyano, and azido;

wherein R₆₂, R₆₃ and R₆₄ are each independently chosen from H, C_1-12 alkyl, C_{6 12} aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C_7-18 aralkyl,

or R₆₃ and R₆₄ are taken together with the nitrogen to form a 3 to 10 member heterocycle.

R₄ is phenyl or benzyl which are unsubstituted or substituted by one or more substituents chosen from halogen, C_{1 6} alkyl, NR₆₃R₆₄, nitro, CONR₆₃R₆₄, C_{1 6} alkyloxy, C(O)OR₆₂, cyano, and azido;

wherein R₆₂, R₆₃ and R₆₄ are each independently chosen from H, C_{1 12} alkyl, C₆.₁₂ aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C₇.₁₈ aralkyl ;

or R₆₃ and R₆₄ are taken together with the nitrogen to form a 3 to 10 member heterocycle.

R₄ is benzyl unsubstituted or substituted by one or more substituents chosen from halogen, Ci_-3 alkoxy, SO₂C₁. ₃alkyl, difluoromethoxy, trifluoromethoxy, trifluoromethyl, CN and pyrazoyl .

In further embodiments:

R₂ is optionally substituted C_6-I2 aryl.

R₂ is phenyl ;

R₂ is phenyl substituted with halogen;

R₂ is phenyl substituted with Cl;

R₂ is phenyl substituted with F;

R₂ is phenyl substituted with at least one halogen.

In a further embodiment, R₃ is chosen from H or optionally substituted Ci_-10 alkyl .

In one embodiment, R₃ is H.

In one embodiment, R₃ is methyl.

In one embodiment, R₄ is chosen from optionally substituted C₆_i₂ aryl or optionally substituted 3 to 10 membered heterocycle.

In a further embodiment, R₄ is optionally substituted C₆. i₂ aryl .

In a further embodiment, R₄ is optionally substituted 3 to 10 membered heterocycle. In a further embodiment, R₄ is optionally substituted C₇ i₂ aralkyl .

In further embodiments :

R₄ is benzyl;

R₄ is benzyl substituted with a halogen;

R₄ is benzyl substituted with Br;

R₄ is benzyl substituted with F;

R₄ is benzyl substituted with Cl;

R₄ is benzyl substituted with at least one halogen,- R₄ is benzyl substituted with a C_{1 3} alkoxy;

R₄ is benzyl substituted with methoxy;

R₄ is benzyl substituted with ethoxy,-

R₄ is benzyl substituted with SO₂Ci.₃alkyl;

R₄ is benzyl substituted with methanesulfonyl;

R₄ is benzyl substituted with difluoromethoxy;

R₄ is benzyl substituted with trifluoromethoxy;

R₄ is benzyl substituted with trifluoromethyl ;

R₄ is benzyl substituted with CN;

R₄ is benzyl substituted with pyrrazoyl;

R₄ is benzyl optionally substituted in the para (p) position .

In one embodiment, the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 99%.

In one embodiment , the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 95%.

In one embodiment, the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 90%.

In one embodiment , the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 99%. In one embodiment , the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 95%. In one embodiment, the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 90%. In one embodiment, there is provided a method of modulating chemokine receptor activity in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In another embodiment, there is provided a method for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In a further embodiment, there is provided a method for prevention or treatment of certain inflammatory diseases, immunoregulatory diseases, organ transplantation reactions and in the prevention and treatment of infectious diseases such as HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In another embodiment, there is provided a method for the prevention or treatment of diseases associated with the modulation of CCR5 chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there is provided a method for blocking cellular entry of HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) to block HIV from cellular entry in said subject .

In still another aspect, there is provided a method for prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there is provided a method for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In a further embodiment, there is provided a method for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent.

In a further embodiment, there is provided a method for the prevention or treatment of diseases associated with the modulation of CCR5 chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent. In still another aspect, there is provided a method for blocking cellular entry of HIV in a subject or for the prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent.

In still another aspect, there is provided a method for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent. In another embodiment, there is provided a combination useful for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity which is a therapeutically effective amount of a compound of formula (I) and therapeutically effective amount of at least one further therapeutic agent.

In one embodiment, combinations of the present invention comprise those wherein the following embodiments are present, either independently or in combination.

In a further embodiment, the pharmaceutical combinations of this invention may contain at least one further therapeutic agent chosen from an agent used in inflammatory diseases, immunoregulatory diseases and in organ transplantation reactions.

In another embodiment, the pharmaceutical combination of this invention may contain at least one further therapeutic agent which is an antiviral agent.

In one embodiment, the pharmaceutical combination of this invention may contain at least one further antiviral agent which is chosen from nucleoside and nucleotide analog reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, protease inhibitors, attachment and fusion inhibitors, integrase inhibitors or maturation inhibitors.

In one embodiment, the pharmaceutical combinations of this invention may contain at least one other antiviral agent which is a nucleoside and nucleotide analog reverse transcriptase inhibitors chosen from 3TC (lamivudine, Epivir^®) , AZT (zidovudine, Retrovir^®), Emtricitabine (Coviracil^®, formerly FTC), d4T ( 2 ' , 3 ' - dideoxy-2 ' , 3 ' -didehydro- thymidine, stavudine and Zerit^®) , tenofovir (Viread^®) , 2 ' , 3 ' -dideoxyinosine (ddl, didanosine, Videx^®) , 2 ' , 3 ' -dideoxycytidine (ddC, zalcitabine, Hivid^®) , Combivir^® (AZT/3TC or zidovudine/lamivudine combination) , Trivizir^® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination), abacavir (1592U89, Ziagen^®) , SPD-754, ACH- 126,443 (Beta-L-Fd4C) , Alovudine (MIV- 310) , DAPD (amdoxovir) , Racivir, 9- [ (2-hydroxymethyl) -1, 3-dioxolan- 4 -yl] guanine or 2 -amino- 9- [ (2-hydroxymethyl ) -1 , 3- dioxolan-4 -yl] adenine . In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune^®, NVP, BI-RG- 587) , delavirdine (Rescriptor^®, DLV) , efavirenz (DMP 266, Sustiva^®) , (+) -Calanolide A, Capravirine (AG1549, formerly S-1153), DPC083, MIV-150, TMC120, TMC125 or BHAP (delavirdine), calanolides or L-697,661 (2- Pyridinone 3benzoxazolMeNH derivative) .

In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a protease inhibitor chosen from nelfinavir (Viracept^®, NFV), amprenavir (141W94, Agenerase^®) , indinavir (MK-639, IDV, Crixivan^®) , saquinavir (Invirase^®, Fortovase^®, SQV) , ritonavir (Norvir^®, RTV), lopinavir (ABT-378, Kaletra^®) , Atazanavir (BMS232632) , mozenavir (DMP-450) , fosamprenavir (GW433908) , RO033-4649, Tipranavir (PNU- 140690), TMC114 or VX-385.

In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon") , T-1249, Schering C (SCH-C), Schering D (SCH-D), FP21399, PRO-140, PRO 542, PRO 452, TNX-355, GW873140 (AK602), TAK-220, UK-427,857 or soluble CD4 , CD4 fragments, CD4 -hybrid molecules, BMS-806, BMS-488043, AMD3100, AMD070 or KRH-2731.

In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an integrase inhibitor chosen from S- 1360, L-870,810, L-870,812 or C-2507. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a maturation inhibitor and is PA-457.

In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA) .

In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is HGTV43. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an immunomodulator, immune stimulator or cytokine chosen from interleukin-2 (IL-2, Aldesleukin, Proleukin) , granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-I Immunogen (Remune) or EP HIV-1090. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent chosen from 2 ' , 3 ' -dideoxyadenosine, 3'- deoxythymidine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, ganciclovir; interferons such as alpha-, beta-and gamma- interferon; glucuronation inhibitors such as probenecid; or TIBO drugs, HEPT, TSAO derivatives. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprises a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

In a further embodiment, the said compound of formula (I) and said therapeutic agent are administered sequentially.

In a further embodiment, the said compound of formula (I) and said therapeutic agent are administered simultaneously. The subject to which the compounds are administered can be, for example, a mammal or a human. Preferably, the subject is a human.

In one embodiment, the present invention further provides a pharmaceutical composition comprising at least one compound having the formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable hydrates or pharmaceutically acceptable solvates thereof and at least one pharmaceutically acceptable carrier or excipient.

In another embodiment, the invention provides the use of a compound having the formula (I) for the manufacture of a medicament for prevention and treatment of diseases associated with the modulation of CCR5 chemokine receptor activity in a host comprising administering a therapeutically effective amount of a compound of formula (I) .

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

The term "alkyl" represents a linear, branched or cyclic hydrocarbon moiety having, for example, 1 to 10 carbon atoms, which may have one or more double bonds or triple bonds in the chain, and is optionally substituted. For example, suitable substituents include halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea, OS(O)₂R_2I (wherein R₂₁ is selected from Ci ₆ alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle) , OS(O)₂OR₂₂ (wherein R₂₂ is selected from H, C_1-6 alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle) , S(O)₂OR₂₃ (wherein R₂₃ is selected from H, C_1-6 alkyl, C_6-12 aryl or 3 to 10 membered heterocycle), S(0)o_₂R₂₄ (wherein R₂₄ is selected from H, C_1-6 alkyl, C₆_₁₂ aryl or 3 to 10 membered heterocycle), OP(O)OR₂₅OR₂₆, P(O)OR₂₅OR₂₆ (wherein R₂₅ and R₂₆ are each independently selected from H or C_{1 6} alkyl), C(O)R₂₇ (wherein R₂₇ is selected from H, C_1-6 alkyl, C₆_i₂ aryl or 3 to 10 membered heterocycle), C(O)OR₂₈ (wherein R₂₈ is selected from H, C_1-6 alkyl, C_{6 12} aryl, C_6-12 aralkyl (e.g. C_7-12 aralkyl) or 3 to 10 membered heterocycle) , NR₂₉C(O)R₃₀, NR₂₉C(O)OR₃₀,

NR₃₁C(O)NR₂₉R₃₀, C(O)NR₂₉R₃₀, OC(O)NR₂₉R₃₀ (wherein R₂₉, R₃₀ and R₃i are each independently selected from H, C_1-6 alkyl, C₆_i₂ aryl, C_6-12 aralkyl (e.g. C_7-12 aralkyl) or 3 to 10 membered heterocycle, or R₂₉ and R₃₀ are taken together with the atoms to which they are attached to form a 3 to 10 membered heterocycle), SO₂NR₃₂R₃₃,

NR₃₂SO₂R₃₃ (wherein R₃₂ and R₃₃ are each independently selected from the group consisting of H, C_1-6 alkyl, C_6-12 aryl, 3 to 10 membered heterocycle and C_6-12 aralkyl

(e.g. C_7-12 aralkyl)), C(R₃₄)NR₃₅ or C(R₃₄)NOR₃₅ (wherein R₃₄ and R₃₅ are each independently selected from the group consisting of H, C_1-6 alkyl, or C_6-12 aryl) . Preferred substituents for the alkyl groups include halogen (Br, Cl, I or F), cyano, nitro, oxo, amino, COOH, COO-C_1-4 alkyl, CO-C_1-4 alkyl, and phenyl.

