WO2010057101A2 - Compounds useful as hiv blockers - Google Patents

Compounds useful as hiv blockers Download PDF

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Publication number
WO2010057101A2
WO2010057101A2 PCT/US2009/064601 US2009064601W WO2010057101A2 WO 2010057101 A2 WO2010057101 A2 WO 2010057101A2 US 2009064601 W US2009064601 W US 2009064601W WO 2010057101 A2 WO2010057101 A2 WO 2010057101A2
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compound according
alkyl
optionally substituted
group
methyl
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PCT/US2009/064601
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French (fr)
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WO2010057101A3 (en
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Gerald W. Shipps, Jr.
Cliff C. Cheng
Abdelghani Abe Achab
Zhiping Yao
Charles E. Whitehurst
Mingxuan Zhang
Xianshu Yang
Robert Jason Herr
Andrew John Zych
Sudipta Roy
Jinhai Yang
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Schering Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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 ah, 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.
  • 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, 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-1 beta) 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., Ce// 86, 367-377(1996)). CXCR4 carries out essential roles in B-cell homeostasis, organ development and angiogenesis.
  • 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
  • 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)).
  • 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 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 ⁇ t al., Proc. Nat. Acad. Sci. USA 91 , 9770-9774 (1994)).
  • Maraviroc is a member of a class of small molecule CCR5 antagonists that inhibit receptor function and gp120 binding (Westby et al., J. Virol. 80, 4909-4920 (2006)). Maraviroc and two other CCR5 antagonists vicriviroc (Strizki et al., Antimicrob. Agents Chemother. 49, 491 1-4919)) and aplaviroc do not directly compete with gp120 for binding, but instead function as allosteric inhibitors that stabilize a confirmation of CCR5 that is unfavorable for gp120 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)).
  • 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.
  • the present invention provides a compound of Formula I
  • R 1 is selected from the group consisting of:
  • each R 2 and R 2 is independently H, C 1-4 alkyl or C 3-7 cycloalkyl, said C 1-4 alkyl and C 3-7 cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R 2 and R 2 together with the carbon or carbons to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; a is an integer from 1-3;
  • R 3 and R 3 are independently H, C 1-4 alkyl, C 3-7 cycloalkyl, or C 6-10 aryl, each of which is independently optionally substituted with methyl, hydroxyl or halogen or R 3 and R 3 together with the carbon to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; b is 0, 1 or 2; R 4 is C 6-10 aryl, C 3-7 cycloalkyl or a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N, wherein said C 6-10 aryl and 5-10 membered heteroaryl ring system are optionally substituted with 1 -3 R 5 and wherein said C 3-7 cycloalkyl is optionally substituted with C 1-4 alkyl or OH; each R 5 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • R 9 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or a 5-10 membered heteroaryl ring system comprising 1 -2 heteroatoms independently selected from O, S and N, wherein each of said C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl ring system independently is optionally substituted with 1-3 R 5 ;
  • R 9 is 1-2 substituents independently selected from H, C 1-4 alkyl and halogen or R ⁇ and the carbon to which it is bonded form a carbonyl group; each R 9a independently is 1-2 substituents independently selected from the group consisting of H and C 1-6 alkyl; each R 9b independently is 1 -2 substituents independently selected from the group consisting of H and C 1-6 alkyl; each X 1 independently is a covalent bond, NR 10 , CR 11 R 11' , O, S, SO or SO 2 ; X 2 is
  • Z is O, S or NR 24 ;
  • R 17 and R 17 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 17 and R 17 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
  • R 18 and R 18 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 18 and R 18 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; e is 0 or 1 ;
  • R 19 and R 19 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 19 and R 19' together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
  • R 21 and R 21 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 21 and R 21 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; f is O or 1 ;
  • R 22 is H or C 1-6 alkyl
  • R 23 and R 23 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 23 and R 23 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
  • R 24 is H, C 1-6 alkyl or COC 1-6 alkyl or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of Formula IA:
  • R 1 is V
  • each R 2 and R 2 is independently H, C 1-4 alkyl or C 3-7 cycloalkyl, said C 1-4 alkyl and C 3 -7cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R 2 and R 2 together with the carbon or carbons to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; a is an integer from 1 -3; R 3 and R 3 are independently H, C 1-4 alkyl or C 3-7 cycloalkyl said C 1-4 alkyl and C 3-7 cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R 3 and R 3 together with the carbon to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; b is O or i ;
  • R 4 is C 6-10 aryl, C 3-7 cycloalkyl or a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N, wherein said C 6-10 aryl and 5-10 membered heteroaryl ring system are optionally substituted with 1 -3 R 5 and wherein said C 3-7 cycloalkyl is optionally substituted with C 1-4 alkyl or OH; each R 5 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, SC 1-6 alkyl, SOC 1-6 alkyl, SO 2 C 1-6 alkyl, COC 1-6 alkyl, NR 6 R 7 , CO 2 R 8 C 6-10 aryl, C 6-10 aryloxy, C 6-10 aryl C 1-2 alkyl, C 6-10 arylC 1-2 alkyloxy, CN, halogen or a 5
  • R 9 is H, C 1-6 alkyl, C 3-7 cycloalkyl or C 6-10 aryl;
  • R 9 is 1-2 substituents independently selected from H, C 1-4 alkyl and halogen or R 9 and the carbon to which it is bonded form a carbonyl group;
  • X 1 is NR 10 , CR 11 R 11' , O, S, SO or SO 2 ;
  • X 2 is NR 10' , O or CH 2 ;
  • d is an integer from 0 to 2 ;
  • Y 1 is N or CR 12 ;
  • Y 2 is N or CR 13 ;
  • Y 3 is N or CR 14 ;
  • Y 4 is N or CR 15 with the proviso that one or two of Y 1 -Y 4 must be N;
  • R 10 and R 10' are independently H, C 1-6 alkyl or COC 1-6 alkyl;
  • R 11 and R 11' are independently H or C 1-6 alkyl;
  • R 12 -R 15 are independently H, C 1-6 alkyl, C 1-6 alkyloxy, halogen, hydroxyl or CN;
  • L is a moiety selected from:
  • Z is O, S or NR 24 ;
  • R 16 and R 16 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 16 and R 16 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
  • R 17 and R 17 are independently H or C 1-6 alkyl optionally substituted with methyl, hyrdroxyl or halogen or R 17 and R 17 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
  • R 21 and R 21 are independently H or C 1-6 alkyl optionally substituted with methyl, hydroxyl or halogen or R 21 and R 21 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; f is 0 or 1 ;
  • R 22 is H or C 1-6 alkyl
  • R 23 and R 23 are independently H or C 1-6 alkyl optionally substituted with methyl, hydroxyl or halogen or R 23 and R 23 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen
  • R 24 is H, C 1-6 alkyl or COC 1-6 alkyl or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides pharmaceutical compositions and kits comprising the aforesaid compounds, and methods of treating or preventing chemokine-mediated disorders such as HIV.
  • C 1-6 alkyl represents a branched or unbranched alkyl group having 1-6 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary butyl and hexyl.
  • C 1-2 alkyl and C 1-4 alkyl represent a branched or unbranched alkyl group having 1 -2 and 1-4 carbon atoms respectively.
  • C 2-6 alkenyl represents a branched or unbranched alkenyl group having 2-6 carbon atoms. Examples of such groups are ethenyl and isopropenyl.
  • C 2-6 alkynyl represents a branched or unbranched alkynyl group having 2-6 carbon atoms. Examples of such groups are ethynyl and propynyl.
  • Ci-6alkyloxy represents a branched or unbranched alkyloxy group having 1-6 carbon atoms. Examples of such groups are methoxy, ethoxy, isopropyloxy and tertiary butyloxy.
  • C 6-10 aryl represents an aromatic group having
  • aromatic group comprising a single ring or two rings fused together at adjacent carbon atoms at least one of which must be aromatic.
  • aromatic groups include phenyl, indenyl and naphthyl.
  • C 6-10 aryloxy represents an OC 6-10 aryl group. Examples of such groups include phenyloxy, indenyloxy and naphthyloxy.
