WO2011060395A1 - Cyclic ureas useful as hiv inhibitors - Google Patents

Abstract

The present invention relates to a compound having the general Formula (I), wherein the variables are as defined in the specification. The present invention further relates to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular for the treatment or prevention of chemokine-mediated disorders such as HIV infection.

Description

CYCLIC UREAS USEFUL AS HIV INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims reference to U.S. Application No. 61/261 ,600, filed on November 16, 2009.

FIELD OF THE INVENTION;

The present invention relates to compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular for the blocking of HTV, or in treatment or prevention of inflammatory and immune disorders such as HIV infection.

BACKGROUND OF THE INVENTION:

Chemotaxis is a phenomenon in which movement of cells is directed by extracellular gradients of chemoattractant cytokines called chemokines (Jin et al., Eur. J. Cell Biol. 85, 905-913 (2006)). Chemotaxis plays critical roles in diverse physiological processes, including the initiation and maintenance of inflammation, trafficking of lymphocytes in the human body, and neuronal cell patterning in the development of the nervous system. More than 50 chemokines have been identified and classified in a family of small proteins (70 - 90 amino acids) that share conserved N-terminal cysteine motifs (Murphy, Pharmacol. Rev. 54, 227-229 (2002)).

Chemokines are further classified according to the number and spacing of cysteines in these motifs into C, CC, CXC and CX subfamilies. Most chemokines can also be classified as inflammatory or homeostatic (Moser et al., Nat. Immunol. 2, 123-128 (2001 )). Inflammatory chemokines are produced in response to pathological conditions, whereas homeostatic chemokines are involved in normal 'housekeeping' functions such as the maturation of leukocytes in the bone marrow.

The cellular receptors for chemokines are a subfamily of G-protein-coupled receptors (GPCRs). Receptor binding of chemokines results in the activation of associated heterotrimeric G-proteins, which stimulates a signaling cascade resulting in chemotaxis. To date 18 chemokine receptors have been identified and are responsible for the effects of the more than 50 known chemokines (Murphy, Pharmacol. Rev. 54, 227-229 (2002)).

Two chemokine receptors CCR5 and CXCR4 have been shown to play essential roles in HIV infection (Alkhatib et al, Science 272, 1 55-1958 (1996), Feng et al., Science 272, 872-877 (1996)). CCR5 normally functions in the inflammatory response to infection, and has 3 natural chemokine binding partners, CCL3 (MIP-1 alpha), CCL4 (MlP-lbeta) and CCL5 (RANTES) (Samson et al, Biochemistry 35, 3362-3367 (1 96)). CCR5 function appears to be redundant as individuals that lack CCR5 do not have any apparent immunological defects (Liu et al., Cell 86, 367-377(1996)). CXCR4 carries out essential roles in B-cell homeostasis, organ development and angiogenesis. To date CXCR4 has been shown to interact with only one chemokine CXCL12 (SDF- 1 ) (Bleul et al., 1996, Oberlin et al., 1996)). Short-term disruption of CXCL12 induced CXCR4 receptor function in humans by AMD3100 induces release of heamatopoetic stem cells and leukocytes from the bone marrow (Flomenberg et al., Blood 106, 1867- 1874 (2005)). CXCR4 or CXCL2 knock-out mice have severe defects in organ vascularization, cardiogenesis and CNS development and die in utero (Zou et al., Nature, 393, 595-599 (1998); Tachibana et al, Nature 393, 591-594 (1998)).

Entry of HIV into target cells is mediated by protein-protein interactions between the viral spikes on the surface of HIV particles and specific receptors on the membranes of T cells or macrophages. HIV spikes consist of a trimer of heterodimers made up of one molecule of the viral g l20 envelope antigen non-covalently attached to a molecule of the gp41 transmembrane glycoprotein. The primary receptor used by HIV for entry is CD4, which is expressed on the surface of a number of cell types that function in the immune system including T helper cells and macrophages. CCR5 or CXCR4 are used as secondary receptors in the infection process and the preferential use of either CCR5 or CXCR4 by HIV strains is used to define HIV tropism (Wilkin et al, Clin. Infect. Dis. 44, 591-595 (2007)).

HIV cellular tropism was originally classified as T-cell line tropic (T-tropic) or macrophage tropic, based on the type of cells a virus was capable of infecting. It is now clear that viral tropism can be explained by differential expression of CCR5 and CXCR4 in these cell types. Currently, viral tropism is defined as the preference of virus to mediate infection via either CCR5 alone (R5-tropic) or CXCR4 alone (X4- tropic). In addition, examples of dual tropic R5/X4 viruses that can use both CCR5 and CXCR4 have been reported. However, dual tropic viruses are relatively rare and may represent transitional viruses that are evolving from CCR5 to CXCR4 tropism.

R5-tropic viruses are largely responsible for viral transmission and predominate in the early stages of the disease, but as HIV infection progresses X4-tropic viruses emerge in about 50% of patients. The majority of these patients are infected with a mixture of R5-tropic and X4-t.ropic and only about 2 percent are infected with X4- tropic virus exclusively. The emergence of X4 virus is often associated increased loss of CD4 cells and progression to AIDS, however it is not known if X4-tropic viruses are the cause or consequence of disease progression.

Various steps in the HIV infection such as CD4 binding, CXCR4 and CCR5 coreceptor binding and membrane fusion represent viable targets for drug intervention. A number of inhibitors that target viral entry have been developed and progressed into the clinic. Two of these enfuviritide (T-20, Fuzeon) and maraviroc (Selezentry) have been approved for treatment of HIV infected subjects. Enfuviritide is a 36 residue peptide mimic of the HR2 domain of gp41 (Wild ei al., Proc. Nat. Acad. Sci. USA 91, 9770-9774 (1994)). Fuzeon binds to the HR1 region of gp41 to prevent formation of the 6-helical bundle and fusion of the viral and cellular membranes. Maraviroc is a member of a class of small molecule CCRS antagonists that inhibit receptor function and gpl20 binding (Westby el al., J. Virol. 80, 4909-4920 (2006)). Maraviroc and two other CCRS antagonists vicriviroc (Strizki et al., Antimicrob. Agents Chemother. 49, 491 1 -491 )) and aplaviroc do not directly compete with gpl20 for binding, but instead function as allosteric inhibitors that stabilize a confirmation of CCRS that is unfavorable for gpl 20 binding.