Examples of alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl , tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl , isohexyl, neohexyl, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl butenyl, isobutenyl, hexenyl , butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octatrienyl, octatetraenyl , propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cycloheptyl, cyclohexenyl , cyclohexdienyl and cyclohexyl .

The term alkyl is also meant to include alkyls in which one or more hydrogen atom is replaced by a halogen, i.e. an alkylhalide. Examples include but are not limited to trifluoromethyl , difluoromethyl , fluoromethyl, trichloromethyl , dichloromethyl, chloromethyl, trifluoroethyl , difluoroethyl, fluoroethyl, trichloroethyl , dichloroethyl, chloroethyl, chlorofluoromethyl , chlorodifluoromethyl , dichlorofluoroethyl .

The term "alkenyl" refers to alkyl groups may have one or more double bonds in the chain. The term "alkynyl" refers to alkyl groups may have one or more triple bonds in their chain. The alkenyl and alkynyl groups can be optionally substituted as described above for the alkyl groups .

The term "alkoxy" represents an alkyl which is covalently bonded to the adjacent atom through an oxygen atom. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy and neohexyloxy.

The term "alkylamino" represents an alkyl which is covalently bonded to the adjacent atom through a nitrogen atom and may be monoalkylamino or dialkylamino, wherein the alkyl groups may be the same or different. Examples include but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert- butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, isohexylamino and neohexylamino . The term "alkyloxycarbonyl " represents an alkyloxy which is covalently bonded to the adjacent atom through carbonyl (C=O) . Examples include but are not limited to methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl , tert-butoxycarbonyl , pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl , tert -pentyloxycarbonyl , hexyloxycarbonyl , isohexyloxycarbonyl and neohexyloxycarbonyl .

The term "amidino" represents

wherein R₁₀, Ri₁ and R₁₂ are each independently selected from H₇ C_1-6 alkyl, C₆-I₂ aryl or C_6-I₂ aralkyl (e.g. C₇-_I2 aralkyl) , or R₁₁ and R₁₂ are taken together with the nitrogen to which they are attached to form a 3 to 10 membered heterocycle .

The term "amido" represents -CONH₂, -CONHR₁₃ and CONR₁₃R₁₄ wherein R₁₃ and R₁₄ are each independently selected from Ci_-6 alkyl, C_6-12 aryl, 3 to 10 membered heterocycle or C_6-12 aralkyl (e.g. C₇-_I2 aralkyl), or R₁₃ and R₁₄ are taken together with the nitrogen to which they are attached to form a 3 to 10 membered heterocycle.

The term "amino" represents a derivative of ammonia obtained by substituting one or more hydrogen atom and include -NH₂, -NHR₁₅ and -NR₁₅R₁₆, wherein R₁₅ and R₁₆ are each independently selected from C_1-6 alkyl, C_6-12 aryl or C_6-I2 aralkyl (e.g. C_7-12 aralkyl) , or R₁₅ and R₁₆ are taken together with the nitrogen to which they are attached to form a 3 to 10 membered heterocycle. The term "aryl" represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e. the aryl group may be monocyclic or polycyclic) , and which is optionally substituted with one or more substituents . For example, suitable substituents include halogen, halogenated C_1-6 alkyl, halogenated Ci_-6 alkoxy, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea, OS(O)₂R_2I (wherein R₂₁ is selected from C_{1 6} alkyl, C₆_₁₂ aryl or 3 to 10 membered heterocycle) , OS(O)₂OR₂₂ (wherein R₂₂ is selected from H, C₁-_S alkyl, C_6-I2 aryl or 3 to 10 membered heterocycle), S(O)₂OR₂₃ (wherein R₂₃ is selected from H, Ci_-6 alkyl, C₆.₁₂ aryl or 3 to 10 membered heterocycle), S (0) ₀.₂R₂₄ (wherein R₂₄ is selected from H, C_{1 6} alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle!, OP(O)OR₂₅OR₂₆, P(O)OR₂₅OR₂₆ (wherein R₂₅ and R₂₆ are each independently selected from H or C_1-6 alkyl), C_1-6alkyl, C_{6 12}aralkyl (e.g. C_{7 12} aralkyl) , C_1-6alkoxy, C₆.₁₂aralkyloxy (e.g. C₇.₁₂ aralkyloxy) , C_{6 12}aryloxy, 3 to 10 membered heterocycle, C(O)R₂₇ (wherein R₂₇ is selected from H, C_x-6 alkyl, C₆_₁₂ aryl or 3 to 10 membered heterocycle), C(O)OR₂₈ (wherein R₂₈ is selected from H, C_{1 6} alkyl, C_6-12 aryl, C_{6 12} aralkyl (e.g. C_{7 12} aralkyl) or 3 to 10 membered heterocycle), NR₂₉C(O)R₃₀, NR₂₉C(O)OR₃₀, NR₃₁C(O)NR₂₉R₃₀, C(O)NR₂₉R₃₀, OC(O)NR₂₉R₃₀ (wherein R₂₉, R₃₀ and R₃₁ are each independently selected from H, C_1-6 alkyl, C₆.₁₂ aryl, C_6-I2 aralkyl (e.g. C_7-I2 aralkyl) or 3 to 10 membered heterocycle, or R₂₉ and R₃₀ are taken together with the atoms to which they are attached to form a 3 to 10 membered heterocycle), SO₂NR₃₂R₃₃, NR₃₂SO₂R₃₃ (wherein R₃₂ and R₃₃ are each independently selected from the group consisting of H, C_1-6 alkyl, C_6-12 aryl, 3 to 10 membered heterocycle and C₆_₁₂ aralkyl (e.g. C_7-I2 aralkyl)), C(R₃₄)NR₃₅ or C(R₃₄)NOR₃₅ (wherein R₃₄ and R₃₅ are each independently selected from the group consisting of H, C_{1 6} alkyl, or C_{6 12} aryl) .

Preferred substituents for the aryl groups include halogen (Br, Cl, I or F) , cyano, nitro, oxo, amino, C_1-4 alkyl (e.g., CH₃, C₂H₅, isopropyl) , Ci₄ alkoxy (e.g.,

OCH₃, OC₂H₅), halogenated C_{1 4} alkyl (e.g., CF₃, CHF₂), halogenated C_1-4 alkoxy (e.g., OCF₃, OC₂F₅), COOH, COO-C_1-4 alkyl, CO-C₁., alkyl, C_{1 4} alkyl -S- (e.g., CH₃S, C₂H₅S), halogenated C_{1 4} alkyl -S- (e.g., CF₃S, C₂F₅S), benzyloxy, and pyrazolyl .

Examples of aryl include but are not limited to phenyl, tolyl, dimethylphenyl , aminophenyl, anilinyl, naphthyl , anthryl, phenanthryl or biphenyl .

The term "aralkyl" represents an aryl group attached to the adjacent atom by a C_1-6alkyl . Examples include but are not limited to benzyl, benzhydryl , trityl, phenethyl, 3 -phenylpropyl , 2-phenylpropyl , 4-phenylbutyl and naphthylmethyl . The aryl and alkyl portions can be optionally substituted as described above.

The term "aralkyloxy" represents an aralkyl which is covalently bonded to the adjacent atom through an oxygen atom. Examples include but are not limited to benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3- phenylpropyloxy, 2-phenylpropyloxy, 4-phenylbutyloxy and naphthylmethoxy. The aryl and alkyl portions can be optionally substituted as described above.

The term "aryloxy" represents an aryl which is covalently bonded to the adjacent atom through an oxygen atom. Examples include but are not limited to phenoxy and naphthyloxy. The aryl portion can be optionally substituted as described above.

There is also provided "enantiomers" and "diastereoisomers" of the present invention. It will be appreciated that the compounds in accordance with the present invention can contain one or more chiral centers. The compounds in accordance with the present invention may thus exist in the form of two different optical isomers, that is (+ ) or (-) enantiomers or in the form of different diastereomers . All such enantiomers, diastereomers and mixtures thereof, including racemic or other ratio mixtures of individual enantiomers and diastereomers, are included within the scope of the invention. The single diastereomer can be obtained by methods well known to those of ordinary skill in the art, such as HPLC, crystallization and chromatography. The single enantiomer can be obtained by methods well known to those of ordinary skill in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary derivatization.

The optical purity is numerically equivalent to the "enantiomeric excess". The term "enantiomeric excess" is defined in percentage (%) value as follows: [mole fraction (major enantiomer) - mole fraction (minor enantiomer)] x 100. An example of enantiomeric excess of 99% represents a ratio of 99.5% of one enantiomer and 0.5% of the opposite enantiomer.

The term " guanidino" represents -NR₁₇C f =NR₁₈ ) NR₁₉R₂₀ wherein R₁₇ , R₁₈ , R₁₉ and R₂₀ are each independently selected from H , C_{1 - 6} alkyl , C₆_₁₂ aryl or C₆.₁₂ aralkyl ( e . g . C₇_₁₂ aralkyl ) , or R₁₉ and R₂₀ are taken together with the nitrogen to which they are attached to form a 3 to 10 membered heterocycle.

The term "halogen" is specifically a fluoride atom, chloride atom, bromide atom or iodide atom.

