WO2011060397A1 - Amino heterocycles substitues utilises comme antagonistes du vih - Google Patents

Amino heterocycles substitues utilises comme antagonistes du vih Download PDF

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WO2011060397A1
WO2011060397A1 PCT/US2010/056780 US2010056780W WO2011060397A1 WO 2011060397 A1 WO2011060397 A1 WO 2011060397A1 US 2010056780 W US2010056780 W US 2010056780W WO 2011060397 A1 WO2011060397 A1 WO 2011060397A1
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pharmaceutically acceptable
group
compound according
alkyl
hiv
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PCT/US2010/056780
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Gerald W. Shipps, Jr.
Cliff C. Cheng
Robert Jason Herr
Jinhai Yang
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Schering Corporation
Albany Molecular Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular for the blocking of HIV, or in treatment or prevention of inflammatory and immune disorders such as HIV infection.
  • 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
  • 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 etal., Nat. Immunol. 2, 123-128 (2001)). Inflammatory chemokines are produced in response to
  • homeostatic chemokines are involved in normal 'housekeeping' functions such as the maturation of leukocytes in the bone marrow.
  • chemokines 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,
  • CCR5 Two chemokine receptors CCR5 and CXCR4 have been shown to play essential roles in HIV infection (Alkhatib et al., Science 272, 1955-1958 (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 (MIP-1beta) and CCL5 (RANTES) (Samson et al., Biochemistry 35, 3362-3367 (1996)).
  • 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)).
  • SDF-1 chemokine CXCL12
  • 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 ( 998);
  • HIV spikes consist of a trimer of
  • heterodimers made up of one molecule of the viral gp120 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.
  • viral tropism is defined as the preference of virus to mediate infection via either CCR5 alone (R5-tropic) or CXCR4 alone (X4- tropic).
  • dual tropic R5/X4 viruses that can use both CCR5 and CXCR4 have been reported.
  • 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
  • X4-tropic viruses 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-tropic 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.
  • Enfuviritide is a 36 residue peptide mimic of the HR2 domain of gp41 (Wild etal., 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 CCR5 antagonists that inhibit receptor function and gp120 binding (Westby etal., J.Virol. 80, 4909-4920 (2006)). Maraviroc and two other CCR5 antagonists vicriviroc (Strizki ef al.,
  • 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 ai, J. Acquir. immune Defic. Syndr. 37, 1253-1262 (2004)).
  • the present invention provides a compound of Formula I:
  • ring A2 is heterocyclyl whose ring heteroatoms consist only of 1 nitrogen atom and which is substituted with x R 5 substituents as shown;
  • R is H, alkyl, or cycloalkyl
  • R' is H or alkyl
  • R 1 is aryl
  • R 2 and R 2' independently are H or alkyl
  • a is an integer from 0 to 3;
  • R 3 and R 3' independently are H or alkyl
  • b is an integer from 0 to 3;
  • R 4 is cycloalkyl or aryl
  • each R 5 independently is alkyl
  • x is an integer from 0 to 3.
  • the present invention also provides pharmaceutical compositions and kits comprising at least one compound of Formula I, and methods of treating or preventing chemokine-mediated disorders such as HIV utilizing the aforesaid compound of formula I.
  • the A2 heterocyclyl ring is a monocyclic or bicycllc ring.
  • the A2 heterocyclic ring is monocyclic and is represented by the formula:
  • d is an integer from 1 to 4,
  • the A2 heterocyclic ring is monocyclic and is represented by the formula:
  • d is 1, 2, or 3.
  • the A2 heterocyclyl is selected from the group consisting of:
  • the A2 heterocyclic ring is bicyclic and is represented by the formula
  • R 1 is phenyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of halo, alkoxy, and alkyl.
  • R 1 is phenyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of chloro, methoxy and methyl.
  • R is alkyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy, and aryl.
  • R is selected from the group consisting of H, ethyl, methyl, cyclopropyl, methoxypropyl, and benzyl.
  • R 2 is selected from the group consisting of H and alkyl, and R 2 is H.
  • R 2 is selected from the group consisting of H and methyl, and R 2 ' is H.
  • b is 0, 1 , or 2
  • R 3 and R 3' are both H.
  • R 4 is phenyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of halo, haloalkyt, haloalkoxy, alkyl, halothioalkyl, and alkoxy.