CXCR4 has also been targeted for antiviral therapy and several small molecule antagonists including, AMD3100, AMD070, KRH 1636 and KRH 3140 have been shown to have potent anti-viral activity in vitro. AMD3100 has been tested in clinical trials that provided proof-of-concept for antagonism of CXCR4 as a treatment for HIV (Hendrix et al., J. Acquir. Immune Defic. Syndr. 37, 1253-1262 (2004)). However, the unfavorable side effects of blocking CXCR4 receptor function have thus far limited the clinical development of CXCR4 antagonists for the HIV indication. This has prompted the need for novel CXCR4 antagonists for use as HIV inhibitors which block viral entry with pharmacologically acceptable abrogation of the signal transduction pathways activated following the CXCL12-CXCR4 interaction.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula I

wherein:

ring A comprising X¹, X², and the -C(=0) group as shown is a five- or six- membered ring, wherein when ring A has substituents on adjacent carbon atoms, said substituents can be taken together with the carbon atoms to which they are attached to form an aryl, cycloalkyl, heterocyclyl or heteroaryl ring;

X¹ and X² independently are N or S;

R1 is selected from the group consisting of:

and wherein:

each R independently is H or alkyl;

each R² and R^2' is independently H, alkyl or cycloalkyl, or R² and R^2' together with the carbon or carbons to which they are shown bonded in formula 1 form a cycloalkyl;

a is an integer from 1 -3;

R3 is selected from the group consisting of H, alkyl, cycloalkyl, heteroacyclyl, aryl, and heteroaryl;

x is 0, 1 , or 2;

each R5 independently is alkyl; is 0, l, or 2;

each R6 independently is alkyl;

each Al ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1-3 N atoms;

each A2 ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1 -3 N atoms;

c is 1, 2, or 3;

Y1 and Y2 independently are C(R) or N;

d is 0, 1, or 2;

Z' is O or S;

Z2 is CR or N;

R7 is -NR2; and

R8 is selected from the group consisting of H, alkyl, -C(= R)-NR2, and a five- or six-membered heteroaryl whose ring atom heteroatoms consist only of 1 -3 N atoms.

The present invention also provides pharmaceutical compositions and kits comprising the aforesaid compounds of Formula I, and methods of treating or preventing chemokine-mediated disorders such as HIV utilizing the aforesaid compounds of formula I. DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, in formula I, X¹ and X² are both N.

In another embodiment, in formula I, substituents on adjacent carbon atoms of ring A together with the carbon atoms to which they are attached form an aryl ring.

In another embodiment, in formula I, substituents on adjacent carbon atoms of ring A together with the carbon atoms to which they are attached form an aryl ring, wherein said aryl ring is phenyl.

In another embodiment, in formula I, ring A optionally with said aryl is selected from the group consisting of:

In another embodiment, in formula I, R is

In another embodiment, in formula I, R is

, wherein ring Al is a six-membered heterocyclyl.

In another embodiment, in formula I, R1 is

, wherein ring A 1 is piperidinyl.

In another embodiment, in formula I, R1 is

, wherein x and y are both 0.

In another embodiment, in formula I, R1 is

In another embodiment, in formula I, R² and R^2' are both H, and a is 2.

In another embodiment, in formula I, R3 is selected from the group consisting of H and aryl.

In another embodiment, in formula I, R3 aryl is phenyl which is unsubstituted or substituted with at least one halo.

In another embodiment, the compound in formula I is selected from the group consisting of;

and

or a pharmaceutically acceptable salt or solvate thereof.

As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Patient" includes both human and animals.

"Mammal" means humans and other mammalian animals.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., = -OH), - NH(alkyl),

-NH(cycloalkyl), -N(alkyl)2, -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -SF₅, carboxy and -C(0)0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.

"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about. 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl. 1,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- ajpyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,

benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrol opyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4- triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl,

tetrahydroquinolyl and the like.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non- limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl, The bond to the parent moiety is through the aryl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.

"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohept.a-l ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.

"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

"Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroaryl alkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,

alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -SF₅, -OSF₅ (for aryl), -O-C(O)- alkyl, -O-C(O-)aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH₂, -C(=NH)-NH₂, -C(=NH)- NH(alkyl), oxime (e.g., =N-OH), -NY₁Y₂, -alkyl-NY₁Y₂, -C(0)NY₁Y₂, -SO₂NY₁Y₂ and -SO₂NY₁Y₂, wherein Y₁ And Y₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, - C(CH₃)₂- and the like which form moieties such as, for example:

"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" also includes heterocyclyl rings as described above wherein =0 replaces two available hydrogens on the same ring carbon atom. Example of such moiety is pyrrolidone:

"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.

"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2- dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofliranyl, 7- oxabicyclo[2.2.1]heptenyl, di ydrothiophenyl, dihydrothiopyranyl, and the like.

"Heterocyclenyl" also includes heterocyclenyl rings as described above wherein =0 replaces two available hydrogens on the same ring carbon atom. Example of such moiety is pyrrolidinone:

"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention.

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin- 3-ylmethyl. The bond to the parent moiety is through the alkyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an H-C(O)-, alkyl-C(0)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described, The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent, moiety is through the ether oxygen,

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl -O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S(02)- group. Preferred groups are those in which the alky] group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

"Aiylsulfonyl" means an aryl-S(02)- group. The bond to the parent moiety is through the sulfonyl.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

The present invention further includes the compound of formula I in all its isolated forms. Thus, for example, the compound of Formula I is intended to encompass all forms of the compound such as, for example, any solvates, hydrates, stereoisomers, tautomers etc.

The present invention further includes the compound of formula I in its purified form.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. And any one or more of these hydrogen atoms can be deuterium.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1 91), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cg)alkyl, (C2- Ci2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,

alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N-

(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1- C2)alkylcarbamoyl-(Cl-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-CsJalkanoyloxvmethyl, l-((Cj- C6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1-CeJalkanoyloxyJethyl, (C1- CeJalkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (Cp Cejalkanoyl, cc-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or c -aminoacyl-a- aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a

carbohydrate), and the like.

If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl,— C(OH)C(0)OYJ wherein Y1 is H, (C1-C6)alkyl or benzyl,— C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-Cfi)alkyl, amino(C1-C4)alkyl or mono-N— or di-N,N-(C1-C6)alkylaminoalkyl,— C(Y )YS wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(C1-C6)alkylamino morpholino. piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sc , 930}, 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar

preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1}, article 12 (2004); and A. L. Bingham et al> Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula 1 with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,

camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfbnates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 31 201-217; Anderson et al, The Practice of Medicinal Chemistry (1 96), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, CMalkyl, or Ci^alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example,

methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoIeucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1.20 alcohol or reactive derivative thereof, or by a 2,3-di (C6.24)acyl glycerol. Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a

diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶C1 and ¹²³I, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays.

Tritiated (i.e., 3H) and carbon- 14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like UC or ¹⁸F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like ¹²³I can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-li e or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half lives (Tl/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.