The term "heterocycle" represents an optionally substituted saturated, unsaturated or aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O) , sulfur (S) or nitrogen (N) . Heterocycles may be monocyclic or polycyclic rings. For example, suitable substituents include halogen, halogenated Ci_-6 alkyl, halogenated Ci_-6 alkoxy, amino, amidino, amido, azido, cyano, guanidino, hydroxyl , nitro, nitroso, urea, OS(O)₂R_2I (wherein R₂₁ is selected from C_1-6 alkyl, C_6-12 aryl or 3 to 10 membered heterocycle), OS(O)₂OR₂₂ (wherein R₂₂ is selected from H, C_{1 6} alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle) , S(O)₂OR₂₃ (wherein R₂₃ is selected from H, C_{1 6} alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle), S (0) ₀-₂R2₄ (wherein R₂₄ is selected from H, C_1-6 alkyl, C_6-12 aryl or 3 to 10 membered heterocycle), OP(O)OR₂₅OR₂₆, P(O)OR₂₅OR₂₆ (wherein R₂₅ and R₂₆ are each independently selected from H or C₁^ alkyl), Ci_-6 alkyl, C_6-I2 aralkyl (e.g. C_7-I2 aralkyl) , C_{1 6} alkoxy, C_6-I2 aryl, C_{6 12} aralkyloxy (e.g. C₇. i₂ aralkyloxy), C_{6 12} aryloxy, C(O)R₂₇ (wherein R₂₇ is selected from H, C_x-6 alkyl, C₆_₁₂ aryl or 3 to 10 membered heterocycle) , C(O)OR₂₈ (wherein R₂₈ is selected from H, C₁-_S alkyl, C_{6 12} aryl, C_6-I2 aralkyl (e.g. C_7-I2 aralkyl) or 3 to 10 membered heterocycle), NR₂₉C(O)R₃₀, NR₂₉C(O)OR₃₀, NR₃₁C(O)NR₂₉R₃₀, C(O)NR₂₉R₃₀, OC(O)NR₂₉R₃₀ (wherein R₂₉, R₃₀ and R₃₁ are each independently selected from H, C_x_₆ alkyl, C₆_₁₂ aryl, C_{6 12} aralkyl (e.g. C_{7 12} aralkyl) or 3 to 10 membered heterocycle, or R₂₉ and R₃₀ are taken together with the atoms to which they are attached to form a 3 to 10 membered heterocycle) , SO₂NR₃₂R₃₃, NR₃₂SO₂R₃₃ (wherein R₃₂ and R₃₃ are each independently- selected from the group consisting of H, Ci_₆ alkyl, C_6-12 aryl, 3 to 10 membered heterocycle and C_6-12 aralkyl (e.g. C₇-_I2 aralkyl) ), C(R₃₄)NR₃₅ or C(R₃₄)NOR₃₅ (wherein R₃₄ and R₃₅ are each independently selected from the group consisting of H, C_1-6 alkyl, or C_6-12 aryl) . Preferred substituents for the heterocycle groups include halogen (Br, Cl, I or F), cyano, nitro, oxo, amino, C_1-4 alkyl (e.g., CH₃, C₂H₅, isopropyl) , C_1-4 alkoxy (e.g., OCH₃, OC₂H₅), halogenated C_1-4 alkyl (e.g., CF₃, CHF₂), halogenated C_1-4 alkoxy (e.g., OCF₃, OC₂F₅), COOH, COO-Ci_₄ alkyl, CO-C₁^₄ alkyl, C_1-4 alkyl -S- (e.g., CH₃S, C₂H₅S), halogenated C_1-4 alkyl -S- (e.g., CF₃S, C₂F₅S), benzyloxy, and pyrazolyl .

Examples of heterocycles include but are not limited to azepinyl, aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl , dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, morpholinyl, morpholino, oxetanyl , oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl , tetrazinyl, thiadiazinyl , triazinyl, thiazinyl, thiopyranyl furoisoxazolyl , imidazothiazolyl, thienoisothiazolyl , thienothiazolyl , imidazopyrazolyl , cyclopentapyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl , thiazolothiazinyl , thiazolopyrimidinyl , thiazolopyridinyl , oxazolopyrimidinyl , oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl , purinyl , pyrazolopyrimidinyl , imidazopyridinyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl , furopyrimidinyl, furopyridyl, benzofuranyl , isobenzofuranyl , thienopyrimidinyl , thienσpyridyl , benzothienyl , cyclopentaoxazinyl, cyclopentafuranyl , benzoxazinyl , benzothiazinyl , quinazolinyl, naphthyridinyl , quinolinyl, isoquinolinyl, benzopyranyl , pyridopyridazinyl and pyridopyrimidinyl .

The term "heteroaralkyl" represents a heterocycle group attached to the adjacent atom by a C_1-6 alkyl . The heterocycle and alkyl portions can be optionally substituted as described above.

The term "independently" means that a substituent can be the same or a different definition for each item. The term "optionally substituted" represents one or more halogen, halogenated C_1-6 alkyl, halogenated C_{1 6} alkoxy, amino, amidino, amido, azido, cyano, guanidino, hydroxyl , nitro, nitroso, urea, OS (O) 2R21 (wherein R₂1 is selected from C_1-6 alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle), OS(O)₂OR₂₂ (wherein R₂₂ is selected from H, C_{1 6} alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle) , S(O)₂OR₂₃ (wherein R₂₃ is selected from H, Ci₆ alkyl, C_6-12 aryl or 3 to 10 membered heterocycle), S (0) ₀.₂R₂₄ (wherein R₂₄ is selected from H, C₁^ alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle), OP(O)OR₂₅OR₂₆, P(O)OR₂₅OR₂₆ (wherein R₂₅ and R₂₆ are each independently selected from H or C_{1 6} alkyl), C_1-6 alkyl, C₆_₁₂ aralkyl (e.g. C₇_₁₂ aralkyl) , C_{6 12} aryl, C_{1 6} alkoxy, C_{6 12} aralkyloxy (e.g. C_{7 12} aralkyloxy) , C_6-12 aryloxy, 3 to 10 membered heterocycle, C(O)R₂₇ (wherein R₂₇ is selected from H, C_1-6 alkyl, C_{6 12} aryl or 3 to 10 membered heterocycle) , C(O)OR₂₈ (wherein R₂₈ is selected from H, Ci ₆ alkyl, C₆-_I2 aryl, C₆.₁₂ aralkyl (e.g. C_{7 12} aralkyl) or 3 to 10 membered heterocycle) , NR₂₉C(O)R₃₀, NR₂₉C(O)OR₃₀,

NR₃₁C(O)NR₂₉R₃₀, C(O)NR₂₉R₃₀, OC(O)NR₂₉R₃₀ (wherein R₂₉, R₃₀ and R₃i are each independently selected from H, C₁. s alkyl, C_6-12 aryl, C_{6 12} aralkyl (e.g. C₇.₁₂ aralkyl) or 3 to 10 membered heterocycle, or R₂₉ and R₃₀ are taken together with the atoms to which they are attached to form a 3 to 10 membered heterocycle) , SO₂NR₃₂R₃₃, NR₃₂SO₂R₃₃ (wherein R₃₂ and R₃₃ are each independently selected from the group consisting of H, C_1-6 alkyl, C₆-_I2 aryl, 3 to 10 membered heterocycle and C₆.₁₂ aralkyl (e.g. C_{7 12} aralkyl) ), C(R₃₄)NR₃₅ or C(R₃₄)NOR₃₅ (wherein R₃₄ and R₃₅ are each independently selected from the group consisting of H, C_1-6 alkyl, or C_{6 12} aryl) .

The term "urea" represents -N(R₃₆)CONR₃₇R₃₈ wherein R₃₆ is H or C_1-6 alkyl and wherein R₃₇ and R₃₈ are each independently selected from the group consisting of H,

C_{1 6} alkyl, C_6-12 aryl, 3 to 10 membered heterocycle and

C₆_₁₂ aralkyl (e.g. C_{7 12} aralkyl), or R₃₇ and R₃₈ are taken together with the nitrogen to which they are attached to form a 3 to 10 membered heterocycle.

"Oxidation levels": When there is a sulfur atom present, the sulfur atom can be at different oxidation levels, i.e., S, SO, or SO₂. All such oxidation levels are within the scope of the present invention. When there is a nitrogen atom present, the nitrogen atom can be at different oxidation levels, i.e. N or NO. All such oxidation levels are within the scope of the present invention. There is also provided "pharmaceutically acceptable hydrates" of the compounds of the present invention. "Hydrates" exist when the compound of the invention incorporates water. The hydrate may contain one or more molecule of water per molecule of compound of the invention. Illustrative non-limiting examples include monohydrate, dihydrate, trihydrate and tetrahydrate . The hydrate may contain one or more molecule of compound of the invention per molecule of water. An illustrative non- limiting example includes semi -hydrate . In one embodiment, the water may be held in the crystal in various ways and thus, the water molecules may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein. The hydrate must be "acceptable" in the sense of not being deleterious to the recipient thereof . The hydration may be assessed by methods known in the art such as Loss on Drying techniques (LOD) and Karl Fisher titration.

There is also provided "pharmaceutically acceptable salts" of the compounds of the present invention. By the term "pharmaceutically acceptable salts" of compounds are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include but are not limited to hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic , formic, benzoic, malonic, naphthalene- 2 -sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal, alkaline earth metal or ammonium salts. The salt(s) must be "acceptable" in the sense of not being deleterious to the recipient thereof. Non-limiting examples of such salts known by those of ordinary skill in the art include without limitation calcium, potassium, sodium, choline, ethylenediamine, tromethamine, arginine, glycinelycine, lycine, magnesium and meglumine . There is also provided a "pharmaceutically acceptable solvates" of the compounds of the present invention. The term "solvate" means that the compound of the invention incorporates one or more pharmaceutically acceptable solvent . The solvate may contain one or more molecule of solvent per molecule of compound of the invention or may contain one or more molecule of compound of the invention per molecule of solvent. In one embodiment, the solvent may be held in the crystal in various ways and thus, the solvent molecule may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein. The solvate (s) must be "acceptable" in the sense of not being deleterious to the recipient thereof. The solvation may be assessed by methods known in the art such as Loss on Drying techniques (LOD) .