  • C 6-10 aryl C 1-2 alkyl represents a C 1-2 alkyl group which is substituted with a C 6-10 aryl group. Examples of such groups are benzyl and phenylethyl.
  • C 6-10 arylC 1-2 alkyloxy represents a C 1-2 alkyloxy group which is substituted with a C 6-10 aryl group. Examples of such groups are benzyloxy and phenylethyloxy.
  • C 3 -7cycloalkyl represents a branched or unbranched cyclic alkyl group having 3-7 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclopentyl.
  • SC 1-6 alkyl represents a thioalkyl group, for example a SCH 3 or SCH 2 CH 3 group.
  • SOC 1-6 alkyl represents an alkylsulfinyl group, for example a SOCH 3 or SOCH 2 CH 3 group and the term SO 2 C 1-6 alkyl, as used herein represents an alkylsulfonyl group, for example a SO 2 CH 3 or SO 2 CH 2 CH 3 group.
  • SO 2 C 1-6 alkyl represents an alkylsulfonyl group, for example a SO 2 CH 3 or SO 2 CH 2 CH 3 group.
  • COC 1-6 alkyl represents an alkylcarbonyl group, also known as a ketone group, for example a COCH 3 or COCH 2 CH 3 group.
  • halogen represents a F, Cl, Br or I atom.
  • solvate refers to a complex of variable stoichiometry formed by a solvent and a solute (in this invention, a compound of Formula I). Such solvents may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol and acetic acid.
  • Non-limiting examples of 5 to 10 membered heteroaryl ring systems comprising 1-3 heteroatoms independently selected from O, S and N include furan, pyrrole, thiophene, imidazole, pyrazole, thiazole, pyridine, pyrimidine, indole and benzthiophene.
  • Non-limiting examples of 5 to 6 membered heteroaryl ring systems comprising 1-2 heteroatoms independently selected from O, S and N include furan, pyrrole, thiophene, imidazole, pyrazole, thiazole, pyridine and pyrimidine.
  • R 1 in formula I or IA is
  • R 1 in formula I or IA is wherein Y 1 is N.
  • R 1 in formula I or IA is
  • Y 1 is N
  • Y 2 , Y 3 and Y 4 respectively are CR 13 , CR 14 , and CR 15 , i.e., R 1 in formula I or IA is
  • R 1 is
  • X 1 is NR 10 or CR 11 R 11' and R 9 -R 11' and R 13 -R 15 have the previously defined meanings.
  • R 1 in formula I or IA is
  • Y 1 is N
  • Y 2 and Y 3 respectively are CR 13 and CR 14 and Y 4 is N.
  • R 1 in formula I or IA is
  • Y 1 is N
  • Y 3 is N
  • Y 2 and Y 4 respectively are CR 13 and CR 15 .
  • R 1 in formula I or IA is
  • Y 1 and Y 3 respectivly are CR 12 and CR 14 , and Y 2 and Y 4 are N.
  • R 1 in formula I or IA is
  • Y 1 and Y 2 are N, and Y 3 and Y 4 respectively are CR 14 and CR 15 , i.e., R 1 in formula I or IA is
  • R 1 in formula I or IA is
  • Y 1 and Y 4 respectively are CR 12 and CR 15
  • Y 2 and Y 3 are N.
  • R 1 in formula I or IA is wherein Y 2 is N, and Y 1 , Y 3 , and Y 4 respectively are CR 12 , CR 14 and CR 15 , i.e., R 1 in formula I or IA is
  • R 1 in formula I or IA is
  • Y 1 is N, Y 2 , Y 3 and Y 4 respectively are CR 13 , CR 14 , and CR 15 , and wherein the compound of formula I or IA is a compound of the formula IX
  • X 1 is selected from the group consisting of a covalent bond, O, and NR 10 wherein R 10 is selected from the group consisting of H and C 1-6 alkyl.
  • b is 0, 1 or 2.
  • R 4 is selected from the group consisting of cyclohexyl, phenyl and pyridyl, wherein said phenyl or said pyridyl is optionally substituted with 1-3 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, isopropyl, trifluoromethyl, and trifluoromethoxy.
  • the compound of Formula IX is selected from the group consisting of:
  • R 1 is
  • R 1 is
  • d is 1 or 2
  • X 1 is NR 10
  • Y 1 is N
  • X 2 is CH 2 or O
  • Y 3 is CR 14
  • Y 4 is CR 15 .
  • R 1 is
  • R 1 is
  • R 9 , R 10 , R 14 and R 15 have the previously defined meanings.
  • R 1 is
  • R 9 , R 10 , R 14 and R 15 have the previously defined meanings.
  • R 1 is independently selected from
  • each R 2 and R 2 is independently H or C 1-4 alkyl. In another embodiment, each R 2 and R 2 is H or methyl. In another embodiment, each R 2 and R 2 is H.
  • a is 1 , 2 or 3. In another embodiment, a is 2. In another embodiment, a is 3.
  • R 3 is H or C 1-4 alkyl. In another embodiment, R 3 is H or methyl. In another embodiment R 3 is H.
  • b is 0. In another embodiment, b is 1.
  • R 4 is is C 6-10 aryl optionally substituted with 1-3 R 5 .
  • R 4 is C-6-ioaryl optionally substituted with 1-3 substituents independently selected from H, Ci-6alkyl, C 2 -6alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, SC 1-6 alkyl, SOC 1-6 alkyl, SO 2 C 1-6 alkyl, COC 1-6 alkyl, NR 6 R 7 , CO 2 R 8 , C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylC 1-2 alkyl, C 6-10 arylC 1-2 alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms independently selected from O, S and N, said C 1-6 alkyl, C 1-6 alkyloxy, SC 1-6 alkyl, and C3-7cyclo
  • R 4 is C 6-10 aryl optionally substituted with 1 -3 substituents independently selected from H, C 1-6 alkyl, C 3 - 7 Cycloalkyl, C 1- 6 alkyoxy, SC 1-6 alkyl, COC 1-6 alkyl, NR 6 R 7 , CO 2 R 8 , C 6-10 aryl, C 6-10 aryloxy, C 6 - ioarylC 1-2 alkyl, C6-ioarylC 1-2 alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1 -2 heteroatoms independently selected from O, S and N, said C 1-6 alkyl, C 1-6 alkyloxy, SC 1-6 alkyl, and C 3-7 cycloalkyl being optionally substituted with 1 or more halogens.
  • R 4 is C 6-10 aryl optionally substituted with 1-3 substituents independently selected from methyl, ethyl, isopropyl, thiomethyl, methoxy, dimethylamino, trifluoromethyl, chloro, fluoro, bromo, acetyl, phenyl or phenyloxy.
  • R 4 is a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N and optionally substituted with 1-3 substituents selected from H, C 1-6 alkyl, C 3 -7Cycloalkyl, C 1-6 alkyloxy, SC 1-6 alkyl, SOC 1-6 alkyl, SO 2 C 1-6 alkyl, COC 1-6 alkyl, NR 6 R 7 , CO 2 R 8 , C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylC 1-2 alkyl, C 6-10 arylC 1-2 alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1 -2 heteroatoms independently selected from O, S and N, said C 1-6 alkyl, C 1-6 alkyloxy, SC 1-6 alkyl and C 3 -7cycloalkyl being optionally substituted with 1 or more halogens.
  • R 4 is a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N and optionally substituted with 1-3 substituents selected from methyl, ethyl, isopropyl, thiomethyl, methoxy, dimethylamino, trifluoromethyl, chloro, fluoro, bromo, acetyl, phenyl or phenyloxy.
  • R 4 is C 3-7 cycloalkyl optionally substituted with C 1-4 alkyl or OH.
  • L is
  • R 16 , R 16 and z have the previously defined meanings.
  • L is
  • R 16 and R 16 have the previously defined meanings.
  • L is
  • R 16 and R 16 have the previously defined meanings.
  • L is
  • R 16 and R 16 are independently H, methyl or ethyl.