In a further aspect, the compounds of the present invention are useful in therapy. In particular, the compounds of the present invention are useful in therapy in humans or animals. As such, the compounds of the present invention are useful in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by chemokines. In particular, the compounds of the present invention are useful in the manufacture of a medicament for the treatment or prevention of inflammatory or immune diseases selected from neurodegenerative diseases, multiple sclerosis, systemic lupus, erythematosis, rheumatoid arthritis, ankylosing, spondylitis, psoriatic arthritis, juvenile rheumatoid arthritis, atherosclerosis, vasculitis, chronic heart failure, cerebrovascular ischemia, encephalitis, meningitis, hepatitis, nephritis, glomerulonephritis, sepsis, sarcoidosis, psoriasis, eczema, urticaria, type 1 diabetes, asthma, conjunctivitis, ophthalmic inflammation, otitis, allergic rhinitis, chronic obstructive pulmonary disease, sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis, Chron's disease. Behcet's syndrome, pulmonary fibrosis,

endometriosis, gout and cachexia.

The compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of cancer. The compounds of the present invention are therefore useful for the manufacture of a medicament for the treatment or prevention of solid tumors and hemoatopoietic tumors associated with breast cancer, renal cancer, non-small cell lung cancer, non-hodgkins lymphoma, metastasis melanoma or leukemia.

The compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of a viral or bacterial infection. The compounds of the present invention are also useful for the manufacture of a

medicament for the treatment or prevention of HIV infection. The compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allegies, and multiple sclerosis. The present invention also includes a compound, for use in the treatment of any of the aforementioned diseases or disorders.

The present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from any of the aforementioned diseases or disorders, which method comprises administering an effective amount of a tricyclic compound according to the present invention or a pharmaceutically acceptable salt or solvate thereof. Such a method of treatment may be oral, intravenous or subcutaneous. In a further embodiment, is a method of inhibiting the replication of

Human Immunodeficiency Virus, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds according to the present invention. Such a method of treatment may be oral, nasal, intravenous or subcutaneous, or other similar suitable method.

The amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

A suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day. The desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.

Whilst it is possible for the active ingredient to be administered alone, it is preferable to present it as a formulation. The present invention therefore also provides a composition comprising a compound according to the present invention in admixture with one or more acceptable excipients. In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound according to the present invention in admixture with one or more pharmaceutically acceptable excipients, such as the ones described in Gennaro et. al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing. The term "acceptable" means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Suitable excipients are described e.g., in the Handbook of

Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P.J.Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1 94.

Compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration or other suitable method.

The mixtures of a compound according to the present invention and one or more pharmaceutically acceptable excipient or excipients may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds of the present invention can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal or buccal spray. For making dosage units e.g., tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive can be used. The compounds of the present invention are also suitable for use in an implant, a patch, a gel or any other preparation for immediate and/or sustained release,

Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in suitable amounts, For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions ma be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.

The present invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.

In a further aspect, the present invention provides a phannaceutical

composition, as hereinbefore described, additionally comprising one or more anti-viral or other agents useful in the treatment of Human Immuno-deficiency Virus. Such antiviral or other agents are well known in the art and include, but are not limited to: CCR5 antagonists (HIV entry inhibitor), nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and other antiviral agents listed below not falling within these classifications. The antiviral agent or agents may be combined with the presently claimed compounds that are CXCR4 antagonists in a single dosage form, or the CXCR4 antagonist and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms.

In particular, the combinations known as HAART (Highly Active

Antiretroviral Therapy) are contemplated for use in combination with the CXCR4 antagonists of this invention or with the combination of the CXCR4 antagonists and CCR5 receptor antagonists.

The term "CCR5 antagonist" as used herein refers to CCR5 receptor antagonists that are well known those of ordinary skill in the art. Suitable CCR5 antagonists include Vicriviroc (Phase III, Schering-Plough), and Maraviroc (Selzentry; marketed by Pfizer).

The term "nucleoside and nucleotide reverse transcriptase inhibitors" ("NRTI" s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV- 1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA.

Typical suitable NRTIs include zidovudine (AZT) available under the

RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, NC 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, NJ 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, NJ 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, J 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, NC 27709; abacavir (1.592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo-Wellcome Research Triangle, NC 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, CA 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb, Princeton, NJ 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH- 1061 ) under development by Biochem Pharnia, Laval, Quebec H7V, 4A7, Canada; emitricitabine [(-)-FTC] licensed from Emory University under Emory Univ. U.S. Patent No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, NC 27707; beta-L-FD4 (also called beta-L-D4C and named beta-L-2', 3'-dideoxy-5- fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven CT 0651 1 ; DAPD, the purine nucleoside, (-)-beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, NC 27707; and lodenosine (FddA), 9- (2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, a acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, PA 19428.

The term "non-nucleoside reverse transcriptase inhibitors" ("NNRTP's) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase.

Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, OH 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co., Bridgewater NJ 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, DE 19880-0723; PNU-142721 , a fiiropyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater NJ 08807; AG- 1549 (formerly Shionogi # S- 1 153); 5-(3,5-dichlorophenyl)- thio-4-isopropyl-1-(4-pyridyl)methyl-IH-imidazol-2- ylmethyl carbonate disclosed in WO 96 /10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; M C-442 (l-(ethoxy- memyl)-5-(l-methyle1hyl)-6- 5henylmethyl)-(2,4(1H^H)-pyi-imidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, NC 27707; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Patent No. 5,489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-Invest as an orally administrable product.

The term "protease inhibitor" ("PI") as used herein means inhibitors of the HIV- 1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN® (available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT® (available from Agouron).

Typical suitable Pis include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE® tradename and as soft gel capsules under the

FORTOUASE® tradename from Roche Pharmaceuticals, Nutley, NJ 071 10- 1199; ritonavir (ABT-538) available under the NORVIR® tradename from Abbott

Laboratories, Abbott Park, IL 60064; indinavir (MK-639) available under the

CRIXIVAN® tradename from Merck & Co., Inc., West Point, PA 19486-0004;

nelfnavir (AG- 1343) available under the VIRACEPT® tradename from Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; amprenavir (141 W94), tradename AGENERASE®, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, MA 02139-421 1 and available from Glaxo- Wellcome, Research Triangle, NC under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, NJ 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS- 2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, NJ 08543, as a 2nd -generation HIV-1 PI; ABT-378 under development by Abbott , Abbott Park, IL 60064; and AG- 1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1 153) and under development by Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Hydroxyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268 , Takeda EP-0176299, and Chiron U. S. Patent Nos. RE 33653, 4530787, 4569790, 4604377, 4748234, 752585, and 4949314 is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, CA 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in W096/25171 and is available from Roche

Pharmaceuticals, Nutley, NJ 07110-1 199 and American Home Products, Madison, NJ 07940; a dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide,disclosed in U.S. Patent No.5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg /day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI's to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 1 1607, a synthetic protein based on the HIV -1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042 , Israel. Ribavirin, l-B-D-ribofuranosyl-1H-1,2,4-triazole-3- carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, CA; its manufacture and formulation are described in U.S. Patent No. 4,21 1,771. The term "anti-HIV-1 therapy" as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part, of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HTV-l drugs selected from two NRTls, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from , NNRTIs and Pis. Typical suitable HAART - multidrug combination therapies include:

(a) triple combination therapies such as two NRTIs and one PI ; or (b) two NRTIs and one NNRTI ; and (c) quadruple combination therapies such as two NRTIs , one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is preferred unless there is intolerance to Pis. Drug compliance is essential.