  • R 4 is phenyl which is unsubstituted or substituted with 1 , 2, or 3 substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, alkyl, halothioalkyl, and alkoxy.
  • R 4 is phenyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of fluoro, chloro, methoxy, trifluoromethoxy, trifluoromethyl, -CH(CH 3 ) 2 , and -S-CF 3 .
  • the R 4 cycloalkyl is cyclohexyl.
  • x is 0 or 1.
  • each R s independently is methyl.
  • the compound of formula I is selected from the group consisting of:
  • 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.
  • 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
  • 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.
  • 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.
  • 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 0 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.
  • 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
  • HeteroaryT may also include a heteroaryl as defined above fused to an aryl as defined above.
  • 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, lmidazo[1,2-a]pyridinyl, imidazol2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimid
  • 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
  • cycloalkyl rings 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.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyc!ohexyi, cycloheptyl and the like.
  • 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.
  • 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.
  • 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.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,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.
  • suitable cycloalkenylalkyls include cyctopentenylmethyl, 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, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • 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.
  • 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.
  • suitable monocyclic heterocyclyl rings include piperldyl, pyrrolldinyl, piperazinyl, morpholinyl, thlomorpholinyl, thiazolidinyl, 1 ,4- dioxanyl, tetrahydrofuranyl, ietrahydrothiophenyl, lactam, lactone, and the like.
  • Example of such moiety is pyrroHdone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or mutticyclic 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 heterocycleriyl 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 substituenf is as defined above.
  • ring system substituenf is as defined above.
  • heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S ⁇ dioxide.
  • 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- imidazoiinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dlhydrothiophenyl, di
  • Example of such moiety is pyrrolidine:
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • 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.
  • N, O or S 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.
  • 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 heteroaratkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolln-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.
  • acyf means an H-C(O)-, alkyl-C(0)- or cycloalkyf-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.
  • suitable acyl groups include formyl, acetyl and propanoyi.
  • 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.
  • suitable groups include benzoyl and 1 - naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • 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.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-0- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benz loxy and 1- or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthlo means an alkyl-S- group in which the alkyl group is as previously described.
  • 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.
  • suitable arylthio groups include phenytthio and naphthylthlo. The bond to the parent moiety is through the sulfur.
  • Alkylthio 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.
  • 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.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyioxycarbony!.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(0 2 )- group. Preferred groups are those in which the alkyl group Is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(0 2 >- group. The bond to the parent moiety is through the sulfonyl.
  • 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
  • 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 “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 compounds of formula I in all its isolated forms.
  • the compounds 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 compounds of formula I in its purified form.
  • 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.
  • protecting groups 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 era/, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • 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.
  • prodrug means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of Formula I 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.
  • prodrugs are 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
  • 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 ⁇ CeJalkyl, (C2- Ci 2 )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
  • N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
  • 1-(N- (alkoxycarbonyl)amlno)ethyl having from 4 to 10 carbon atoms 3-phthalidyl, 4- crotonotactonyl, gamma-butyrolacton-4-yl, di-N, N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(C 1 -C 2 )alkyl, N,N-di (C 1
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyH- «CrC6)alkanoyloxy)ethyl, (d- Ce)alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci- C 6 )alkanoyl, a-amino(Ci-C4)alkanyl, arylacyl and a-aminoacyl, or a-a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyH- «CrC6)alkanoyloxy)ethyl, (d- Ce)
  • 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 (Ci-Ci 0 )alkyl, (C3-C7) cycloaikyl, benzyl, or R-carbonyl Is a natural -aminoacyl or natural ⁇ -aminoacyl,— ⁇ 5(OH)C(0)OY 1 wherein Y 1 is H, (C C 6 )alkyl or benzyl, --C(OY 2 )Y 3 wherein Y 2 is (C1-C4) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy (CrCe)alkyl, amino(C C4)alkyl or mono-N— or di-N,N-(Ci- Ce)alkylamin
  • 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.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceu cal ScL, 93(3). 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, MPS 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
  • 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 compounds of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s) B denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I 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, bisurfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • 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.
  • 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 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
  • 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, C 1-4 alkyl, 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-isoleucyl); (4)
  • the compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomers forms. It is intended that all
  • 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.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • 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.
  • 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).
  • positional isomers such as, for example, 4-pyridyl and 3-pyridyl.