  • L is
  • L is
  • R 17 , R 17 , R 18 , R 18 , Z and e have the previously defined meanings.
  • L is
  • R 17 , R 17 , R 18 , R 18 and e have the previously defined meanings.
  • L is
  • R 17 , R 17 , R 18 , R 18 and e have the previously defined meanings.
  • L is
  • R 17 , R 17' , R 18 and R 18' are independently H, methyl or ethyl and wherein e has the previously defined meanings.
  • L is wherein R 17 and R 17 or R 18 and R 18 together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen and wherein e has the previously defined meanings.
  • L is
  • R 19 , R 19' , R 20 , R 20' , R 21 , R 21' and f have the previously defined meanings.
  • L is
  • R 19 , R 19' , R 20 , R 20' , R 21 and R 21' are independently H, methyl or ethyl and wherein f has the previously defined meanings.
  • L is
  • R 19 and R 19' or R 20 and R 20' or R 21 and R 21' together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen and wherein f has the previously defined meanings.
  • L is
  • R 22 has the previously defined meanings.
  • L is
  • R 22 is H, methyl or ethyl.
  • L is
  • R 23 and R 23 have the previously defined meanings.
  • L is
  • R 23 and R 23 are independently H, methyl or ethyl.
  • L is wherein R 23 and R 23 together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen.
  • R 4 , R 9' , R 10 , R 14 , R 15 , R 16 , R 16' and b have the previously defined meanings.
  • R 4 , R 9' , R 10 , R 14 , R 15 , R 16 , R 16' and b have the previously defined meanings.
  • R 4 , R 9' , R 10 , R 14 , R 15 , R 16 , R 16' and b have the previously defined meanings.
  • R 4 , R 9' , R 10 , R 14 , R 15 , R 16 , R 16' and b have the previously defined meanings.
  • R 3 and R 3 are independently H, C 1-4 alkyl, or C ⁇ -ioaryl.
  • R 3 and R 3 are independently H, methyl, or phenyl.
  • R 4 is selected from the group consisting of phenyl, thiophenyl, and naphthyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
  • R 9 ' is H
  • R 14 , R 15 , R 16 , and R 16' are all H.
  • R 9 ' is H
  • R 14 , R 15 , R 16 , and R 16' are all H.
  • the compound of formula HA is selected from the group consisting of:
  • the present invention provides a compound of formula IIB:
  • R 3 and R 3 are independently H.
  • R 4 is phenyl, which is optionally substituted with 1 -3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
  • R 9 ' is H, or R 9 ' and the carbon to which it is bonded form a carbonyl group ;
  • R 10 is H; and
  • R 14 , R 15 , R 16 , and R 16' are all H.
  • the compound of formula MB selected from the group consisting of: pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula HC:
  • R 4 , R 9> , R 10 , R 14 , R 15 , R 16 , and R 16' have the previously defined meanings.
  • R 3 and R 3 are independently H.
  • R 4 is phenyl, which is optionally substituted with 1 -3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
  • R 9 ' is H; R 10 is H; and R 14 , R 15 , R 16 , and R 16' are all H.
  • the compound of Formula HC is a compound of
  • R 4 , R 9' , R 10 , R 14 , R 15 , R 16 and R 16' have the previously defined meanings.
  • R 4 is selected from the group consisting of phenyl, naphthyl, indanyl, indolyl, isoxazolyl, cyclohexyl,
  • R 9 ' is H
  • R 14 and R 15 are H
  • R 16 , and R 16 are independently H or alkyl.
  • the compound of formula III' is selected from the group consisting of:
  • the present invention provides a compound of the formula IHA
  • R 4 is selected from the group consisting of phenyl, naphthyl, indanyl, isoxazolyl, and
  • R 9 ', R 10 , R 14 , R 15 , R 16 , and R 16> are all H.
  • the compound of formula MIA is selected from the group consisting of:
  • the present invention provides a compound of formula IV,
  • R 4 , R 9 , R 10 , R 14 , R 15 , R 18 and b have the previously defined meanings.
  • b is 1 or 2.
  • R 4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro, methoxy, and fluoro.
  • R 9> , R 10 , R 14 , R 15 , and R 18 are all H.
  • the compound of formula IV is selected from the group consisting of:
  • the present invention provides a compound of formula V,
  • b is 0 or 1.
  • R 4 is phenyl which is optionally substituted with 1 -3 substituents selected from the group consisting of chloro and trifluorom ethyl.
  • R 9' , R 1 0 , R 14 , and R 1 5 are all H;
  • R 1 ' is H or methyl.
  • the compound of formula V from the group consisting of: thereof.
  • the present invention provides a compound of formula Vl,
  • R 9' , R 10 , R 14 , R 15 , and R 21 are all
  • the compound of formula Vl is selected from the group consisting of:
  • the present invention provides a compound of formula VII,
  • R 4 , R 9 , R 10 , R 14 , R 15 , R 22 and b have the previously defined meanings.
  • b is 0.
  • R 4 is selected from the group consisting of phenyl and naphthyl, each of which independently is optionally substituted with 1 -3 substituents selected from the group consisting of: trifluoromethyl, chloro, bromo, and methyl.
  • R 9' , R 10 , R 14 , and R 15 are all H and R 22 is H or methyl.
  • the compound of formula VIII is selected from the group consisting of:
  • R 1 is
  • R 1 is
  • X 1 is NR 10 .
  • R 1 is
  • R 1 is
  • R aa is H
  • R 1 is
  • R 9b is H.
  • the present invention provides a compound of the formula X
  • R 4 , R 16 , and R 16 have the previously defined meanings.
  • R 4 is selected from the group consisting of phenyl, indolyl, naphthyl, each of which independently is optionally substituted with 1-3 substituents selectd from the group consisting of trifluoromethyl, chloro, methoxy, isopropyl, bromo, and methyl.
  • R 16 and R 16 are both H.
  • the compound of Formula X is selected from the group
  • the present invention provides a compound of formula Xl
  • R 4 is selected from the group phenyl and napthyl each of which is independently optionally substituted with 1- 3 substituents selected from the group consisting of: bromo, methyl, trifluoromethyl, methoxy, and chloro.
  • R 22 is H.
  • the compound of Formula Xl is selected from the group consisting of: thereof.
  • the present invention provides a compound of the formula Xl
  • R 4 is selected from the group phenyl and napthyl each of which is independently optionally substituted with 1- 3 substituents selected from the group consisting of: bromo, methyl, trifluoromethyl, methoxy, and chloro.
  • R 22 is H.
  • the compound of Formula Xl is selected from the group consisting of:
  • R 1 is
  • R 1 is
  • R 1 is wherein d is 1.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 9b is H.
  • the present invention provides a compound of the formula XI
  • R 2 , R 2 , R 5 , R 16 , and R 16 have the previously defined meanings.
  • a is 2, and R 2 and R 2 are independently H and methyl.
  • R 5 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro and trifluoromethyl.
  • the compound of Formula Xl is selected from the group consisting of:
  • R 1 is
  • R 1 is
  • R 1 is
  • R 9a and R 9b are both H.
  • the present invention provides a compound of the formula XII:
  • R 4 is phenyl which is optionally substituted with a trifluoromethyl.
  • R 16 and R 16 are both H.
  • the compound of Formula XII is
  • R 1 is
  • R 4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of trifluoromethyl and chloro.
  • R 16 and R 16 are both H.
  • the compound of Formula XIII is selected from the group consisting of:
  • R 1 is
  • Y 1 is CR 12
  • Y 2 is CR 13
  • Y 3 is CR 14
  • Y 4 is CR 15 .
  • the present invention provides a compound of the formula XIV
  • b, R 3 , R 3 , R 4 , R 16 , and R 16 have the previously defined meanings.
  • b is 1.
  • R 3 and R 3 are both H.
  • R 16 and R 16 are both H.
  • R 4 is phenyl which is optionally substituted with 1-3 chloro substituents.
  • the compound of Formula XIV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the present invention provides a compound of the formula XV
  • b, R 3 , R 3 , R 4 , R 16 , and R 16 have the previously defined meanings.
  • b is 1.