Reference hereinafter to a compound according to the invention includes compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and solvates.

"Polymorphs": It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can exist in several different crystalline forms due to a different arrangement of molecules in the crystal lattice. This may include solvate or hydrate (also known as pseudopolymorphs) and amorphous forms. All such crystalline forms and polymorphs are included within the scope of the invention. The polymorphs may be characterized by methods well known in the art. Examples of analytical procedures that may be used to determine whether polymorphism occurs include: melting point (including hot-stage microscopy) , infrared (not in solution) , X-ray powder diffraction, thermal analysis methods (e.g. differential scanning calorimetry (DSC) , differential thermal analysis (DTA) , thermogravimetric analysis (TGA) ) , Raman spectroscopy, comparative intrinsic dissolution rate, scanning electron microscopy (SEM) .

In one aspect, the present invention provides novel compounds including:

{ (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l-oxa-3 , 8-diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -carbamic acid fcerfc- butyl ester

8- ( (S) -3 -Amino- 3 -phenyl-propyl) -3- (4-methoxy-benzyl) -1- oxa-3 , 8-diaza-spiro [4.5] decan-2-one

{ (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l, 3 , 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl} -carbamic acid tert- butyl ester 8- ( (S) -3 -Amino-3 -phenyl -propyl) -3- (4-methoxy-benzyl) - 1,3, 8-triaza-spiro [4.5] decan-2-one

{ (S) -3- [2- (4-Methoxy-benzyl) -3-oxo-l, 2, 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl-propyl} -carbamic acid tert- butyl ester

8- ( (S) -3 -Amino- 3 -phenyl -propyl) -2- (4-methoxy-benzyl) - 1,2, 8-triaza-spiro [4.5] decan-3-one

{ (S) -3- [2- (4-Methoxy-benzyl) -1, 3-diσxo-2, 8-diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester

8- ( (S) -3-Amino-3-phenyl-propyl) -2- (4-methoxy-benzyl) - 2 , 8-diaza-spiro [4.5] decane-1 , 3 -dione

N- { (S) -3- [3- (4-methoxy-benzyl) -2-oxo-l-oxa-3 , 8-diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -isobutyramide hydrochloride

Cyclopropanecarboxylic acid { (S) -3- [3- (4-methoxy- benzyl) -2-oxo-l-oxa-3 , 8-diaza-spiro [4.5] dec-8-yl] -1- phenyl -propyl } -amide hydrochloride

4 , 4 -Difluoro-cyclohexanecarboxylic acid { (S) -3- [3- (4- methσxy-benzyl) -2-oxo-l-oxa-3 , 8-diaza-spiro [4.5] dec-8- yl] -1 -phenyl -propyl} -amide hydrochloride

N- { (S) -3- [2- (4-Methoxy-benzyl) -3-oxo-l, 2, 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl} -isobutyramide di- hydrochloride

Cyclopropanecarboxylic acid { (S) -3- [2- (4-methoxy- benzyl) -3-oxo-l, 2 , 8-triaza-spiro [4.5] dec-8-yl] - 1-phenyl - propyl } -amide dihydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [2- (4- methoxy-benzyl) -3-oxo-l, 2, 8-triaza-spiro [4.5] dec-8-yl] - 1 -phenyl-propyl } -amide dihydrochloride

N- { (S) -3- [2- (4-Methoxy-benzyl) -1, 3-dioxo-2, 8-diaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl } -isobutyramide hydrochloride Cyclopropanecarboxylic acid { (S) -3- [2- (4-methσxy- benzyl) -1, 3-dioxo-2, 8-diaza-spiro [4.5] dec-8-yl] -1- phenyl -propyl } -amide hydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [2- (4- methoxy-benzyl) -1, 3-dioxo-2 , 8-diaza-spiro [4.5] dec-8-yl] - 1-phenyl-propyl } -amide hydrochloride

N- { (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l, 3 , 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl-propyl} -isobutyramide hydrochloride

Cyclopropanecarboxylic acid { (S) -3- [3- (4-methoxy- benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] dec-8-yl] -1-phenyl - propyl } -amide hydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [3- (4- methoxy-benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] dec-8-yl] - 1 -phenyl-propyl} -amide hydrochloride and pharmaceutically acceptable salts, hydrates or solvates thereof . It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.

The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day. The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.

Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 μM, preferably about 2 to 50 μM, most preferably about 3 to about 30 μM . This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Pharmaceutical formulation suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. The compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen- free water, before use.

For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and. acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.

Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier (s) followed by chilling and shaping in moulds.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate .

For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops . Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilising agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.

For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane , trichlorofluoromethane, dichlorotetrafluoroethane , carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

When desired the above described formulations adapted to give sustained release of the active ingredient may be employed.

When the compound (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is used in combination with a second therapeutic active agent, the dose of each compound may be either the same as or different from that when the compound is used alone. Conventional doses and regimens are readily appreciated by those skilled in the art, including doses described in the Physicians" Desk Reference, 56^th edition, 2002.

The present invention is directed to the use of the compounds as modulators of CCR5 chemokine receptor activity. In particular, the compounds of the invention have been found to have activity in binding to the CCR5 receptor in the biological assay, as described in Example 10, generally with an IC₅₀ value of less than 25 μM. The terms "modulator" or "modulation" are meant to include antagonism, agonism, mixed and partial antagonism and agonism.

Certain compounds of the present invention have also been tested in an assay for HIV activity, as described in Example 10, and generally having an IC₅₀ value of less than 1 μM.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees

Celsius; and, unless otherwise indicated, all parts and percentages are by weight .

The entire disclosure of all applications, patents and publications, cited above and below, is hereby incorporated by reference.

The purity and mass of the following examples were characterized by mass spectra (LC/MS) and or NMR spectra.

The following general schemes and examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope .

The following abbreviations may be used as follows: br broad

DCE 1,2-dichloroethane

DCM dichloromethane

DIPEAW, N-diisopropylethylamine

DMF N, ZV-dimethylformamide

Sept. septuplet TFA trifluoroacetic acid

THF tetrahydrofuran

Semi-preparative HPLC purification procedures:

Column: Phenomenex Luna C₁₈ (2), 5 microns, 10 x 250 mm Buffer A: 3 JiM HCl in H₂O (pH 2.4-2.6)

Buffer B: acetonitrile

- Method A: 0-25% B in 25 min. (1%/min)

Method A: 15-40% B in 25 min. (1%/min)

Base, NaBH(OAc)₃, DCE

Scheme 1 Preparation 1

3 - (4 -Methoxy-benzyl) - l-oxa-3 , 8-diaza-spiro [4 . 5] decan-2- one hydrochloride

Step 1: Sodium hydride 476 mg (11.7 mmol) (60% suspension in mineral oil) was added in a 500 mL round bottom flask under nitrogen followed by 30 mL of anhydrous DMF and 2 g (7.8 mmol) of 2 -oxo-l-oxa-3 , 8- diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester (see preparation : Smith P. W. et al . J. Med. Chem. 1995, 38, 3772-3779) previously dissolved in 30 mL of anhydrous DMF. After agitating one hour at room temperature, 1.08 mL (7.8 mmol) of 4- methoxybenzylchloride was added and the reaction mixture was agitated overnight at room temperature. Then 50 mL of water were added and the solution was extracted with diethyl ether (2 x 100 mL) . The combined organic layers were dried (Na₂SO₄) , filtered and evaporated under reduced pressure to yield 2.75 g (93.8%) of 3- (4- methoxy-benzyl) -2-oxo-l-oxa-3 , 8-diaza-spiro [4.5] decane- 8-carboxylic acid tert-butyl ester as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] 7.15 (d, 2H), 6.89 (d, 2H), 4.24 (s, 2H), 3.72 (s, 3H), 3.52 (m, 2H), 3.12 (m, 4H), 1.63 (m, 4H), 1.35 (s, 9H).

Step 2: To 2.75 g of crude 3- (4-methoxy-benzyl) -2-oxo-l- oxa-3 , 8-diaza-spiro [4.5] decane-8-carboxylic acid terfc- butyl ester from step 1 was added 10 mL of 4N solution of dioxane/HCl . The reaction mixture was agitated one hour at room temperature and 1.28 g (56.1%) of 3- (4- methoxy-benzyl) -l-oxa-3 , 8-diaza-spiro [4.5] decan-2 -one hydrochloride was collected, as a colorless solid, by filtration followed by trituration with diethyl ether.

¹H NMR (400 MHz, DMS0-d_s): δ [ppm] 8.91 (br S, 2H), 7.17 (d, 2H), 6.89 (d, 2H), 4.25 (s, 2H), 3.71 (s, 3H), 3.21 (s, 2H), 3.13 (m, 2H), 3.03 (m, 2H), 1.90 (m, 4H). Preparation 2

3 - ( 4 -Methoxy-benzyl ) - 1 , 3 , 8 - triaza - spiro [4 . 5 ] decan- 2 -one hydrochloride

Step 1: To 1 g (3.7 mmol) of 2 , 4-dioxo-l, 3, 8-triaza- spiro [4.5] decane-8-carboxylic acid tert-butyl ester were added successively 554 μL (4.08 mmol) of 4-methoxybenzyl chloride, 565 mg (4.08 mmol) of potassium carbonate and 37 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then 250 mL of water were added and a white precipitated solid was collected by filtration. This crude material was back washed with diethyl ether and dried under reduced pressure yielding 1.15 g (79%) of 3- (4-methoxybenzyl) -2, 4-dioxo-l, 3, 8- triazaspiro [4.5] decane-8-carboxylic acid fcert-butyl ester as a white solid.