  • 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 lUPAC 1974
  • 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.
  • 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 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, *S, 18 F, 3e CI and 123 l, respectively.
  • Certain isotopically-labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) 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 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting Isotopes like 123 l can be useful for application in Single photon emission computed
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) 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.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) 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.
  • 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 (T1/2 >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.
  • the compounds of the present invention are useful in therapy.
  • the compounds of the present invention are useful in therapy in humans or animals.
  • 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.
  • 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, erythematous, 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.
  • a method of treatment may be oral, intravenous or subcutaneous.
  • 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.
  • the present invention therefore also provides a composition comprising a compound according to the present invention in admixture with one or more acceptable excipients.
  • 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, 20 th Edition, Lippincott, Williams and
  • 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, 2 nd Edition; Editors A. Wade and P.J. elter, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994.
  • 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.
  • solid dosage units such as tablets
  • 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.
  • a spray e.g., a nasal or buccal spray.
  • dosage units e.g., tablets
  • the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated.
  • 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.
  • aqueous suspensions, isotonic saline solutions and sterile injectable solutions may 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.
  • the present invention provides a pharmaceutical composition, as hereinbefore described, additionally comprising one or more anti- viral or other agents useful in the treatment of Human Immuno-deficiency Virus.
  • 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-nucfeoside reverse transcriptase inhibitors, protease inhibitors, and other antiviral agents listed below not falling within these classifications.
  • CCR5 antagonists HIV entry inhibitor
  • nucleoside reverse transcriptase inhibitors nucleoside reverse transcriptase inhibitors
  • non-nucfeoside reverse transcriptase inhibitors non-nucfeoside 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.
  • HAART Highly Active Antiretroviral Therapy
  • CCR5 antagonisf 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
  • NRTT s nucleoside and nucleotide reverse transcriptase inhibitors
  • Typical suitable NRTIs include zidovudine (AZT) available under the
  • NNRTIs non-nucleoside reverse transcriptase inhibitors
  • 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 RESCR1PTOR 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 furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater NJ 08807; AG-1549 (formerly Shionogi # S- 1153); 5-(
  • 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
  • antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Hydroxyurea Droxia
  • IL-2 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, 4752585, 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 lU/day, sc is preferred; a dose of about 15 million lU/day, sc is more preferred.
  • IL-12 is disclosed in W096/25171 and is available from Roche Pharmaceuticals, Nutley, NJ 07110- 199 and American Home Products, Madison, NJ 07940; a dose of about 0.5 microgram/kg/day to about 10
  • Pentafuside DP-178, T-20
  • DP-178, T-20 36-amino acid synthetic peptide.disclosed in U.S. Patent No.5,464,933 licensed from Duke
  • 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. 11607 a synthetic protein based on the HIV -1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042 , Israel.
  • Ribavirin, 1-R-D- ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN
  • anti-HIV-1 therapy 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-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from , NNRTls and Pis.
  • Typical suitable HAART - multidrug combination therapies include:
  • 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.
  • triple combination therapies such as two NRTIs and one PI
  • two NRTIs and one NNRTI two NRTIs and one NNRTI
  • quadruple combination therapies such as two NRTIs , one PI and a second PI or one NNRTI.
  • Drug compliance is essential.
  • the CD4 + and HIV- -RNA 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:
  • immune suppressants such as cyclosporine and lnterleukin-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;
  • multiple sclerosis interferon-beta, interferon-alpha, and steroids.
  • 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, iodenosine, 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. 11607 and AG-1549.
  • 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.
  • kits 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.
  • temperature is in °C or is at ambient temperature
  • pressure is at or near atmospheric.