  • R 3 and R 3 are both H.
  • R and R are both H.
  • R 4 is phenyl which is optionally substituted with 1-3 chloro substituents.
  • the compound of formula XV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compounds of Formula I are prepared by methods well known in the art of organic chemistry, see for example, J. March, 'Advanced Organic Chemistry' 4 th Edition, John Wiley and Sons. Specific synthetic routes are described in the generalized Schemes 1-6 depicted below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P. G. M. Wutts 'Protective Groups in Organic Synthesis' 3 rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art of organic chemistry.
  • isocyanates can be conveniently prepared in situ by reaction of a suitably functionalised carboxylic acid with, for example, diphenylphosphoryl azide (DPPA) in the presence of a suitable base, for example di-isopropylethylamine (DIPEA).
  • DPPA diphenylphosphoryl azide
  • DIPEA di-isopropylethylamine
  • Z is O, S, NR Scheme 1
  • a resin bound amine prepared by coupling a resin bound aldehyde with a suitable amine in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride and in a suitable solvent system, for example acetic acid and dichloroethane
  • a suitable reducing agent for example sodium triacetoxyborohydride and in a suitable solvent system, for example acetic acid and dichloroethane
  • an isocyanate to form a resin bound urea which is subsequently cleaved under acidic conditions (for example, using trifluoroacetic acid) to provide the desired urea product.
  • isocyanate may be prepared in situ by reaction of a suitably functionalised carboxylic acid with diphenylphosphoryl azide (DPPA) in the presence of a suitable base, for example di-isopropylethylamine (DIPEA).
  • DPPA diphenylphosphoryl azide
  • DIPEA di-isopropylethylamine
  • a suitably functionalised carboxylic acid is coupled with a suitably functionalised amine in the prersence of a suitable coupling agent, for example, O-(7- Azabenzotriazole-1 -yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate (HATU) and in the presence of a suitable base, for example, di- isopropylethylamine (DIPEA) and solvent, for example N,N-dimethylformamide (DMF).
  • a suitable coupling agent for example, O-(7- Azabenzotriazole-1 -yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate (HATU) and in the presence of a suitable base, for example, di- isopropylethylamine (DIPEA) and solvent, for example N,N-dimethylformamide (DMF).
  • DIPEA di- isopropylethyl
  • the present invention also includes within its scope all stereoisomeric forms of the compounds of Formula I resulting, for example, because of configurational isomerism. Such stereoisomeric forms are enantiomers, or diastereoisomers.
  • 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.
  • 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.
  • the compound exists as a pair of enantiomers.
  • the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other enantiomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present 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.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • 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
  • 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
  • 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).
  • salt 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.
  • chiral compounds For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g., synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.
  • 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.
  • 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.
  • 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 compound is at least 90% pure, in another embodiment at least 95% pure, and in another embodiment, at least 99% pure.
  • the present invention further includes the compound of formula I in all its isolated forms.
  • 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.
  • 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.
  • 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. CS. 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 (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.
  • 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, (C 1 -C 8 )alkyl, (C 2 -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, 1 -methyl-1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6 )alkanoyloxymethyl, 1-((C r C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C r C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl,(C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ - aminoacyl-u-aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)
  • 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 (C 1 -C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 -C 6 )alkyl, carboxy (C 1- C 6 )alkyl, amino(C 1 -C 4 )alkyl or mono-N —
  • R-carbonyl RO-carbonyl
  • 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 H20.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et a! J. Pharmaceutical Sci., 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, 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.
  • 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, bisulfates, 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.
  • 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 quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • 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, C1-4alkyl, or C1-4alkoxy 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) phosphoric acid
  • 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.
  • 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.
  • 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 O, 17 O, 31 P, 32 P 1 35 S, 18 F 1 36 CI and 123 I, 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.
  • 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 I can be useful for application in Single photon emission computed tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single photon emission computed tomography
  • 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
  • lsotopically labeled compounds of Formula (I) in particular those containing isotopes with longer half lives (T1/2 >1 day)
  • 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.
  • 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.
  • 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, 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,
  • 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 a/., Remmington: The Science and Practice of Pharmacy, 20 th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing.
  • pharmaceutically acceptable excipients such as the ones described in Gennaro et a/., Remmington: The Science and Practice of Pharmacy, 20 th 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, 2 nd Edition; Editors A. Wade and P.J.Well
  • 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.
  • 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.
  • dosage units e.g., tablets
  • 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-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.
  • the combinations known as HAART Highly Active Anti retroviral Therapy
  • CCR5 antagonist 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).
  • nucleoside and nucleotide reverse transcriptase inhibitors 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, NJ 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Welicome Research Triangle, NC 27709; abacavir (1592U89) 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
  • NNRTI 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 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 furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater NJ 08807; AG-1549 (formerly Shionogi # S-1 153); 5-(3,
  • HIV protease inhibitor 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., LaJoIIa CA 92037-1020; amprenavir (141W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, MA 02139-4211 and available from Glaxo-Wellcome, Research Triangle, NC under an expanded access program; lasina
  • antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Hydroxyurea Droxia
  • Droxia a ribonucleoside triphosphate reductase inhibitor
  • 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 IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred.
  • IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, NJ 071 10-1199 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
  • Pentafuside 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. 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- ⁇ -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. 4,211 ,771.
  • 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 Pl, a second Pl, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from , NNRTIs and PIs.
  • Typical suitable HAART - multidrug combination therapies include:
  • 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.
  • 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, 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. 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.
  • Final compounds were purified by PrepLC using the column of Varian Pursuit XRs C18 10 ⁇ m 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 H 2 O and the mobile phase B is composed of CH 3 CN (95%) / H 2 O (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.
  • Acetic acid (AcOH), N,N-Dimethylformamide (DMF), dichloroethane (DCE), dichloromethane (DCM), dimethylsuphoxide (DMSO), diphenylphosphoryl azide (DPPA), ethanol (EtOH), ethyl acetate (EtOAc), 0-(7-Azabenzotriazole-1- yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate (HATU), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (TEA), trifluoroacetic acid (TFA), water (H 2 O) and StratospheresTM 4-formyl-3,5-dimethoxyphenoxy resin (PL-FDMP) Preparation of Examples 1-1 - 1-124.
  • the amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine for Example 1.1) was weighed into a 4 mt_ scintillation vial and then dissolved in 0.5 mt_ 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 mt_ scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • Step 1 A solution of diphenylphosphoryl azide (1.1O g, 4.0 mmol) in anhydrous methylene chloride (5 mL) was added dropwise to a solution of 3-(8-(tert- butoxycarbonyl)-5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)propanoic acid (1.22 g, 4.0 mmol) and diisopropylethylamine (0.86 mL, 4.0 mmol) in anhydrous methylene chloride (10 mL) at 0 °C under nitrogen, after which the mixture was slowly warmed to room temperature, stirring for a total of 2 h.
  • Step 3 Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 7-(2-(3- benzo[d]oxazol-4-ylureido)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)- carboxylate (65 mg, 0.15 mmol) in anhydrous methylene chloride (1 mL) at room temperature under nitrogen, and the mixture was stirred for 3 h. The solvents were removed under reduced pressure and the residue was dissolved in anhydrous methanol at room temperature under nitrogen.
  • Macroporous triethylammonium methylpolystyrene carbonate (1 g) was added and the mixture was stirred for 30 min. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 1 -(benzo[ ⁇ xazol-4-yl)-3-(2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)urea (20 mg, 40%) as a white solid: 1 H NMR (300 MHz, CDCI 3 ) ⁇ 8.03-7.98 (m, 2H), 7.64 (s, 1H), 7.32 (t, 1H), 7.18 (d, 1H), 7.05 (d, 1 H), 6.36 (d, 1 H), 6.09 (br s, 1 H), 5.03 (br s, 1 H), 3.67-3.
  • 3,4-Dichlorobenzyl isothiocyanate (123 mg, 0.56 mmol) was added to a solution of 2-(5,6,7 ) 8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine (100 mg, 0.56 mmol) and diisopropylethylamine (0.12 mL, 0.68 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen, and the mixture was stirred for 5 h. Silica gel (5 g) was added to the mixture and the solvent was removed under reduced pressure.