1H NMR (400 MHz, CD₂Cl₂): δ [ppm] 7.27 (d, 2H), 6.85 (d, 2H), 6.16 (S, IH), 4.57 (s, 2H), 3.96 (m, 2H), 3.78 (S, 3H), 3.17 (m, 2H), 1.95 (m, 2H), 1.58 (m, 2H), 1.45 (s, 9H) . Step 2: To a solution of 3- (4-methoxybenzyl) -2, 4 -dioxo- 1 , 3 , 8-triaza-spiro [4.5] decane-8-carboxylic acid tert- butyl ester (920 mg, 2.36 mmol) in anhydrous THF (20 mL) was added lithium aluminium hydride in THF (IM in solution, 2.38 mL, 2.38 mmol) under nitrogen with cooling in an ice bath. The reaction mixture was then warmed to room temperature and agitated overnight. The reaction was quenched by cautious addition of wet THF and then the mixture concentrated to a small volume and partitioned between dilute hydrochloric acid (0.5 M aqueous, 50 mL) and ethyl acetate (50 mL) . The ethyl acetate layer was washed with water, dried over sodium sulphate and then concentrated to give 4-hydroxy-3- (4- methoxy-benzyl) -2-oxo-l , 3 , 8-triaza-spiro [4.5] decane-8- carboxylic acid tert-butyl ester as a colorless solid (836 mg, 90.5%) .

1H NMR (400 MHz, DMSO-dJ : δ [ppm] 7.13 (d, 2H), 7.12 (s, IH), 6.85 (d, 2H), 5.94 (d, IH), 4.17 (AB system, 2H), 4.40 (d, IH), 3.70 (S, 3H), 3.43 (m, 2H), 3.20 (m, 2H), 1.62 (m, IH), 1.44 (m, IH), 1.34 (s, 9H), 1.31 (m, 2H). Step 3: Crude compound from step 2 (450 mg, 1.15 mmol) was dissolved in 5 mL of formic acid and cooled to 0⁰C. To this solution was added sodium borohydride (177 mg, 4.6 mmol) in small portions over 5 minutes. The solution was allowed to warm to room temperature and then diluted with water and extracted with dichloromethane (50 mL) . The organic layer was washed with brine, water and dried over sodium sulfate to give after evaporation 147 mg (34.1%) of 3- (4-methoxy-benzyl) -2-oxo-l, 3 , 8-triaza- spiro [4.5] decane-8-carboxylic acid tert-butyl ester as a colorless solid.

¹H NMR (400 MHz, DMS0-d₆): δ [ppm] 7.10 (d, 2H), 6.98 (s, IH), 6.86 (d, 2H), 4.13 (s, 2H), 3.70 (s, 3H), 3.28 (m, 4H), 2.94 (S, 2H), 1.44 (m, 4H), 1.34 (s, 9H). Step 4: To 145 mg (0.38 mmol) of crude 3- (4-methoxy- benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester from step 3 was added 3 mL of 4N solution of dioxane/HCl. The reaction mixture was agitated 2 hours at room temperature and evaporated in vacuo. The crude was suspended in diethyl ether and the precipitate was collected after filtration to give 115.3 mg (97.4%) of 3- (4 -methoxy-benzyl) -1, 3 , 8-triaza- spiro [4.5] decan-2-one hydrochloride as a colorless solid. ¹H NMR (400 MHz, DMSOd₆) : δ [ppm] 8.83 (br S, 2H) , 7.24 (S, IH) , 7.11 (d, 2H) , 6.87 (d, 2H) , 4.14 (s, 2H) , 3.70 (S, 3H) , 3.08 (m, 4H) , 3.0 (s, 2H) , 1.70 (m, 4H) .

Preparation 3

2- (4-Methoxy-benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one dihydrochloride

Step 1: To 611 mg (2.71 mmol) of (4-methoxy-benzyl) - hydrazine dihydrochloride diluted in 10 mL of ethanol was added successively 750 μL (5.41 mmol) of triethylamine and 628 mg (2.46 mmol) of 4- methoxycarbonylmethylene-piperidine-l-carboxylic acid tert-butyl ester. The reaction mixture was refluxed for 48 hours and then evaporated in vacuo. The yellow crude was suspended in ethyl acetate (50 mL) and washed with brine, dried over sodium sulphate. The crude material was purified by flash chromatography on silica gel eluting with hexanes/ethyl acetate (100:0 to 0:100) and yielding 302 mg (32.7%) of 2- (4-methoxy-benzyl) -3-oxo- 1 , 2 , 8-triaza-spiro [4.5] decane-8-carboxylic acid tert- butyl ester as a yellowish solid.

1H NMR (400 MHz, DMSO-d₆) : δ [ppm] 7.16 (d, 2H), 6.85 (d, 2H), 5.43 (s, IH), 4.30 (s, 2H), 3.70 (s, 3H), 3.23 (m, 2H), 3.11 (m, 2H), 2.25 (s, 2H), 1.36 (m, 4H), 1.33 (s, 9H) .

Step 2: 300 mg (0.8 mmol) of 2- (4-methoxy-benzyl) -3-oxo- 1, 2 , 8-triaza-spiro [4.5] decane-8-carboxylic acid tert- butyl ester was diluted in 6 mL of methanol and 2 mL of concentrated aqueous hydrochloric acid. The reaction mixture was agitated overnight at room temperature and then evaporated in vacuo. The residue was suspended in diethyl ether and the precipitate was filtered off to give 220 mg (77%) of 2- (4-methoxy-benzyl) -1, 2 , 8-triaza- spiro [4.5] decan-3-one dihydrochloride as a brown solid. ¹H NMR (400 MHz, DMSO-Ci₆): δ [ppm] 8.89 (br d, 2H), 7.16 (d, 2H), 6.85 (d, 2H), 5.37 (br S, 2H), 4.32 (s, 2H), 3.70 (S, 3H), 2.90 (m, 4H), 2.34 (s, 2H), 1.64 (m, 4H).

Preparation 4

2- (4-Methoxy-benzyl) -2, 8-diaza-spiro [4.5] decane-1, 3- dione

To 1 g (2.64 mmol) of 8 ~benzyl-2- (4-methoxy-benzyl) -2, 8- diaza-spiro [4.5] decane-1, 3-dione dissolved in 30 mL of ethanol was added 1.66 g (26.4 mmol) of ammonium formate and 364 mg (0.26 mmol) of palladium hydroxide (20% wt on C) . The reaction mixture was refluxed for one hour and then allowed to cool before filtering over celite. The mother liquor was evaporated in vacuo to give access to 764 mg (100%) of 2- (4-methoxy-benzyl) -2, 8-diaza- spiro [4.5] decane-1, 3-dione as a pale yellow oil.

1H NMR (400 MHz, DMSO-d₆): δ [ppm] 7.11 (d, 2H), 6.84 (d, 2H), 4.43 (s, 2H), 3.68 (s, 3H), 2.82 (br d, 2H), 2.64 (S, 2H), 2.46 (m, 2H), 1.64 (m, 2H), 1.34 (br d, 2H).

Example 1. { (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l-oxa-3, 8- diaza-spiro [4.5] dec-8-yl] -1 -phenyl -propyl }-carbamic acid

tert -butyl ester

To a solution of 806 mg (2.58 mmol) of 3- (4-methoxy- benzyl) -l-oxa-3 , 8-diaza-spiro [4.5] decan-2-one

hydrochloride in 50 mL of anhydrous DCE were added successively 643 mg (2 58 mmol) of ( (S) -3 -oxo-1 -phenyl - propyl) -carbamic acid tert-butyl ester and 360 μL (2.58 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 860 mg (3.87 mmol) of sodium triacetoxyborohydπde . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated m vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0% to 2%) giving { (S) -3- [3- (4-methoxy- benzyl) -2-oxo- l-oxa-3 , 8-diaza-spiro [4.5] dec-8-yl] -1- phenyl -propyl} -carbamic acid tert-butyl ester as a white solid (922 mg, 70 4%) .

1H NMR (400 MHz, DMSO-d₆) . δ [ppm] 7.39 (d, IH), 7.26 (m, 4H), 7.16 (m, 3H), 6.89 (d, 2H), 4.48 (m, IH), 4.23 (s, 2H), 3.70 (s, 3H), 3.10 (s, 2H), 2.31 (m, 4H), 2 18 (m, 2H) , 1.70 (m, 6H) , 1.31 (s, 9H) . Example 2. 8- ( (S) -3-Amino-3 -phenyl-propyl) -3- (4-methoxy- benzyl) -l-oxa-3, 8-diaza-spiro [4.5] decan-2-one

To 895 mg (1.75 mmol) of { (S) -3- [3- (4 -methoxy-benzyl) -2- oxo-l-oxa-3 ,8-diaza-spiro[4.5]dec-8-yl] - 1 -phenyl - propyl} -carbamic acid tert-butyl ester was added 24 mL of a 20% TFA solution in DCM. The reaction mixture was agitated one hour at room temperature before neutralizing with 60 mL of an aqueous solution of sodium hydroxide (IN) . The solution was then extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo yielding 8- ( (S) -3 -amino- 3 -phenyl -propyl) -3- (4- methoxy-benzyl) -l-oxa-3 , 8-diaza-spiro [4.5] decan-2-one as a colorless oil (717 mg, 100%) .

¹H NMR (400 MHz, DMSO-d_e) : δ [ppm] 7.30-7.22 (m, 4H), 7.14 (m, 3H), 6.89 (d, 2H), 4.23 (s, 2H), 3.77 (m, IH), 3.70 (s, 3H), 3.09 (s, 2H), 2.38-2.16 (m, 8H), 1.66 (m, 6H).

Example 3. { (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l, 3, 8- triaza-spiro [4.5] dec-8-yl] -1-phenyl -propyl}-carbamic

acid tert-butyl ester

To a solution of 109 mg (0.35 mmol) of 3- (4-methoxy- benzyl) -1,3, 8-triaza-spiro [4.5] decan-2-one hydrochloride in 10 mL of anhydrous DCE were added successively 87.1 mg (0.35 mmol) of ( (S) -3-oxo-l-phenyl-propyl) -carbamic acid tert-butyl ester and 49 μL (0.35 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 117 mg (0.525 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0% to 4%) giving { (S) -3- [3- (4-methoxy-benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl } -carbamic acid tert-butyl ester as a white solid (104.6 mg, 58.7%).

¹H NMR (400 MHz, DMSO-d_s): δ [ppm] 7.38 (d, IH), 7.28- 7.14 (m, 5H), 7.10 (d, 2H), 6.86 (d, 2H), 6.78 (br S, IH), 4.46 (q, IH), 4.12 (s, 2H), 3.70 (s, 3H), 3.28 (m, 2H), 2.90 (s, 2H), 2.14 (m, 4H), 1.72 (m, 2H), 1.51 (m, 4H) , 1.31 (S, 9H) .