  • Acetic acid (AcOH), W,N-Dimethylformamide (DMF), dichloroethane (DCE), dichloromethane (DCM), dimethylsuphoxide (DMSO), diphenylphosphoryl azide (DPPA), ethanol (EtOH), ethyl acetate (EtOAc), 0-(7-Azabenzotrlazo1e-1-yl)- /V,/V,N,W-tetramethyluronium hexafluoro phosphate (HATU), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropyiethylamine (DIPEA), triethylamine (TEA), trifluoroacetic acid (TFA), water (H 2 0) and StratospheresTM 4- formyl-3,5-dimethoxyphenoxy resin (PL-FDMP) Detailed Experimental Procedures:
  • Step 1 3,4-Dichlorobenzyl chloride (0.11 mL, 0.80 mmol) was added dropwise to a solution of (+/-)-/V-ethylpyrrolidin-3-amine (100 mg, 0.88 mmol) and
  • Step 2 4-Fluoro-3-trifluoromethylphenyl isocyanate (0.04 mL, 0.26 mmol) was added to a solution of (+/-)-1-(3,4-dichlorobenzyl)-A -ethylpyrrOlldin-3-amine (70 mg, 0.26 mmol) and diisopropylethylamine (0.05 mL, 0.31 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen, and the mixture was stirred for 24 h. The mixture was directly purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:9), to provide a colorless oil.
  • Step 1 Benzoyl chloride (0.092 mL, 0.80 mmol) was added dropwise to a solution of (+/-)-/V-ethylpyrrolidin-3-amine (100 mg, 0.88 mmol) and diisopropylethylamine (0.15 mL, 0.88 mmol) in anhydrous methylene chloride (3 mL) at room temperature under nitrogen, and the mixture was stirred for 24 h.
  • Step 2 4-Fluoro-3-trrfluoromethylphenyl isocyanate (0.053 mL, 0.37 mmol) was added to a solution of (+/-H 3 -(ethyla m ino)pyrrolidin-1-ylXphenyl)methanone (80 mg F 0.37 mmol) and diisopropylethylamine (0.071 mL, 0.40 mmol) In anhydrous methylene chloride (3 mL) at room temperature under nitrogen, and the mixture was stirred for 24 h.
  • (+/-H 3 -(ethyla m ino)pyrrolidin-1-ylXphenyl)methanone 80 mg F 0.37 mmol
  • diisopropylethylamine 0.071 mL, 0.40 mmol
  • Step 1 A solution of HCI in dioxane (6.0 mL, 24 mmol, 1 M in dioxane) was added to a solution of commercially available terf-butyl 1-benzylazetidin-3-ylcarbamate (455 mg, 1.73 mmol) in anhydrous methylene chloride (3 mL) at room temperature under nitrogen and the mixture was stirred for 18 h. The solvents were removed under reduced pressure and further dried under high vacuum to provide 1-benzylazetidin-3- amine dihydrochloride (404 mg, 99%) as a white solid that was used without further purification: ESI MS m/z 163 [M + Hf .
  • Step 2 Triethylamine (1.45 mL, 10.4 mmol) was added to a suspension of 1- benzylazetidin-3-amine dihydrochloride (404 mg, 1.72 mmol) in anhydrous
  • Hygroscopic white solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 7.78 (t, 1H), 7.62-7.42 (m, 6H), 7.39 (t, 1H), 4,35 (q, 2H), 4.25-4.10 (m, 2H), 3.80-3.75 (m, 1H), 3.65-3.52 (m, 1H), 3.50-3.35 (m, 2H), 3.18-3.03 (m, 1H), 1.15 (t, 3H) ppm; ESI MS m/z 396 [M + Hf.
  • Hygroscopic white solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 7.57-7.42 (m, 4H), 7.40-7.20 (m r 4H), 4.80-4.70 (m, 1H) t 4.60-4.20 (m, 6H), 3.98-3.80 (m, 1H), 3.60-3.35 (m, 2H), 3.10-2.89 (m, 1 H), 1.18 (t, 3H) ppm; ESI MS m/z 392 [M + Hf .
  • Hygroscopic white solid H NMR (400 MHz, CD 3 OD) ⁇ 7.55 (d, 2H), 7.54-7.40 (m, 5H), 7.20 (d, 2H), 4.70-4.18 (m, 7H), 3.48 (q, 2H), 1.16 (t, 3H) ppm; ESI MS m z 394 [M + Hf.
  • the following examples were prepared using General Method B as described in the previous report:
  • Hygroscopic light brown solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.61 (d, 2H), 7.52 (d, 2H), 7.48 (d, 2H), 7.20 (d, 2H), 6.26 (s, 2H), 4.45 (d, 1 H), 4.33-4.25 (m, 1 H), 4.22 (d, 1H), 3.85-3.73 (m, 1H), 3.59-3.39 (m, 3H), 3.30-3.22 (m, 1H), 3.18-3.00 (m, 1H), 2.66-2.52 (m, 1H), 2.35-2.22 (m, 1H), 1.20 (t, 3H) ppm; ESI MS m/z 409 [M + H] + .