  • Step 1 A solution of carbonyl diimidazole (380 mg, 3.4 mmol) in anhydrous methylene chloride (2 mL) was added to a solution of 1-(3,4-dichlorophenyl)-N- methylmethanamine (560 mg, 2.0 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen and the mixture was stirred for 1 h.
  • Step 2 lodomethane (0.19 mL, 3.04 mmol) was added dropwise to a solution of N-(3,4-dichlorobenzyl)-A/-methyl-1 H-imidazole-1-carboxamide (205 mg, 0.76 mmol) in anhydrous acetonitrile at room temperature under nitrogen and the mixture was stirred for 20 h. The solvent was removed under reduced pressure to provide 1-((3,4-dichlorobenzyl)(methyl)carbamoyl)-3-methyl-1 H-imidazol-3- ium iodide as a yellow oil (201 mg, 63%) that was used in the next step without further purification.
  • Step 3 A mixture of 1-((3,4-dichlorobenzyl)(methyl)carbamoyl)-3-methyl-1 H- imidazol-3-ium iodide (160 mg, 0.38 mmol), N-methyl-2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine (40 mg, 0.21 mmol) and resin-bound diisopropylethylamine (200 mg, 0.80 mmol) in anhydrous dichloroethane was stirred at room temperature under nitrogen for 12 h. The solids were removed by filtration and the filtrate solvents were removed under reduced pressure.
  • the amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethanamine for Example 2.1) 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 the amine dissolved. Triethylamine (0.36 mmol) was then added.
  • the isocyanate component (0.05 mmol) (4-trifluoromethylphenylisocyanate for Example 2.1) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • Step C Cleavage of the Urea Product from the Resin.
  • To each resin in a Bohdan tube was added 1.5 mL of 95% TFA/H 2 O at rt for 2 h.
  • the resin was filtered and washed with acetonitrile (1 mL).
  • Water (1 mL) was added and the filtrate was savanted to dryness.
  • the residue was dissolved in acetonitrile (1 mL), followed by the addition of water (1 mL) and the mixture was shaken at rt for 2 h and then lyophilized.
  • 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)), allowed to shake for 1 h at rt and further purified by HPLC using the general purification conditions descriobed above to provide the desired products.
  • the amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine for Example 4.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then placed in a 4mL scintillation vial and added to 0.36 mmol of DIPEA. The vial was stirred until dissolved.
  • the acid component (0.1 mmol) (3,4-dichlorophenylacetic acid for Example 4.1) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • Carbonyldiimidazole (96 mg, 0.59 mmol) was added in one portion to a suspension of 2-(3-fluorophenylamino)acetic acid (100 mg, 0.59 mmol) in anhydrous methylene chloride (2 mL) at 0 °C under nitrogen and the resulting mixture was stirred for 30 min.
  • a solution of 2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine (104 mg, 0.59 mmol) in anhydrous methylene chloride (1 mL) was added and the resulting mixture was slowly warmed to room temperature, stirring for a total of 8 h.
  • the amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethanamine for Example 5.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then added to triethylamine (0.36 mmol) cooled at 0 °C in an ice bath.
  • the sulfonyl chloride component (0.05 mmol) (4- trifluorophenylsulfonyl chloride for Example 5.1) was then weighed into a 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • the amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethanamine for Example 6.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then added to triethylamine (0.36 mmol) cooled at 0 °C in an ice bath.
  • the chloroformate component (0.05 mmol) (3-trifluorophenyl chloroformate for Example 6.1) was then weighed into a 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • Step 1 A solution of fe/t-butyl 7-(2-methoxy-2-oxoethyl)-3,4-dihydro-1 ,8- naphthyridine-1 (2H)-carboxylate (150 mg, 0.50 mmol) in anhydrous THF (3 mL) was added dropwise to a suspension of sodium borohydride (38 mg, 1.0 mmol) and lithium chloride (43 mg, 1.0 mmol) in ethanol (4.5 mL) at 0 °C under nitrogen after which the mixture was slowly warmed to room temperature, stirring for a total of 14 h. The solids were removed by vacuum filtration, washing with ethanol.
  • Step 2 A solution of 3-fluorophenyl isocyanate (353 mg, 0.25 mmol) in anhydrous methylene chloride (1 mL) was added to a solution of fe/t-butyl 7-(2- hydroxyethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)-carboxylate (65 mg, 0.23 mmol) and pyridine (20 mg, 0.25 mmol) in anhydrous methylene chloride (5 mL) at 0 °C under nitrogen after which the mixture was slowly warmed to room temperature, stirring for a total of 28 h.
  • Step 3 Trifluoroacetic acid (1 mL) was added to a solution of fe/t-butyl 7-(2-(3- fluorophenylcarbamoyloxy)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)- carboxylate (80 mg, 0.19 mmol) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen and the mixture was stirred for 16 h. The solvent was removed under reduced pressure and the residue was diluted with anhydrous methanol (10 mL), macroporous triethylammonium methylpolystyrene carbonate (1 g) was added and the mixture was stirred for 10 min.
  • Acetic anhydride (0.06 mL, 0.6 mmol) was added to a mixture of 1-(3,4- dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (115 mg, 0.30 mmol) and triethylamine (0.12 mL, 0.90 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen and the mixture was heated at reflux for 48 h.
  • Step 1 A solution of 2-bromoethanol (0.64 mL, 9.0 mmol) in anhydrous methylene chloride (5 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (0.78 mL, 9.0 mmol) in anhydrous methylene chloride (18 mL) at 0 °C under nitrogen and the mixture was stirred for 30 min.
  • Step 3 Triethylamine (0.04 mL, 0.2 mmol) was added to a mixture of provide N-(3,4-dichlorobenzyl)-2-oxooxazolidine-3-sulfonamide (33 mg, 0.10 mmol), 2- (5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine hydrochloride (21 mg, 0.10 mmol) and resin-bound diisopropylethylamine (50 mg, 0.20 mmol) in anhydrous acetonitrile (2 mL) at room temperature under nitrogen and the mixture was heated at 75 °C for 12 h.
  • Example 12 Preparation of Examples 12-1 - 12-51
  • Method 12 Preparation of 1-(3,4-dichlorobenzyl)-3-(2-(6- (methylamino)pyridin-2-yl)ethyl)urea (12-1 )
  • Step 1 A solution of 9-BBN dimmer (8.0 mL, 4.0 mmoi, 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.
  • 9-BBN dimmer 8.0 mL, 4.0 mmoi, 0.5 M solution in THF
  • 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 warmed to room temperature, stirring for a total of 24 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. Many of the above-noted compounds exhibited AC-MS based Kd values above 3 ⁇ M in this assay, whilst several others exhibited Kd values ranging from 3 ⁇ M to less than 500 nM.
  • Luciferase reporter viruses (ADA, YU-2) were generated as described by Connor et al. (J. Virol., 1996, 70, 5206-5311). Primary H IV-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.
  • 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 10 6 /ml 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 50 ) per well of an HIV-1 primary isolate for 3-4 h.
  • the cells were washed twice in PBS to remove residual virus and cultured in the presence of inhibitor for 4-6 days. HIV-1 replication was quantitatied by measurement of extracellular p24 antigen by ELISA.
  • the IC 50 and IC 90 values for each virus were determined by using GRPAHPAD PRISM software. Chemotaxis
  • 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.
  • the compounds of the present invention have IC5 0 values of less than 5 uM ( ⁇ 5 ⁇ M), in another embodiment, they range from 5 uM to 20 ⁇ M, in another embodiment from 20 ⁇ M to 50 uM, and in another embodiment, more than 50 ⁇ M (>50 ⁇ M).
  • the compounds in table 1 below were prepared according to the experimental procedures set forth above.

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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

COMPOUNDS USEFUL AS HIV BLOCKERS
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 HIV, 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 ah, 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, 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-1 beta) 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., Ce// 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 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. 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-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.