The CD4 and HIV-1 -RN A plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug,e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:

Footnotes to Table

1. One of the following: zidovudine + lamivudine; zidovudine + didanosine;

stavudine + lamivudine; stavudine + didanosine; zidovudine + zalcitabine

2. Indinavir, nelfmavir, ritonavir or saquinavir soft gel capsules.

3. Nevirapine or delavirdine.

4. See A-M. Vandamne et al Antiviral Chemistry & Chemotherapy 9: 187 at p 193- 197 and Figures 1 + 2.

5. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients.

6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).

7. Zidovudine, stavudine or didanosine. Agents known in the treatment of rheumatoid arthritis, solid organ transplant rejection, graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the presently claimed CXCR4 antagonists of the present invention are as follows:

solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;

inflammatory bowel disease: IL-10 (see US 5,368,854), steroids and azulfidine;

rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; and, multiple sclerosis: interferon-beta, interferon- alpha, and steroids.

In a further embodiment of the present invention is a pharmaceutical composition comprising one or more anti-viral agents selected from zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4, DAPD, lodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 1 1607 and AG-1549. The anti-viral agent component of said pharmaceutical composition may be present in fixed dosage amounts or in variable dosage amounts.

In a further embodiment of the present invention is a method of inhibiting the replication of Human Immunodeficiency Virus, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention as hereinbefore described optionally comprising one or more anti-viral agents useful in the treatment of Human Immuno-deficiency Virus.

In a further embodiment of the present invention is a kit comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat Human Immunodeficiency Virus which comprises, in one container, a

pharmaceutical composition comprising at least one compound according to the present invention, in one or more pharmaceutically acceptable carriers, and in a separate container, one or more pharmaceutical composition comprising one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus in one or more pharmaceutically acceptable carriers.

The present invention is further illustrated by the following examples which are not intended to limit the scope thereof, Unless otherwise indicated, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Commercial reagents and solvents were used without further purification.

Methods

General Chemical Procedures: All reagents were either purchased from common commercial sources or synthesised according to literature procedures using commercial sources.

All NM spectra were recorded using a Varian AS-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hz indicated parenthetically. Where LC MS data are presented, analyses was performed using an Applied Biosystems API- 100 mass spectrometer and Shimadzu SCL-IOA LC column: Altech platinum CI 8, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The retention time and observed parent ion are given. MS data were obtained using Agilent Technologies LC/MSD SL or 1 100 series LC/MSD mass spectrometer.

Purification of Final Products

Final compounds were purified by PrepLC using the column of Varian Pursuit XRs C 18 10m 250 x 21.2 mm and an eluent mixture of mobile phase A and B. The mobile phase A is composed of 0.1% TFA in H2O and the mobile phase B is composed of CHjCN (95%) / H20 (5%) / TFA (0.1%). The mixture of mobile phase A and B was eluted through the column at a flow rate of 20 mL/min at room temperature. The purity of all the final discrete compounds was checked by LCMS using a Higgins Haisil HL CI 8 5m 150 x 4.6 mm column and an eluent mixture of mobile phase A and B, wherein mobile phase A is composed of 0.1% TFA in H2O and the mobile phase B is composed of CH3CN (95%) / H20 (5%) / TFA (0.1%). The column was eluted at a flow rate of 3 mL/min at a temperature of 60 °C. Intermediate compounds were characterized by LCMS using a Higgins Haisil HL CI 8 5Gm 50 x 4.6 mm column and an eluent mixture of mobile phase A and B, wherein mobile phase A is composed of 0.1 % TFA inな0 and the mobile phase B is composed of CH3CN (95%) / H20 (5%) / TFA (0.1 %). The column was eluted at a flow rate of 3 mlJmin at a column temperature of 60 °C.

Following purification, to each Vial was added 1 mL of acetonitrile and 1 mL of 1 N hydrochloric acid standard solution in water. The vials were shaken for few minutes and transferred into a bar-coded 4 mL scintillation vial previously tarred. The tubes were lyophilized overnight then weighed, yields were calculated.

Abbreviations

Acetic acid (AcOH), N,N-Dimethylformamide (DMF), dichloroethane (DCE), dichloromethane (DCM), dimethylsuphoxide (DMSO), diphenylphosphoryl azide (DPP A), ethanol (EtOH), ethyl acetate (EtOAc), 0-(7-Azabenzotriazole-l -yl)-N,N,N,N- tetramethyluronium hexafluoro phosphate (HATU), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (TEA), trifluoroacetic acid (TFA), water (H20) and Stratospheres1 M 4- formyl-3,5-dimethoxyphenoxy resin (PL-FDMP)

Method 1

Preparation of Examples 1-1 - 1-27.

Procedure 1 - Synthesis of Heterocyclic Derivatives of Formula I. wherein L is a Urea or Thiourea by Solution Phase (Method A)

The amine component (0, 14 mmol) (2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethanamine for Example 1.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. The vial was stirred until dissolved. The isocyanate or thioisocyanate component (0, 1 mmol) (3- methylthiophenylisocyanate for Example 1.1 ) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF. All of the isocyanate or thioisocyanate solution was added to the appropriate 4 mL vial containing the amine and the reactions were shaken overnight at room temperature. The samples were analysed by LC-MS and the solvent removed under reduced pressure (Genevac). The samples were then resolubilised (1.5 mL of DMSO/acetonitrile (3:1)) and further purified by HPLC using the general purification conditions descriobed above to provide the desired products.