  • Hygroscopic light brown solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.60 (d, 2H), 7,50 (d, 2H), 7.49-7.40 (m, 2H), 7.19 (d, 1H), 6.26 (s, 2H), 4.51 (d, 1H), 4.33 (q, 2H), 4.22 (d, 1H), 4.22-4.12 (m, 1H), 3.89-3.75 (m, 1H), 3.45-3.22 (m, 4H), 3.20-3.09 (m, 1H), 2.68-2.52 (m, 1 H), 2.28-2.12 (m, 1H), 1.12 (t, 3H) ppm; ESI MS m/z 407 [M + HJ + .
  • Hygroscopic light brown solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.62 (d, 2H), 7.88-7.80 (m, 1H), 7.67-7.60 (m, 1H), 7.55 (d, 2H) f 7.25 (t, H), 6.26 (s, 2H) f 4.50 (d, 1H), 4.32- 4.25 (m, 1H), 4.22 (d, 1H), 3.89-3.75 (m, 1H), 3.58-3.35 (m, 4H), 3.20-3.05 (m, 1H), 2.68-2.52 (m, 1H), 2.38-2.23 (m, 1H), 1.22 (t, 3H) ppm; ESI MS m z 411 [M + Hf.
  • Hygroscopic white solid 1 H NMR (400 MHz, CD 3 OD) 59.05 (s, 1H), 8.95 (d, 1H), 8.70 (d, 1H), 8.18-8.05 (m, 1H), 7.50-7.38 (m, 2H), 7.20(d, 1H), 4.74 (d, 1H), 4.55 (d, 1H), 4.35 (s, 2H), 4.38-4.20 (m, 1H), 3.99-3.85 (m, 1H), 3.80-3.42 (m, 2H), 3.42-3.30 (m, 2H), 3.30-3.18 (m, 1H), 2.75-2.60 (m, 1H), 2.28-2.10 (m, 1H), 1.15 (t, 3H) ppm; ESI MS m z407 [M + Hf.
  • Hygroscopic white solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 9.00 (s, 1H), 8.90 (d, 1H), 8.60 (d, 1H), 8.10-7.98 (m, 1H), 7.75-7.60 (m, 1H), 7.50 (t, 1H), 7.30 (t, 1H), 4.72 (d, 1H), 4.52 (d, 1H), 4.40-4.28 (m, 1H), 4.00-3.88 (m, 1H), 3.82-3.60 (m, 2H), 3.60-3.40 (m, 3H), 2.80-2.61 (m, 1H), 2.52-2.25 (m, 1H), 1.25 (t, 3H) ppm; ESI MS m z 411 [M + Hf.
  • Hygroscopic white solid 1 H NMR (400 MHz, CD 3 OD) ⁇ 9.09 (s, 1H), 8.95 (d, 1H), 8.75 (d, 1H), 8.19-8.10 (m, H), 7.48 (d, 2H), 7.18 (d, 2H), 4.78 (d, 1H), 4.60 (d, 1H), 4.39-4.22 (m, 1H), 4.05-3.92 (m, 1H), 3.85-3.60 (m, 2H), 3.60-3.40 (m, 3H), 2.78- 2.62 (m, 1 H), 2.52-2.25 (m, 1 H), 1.25 (t, 3H) ppm; ESI MS m/z 409 [M + H] + .
  • 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 ligand binding assays described in J. Biomol. Screening., 2006, 11, 194-207 and Comb. Chem. And High Throughput Screen, 2008,11, 427-438.
  • Luciferase reporter viruses (ADA, YU-2) were generated as described by Connor et ai. (J. Virol., 1996, 70, 5206-5311). Primary HIV-1 isolates were obtained from commercial sources. Viral Stocks were propagated in phytohemagglutinin (5 ⁇ ml) and IL-2 (50 units/ml)-stimulated peripheral blood mononuclear cells (PBMC) obtained from healthy donors.
  • PBMC peripheral blood mononuclear cells
  • test compounds were added and incubated for and additional 1 hr period.
  • 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.