Example 4. 8- ( (S) -3 -Amino-3 -phenyl -propyl) -3- (4-methoxy- benzyl) -1,3, 8-triaza-spiro [4.5] decan-2-one

To 103 mg (0.2 mmol) of { (S) -3- [3- (4-methoxy-benzyl) -2- oxo-1, 3 , 8-triaza-spiro [4.5] dec-8-yl] -1 -phenyl -propyl} - carbamic acid tert-butyl ester was added 4 mL of a 20% TFA solution in DCM. The reaction mixture was agitated one hour at room temperature before neutralizing with 15 mL of an aqueous solution of sodium hydroxide (IN) . The solution was then extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo yielding 8- ((S) -3 -amino- 3 -phenyl -propyl) -3- (4-methoxy-benzyl) - 1 , 3 , 8-triaza-spiro [4.5] decan-2-one as a colorless oil (67.3 mg, 82.3%) . ¹H NMR (400 MHz, DMSO-d_s) : δ [ppm] 7.29-7.23 (m, 4H),

7.17-7.08 (m, 3H), 6.86 (d, 2H), 6.75 (br S, IH), 4.12

(S, 2H), 3.79 (br t, IH), 3.70 (s, 3H), 2.89 (s, 2H), 2.44 (m, 2H), 2.20-2.03 (m, 4H), 1.67-1.58 (m, 6H) .

Example 5. { (S) -3- [2- (4-Methoxy-benzyl) -3-oxo-l, 2 , 8- triaza-spiro [4.5] dec-8-yl] -1 -phenyl-propyl}-carbamic acid tert-butyl ester

To a solution of 220 mg (0.63 mmol) of 2- (4-methoxy- benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one

dihydrochloride in 12 mL of anhydrous DCE were added successively 157.5 mg (0.63 mmol) of ( (S) -3-oxo-l- phenyl -propyl ) -carbamic acid tert-butyl ester and 176 μL (1.26 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 209 mg (0.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0% to 6%) giving 269.6 mg (84.1%) of ((S)- 3- [2- (4-methoxy-benzyl) -3-oxo-l, 2 , 8-triaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a pale yellow oil.

¹H NMR (400 MHz, DMSO-d₆) : δ [ppm] 7.41 (d, IH), 7.27- 7.14 (m, 7H), 6.84 (d, 2H), 5.31 (s, IH), 4.46 (q, IH), 4.29 (S, 2H) , 3.69 (s, 3H) , 2.26 (m, 2H) , 2.20 (s, 2H) , 2.12 (m, 4H) , 1.68 (m, 2H) , 1.45 (m, 4H) , 1.31 (s, 9H) .

Example 6. 8- ( (S) - 3 -Amino-3 -phenyl-propyl) -2- (4-methoxy- benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one

To 247 mg (0.48 mmol) of { (S) -3- [2- (4-methoxy-benzyl) -3- oxo-1, 2 , 8-triaza-spiro [4.5] dec-8-yl] -1-phenyl-propyl} - carbamic acid tert-butyl ester was added 8 mL of a 20% TFA solution in DCM. The reaction mixture was agitated one hour at room temperature before neutralizing with 30 mL of an aqueous solution of sodium hydroxide (IN) . The solution was then extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo giving access to 180 mg (91.8%) of 8- ( (S) -3 -amino-3-phenyl-propyl) -2- (4-methoxy-benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one as a colorless oil .

¹H NMR (400 MHz, DMS0-d₆): δ [ppm] 7.24 (m, 4H), 7.15 (d, 3H), 6.84 (d, 2H), 5.29 (s, IH), 4.28 (s, 2H), 3.77 (br t, IH), 3.69 (s, 3H), 2.20 (m, 8H), 1.66-1.57 (m, 2H), 1.43 (m, 4H) .

Example 7. { (S) -3- [2- (4-Methoxy-benzyl) -1, 3-dioxo-2, 8- diaza-spiro [4.5] dec-8-yl] -1-phenyl-propyl) -carbamic acid tert-butyl ester

To a solution of 374 mg (1.29 mmol) of 2- (4-methoxy- benzyl) -2, 8-diaza-spiro [4.5] decane-1, 3-dione in 20 mL of anhydrous DCE was added 322 mg (1.29 mmol) of ((S) -3- oxo-1-phenyl -propyl) -carbamic acid tert-butyl ester. The reaction mixture was agitated at room temperature for 10 minutes before adding 432 mg (1.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0% to 3%) giving 466.9 mg (69.4%) of ((S)- 3- [2- (4-methoxy-benzyl) -1, 3-dioxo-2 , 8-diaza- spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a colorless solid.

¹H NMR (400 MHz, DMSOd₆): δ [ppm] 7.43 (d, IH), 7.26 (m, 4H), 7.18 (m, IH), 7.13 (d, 2H), 6.84 (d, 2H), 4.51 (q, IH), 4.44 (S, 2H), 3.69 (s, 3H), 2.70 (m, 2H), 2.60 (s, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.80-1.72 (m, 4H), 1.47 (d, 2H) , 1.33 (S, 9H) .

Example 8 . 8 - ( (S) - 3 -Amino - 3 -phenyl - propyl ) - 2 - ( 4 -methoxy- benzyl) - 2 , 8 -diaza-spiro [4 . 5] decane- 1 , 3 -dione

To 445 mg (0.85 mmol) of { (S) -3- [2- (4 -methoxy-benzyl) -

1, 3-dioxo-2 , 8-diaza-spiro [4.5] dec-8-yl] - 1-phenyl- propyl} -carbamic acid tert-butyl ester was added 15 mL of a 20% TFA solution in DCM. The reaction mixture was agitated one hour at room temperature before neutralizing with 50 mL of an aqueous solution of sodium hydroxide (IN). The solution was then extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo to give 275.3 mg (76.9%) of 8- ( (S) -3-amino-3- phenyl-propyl) -2- (4-methoxy-benzyl) -2 , 8-diaza- spiro [4.5] decane-1, 3-dione as.

¹H NMR (400 MHz, DMSO-d₆) : δ [ppm] 7.31-7.23 (m, 4H), 7.17-7.10 (m, 3H), 6.83 (d, 2H), 4.43 (s, 2H), 3.80 (br t, IH), 3.68 (S, 3H), 2.72 (d X d, 2H), 2.58 (s, 2H), 2.20 (m, 2H), 1.85-1.61 (m, 6H), 1.46 (br d, 2H).

Scheme 2 General procedure: the free amine 2-1 is condensed with preactivated carboxylic acid R₇COOH on polymeric 4- hydroxy-2 , 3 , 5 , 6-tetrafluorobenzamido (TFP) resin (see preparation in J. M. Salvino et al. J. Comb. Chem. 2000, 2, 691-697) in solvent such as DMF, or condensed with acid chloride R₇COCl in solvent such as DCM in presence of a base such as triethylamine or diisopropylethylamine, or condensed with a carboxylic acid R₇COOH in solvent such as DMF with coupling agents such as HOBt, DIC, HATU, BOP, PyBOP, to provide acylated compound 2-2.

Example 9. N-{ (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l-oxa-

3 , 8 -diaza- spiro [4 . 5] dec - 8 -yl] - 1 -phenyl -propyl } - isobutyramide hydrochloride

To 100 mg (100 μmol , loading of 1 mmol/g) of isopropylcarboxyl activated ester on polymeric 4- hydroxy-2, 3 , 5, 6-tetrafluorobenzamido (TFP) resin (see preparation in J. M. Salvino et al . J. Comb. Chem. 2000, 2, 691-697), preswollen with 0.5 mL of anhydrous DMF, was added mg (60 μmol) of 8- ( (S) - 3 -amino-3 -phenyl - propyl) -3- (4 -methoxy-benzyl) -l-oxa-3 , 8-diaza- spiro [4.5] decan-2-one dissolved in 1 mL of DMF. The reaction was agitated overnight at room temperature. The mixture was filtered and washed with DCM (2 x 2 mL) . The filtrates were collected and evaporated in vacuo. The crude mixture was purified by semi-preparative HPLC (method A) and 16.5 mg (53.3%) of N- { (S) -3- [3- (4- methoxy-benzyl) - 2 -oxo- l-oxa-3 , 8-diaza-spiro [4.5] dec- 8- yl] -1 -phenyl -propyl} -isobutyramide hydrochloride was isolated as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) : δ [ppm] 10.23 (br S, IH) , 8.27 (d, IH) , 7.32-7.15 (m, 7H) , 6.90 (d, 2H) , 4.82 (m, IH) , 4.26 (S, 2H) , 3.71 (s, 3H) , 3.40 (m, 2H) , 3.19 (s, 2H) , 3.01 (m, 4H) , 2.40 (Sept. , IH) , 2.13-1.99 (m, 6H) , 1.02- 0.92 (m, 6H) .

Table 1 of compounds illustrates some of the compounds of the present invention that could be synthesized using the procedure described in scheme 2.

Table 1.