Method 2

Preparation of Examples 2-1

Preparation of l-(3,4-dichlorobenzyI)-3-(3-guanidinopropyl)urea hydrochloride (2-1)

Step 1. A solution of tert-butyl 3-aminopropylcarbamate (418 mg, 2.4 mmol) in anhydrous methylene chloride (4 mL) was added dropwise to a solution of 3,4- dichlorobenzyl isocyanate (404 mg, 2.0 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen and the mixture was stirred for 18 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 : 1), to provide tert-butyl 3-(3-(3,4-dichlorobenzyl)ureido)propylcarbamate (566 mg, 75%) as a white solid: ^IH NMR (500 MHz, CDCl₃) δ 7.41-7.36 (m, 2H), 7.15 (d, 1H), 5.26 (br s, 1H), 5.84 (br s, 2H), 4.33 (d, 2H), 3.27-3.21 (m, 2H), 3.21-3.15 (m, 2H), 1.62-1.56 (m, 2H), 1.42 (s, 9H) ppm; ESI MS m/z 276 [M - Boc + H]⁺. Step 2. A solution of HC1 in dioxane (3.76 mL, 15 mmol, 4 M in dioxane) was added to a solution of tert-butyl 3-(3-(3,4-dichlorobenzyl)ureido)propylcarbamate (566 mg, 1.5 mmol) in anhydrous 1,4-dioxane (4 mL) at room temperature under nitrogen and the mixture was stirred for 16 h. The solvent was removed under reduced pressure to provide l-(3-aminopropyl)-3-(3,4-dichlorobenzyl)urea hydrochloride (466 mg, 99%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.49-7.42 (m, 2H), 7.20 (d, 1H), 4.28 (s, 2H), 3.25 (t, 2H), 2.93 (t, 2H), 1.88-1.78 (m, 2H) ppm; APCI MS m/z 276, Step 3. A mixture of l-(3-aminopropyl)-3-(3,4-dichlorobenzyl)urea hydrochloride (235 mg, 0.75 mmol), 1,3-di-BOC-2-(trifluoromethylsulfonyl)guanidine (440 mg, 1.1 mmol) and diisopropylethylamine (0.40 mL, 2.3 mmol) in anhydrous methanol (5 mL) at room temperature under nitrogen was stirred for 18 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :1), to provide tert-butyl l-(3,4- dichlorophenyl)-l 3 , 13-dimethyl-3,l 1 -dioxo- 12-oxa-2,4,8, 1 O-tetraazat.etradecan-9- ylidenecarbamate (299 mg, 77%) as a colorless oil: Ή NMR (300 MHz, CDCl₃) δ 8.49 (br s, 1H), 7.40-7.32 (m, 2H), 7.18-7.09 (m, 1H), 6.95 (br s, 1H), 5.12 (t, 1 H), 4.31 (d, 2H), 3.50-3.39 (m, 2H), 3.25-3.12 (m, 2H), 1.75-1.60 (m, 2H), 1.49 (s, 9H), 1.39 (s, 9H) ppm; ESI MS m/z 518.

Step 4. A solution of HCl in dioxane (1.4 mL, 5.6 mmol, 4 M in dioxane) was added to a solution of tert-butyl l-(3,4-dichlorophenyl)-13, 13-dimethyl-3,l 1 -dioxo- 12-oxa- 2,4,8, 10-tetraazatetradecan-9-ylidenecarbamate (299 mg, 0.58 mmol) in anhydrous 1 ,4- dioxane (3 mL) at room temperature under nitrogen and the mixture was stirred for 18 h. The mixture was diluted with diethyl ether (10 mL) and the solids were collected by vacuum filtration to provide l-(3,4-dichlorobenzyl)-3-(3-guanidinopropyl)urea hydrochloride (188 mg, 92%) as a white solid: Ή NMR (300 MHz, CD3OD) 6 7.59- 7.49 (m, 2H), 7.20 (d, 1H), 4.29 (s, 2H), 3.28-3.15 (m, 4H), 1.80-1.68 (m, 2H) ppm; ESI MS m/z 318.

Method 3 Preparation of Examples 3-1 - 3-4

Preparation of N-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)benzo[d]oxazol-2-amine (3-2)

A mixture of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethanamine (92 mg, 0.52 mmol) and 2-chlorobenzo[d]oxazole (66 mg, 0.43 mmol) in anhydrous acetonitrile (4 mL)in a sealed reactor vial was heated at 170 °C in a microwave synthesizer for 10 min. The solvent was removed from the cooled mixture under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :4), to provide N-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)benzo[d]oxazol-2-amine (29 mg, 19%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.25 (d, 1 H), 7.18-7.08 (m, 3H), 7.00 (d, 1 H), 6.41 (d, 1H), 3.63 (t, 2H), 3.35 (t, 2H), 2.83 (t, 2H), 2.67 (t, 2H), 1.85-1.80 (m, 2H) ppm; ESI MS m/z 295.

Method 4

Preparation of Examples 4-1 - 4-2

Preparation of 2-cyano-1-(3,4-dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yI)ethyl)guanidine (2-1)

Silver(I) acetate (52 mg, 0.80 mmol) was added to a solution of l-(3,4-dichlorobenzyl)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)thiourea (160 mg, 0.40 mmol) and sodium cyanamide (132 mg, 0.80 mmol) in anhydrous DMF (2 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. Additional silver(I) acetate (52 mg, 0,80 mmol) and sodium cyanamide (132 mg, 0.80 mmol) were added and stirring was continued for a total of 40 h. The mixture was diluted with ethyl acetate (25 mL), washed with brine (3 x 50 mL), dried Na₂SO₄), filtered and the solvents were removed under reduced pressure. The residue was triturated with methylene chloride (4 mL) and the solids were collected by vacuum filtration, washing with methylene chloride (10 mL) to provide 2-cyano-1-(3,4-dichlorobenzyl)-3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)guanidine (95 mg, 59%) as a white solid: ¹H NMR (300 MHz, CD3OD) £7.47 (d, 1H), 7.40 (s, 1H), 7.13 (d, 2H), 6.35-6.31 (m, 1 H), 4.42 (s, 2H), 4.88 (s, 2H), 2.72 (d, 4H), 1.85 (s, 2H) ppm; ESI MS m/z 403.

Method 5

Preparation of Examples 5-1 - 5-9

Preparation of N-(3-fluorophenyl)-1,2,3,4,8,9-hexahydropyridof2,3- ->][1,6]naphthyridine-7(6//)-carboxamide hydrochloride (5-1)

Step 1. 3 -Fluorophenyl isocyanate (250 mg, 1.8 mmol) was added to a solution of 6,7,8,9-tetrahydropyrido[2,3-6][1,6]naphthyridine (405 mg, 2.2 mmol) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen and the mixture was stirred for 18 h. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with

methanol/methylene chloride (1 :1), to produce N-(3-fluorophenyl)-8,9- dihydropyrido[2,3-b][1,6]naphthyridine-7(6H)-carboxamide (419 mg, 71%) as a white solid: Ή NMR (300 MHz, CD3OD) δ 9.03-9.00 (m, 1H), 8.41 (dd, 1H), 8.26 (s, 1 H), 7.60 (dd, 1H), 7.38-7.15 (m, 3H), 6.78-6.70 (m, 1 H), 5.02-4.90 (m, 2H), 4.55 (s, 2H), 3.99 (t, 2H) pprn; ESI MS m/z 323.