  • luciferase acitivity was measured using Glo Lysis buffer (Promega) and the Brightlite reagent (PerkinElmer). 1. Ogert, R. A., L. Ba, Y. Hou, C. Buontempo, P. Qiu, J. Duca, N.
  • Ficoli-purified PBMC were stimulated in vitro with 5 mg/ml phytohemagglutin and 50 units/m! IL-2 for 3 days.
  • the cells were resuspended at 4 x 10 6 /mi in complete medium (RPMI, 10% FBS/50 units/ml IL-2), seeded into 96 well plates (2 x 10 5 well), incubated with inhibitor for 1h at 37 °C and infected in triplicate with 25- 100 tissue culture 50% ineffective dose (TCID 5 o) per well of an HIV-1 primary isolate for 3-4 h.
  • the cells were washed twice in PBS to remove residua! virus and cultured in the presence of inhibitor for 4-6 days. HIV-1 replication was quantitatied by measurement of extracellular p24 antigen by ELISA.
  • the iC 50 and ICgo values for each virus were determined by using GRPAH AD PRISM software.
  • CXCR4 IC50 values refer to assay results that used a live virus.
  • CXCR4 PV IC50 values refer to assay results that used a pseudovirus. IC50 listings of 50 indicate actual values of 50 or greater.
  • the compounds of the present invention have IC50 values of less than 5 uM ( ⁇ 5 ⁇ ), In another embodiment, they range from 5 uM to 20 ⁇ , in another embodiment from 20 ⁇ to 50 uM, and in another embodiment, more than 50 ⁇ (>50 ⁇ ).

Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle les variables sont telles que définies dans la spécification. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et leur utilisation en thérapie, en particulier pour traiter ou prévenir les troubles induits par la chemokine, tels qu'une infection par le VIH.
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US9815861B2 (en) 2010-12-23 2017-11-14 Alectos Therapeutics, Inc. Selective glycosidase inhibitors and uses thereof
EP2678017A4 (fr) * 2011-02-25 2015-05-20 Helsinn Healthcare Sa Urées asymétriques et utilisations médicales de celles-ci
AU2012220531B2 (en) * 2011-02-25 2017-02-23 Helsinn Healthcare Sa Asymmetric ureas and medical uses thereof
US9718854B2 (en) 2011-03-31 2017-08-01 Alectos Therapeutics Inc. Selective glycosidase inhibitors and uses thereof
US9701693B2 (en) 2011-06-27 2017-07-11 Alectos Therapeutics Inc. Selective glycosidase inhibitors and uses thereof
US9809537B2 (en) 2012-08-31 2017-11-07 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
EP2890676A4 (fr) * 2012-08-31 2016-04-20 Alectos Therapeutics Inc Inhibiteurs de glycosidases et leurs utilisations
WO2014032185A1 (fr) 2012-08-31 2014-03-06 Alectos Therapeutics Inc. Inhibiteurs de glycosidases et leurs utilisations
US9670195B2 (en) 2012-08-31 2017-06-06 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9695197B2 (en) 2012-10-31 2017-07-04 Alectos Therapeutics Inc. Glycosidase inhibitors and uses thereof
US9546157B2 (en) 2014-03-07 2017-01-17 Helsinn Healthcare Sa Asymmetric piperidinyl-substituted ureas as medicines
WO2015134839A1 (fr) * 2014-03-07 2015-09-11 Helsinn Healthcare Sa Urées asymétriques p-substituées et utilisations médicales de celles-ci
US9926337B2 (en) 2014-03-07 2018-03-27 Helsinn Healthcare Sa Substituted asymmetric ureas as modulators of ghrelin receptor activity
EA032847B1 (ru) * 2014-03-07 2019-07-31 Хелсинн Хелскеа Са П-замещенные асимметричные мочевины и их применение в медицине
US10577384B2 (en) 2014-03-07 2020-03-03 Helsinn Healthcare Sa Substituted asymmetric ureas as modulators of ghrelin receptor activity
US10501479B2 (en) 2016-03-22 2019-12-10 Helsinn Healthcare Sa Benzenesulfonyl-asymmetric ureas and medical uses thereof
US11299472B2 (en) 2017-12-11 2022-04-12 Helsinn Healthcare Sa Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2- trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea, methods of preparation, and uses thereof
US11884646B2 (en) 2017-12-11 2024-01-30 Helsinn Healthcare Sa Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, methods of preparation, and uses thereof
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