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 θt 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 CCR5 antagonists that inhibit receptor function and gp120 binding (Westby et al., J. Virol. 80, 4909-4920 (2006)). Maraviroc and two other CCR5 antagonists vicriviroc (Strizki et al., Antimicrob. Agents Chemother. 49, 491 1-4919)) and aplaviroc do not directly compete with gp120 for binding, but instead function as allosteric inhibitors that stabilize a confirmation of CCR5 that is unfavorable for gp120 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
Figure imgf000005_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from the group consisting of:
Figure imgf000005_0002
Figure imgf000006_0001
and wherein: each R2 and R2 is independently H, C1-4alkyl or C3-7cycloalkyl, said C1-4alkyl and C3-7cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R2 and R2 together with the carbon or carbons to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; a is an integer from 1-3;
R3 and R3 are independently H, C1-4alkyl, C3-7cycloalkyl, or C6-10aryl, each of which is independently optionally substituted with methyl, hydroxyl or halogen or R3 and R3 together with the carbon to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; b is 0, 1 or 2; R4 is C6-10aryl, C3-7cycloalkyl or a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N, wherein said C6-10aryl and 5-10 membered heteroaryl ring system are optionally substituted with 1 -3 R5 and wherein said C3-7cycloalkyl is optionally substituted with C1-4alkyl or OH; each R5 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkyloxy, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, COC1-6alkyl, NR6R7, CO2R8 C6-10aryl, C6-10aryloxy, C6-10arylC1-2alkyl, C6-10arylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1- 6alkyl and C3-7cycloalkyl being optionally substituted with 1 or more halogens or two adjacent R5 together form -O-(CH2)C-O, wherein c is an integer from 1 to 3; R6 and R7 are independently H or C1-6alkyl, optionally substituted with methyl, hydroxyl or halogen or R6 and R7 together with the N to which they are bonded form a 5-7 membered heterocyclic ring optionally substituted with methyl, hydroxyl or halogen; each R8 independently is H, C1-6alkyl;
R9 is H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl or a 5-10 membered heteroaryl ring system comprising 1 -2 heteroatoms independently selected from O, S and N, wherein each of said C1-6alkyl, C3-7cycloalkyl, C6-10aryl or 5-10 membered heteroaryl ring system independently is optionally substituted with 1-3 R5; R9 is 1-2 substituents independently selected from H, C1-4alkyl and halogen or R^ and the carbon to which it is bonded form a carbonyl group; each R9a independently is 1-2 substituents independently selected from the group consisting of H and C1-6alkyl; each R9b independently is 1 -2 substituents independently selected from the group consisting of H and C1-6alkyl; each X1 independently is a covalent bond, NR10, CR11R11', O, S, SO or SO2; X2 is NR10', O or CH2; X3 is N or S; d is an integer from 0 to 2 ; each Y1 independently is N or CR12; each Y2 independently is N or CR13; each Y3 independently is N or CR14; each Y4 independently is N or CR15 with the proviso that one or two of Y1 -Y4 must be N; R10 and R10' are independently H, C1-6alkyl, -C(=O)C1-6alkyl wherein said C1- 6alkyl is optionally substituted with a halogen, -C(=O)OC1-6alkyl, -C(=O)C6- iOaryl, -S(=O)2C1-6alkyl, -S(=0)2C6-10aryl, and -C(=O)NR8- C6-10aryl wherein said C6-10aryl is optionally substituted with at least 1-3 substituents selected from the group consisting of fluoro, difluoromethoxy, and phenoxy; R11 and R11' are independently H or C1-6alkyl; R12-R15 are independently H, C1-6alkyl, C1-6alkyloxy, halogen, hydroxyl or CN; L is a moiety selected from:
Figure imgf000008_0001
Figure imgf000008_0002
Z is O, S or NR24; R16 and R16' are independently H, -C(=O)NR8C6-10aryl or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R16 and R16 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R17 and R17 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R17 and R17 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R18 and R18 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R18 and R18 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; e is 0 or 1 ; R19 and R19 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R19 and R19' together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R20 and R20 are independently H or Chalky! optionally substituted with methyl, hyrdroxyl or halogen or R20 and R20 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R21 and R21 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R21 and R21 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; f is O or 1 ;
R22 is H or C1-6alkyl; R23 and R23 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R23 and R23 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R24 is H, C1-6alkyl or COC1-6alkyl or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the present invention provides a compound of Formula IA:
Figure imgf000009_0001
wherein, R1 is
Figure imgf000010_0001
V
each R2 and R2 is independently H, C1-4alkyl or C3-7cycloalkyl, said C1-4alkyl and C3-7cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R2 and R2 together with the carbon or carbons to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; a is an integer from 1 -3; R3 and R3 are independently H, C1-4alkyl or C3-7cycloalkyl said C1-4alkyl and C3-7cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R3 and R3 together with the carbon to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; b is O or i ;
R4 is C6-10aryl, C3-7cycloalkyl or a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N, wherein said C6-10aryl and 5-10 membered heteroaryl ring system are optionally substituted with 1 -3 R5 and wherein said C3-7cycloalkyl is optionally substituted with C1-4alkyl or OH; each R5 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkyloxy, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, COC1-6alkyl, NR6R7, CO2R8 C6-10aryl, C6-10aryloxy, C6-10aryl C1-2alkyl, C6-10arylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1- 6alkyl and C3-7cycloalkyl being optionally substituted with 1 or more halogens or two adjacent R5 together form -0-(CH2)C-O, wherein c is an integer from 1 to 3; R6 and R7 are independently H or C1-6alkyl, optionally substituted with methyl, hydroxyl or halogen or R6 and R7 together with the N to which they are bonded form a 5-7 membered heterocyclic ring optionally substituted with methyl, hydroxyl or halogen; R8 is H or C1-6alkyl;
R9 is H, C1-6alkyl, C3-7cycloalkyl or C6-10aryl;
R9 is 1-2 substituents independently selected from H, C1-4alkyl and halogen or R9 and the carbon to which it is bonded form a carbonyl group; X1 is NR10, CR11R11', O, S, SO or SO2; X2 is NR10', O or CH2; d is an integer from 0 to 2 ; Y1 is N or CR12; Y2 is N or CR13; Y3 is N or CR14;
Y4 is N or CR15 with the proviso that one or two of Y1-Y4 must be N; R10 and R10' are independently H, C1-6alkyl or COC1-6alkyl; R11 and R11' are independently H or C1-6alkyl; R12-R15 are independently H, C1-6alkyl, C1-6alkyloxy, halogen, hydroxyl or CN; L is a moiety selected from:
Figure imgf000012_0001
Figure imgf000012_0002
Z is O, S or NR24; R16 and R16 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R16 and R16 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R17 and R17 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R17 and R17 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R18 and R18 are independently H or C1-6alkyl optionally substituted with methyl, hydroxyl or halogen or R18 and R18 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; e is 0 or 1 ; R and R are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R19 and R19 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R20 and R20 are independently H or C1-6alkyl optionally substituted with methyl, hydroxyl or halogen or R20 and R20' together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R21 and R21 are independently H or C1-6alkyl optionally substituted with methyl, hydroxyl or halogen or R21 and R21 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; f is 0 or 1 ;
R22 is H or C1-6alkyl; R23 and R23 are independently H or C1-6alkyl optionally substituted with methyl, hydroxyl or halogen or R23 and R23 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R24 is H, C1-6alkyl or COC1-6alkyl or a pharmaceutically acceptable salt or solvate thereof.
The present invention also provides pharmaceutical compositions and kits comprising the aforesaid compounds, and methods of treating or preventing chemokine-mediated disorders such as HIV.
Description of the Invention
The term C1-6alkyl, as used herein, represents a branched or unbranched alkyl group having 1-6 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary butyl and hexyl. Similarly the terms C1-2alkyl and C1-4alkyl, as used herein, represent a branched or unbranched alkyl group having 1 -2 and 1-4 carbon atoms respectively. The term C2-6alkenyl, as used herein, represents a branched or unbranched alkenyl group having 2-6 carbon atoms. Examples of such groups are ethenyl and isopropenyl.