Stq? 2. A mixture of N-(3-fluorophenyl)-8,9-dihydropyrido[2,3-b][ 1 ,6]naphthyridine-

7(6H)-carboxamide (292 mg, 0.91 mmol) and 10% palladium on charcoal (200 mg) in methanol (8 mL) and methylene chloride (8 mL) was stirred under one atmosphere of hydrogen at room temperature for 18 h. The solids were removed by vacuum filtration and the filtrate solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with

methanol/methylene chloride (1 : 1), to provide N-(3-fiuorophenyl)-l , 2,3,4,8,9- hexahydropyiido[2,3-b][1,6]naphthyridine-7(6H)-carboxamide (207 mg, 70%) as a white solid: ¹H NMR (300 MHz, CD₃OD) 6 7.42-7.10 (m, 3H), 7.05 (s, 1H), 6.85-6.70 (m, 1H), 4.51 (s, 2H), 3.80 (t, 2H), 3.49-3.42 (m, 2H), 2.90-2.68 (m, 4H), 2.00-1.82 (m, 2H) pprn; ESI MS m/z 327.

Step 2. A solution of HCl in dioxane (0.8 mL, 1 .6 mmol, 4 M in dioxane) was added to a solution of N-(3-fluorophenyl)-l )2,3,4,8,9-hexahydropyrido[2,3-b][1,6]naphthyridine- 7(6H)-carboxamide (109 mg, 0.33 mmol) in anhydrous methanol (5 mL) and anhydrous methylene chloride (5 mL) at room temperature under nitrogen and the mixture was stirred for 10 min. The solvent was removed under reduced pressure to provide N-(3-fluorophenyl)-1,2,3,4,8,9-hexahydropyrido[2,3-b][l ,6]naphthyridine- 7(6H)-carboxamide hydrochloride (1 12 mg, 92%) as a white solid: ¹H NMR (500 MHz, CD3OD) δ 7.50 (s, 1H), 7.32-7.22 (m, 2H), 7.15 (d, 1H), 6.78-6.70 (m, 1 H), 4.55 (s, 2H), 3.85 (t, 2H)t 3.50 (t, 2H), 2.92-2.82 (m, 4H), 2.01-1.93 (m, 2H) pprn; ESI MS m/z 327.

Method 6

Preparation of Examples 6-1 - 6-6

Preparation of l-(3,4-dichlorobenzyl)-3-(2-(6-(niethylamino)pyridin-2- yl)ethyl)urea

Step 1. A solution of 9-BBN dimmer (8,0 mL, 4.0 mmol, 0.5 M solution in THF) was added dropwise to a solution of benzyl vinylcarbamate (850 mg, 4.8 mmol) in anhydrous THF (6 mL) at 0 °C under a nitrogen atmosphere after which the mixture was slowly warmed to room temperature, stirring for a total of 16 h. The mixture was cooled to 0 °C and 3 M NaOH (3.6 mL) was added dropwise, after which the mixture was warmed to room temperature, stirring for a total of 90 min. The resulting mixture was then added dropwise to a solution of 6-bromo-N-methylpyridin-2-amine (375 mg, 2.0 mmol) and PdCl₂(dppf)●CH₂Cl₂ (146 mg) in anhydrous THF (10 mL) and the resulting suspension was stirred heated to 65 °C to stir for 18 h. The cooled mixture was diluted with saturated NaHCO₃ solution (75 mL), extracted with ethyl acetate (3 x 100 mL), dried (Na₂SO ₄), filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide benzyl 2-(6- (methylamino)pyridin-2-yl)ethylcarbamate (407 mg, 71 %) as a white solid: Ή NMR (CDClj, 300 MHz) δ 7.36-7.28 (m, 6H), 6.40 (d, 1H), 6.21 (d, 1H), 5.86 (brs, 1H), 5.09 (s, 2H), 4.56 (brs, 1H), 3.55 (q, 2H), 2.86 (d, 3H), 2.79 (t, 2H); ESI MS m/z 286 [M + H]+,

Step 2. A mixture of benzyl 2-(6-(methylamino)pyridin-2-yl)ethylcarbamate (388 mg, 1.36 mmol) and 10% palladium on charcoal (300 mg) in ethanol (10 mL) was stirred under one atmosphere of hydrogen at room temperature for 24 h. The solids were removed by vacuum filtration and the filtrate solvents were removed under reduced pressure to provide 6-(2-aminoethyl)-N-methylpyridin-2-amine (200 mg, 97%) which was suitable for use without further purification: ESI MS m/z 152 [M + H]+. Step 3. A solution of 3,4-dichlorobenzyl isocyanate (121 mg, 0,60 mmol) in anhydrous methylene chloride (1 mL) was added dropwise to a solution of 6-(2-aminoethyl)-N- methylpyridin-2-amine (120 mg, 0.8 mmol) in anhydrous methylene chloride (3 mL) at 0 °C under nitrogen, and the mixture was slowly wanned to room temperature, stirring for a total of 24 h. The mixture was directly purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 1 -(3,4- dichlorobenzyl)-3-(2-(6-(methylamino)pyridin-2-yl)ethyl)urea (101 mg, 48%) as a white solid: Ή NMR (300 MHz, DMSO-c?6) δ 7.56 (d, 1H), 7.45 (s, 1H), 7.31 -7.20 (m, 2H), 6.49 (t, 1H), 6.34-6.23 (m, 3H), 6.03 (t, 1H), 4.18 (d, 2H), 3.37-3.31 (m, 2H), 2.75 (d, 3H), 2.63 (t, 2H) ppm; ESI MS m/z 353 [M + H]+.

Method 7

Preparation of Examples 7-1 - 7-2

Preparation of 3-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)-3,4- dihydroquinazolin-2(lH)-one (7-1)

Step 1. 2-Nitrobenzaldehyde (380 mg, 2.5 mmol) was added to a mixture of 2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethanamine hydrochloride (353 mg, 2.5 mmol), sodium triacetoxyborohydride (585 mg, 2.8 mmol) and resin-bound

diisopropylethylamine (750 mg, 3.0 mmol) in anhydrous methylene chloride (20 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. The mixture was slowly diluted with 0.2 N HCl (125 mL), extracted with ethyl acetate (2 x 75 mL), washed with brine (20 mL), dried (^SC^), filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide N-(2- nitrobenzyl)-2-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)ethanamine (300 mg, 38%) as a yellow oil: 1H NMR (300 MHz, CDCl₃) δ 7.96 (d, 1H), 7.66 (d, 1H), 7.57 (t, 1H), 7.40 (t, 1H), 7.07 (d, 1 H), 6.37 (d, 1H), 4.93 (br s, 1H), 4.07 (s, 2H), 3.45-3.37 (m, 2H), 2.96 (t, 2H), 2.78-2.70 (m, 5H), 1 ,94-1.88 (m, 2H) ppm.