STRUCTURE COMPOUND NAME MOLWT N-((S)-3-[3-(4-methoxy-benzyl)-2- oxo-1 -oxa-3,8-diaza-spiro[4.5]dec- 8-yl]- 1 -phenyl -propyl } -

isobutyramide hydrochloride 516.078

Cyclopropanecarboxylic acid ((S)- 3-[3-(4-methoxy-benzyl)-2-oxo-l - oxa-3,8-diaza-spiro[4.5]dec-8-yl]- 1 -phenyl-propyl } -amide

514.062 hydrochloride

4,4-Difluoro- cyclohexanecarboxylic acid {(S)-3- [3-(4-methoxy-benzyl)-2-oxo-l- oxa-3,8-diaza-spiro[4.5]dec-8-yl]- 592.123

1 -phenyl-propyl } -amide

hydrochloride N-{(S)-3-[2-(4-Methoxy-benzyl)-3- oxo-1 ,2,8-tri aza-spiro[4.5]dec-8- yl]- 1 -phenyl-propyl} -isobutyramide

di-hydrochloride 551.555

Cyclopropanecarboxylic acid ((S)- 3-[2-(4-methoxy-benzyl)-3-oxo- l ,2,8-triaza-spiro[4.5]dec-8-yl]-l - phenyl-propyl} -amide 549.539 dihydrochloride

4,4-Difluoro- cyclohexanecarboxylic acid {(S)-3- [2-(4-methoxy-benzyl)-3-oxo-l ,2,8- triaza-spiro[4.5]dec-8-yl]- 1 -phenyl- 627.6

propyl} -amide dihydrochloride

N-((S)-3-[2-(4-Methoxy-benzyl)- l ,3-dioxo-2,8-diaza-spiro[4.5]dec- 8 -yl] - 1 -phenyl-propyl } -

isobutyramide hydrochloride 528.089 Cyclopropanecarboxylic acid ((S)- 3-[2-(4-methoxy-benzyl)-l ,3-dioxo- 2,8-diaza-spiro[4.5]dec-8-yl]-l- phenyl-propyl} -amide ^ΌΪV.^{U I O} hydrochloride 4,4-Difluoro- cyclohexanecarboxylic acid {(S)-3- [2-(4-methoxy-benzyl)-l ,3-dioxo- 2,8-diaza-spirot4.5]dec-8-yl]-l- 604.134

phenyl-propyl} -amide

hydrochloride

N-{(S)-3-[3-(4-Methoxy-benzyl)-2- oxo-1 , 3,8-triaza-sρiro[4.5]dec-8- yl]- 1 -phenyl-propyl} -isobutyramide hydrochloride 515.094 Cyclopropanecarboxylic acid ((S)- 3-[3-(4-methoxy-benzyl)-2-oxo- l,3,8-triaza-spiro[4.5]dec-8-yl]-l- phenyl-propyl} -amide 513.078 hydrochloride 4,4-Difluoro- cyclohexanecarboxylic acid {(S)-3- [3-(4-methoxy-benzyl)-2-oxo-l ,3,8- triaza-spiro[4.5]dec-8-yl]-l-phenyl- 591 139

propyl} -amide hydrochloride

Scheme 3 General procedure: the free amine 2-1 is condensed with preactivated sulfonyl chloride R₇SO₂Cl on polymeric 4- hydroxy-2 , 3 , 5, 6-tetrafluorobenzatnido (TFP) resin (see preparation in J. M. Salvino et al . J. Comb. Chem. 2000, 2, 691-697) in solvent such as DMF, or with sulfonyl chloride R₇SO₂Cl in solvent such as DCM in presence of a base such as triethylamine or diisopropylethylamine to provide the sulphonamide 3-1.

R₇NCO

Scheme 4

General procedure: the free amine 2-1 is submitted to reaction with isocyanate in solvent such as THP, or condensed with carbamoyl chloride derivative or with cationic carbamoyl imidazolium intermediate 4-1 (see

R. A. Batey et al. Comb. Chem. High Throughput Screening

2002, 5, 219-232) in solvent such as DCM in presence of base such as triethylamine or diisopropylethylamine to provide the urea 4-2. x-

Scheme 5 General procedure: the free amine 2-1 is condensed with chloroformate or symmetric anhydride in solvents such as DCM or 1 , 2-dichloroethane in the presence of a base such as triethylamine or diisopropylethylamine to provide the carbamate 5-1.

Example 10.

Chemokine Binding assay: Membranes (lμg/well) from human embryonic kidney (HEK-293) cells expressing human CCR5 were incubated with 0.1 nM ¹²⁵I -labeled MIP- lα (Amersham) in the presence of varying concentrations of a test compound (10000-0.01 nM) in buffer (50 mM Hepes, pH 7.3/5 mM MgCl₂/l mM CaCl₂/0.5% BSA) for 90 min at room temperature. Reaction mixtures (100 μL) were filtered through Multiscreen GFB filters (Millipore) and washed six times with cold wash buffer (50 mM Hepes, pH 7.3/0.5 M NaCl, 0.1% BSA). Bound ¹²⁵I-MIP-Ia was quantitated by liquid scintillation counting. The nonspecific binding of ¹²⁵I- labeled MIP- lα to the membrane was determined based on the radioactivity from the wells added with 100 nM non-radiolabeled MIP- lα. IC₅₀ and K₀ values were calculated by using GRAPHPAD PRISM software (Intuitive Software for Science, San Diego) .

HIV-I Replication in PBMC Cultures. Isolated PBMC were stimulated in vitro with 5 μg/ml phytohemagglutinin and 50 units/ml IL-2 for 3 days. The cells were resuspended at 4 x 10⁶/ml in complete medium (RPMI, 10% FBS/50 units/ml IL-2) , seeded into 96-well plates (2 x 10⁵/well) , incubated with inhibitor for 1 h at 37°C, and infected in triplicate with 25-100 tissue culture 50% infective dose (TCID₅₀) per well of the R5 HIV-1_JR__FL strain for 3-4 h. The cells were washed twice in PBS to remove residual virus and cultured in the presence of inhibitor for 4-6 days. HIV-I replication was determined by the presence of viral RT activity in harvested supernatant fluid. The IC₅₀ values for the virus were determined by using GRAPHPAD PRISM software.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

We claim :

1. A compound represented by formula (I) :

(D or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein

R₁ is chosen from NR₈R₉,

(ID :III⁾

:iv) (V)

R₂ is chosen from optionally substituted C_{1 10} alkyl , optionally substituted C_{2 10} alkenyl (e.g. C_{2 6} alkenyl) , optionally substituted C_{2 10} alkynyl (e.g. C_{2 6} alkynyl) , optionally substituted C_6-12 aryl or optionally substituted 3 to 10 membered heterocycle;

R₃ is chosen from H, optionally substituted C₁-_X0 alkyl or optionally substituted C_{6 12} aryl;

R₄, R₅, R' ₅ and R"₅ are each independently chosen from H, optionally substituted C_{1 10} alkyl, optionally substituted C_{2 10} alkenyl (e.g. C₂-₆ alkenyl), optionally substituted C_2-10 alkynyl (e.g. C_{2 6} alkynyl), optionally substituted C_6-12 aryl, optionally substituted 3 to 10 membered heterocycle, optionally substituted C_{6 lz} aralkyl (e.g. C_{7 12} aralkyl) or optionally substituted heteroaralkyl (e.g., wherein the heteroaryl potion has 3 to 10 members and the alkyl portion has 1 to 6 carbon atoms) ; R₆ and R"₆ are each independently H, optionally substituted Ci ₁₀ alkyl (e.g. C_1-4 alkyl) , optionally substituted C₂ i₀ alkenyl (e.g. C₂_₄ alkenyl) , or optionally substituted C_{2 I0} alkynyl (e.g. C₂.₄ alkynyl) ;

R₇ is H, optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_{2 10} alkynyl, optionally substituted C_6-12 aryl, optionally substituted 3 to 10 membered heterocycle, optionally substituted C₆_₁₂ aralkyl (e.g. C_{7 12} aralkyl) or optionally substituted heteroaralkyl (e.g., wherein the heteroaryl potion has 3 to 10 members and the alkyl portion has 1 to 6 carbon atoms) , or R"₆ and R₇ can also be taken together to form an optionally substituted 3 to 10 membered heterocycle; and

R₈ and R₉ are each independently chosen from H or optionally substituted Ci ₁₀ alkyl.

2. The compound as defined in claim 1 wherein said compound is in the form of the R isomer.

3. The compound as defined in claim 1 wherein said compound is in the form of the S isomer.

4. The compound as defined in any one of claims 1 to 3 wherein R₂ is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from halogen, nitro, nitroso, SO₃R₆₂, PO₃R₆₅R₆₆, CONR₆₃R₆₄, C^₆ alkyl, C₂.₆ alkenyl, C_{2 6} alkynyl, C_{7 12} aralkyl, C₆_₁₂ aryl, C_1-6 alkyloxy, C_{2 6} alkenyloxy, C₂. 6 alkynyloxy, C_6-12 aryloxy, C(O)C_1-6 alkyl, C(O)C_{2 6} alkenyl, C(O)C_{2 6} alkynyl, C(O)C_6-12 aryl, C(O)C_{7 12} aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl , hydroxyl, NR₆₃R₆₄, C(O)OR₆₂/ cyano, azido, amidmo and guanido,

wherein R₆₂, R₆₅, R₆₆, R₆₃ and R₆₄ are each independently chosen from H, C_{1 12} alkyl, C_{2 12} alkenyl, C_{2 12} alkynyl, C₆ i₂ aryl , 3-10 member heterocycle, 4-16 member heteroaralkyl, C_{7 18} aralkyl,

or R₆₅ and R₆₆ are taken together with the oxygen atoms to form a 5 to 10 member heterocycle,

or R₆₃ and R₆₄ are taken together with the nitrogen atom to form a 3 to 10 member heterocycle The compound of claim 4 wherein R₂ is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from a halogen, Ci ₆ alkyl, C_{1 6} alkyloxy, CF₃, COOH, COOC_{1 6} alkyl, cyano, NH₂, nitro, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂ and a 3-8 member heterocycle The compound as defined in any one of claims 1 to 5 wherein R₁ is chosen from

(ID (III)

(IV) (V)

Wherein:

R₆ is H; and

R₇ is cyclohexyl, cyclopentyl or cyclobutyl unsubstituted or substituted by one or more substituents independently chosen from halogen, nitro, nitroso, SO₃Rf, SO₂Rf, PO₃R₆₅R₆₆, CONRgRh, C_{1 6} alkyl , C_{7 I8} aralkyl, C₆.u aryl, Ci_-6 alkyloxy, C_{6 12} aryloxy, C(O)C₁-_S alkyl, C(O)C₆.₁₂ aryl, C(O)C_{7 12} aralkyl, C(O)NHRf, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl , oxo, oxime, NRgRh, C(O)ORf, cyano, azido, amidino and guanido ;

wherein Rf, R₆₅, R₆₆, Rg and Rh in each case are independently H, Ci_-6 alkyl, C_2-6 alkenyl ,

C_{2 6} alkynyl, C_{6 12} aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, or C_{7 I8} aralkyl .