The term C2-6alkynyl, as used herein, represents a branched or unbranched alkynyl group having 2-6 carbon atoms. Examples of such groups are ethynyl and propynyl.
The term Ci-6alkyloxy, as used herein, represents a branched or unbranched alkyloxy group having 1-6 carbon atoms. Examples of such groups are methoxy, ethoxy, isopropyloxy and tertiary butyloxy. The term C6-10aryl, as used herein, represents an aromatic group having
6-10 carbon atoms, said aromatic group comprising a single ring or two rings fused together at adjacent carbon atoms at least one of which must be aromatic. Examples of such groups include phenyl, indenyl and naphthyl.
The term C6-10aryloxy, as used herein, represents an OC6-10aryl group. Examples of such groups include phenyloxy, indenyloxy and naphthyloxy.
The term C6-10aryl C1-2alkyl, as used herein, represents a C1-2alkyl group which is substituted with a C6-10aryl group. Examples of such groups are benzyl and phenylethyl.
The term C6-10arylC1-2alkyloxy, as used herein, represents a C1-2alkyloxy group which is substituted with a C6-10aryl group. Examples of such groups are benzyloxy and phenylethyloxy.
The term C3-7cycloalkyl, as used herein, represents a branched or unbranched cyclic alkyl group having 3-7 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclopentyl. The term SC1-6alkyl, as used herein represents a thioalkyl group, for example a SCH3 or SCH2CH3 group. Similarly the term SOC1-6alkyl, as used herein represents an alkylsulfinyl group, for example a SOCH3 or SOCH2CH3 group and the term SO2C1-6alkyl, as used herein represents an alkylsulfonyl group, for example a SO2CH3 or SO2CH2CH3 group. The term COC1-6alkyl, as used herein represents an alkylcarbonyl group, also known as a ketone group, for example a COCH3 or COCH2CH3 group.
The term halogen, as used herein, represents a F, Cl, Br or I atom.
The term solvate, as used herein, refers to a complex of variable stoichiometry formed by a solvent and a solute (in this invention, a compound of Formula I). Such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid.
Non-limiting examples of 5 to 10 membered heteroaryl ring systems comprising 1-3 heteroatoms independently selected from O, S and N include furan, pyrrole, thiophene, imidazole, pyrazole, thiazole, pyridine, pyrimidine, indole and benzthiophene.
Non-limiting examples of 5 to 6 membered heteroaryl ring systems comprising 1-2 heteroatoms independently selected from O, S and N include furan, pyrrole, thiophene, imidazole, pyrazole, thiazole, pyridine and pyrimidine.
The skilled person will appreciate that when either b, e or f is 0, the groups attached to the respective carbons either side of the carbon to which the b, e, or f refers are directly bonded. Thus, for example, when b is 0, L is directly bonded to R4. The skilled person will also appreciate that the moieties shown for L are attached to formula I or IA in the direction from left to right as shown on the page.
In one embodiment of the present invention, R1 in formula I or IA is
Figure imgf000015_0001
wherein X1, Y1-Y4 and R9 have the previously defined meanings as set forth for formula I or IA .
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000016_0001
wherein Y1 is N.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000016_0002
wherein Y1 is N, and Y2, Y3 and Y4 respectively are CR13, CR14, and CR15 , i.e., R1 in formula I or IA is
Figure imgf000016_0003
wherein X1, R9 and R13-R15 have the previously defined meanings. In another embodiment, R1 is
Figure imgf000016_0004
wherein X1 is NR10 or CR11R11' and R9-R11' and R13-R15 have the previously defined meanings.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000016_0005
wherein Y1 is N, Y2 and Y3 respectively are CR13 and CR14 and Y4 is N. In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000017_0001
wherein Y1 is N, Y3 is N, and Y2 and Y4 respectively are CR13 and CR15.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000017_0002
wherein Y1 and Y3 respectivly are CR12 and CR14, and Y2 and Y4 are N.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000017_0003
wherein Y1 and Y2 are N, and Y3 and Y4 respectively are CR14 and CR15, i.e., R1 in formula I or IA is
Figure imgf000017_0004
wherein X1, R9 , R14 and R15 have the previously defined meanings.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000017_0005
wherein Y1 and Y4 respectively are CR12 and CR15, and Y2 and Y3 are N.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000018_0001
wherein Y2 is N, and Y1, Y3, and Y4 respectively are CR12, CR14 and CR15, i.e., R1 in formula I or IA is
Figure imgf000018_0002
wherein X1, R9, R12, R14 and R15 have the previously defined meanings.
In another embodiment of the present invention, R1 in formula I or IA is
Figure imgf000018_0003
wherein Y1 is N, Y2, Y3 and Y4 respectively are CR13, CR14, and CR15, and wherein the compound of formula I or IA is a compound of the formula IX
Figure imgf000018_0004
F wherein b, X1, R3, R3', R4, R9, R14, R15, R16 and R16' are as defined in formula I or IA.
In another embodiment of the present invention, in Formula IX, X1 is selected from the group consisting of a covalent bond, O, and NR10 wherein R10 is selected from the group consisting of H and C1-6alkyl. In another embodiment of the present invention, in Formula IX, R9 is selected from the group consisting of H, C1-6alkyl, -C(=O)-O-C1-6alkyl, -C(=O)- C1-6alkyl, and a 5-10 membered heteroaryl ring sytem comprising 1-3 heteroatoms independently sleected from the group consisting of O, S and N, wherein said 5-10 membered heteroaryl ring sytem is optionally substituted with 1-3 C1-6alkyl substituents.
In another embodiment of the present invention, in Formula IX, R9 is selected from the group consisting of H, C1-6alkyl, -C(=O)-O-C1-6alkyl, -C(=O)- C1-6alkyl, and a 5-10 membered heteroaryl ring sytem comprising 1-3 heteroatoms independently sleected from the group consisting of O, S and N, wherein said 5-10 membered heteroaryl ring sytem is optionally substituted with 1-3 C1-6alkyl substituents, wherein said 5-10 membered heteroaryl ring sytem is selected from the group consisting of imidazolyl, pyrazolyl, benzimidazolyl, pyridopyrazolyl, each of which independently is optionally substituted with 1-3 C1-6alkyl substituents.
In another embodiment of the present invention, in Formula IX, b is 0, 1 or 2.
In another embodiment of the present invention, in Formula IX, R3, R3 , R14, R15, R16 are all H, and R16' is H or -C(=O)-NH-C6-10aryl, wherein said said C6-10aryl is optionally substituted with a halogen.
In another embodiment of the present invention, in Formula IX, R4 is selected from the group consisting of cyclohexyl, phenyl and pyridyl, wherein said phenyl or said pyridyl is optionally substituted with 1-3 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, isopropyl, trifluoromethyl, and trifluoromethoxy.
In another embodiment of the present invention, the compound of Formula IX is selected from the group consisting of:
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0002
or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment of the present invention, in formula I or IA, R1 is
Figure imgf000022_0003
wherein X1, X2, Y1, Y3, Y4, R9 and d have the previously defined meanings as set forth in formula I or IA.
In another embodiment of the present invention, in formula I or IA, R1 is
Figure imgf000022_0004
wherein d is 1 or 2, X1 is NR10, Y1 is N, X2 is CH2 or O; Y3 is CR14 and Y4 is CR15.
In a further embodiment of the present invention, R1 is
Figure imgf000023_0001
wherein X1, X2, R9 , R14, R15 and d have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000023_0002
wherein X1, X2, R9 , R12, R14 and d have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000023_0003
wherein X , X , R , R , R and d have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000023_0004
wherein X1, X2, R9', R15, and have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000024_0001
wherein X1, X2, R9, R14 and d have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000024_0002
wherein R9 , R10, R14 and R15 have the previously defined meanings. In a further embodiment of the present invention, R1 is
Figure imgf000024_0003
wherein R9 , R10, R14 and R15 have the previously defined meanings. In a further embodiment of the present invention, R1 is independently selected from
N
and
Figure imgf000025_0001
In a further embodiment of the present invention each R2 and R2 is independently H or C1-4alkyl. In another embodiment, each R2 and R2 is H or methyl. In another embodiment, each R2 and R2 is H.