Step 2. A mixture of N-(2-nitrobenzyl)-2-(5,6,7,8-te1.rahydro-l ,8-naphthyridin-2- yl)ethanamine (100 mg, 0.32 mmol) and platinum(IV) oxide (35 mg) in ethanol (2 mL) and ethyl acetate (2 mL) was stirred under one atmosphere of hydrogen at room temperature for 2 h. The solids were removed by vacuum filtration and the filtrate solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :4), to provide 2-((2-(5,6,7,8-tetrahydro-l ,8-naphtliyridin-2-yl)ethylamino)methyl)aniline (62 mg, 69%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.10-6.95 (m, 3H), 6.69- 6.60 (m, 2H), 6.34 (d, 1 H), 4.77 (br s, 2H), 3.79 (s, 2H), 3.42-3.36 (m} 2H), 2.94 (t, 2H), 2.74-2.67 (m, 4H), 1.91-1.87 (m, 2H) ppm.

Step 3. Carbonyl diimidazole (32 mg, 0.20 mmol) was added to a solution of 2-((2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethylamino)methyl)ai.iline (60 mg, 0.20 mmol) in anhydrous methylene chloride (1 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (15:85), to provide 3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)-3,4-dihydroquinazolin-2(lH)-one (12 mg, 19%) as an off- white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.18-6.85 (m, 3H), 6.78 (s, 1H), 6.63 (d, 1H), 6.42 (d, 1H), 4.75 (s, 1H), 4.38 (s, 2H), 3.72 (t, 2H), 3.42-3.38 (m, 2H), 2.87 (t, 2H), 2.72-2.68 (m, 2H), 1.89-1.85 (m, 2H) ppm; ESI MS m/z 309 [M + Hf .

Method 8

Preparation of Examples 8-1 Preparation of l-(3-fluorophenyl)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yI)ethyl)imidazolidin-2-one (8-1)

Step 1. Diisopropylethylamine (0.17 mL, 1.0 mmol) was added to a suspension of 2- (3-fluorophenylamino)acetic acid (85 mg, 0.50 mmol) PyBop (260 mg, 0.50 mmol) in anhydrous methylene chloride (3 mL) at room temperature under nitrogen and the resulting mixture was added immediately to a mixture of 2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethanamine hydrochloride (307 mg, 0.50 mmol) and

diisopropylethylamine (0.09 mL, 0.52 mmol) in anhydrous methylene chloride (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 10 min, after which the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 2-(3-fluorophenylamino)-N-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)acetamide (35 mg, 21 %) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) 6 7.15-7.1 1 (m, 1H), 6.98 (d, 1H), 6.47 (t, 1H), 6.39 (d, 1H), 6.31 (d, 1H), 6.24 (d, 1H), 4.45 (t, 1H), 4.28 (br s, 1 H), 3.79 (d, 2H), 3.59 (q, 2H), 3.26-3.20 (m, 2H), 2.70 (t, 2H), 2.62 (t, 2H), 1.85-1.79 (m, 2H) ppm; ESI MS m/z 329 [M + H]+.

Step 2. A solution of borane in THF (2.43 mL, 2.43 mmol, 1 M solution in THF) was added solution of 2-(3-fluorophenylamino)-N-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin- 2-yl)ethyl)acetamide (267 mg, 0.81 mmol) in anhydrous THF (10 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. The mixture was diluted with 2 HCl (5 mL) and stirred for 10 min, after which the mixture was neutralized by the addition of solid NaHCO₃. The mixture was extracted with ethyl acetate (10 mL), dried (Na₂SO₄), filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (3:7), to provide Nl-(3-fluorophenyl)-N2-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)etliane-1,2-diamine (50 mg, 19%) as a colorless oil: ESI MS m/z 315 [M + H]+.

Step 3. Carbonyl diimidazole (25 mg, 0.15 mmol) was added to a solution of/v-l-(3- fluorophenyl)-N2-(2-(5 ,6,7, 8-teu-ahydro- 1

diamine (50 mg, 0.15 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen and the mixture was stirred for 15 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 : 1 ), to provide N-(2-(3-iluorophenylamino)ethyl)-N-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)-lH-imidazole-1-carboxamide (24 mg, 37%) as a white solid: lH NMR (400 MHz, CDCls) δ 7.08 (d, 1 H), 6.35 (d, 1 H), 5.51 (br s, 1H), 4.98 (br s, 1H), 3.70-3.60 (m, 3H), 3.53-3.48 (m, 2H), 3,43-3.38 (m, 2H), 2.77-2.66 (m, 4H), 1.99-1.93 (m, 2H) ppm; ESI MS m/z 341 [M + H]+.

Step 4. A solution of N-(2-(3-fluorophenylamino)ethyl)-N-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)-lH-imidazole-l -carboxamide (24 mg, 0.059 mmol) in anhydrous chloroform (1 mL) was heated at 60 °C under nitrogen for 2 days. The mixture was directly purified by preparative thin-layer chromatography on silica gel, eluting with methanol/methylene chloride (15:85) to provide l-(3-fluorophenyl)-3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)imidazolidin-2-one (9 mg, 53%) as an off-white solid: Ή NMR (400 MHz, CDClj) δ 7.44 (d, 1H), 7.29-7.19 (m, 2H), 7.12 (d, 1H), 6.70 (t, 1H), 6.45 (d, 1H), 3,79-3.73 (m, 2H), 3.64 (t, 2H), 3.49 (t, 2H), 3.43-3.38 (m, 2H), 2.85 (t, 2H), 2.70 (t, 2H) 1.93-1.88 (m, 2H) ppm; ESI MS m/z 341 [M + H]+. Method 9- Biological Assays

9.1 Affinity Selection mass Spectrometry

Compound binding affinities at CXCR4 were determined using affinity purified

CXCR4 that was isolated from a permanent mammalian cell line (HEK-293-EbNA) expressing an epitope-tagged recombinant form of CXCR4 at 10 pmol/mg of membrane in adherent growth mode and using the general screening and Iigand binding assays described in J. Biomol. Screening., 2006, 11, 194-207 and Comb. Chem. And High Throughput Screen, 2008,11, 427-438.

Many of the above-noted compounds exhibited AC-MS based Kd values above 3 μΜ in this assay, whilst several others exhibited Kd values ranging from 3 μΜ to less than 500 nM. AS-MS based competition binding experiments showed that certain compounds bound to competing orthosteric sites on CXCR4 whilst other compounds bound to non-competing 'allosteric' binding sites on CXCR4.