7. The compound according to claim 8 wherein R₄ is C₁. i₂ alkyl, C_6-12 aryl, C_{7 12} aralkyl, 3 to 10 membered heterocycle or optionally substituted which are unsubstituted or substituted by one or more substituents chosen from a halogen, C_1-6 alkyl, Ci_-6 alkyloxy, CF₃, COOH, COOC_{1 6} alkyl, cyano, NH₂, nitro, NH(C₁-_S alkyl), N(C_{1 6} alkyl) ₂ and a 3-8 member heterocycle.

8. The compound according to claim 8 wherein R₄ is phenyl or benzyl which are unsubstituted or substituted by one or more substituents chosen from halogen, nitro, CONR₆₃R₆₄, C_1-6 alkyl, C₂-₆ alkenyl, C_1-6 alkyloxy, C_{2 6} alkenyloxy, C₂-₆ alkynyloxy, C_G_₁₂ aryl, 3-10 member heterocycle, 4- 16 member heteroaralkyl, hydroxyl, NR₆₃R₆₄, C(O)OR₆₂, cyano, and azido;

wherein R₆₂, R₆₃ and R₆₄ are each independently chosen from H, C_1-12 alkyl, C_6-12 aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C_7-18 aralkyl,

or R₆₃ and R₆₄ are taken together with the nitrogen to form a 3 to 10 member heterocycle .

9. The compound according to claim 8 wherein R₄ is phenyl or benzyl which are unsubstituted or substituted by one or more substituents chosen from halogen, C_1-6 alkyl, NR₆₃R₆₄, nitro, CONR₆₃R₆₄, C_1-6 alkyloxy, C(O)OR₆₂, cyano, and azido;

wherein R₆₂, R₆₃ and R₆₄ are each independently chosen from H, C_{1 12} alkyl, C_{6 12} aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C_7-18 aralkyl ;

or R₆₃ and R₆₄ are taken together with the nitrogen to form a 3 to 10 member heterocycle .

10. The compound according to claim 8 wherein R₄ is benzyl unsubstituted or substituted by one or more substituents chosen from halogen, C_1-3 alkoxy, SO₂C₁_₃alkyl , difluoromethoxy, trifluoromethoxy, trifluoromethyl , CN and pyrazoyl .

11. A compound selected from

{ (S) -3- [3- (4-Methoxy-benzyl) -2 -oxo-l-oxa-3 , 8-diaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl} -carbamic acid tert-butyl ester

8- ( (S) -3 -Amino- 3 -phenyl -propyl) -3- (4-methoxy- benzyl) -l-oxa-3 ,8-diaza-spiro[4.5] decan-2-one

{ (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l, 3, 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl} -carbamic acid tert-butyl ester

8- ( (S) -3 -Amino- 3 -phenyl-propyl) -3- (4-methoxy- benzyl) - 1, 3, 8-triaza-spiro[4.5] decan-2-one

{ (S) -3- [2- (4-Methoxy-benzyl) -3-oxo-l,2, 8-triaza- spiro [4.5] dec-8-yl] - 1-phenyl-propyl} -carbamic acid tert-butyl ester

8- ( (S) -3 -Amino- 3 -phenyl-propyl) -2- (4-methoxy- benzyl) -l,2,8-triaza-spiro[4.5] decan-3 -one

{ (S) -3- [2- (4-Methoxy-benzyl) -1, 3-dioxo-2, 8-diaza- spiro [4.5] dec-8 -yl] -1-phenyl -propyl } -carbamic acid tert-butyl ester

8- ( (S) -3 -Amino-3 -phenyl -propyl) -2- (4-methoxy- benzyl) -2,8-diaza-spiro[4.5] decane-1, 3 -dione

N-.{ (S) -3- [3- (4-methoxy-benzyl) -2 -oxo-l-oxa-3 , 8- diaza-spiro [4.5] dec-8-yl] -1 -phenyl -propyl} - isobutyramide hydrochloride Cyclopropanecarboxylic acid { (S) -3 - [3 - (4-methoxy- benzyl) -2-oxo-l-oxa-3 ,8-diaza-spiro[4.5]dec-8-yl] - 1 -phenyl -propyl } -amide hydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [3- (4-methoxy-benzyl) -2 -oxo-l-oxa-3 , 8 -diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl } -amide

hydrochloride

N- { (S) -3- [2- (4-Methoxy-benzyl) -3-oxo-l, 2, 8-triaza- spiro [4.5] dec-8-yl] -1-phenyl -propyl} -isobutyramide di -hydrochloride

Cyclopropanecarboxylic acid { (S) -3- [2- (4-methoxy- benzyl) -3-oxo-l, 2,8-triaza-spiro[4.5]dec-8-yl]-l- phenyl -propyl } -amide dihydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [2- (4 -methoxy-benzyl) -3-oxo-l ,2,8-triaza- spiro [4.5] dec-8-yl] - 1-phenyl -propyl} -amide

dihydrochloride

N- { (S) -3- [2- (4-Methoxy-benzyl) -1 , 3 -dioxo-2 , 8 -diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl } -isobutyramide hydrochloride

Cyclopropanecarboxylic acid { (S) -3 - [2- (4-methoxy- benzyl) -1, 3 -dioxo-2 ,8-diaza-spiro[4.5]dec-8-yl] -1- phenyl -propyl } -amide hydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [2- (4-methoxy-benzyl) -1,3 -dioxo-2 , 8-diaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl } -amide

hydrochloride

N- { (S) -3- [3- (4-Methoxy-benzyl) -2-oxo-l, 3, 8-triaza- spiro [4.5] dec-8-yl] - 1-phenyl-propyl} -isobutyramide hydrochloride

Cyclopropanecarboxylic acid { (S) -3 - [3- (4 -methoxy- benzyl) -2-oxo-l, 3,8-triaza-spiro[4.5] dec-8 -yl] -1- phenyl -propyl } -amide hydrochloride

4 , 4-Difluoro-cyclohexanecarboxylic acid { (S) -3- [3- (4 -methoxy-benzyl) -2-oxo-l, 3,8-triaza- spiro [4.5] dec-8 -yl] -1-phenyl -propyl} -amide

hydrochloride

or pharmaceutically acceptable salts, hydrates or solvates thereof .

12. A method of modulating chemokine receptor activity in a subject comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 11.

13. A method for prevention or treatment of certain inflammatory diseases, immunoregulatory diseases, organ transplantation reactions and in the prevention and treatment of infectious diseases such as HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 11. 14. A method for the prevention or treatment of diseases associated with the modulation of CCR5 chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound a compound according to any one of claims 1 to 11.

15. A method for blocking cellular entry of HIV in a subject comprising administering to the subject in need thereof an effective amount of a compound according to any one of claims 1 to 11 to block HIV from cellular entry in said subject.

16. A method for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound according to any one of claims 1 to 11 and at least one further therapeutic agent .

17. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 11 in combination with a pharmaceutically acceptable carrier or excipient .

18. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity. 19. A combination useful for the prevention or treatment of diseases associated with the modulation of chemokine receptor activity which comprises a therapeutically effective amount of a compound as defined in any one of claims 1 to 11 and therapeutically effective amount of at least one further therapeutic agent.

20. The pharmaceutical combination of claim 19 wherein said combination comprises at least one other antiviral agent chosen from 3TC (lamivudine, Epivir^®) , AZT (zidovudine, Retrovir^®) , Emtricitabine (Coviracil^®, formerly FTC) , d4T (2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydro-thymidine,

stavudine and Zerit^®) , tenofovir (Viread^®) , 2 ',3'- dideoxyinosine (ddl, didanosine, Videx^®) , 2',3^T- dideoxycytidine (ddC, zalcitabine, Hivid^®) , Combivir^® (AZT/3TC or zidovudine/lamivudine combination) , Trivizir^® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination) , abacavir (1592U89, Ziagen^®) , SPD-754, ACH-126,443 (Beta-L-Fd4C) , Alovudine (MIV-310) , DAPD (amdoxovir) , Racivir, 9- [ (2-hydroxymethyl) -1, 3- dioxolan-4-yl] guanine , 2-aτnino-9- [ (2- hydroxymethyl) -1, 3 -dioxolan-4-yl] adenine

Nevirapine (Viramune^®, NVP, BI-RG-587) , delavirdine (Rescriptor^®, DLV) , efavirenz (DMP 266, Sustiva^®) , (+) -Calanolide A, Capravirine (AG1549, formerly S-1153) , DPC083, MIV-150, TMC120, TMC125 or BHAP (delavirdine), calanolides, L-697,661 (2-Pyridinone

3benzoxazolMeNH derivative nelfinavir (Viracept^®, NFV), amprenavir (141W94, Agenerase^®) , indinavir (MK-639, IDV, Crixivan^®) , saquinavir (Invirase^®, Fortovase^®, SQV) , ritonavir (Norvir^®, RTV) , lopinavir (ABT-378, Kaletra^®) , Atazanavir (BMS232632) , mozenavir (DMP-450) , fosamprenavir (GW433908) , RO033-4649, Tipranavir (PNU-140690) , TMC114, VX-385, T-20 (enfuvirtide , Fuzeon") , T- 1249, Schering C (SCH-C), Schering D (SCH-D), FP21399, PRO-140, PRO 542, PRO 452, TNX-355, GW873140 (AK602) , TAK-220, TAK-652, UK-427,857 or soluble CD4 , CD4 fragments, CD4 -hybrid molecules, BMS-806, BMS-488043, AMD3100, AMD070, KRH-2731, S- 1360, L-870,810, L-870,812, JTK-303, C-2507, maturation inhibitor, zinc finger inhibitor, antisense drug, interleukin-2 (IL- 2, Aldesleukin, Proleukin) , granulocyte macrophage colony stimulating factor (GM-CSF) , erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-I Immunogen (Remune) , EP HIV- 1090, 2 ' , 3 ' -dideoxyadenosine, 3'- deoxythymidine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' - didehydrocytidine, ribavirin, acyclic nucleosides (such as acyclovir or ganciclovir) ; interferons (such as alpha-, beta-and gamma- interferon) , glucuronation inhibitors (such as probenecid) TIBO drugs, HEPT, or TSAO derivatives.