9.2 HIV Replication Assay

Vims Stocks and Reagents

Luciferase reporter viruses (ADA, YU-2) were generated as described by Connor et al. (J. Virol, 1996, 70, 5206-531 1), Primary HIV-1 isolates were obtained from commercial sources. Viral Stocks were propagated in phytohemagglutinin (5

□ g/ml) and IL-2 (50 units/ml)- stimulated peripheral blood mononuclear cells (PBMC) obtained from healthy donors.

HIV1- and HIV1- pseudovirus luciferase expression assays

A modified version of the antiviral luciferase expression assays described previously (1 , 2) was used for this study. Briefly, U87 CXCR4/CD4 astroglioma cells were plated at 2500 cells / well into white-walled 384-well luminometer plates.

Following overnight incubation in a humidified CO2 incubator (37°C) diluted test compounds were added and incubated for and additional 1 hr period. At this time point either CXCR4-tropic HXB2 virus (3), or HIV-1 particles pseudotyped with the HXB2 envlelope ( 1 ), both of which were engineered to express the firefly luciferase gene , were added to the test wells. After three days of HIV-1 infection luciferase acitivity was measured using Glo Lysis buffer (Promega) and the Brightlite reagent (PerkinElmer).

HIV-1 Replication in PBMC Cultures

Ficoll-purified PBMC were stimulated in vitro with 5 mg/ml phytohemagglutin 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 lh at 37 °C and infected in triplicate with 25-100 tissue culture 50% ineffective dose (TCID5o) per well of an HIV-1 primary isolate for 3-4 h. The cells were washed twice in PBS to remove residual vims and cultured in the presence of inhibitor for 4-6 days. HIV-1 replication was quantitatied by measurement of extracellular p24 antigen by EL1SA. The IC₅₀ and IC₉₀ values for each virus were determined by using GRPAHPAD PRISM software.

Chemotaxis

SDF-1 alpha induced chemotaxis of human Jurkat T-cells was analysed using a two- chamber method using 96-welI Transwell plates (Corning Life Sciences, Corning NY). For the assay, Jurkat cells in phenol red free RPMI medium (supplemented with 1% fetal bovine serum) were preincubated with diluted test compound at 37 °C for lh. Following preincubation 400 000 Jurkat cells, in 100 μl of medium with diluted compound, were plated in the upper chamber of the Transwell plate in which the bottom chamber contained 25 nM of SDF-1 alpha (R&D systems, Minneapolis, MN), in 250 μl of cell culture media also with appropriately diluted compound, After a 4h incubation at 37 °C, 150 μl of media was removed from the bottom chamber and CyQUANT Gr (InVitrogen, Carlsbad CA) cell proliferation assay lysis substrate was added. CyQuant Gr signal, which provides a measure of Jurkat cell density in the bottom chamber, was read on an Envision (Perkin Elmer, Waltham, MS) multi-label plate reader. Alternatively, the migrated cells were counted on a flow cytometer. Many of the compounds of the invention had IC₅₀ values less than 25 μΜ in the chemotaxis assay. The "CXCR4 IC50" values refer to assay results that used a live virus. The "CXCR4 PV IC50" values refer to assay results that used a pseudovirus. Listings in tables of SO indicate actual values of SO or greater.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I

wherein:

ring A comprising X¹, X², and the -C(=0) group as shown is a five- or six-membered ring, wherein when ring A has substituents on adjacent carbon atoms, said substituents can be taken together with the carbon atoms to which they are attached to form an aryl, cycloalkyl, heterocyclyl or heteroaryl ring;

X¹ and X² independently are N or S;

R¹ is selected from the group consisting of:

and wherein:

each R independently is H or alkyl;

each R² and R^2' is independently H, alkyl or cycloalkyl, or R² and R^2' together with the carbon or carbons to which they are shown bonded in formula I form a cycloalkyl;

a is an integer from 1-3;

R³ is selected from the group consisting of H, alkyl, cycloalkyl, heteroacyclyl, aryl, and heteroaryl;

x is 0, 1 , or 2;

each R⁵ independently is alkyl;

y is O, 1 , or 2;

each R⁶ independently is alkyl;

each Al ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1-3 N atoms;

each A2 ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1-3 N atoms;

c is 1, 2, or 3; Y¹ and Y² independently are C(R) or N;

d is 0, 1 , or 2;

Z¹ is O or S;

Z² is CR or N;

R⁷ is -NR₂; and

R⁸ is selected from the group consisting of H, alkyl, -C(=NR)-NR₂, and a five- or six- membered heteroaryl whose ring atom heteroatoms consist only of 1-3 N atoms, and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein X¹ and X² are both N, and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, wherein substituents on adjacent carbon atoms of ring A together with the carbon atoms to which they are attached form an aryl ring, and pharmaceutically acceptable salts thereof,

4. The compound according to claim 1, wherein ring A optionally with said aryl is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

6. The compound according to claim 5, wherein ring Al is a six-membered heterocyclyl, and pharmaceutically acceptable salts thereof.

7. The compound according to claim 6, wherein ring Al is piperidinyl, and pharmaceutically acceptable salts thereof.

8. The compound according to claim 5, wherein x and y are both 0, and pharmaceutically acceptable salts thereof.

9. The compound according to claim 5, wherein R1 is

, and pharmaceutically acceptable salts thereof.

10. The compound according to claim 1 , wherein R² and R² are both H, and a is 2, and pharmaceutically acceptable salts thereof.

11. The compound according to claim 1 , wherein R3 is selected from the group consisting of H and aryl, and pharmaceutically acceptable salts thereof.

12. The compound according to claim 1 1, wherein said aryl is phenyl which is unsubstituted or substituted with at least one halo, and pharmaceutically acceptable salts (hereof.

13. The compound according to claim 1, selected from the group consisting of:

or a

pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable earner.

15. A method of treating a disease selected from the group consisting of HIV, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allegies, and multiple sclerosis in a patient in need thereof by administering a therapeutically effective amount of at least one compound claim 1.

16. The method according to claim 15, wherein said disease is HIV.

17. The method according to claim 16, further comprising administering one or more antiviral or other agents useful in the treatment of HIV.

18. The method according to claim 17, wherein the antiviral agent is selected from the group consisting of nucleoside reverse transciptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and CCR5 receptors antagonists.

19. The method according to claim 15, for the treatment of solid organ transplant rejection, arthritis, rheumatoid arthritis, or multiple sclerosis, further comprising administering one or more other agents useful in the treatment of said disease.

20. A kit comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat HIV which comprises in one container a pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 in a pharmaceutically acceptable earner, and in separate containers one or more pharmaceutical compositions comprising an effective amount of an antiviral agent useful in the treatment of HIV in a pharmaceutically acceptable carrier.