In a further embodiment of the present invention a is 1 , 2 or 3. In another embodiment, a is 2. In another embodiment, a is 3.
In a further embodiment of the present invention, R3 is H or C1-4alkyl. In another embodiment, R3 is H or methyl. In another embodiment R3 is H.
In a further embodiment of the present invention, b is 0. In another embodiment, b is 1.
In a further embodiment of the present invention, R4 is is C6-10aryl optionally substituted with 1-3 R5. In a further embodiment, R4 is C-6-ioaryl optionally substituted with 1-3 substituents independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkyloxy, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, COC1-6alkyl, NR6R7, CO2R8, C6-10aryl, C6-10aryloxy, C6-10arylC1-2alkyl, C6-10arylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1-6alkyl, and C3-7cycloalkyl being optionally substituted with 1 or more halogens. In a further embodiment, R4 is C6-10aryl optionally substituted with 1 -3 substituents independently selected from H, C1-6alkyl, C3-7Cycloalkyl, C1- 6alkyoxy, SC1-6alkyl, COC1-6alkyl, NR6R7, CO2R8, C6-10aryl, C6-10aryloxy, C6- ioarylC1-2alkyl, C6-ioarylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1 -2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1-6alkyl, and C3-7cycloalkyl being optionally substituted with 1 or more halogens.
In a further embodiment, R4 is C6-10aryl optionally substituted with 1-3 substituents independently selected from methyl, ethyl, isopropyl, thiomethyl, methoxy, dimethylamino, trifluoromethyl, chloro, fluoro, bromo, acetyl, phenyl or phenyloxy. In a further embodiment, R4 is a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N and optionally substituted with 1-3 substituents selected from H, C1-6alkyl, C3-7Cycloalkyl, C1-6alkyloxy, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, COC1-6alkyl, NR6R7, CO2R8, C6-10aryl, C6-10aryloxy, C6-10arylC1-2alkyl, C6-10arylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1 -2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1-6alkyl and C3-7cycloalkyl being optionally substituted with 1 or more halogens.
In a further embodiment, R4 is a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N and optionally substituted with 1-3 substituents selected from methyl, ethyl, isopropyl, thiomethyl, methoxy, dimethylamino, trifluoromethyl, chloro, fluoro, bromo, acetyl, phenyl or phenyloxy.
In a further embodiment, R4 is C3-7cycloalkyl optionally substituted with C1-4alkyl or OH. In a further embodiment of the present invention, L is
Figure imgf000027_0001
wherein R16, R16 and z have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000027_0002
wherein R16 and R16 have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000027_0003
wherein R16 and R16 have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000027_0004
wherein R16 and R16 are independently H, methyl or ethyl. In a further embodiment of the present invention, L is
Figure imgf000027_0005
wherein R16 and R16 together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen. In a further embodiment of the present invention, L is
Figure imgf000028_0001
wherein R17, R17 , R18, R18 , Z and e have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000028_0002
wherein R17, R17 , R18, R18 and e have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000028_0003
wherein R17, R17 , R18, R18 and e have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000028_0004
wherein R17, R17', R18 and R18' are independently H, methyl or ethyl and wherein e has the previously defined meanings.
In a further embodiment of the present invention, L is
Figure imgf000029_0001
wherein R17 and R17 or R18 and R18 together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen and wherein e has the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000029_0002
wherein R19, R19', R20, R20', R21, R21' and f have the previously defined meanings.
In a further embodiment of the present invention, L is
Figure imgf000029_0003
wherein R19, R19', R20, R20', R21 and R21' are independently H, methyl or ethyl and wherein f has the previously defined meanings.
In a further embodiment of the present invention, L is
Figure imgf000029_0004
wherein R19 and R19' or R20 and R20' or R21 and R21' together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen and wherein f has the previously defined meanings.
In a further embodiment of the present invention, L is
Figure imgf000030_0001
wherein R22 has the previously defined meanings.
In a further embodiment of the present invention, L is
Figure imgf000030_0002
wherein R22 is H, methyl or ethyl.
In a further embodiment of the present invention, L is
Figure imgf000030_0003
wherein R23 and R23 have the previously defined meanings. In a further embodiment of the present invention, L is
Figure imgf000030_0004
wherein R23 and R23 are independently H, methyl or ethyl.. In a further embodiment of the present invention, L is
Figure imgf000031_0001
wherein R23 and R23 together with the atoms to which they are bonded form a 5 or 6 membered ring optionally substituted with methyl, hydroxyl or halogen.
In a further embodiment of the present invention is a compound of formula II,
Figure imgf000031_0002
wherein R4, R9', R10, R14, R15, R16, R16' and b have the previously defined meanings. In a further embodiment of the present invention is a compound of formula HA
Figure imgf000031_0003
wherein b is 1 or 2, and R4, R9', R10, R14, R15, R16, and R16' have the previously defined meanings, as set forth in formula I or IA. In another embodiment, in formula HA, R3 and R3 are independently H, C1-4alkyl, or Cβ-ioaryl.
In another embodiment, in formula HA, R3 and R3 are independently H, methyl, or phenyl. In another embodiment, in formula UA, R4 is selected from the group consisting of phenyl, thiophenyl, and naphthyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
In another embodiment, in formula HA, R9' is H; R10 is selected from the group consisting of H, C1-6alkyl, -C(=O)C1-6alkyl, -C(=O)C6-10aryl, -S(=O)2C1- 6alkyl, and -S(=O)2C6-10aryl; and R14, R15, R16, and R16' are all H.
In another embodiment, in formula HA, R9' is H; R10 is selected from the group consisting of H, methyl, 2-methylpropyl, , -C(=O)methyl, -C(=O)phenyl, - S(=O)2methyl, and -S(=O)2phenyl; and R14, R15, R16, and R16' are all H. In another embodiment, the compound of formula HA is selected from the group consisting of:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a compound of formula IIB:
Figure imgf000034_0002
wherein b is 1 or 2, and R4, R9', R10, R14, R15, R16, and R16> have the previously defined meanings. In another embodiment, in formula HB, R3 and R3 are independently H.
In another embodiment, in formula MB, R4 is phenyl, which is optionally substituted with 1 -3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
In another embodiment, in formula MB, R9' is H, or R9' and the carbon to which it is bonded form a carbonyl group ; R10 is H; and R14, R15, R16, and R16' are all H.
In another embodiment, the compound of formula MB selected from the group consisting of:
Figure imgf000035_0001
pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a compound of formula HC:
Figure imgf000035_0002
wherein b is 1 or 2, and R4, R9>, R10, R14, R15, R16, and R16' have the previously defined meanings.
In another embodiment, in Formula HC, R3 and R3 are independently H. In another embodiment, in Formula HC, R4 is phenyl, which is optionally substituted with 1 -3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
In another embodiment, in Formula HC, R9' is H; R10 is H; and R14, R15, R16, and R16' are all H. In another embodiment, the compound of Formula HC is a compound of
the forumula
Figure imgf000035_0003
or a pharmaceutically acceptable salt or solvate thereof.
In a further embodiment of the present invention is a compound of formula III,
Figure imgf000036_0001
wherein R4, R9', R10, R14, R15, R16 and R16' have the previously defined meanings. In another embodiment, the present invention provides a compound of formula III':
Figure imgf000036_0002
wherein R4, R9', R10, R14, R15, R16 and R16' have the previously defined meanings.
In another embodiment, in formula III', R4 is selected from the group consisting of phenyl, naphthyl, indanyl, indolyl, isoxazolyl, cyclohexyl,
Figure imgf000036_0003
each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, ethoxy- C(=O)-, methoxy-C(=O)-, thiomethyl, methoxy, dimethylamino, trifluoromethyl, trifluoromethoxy, difluoromethoxy, chloro, fluoro, bromo, acetyl, phenyl and phenyloxy. In another embodiment, in formula III1, R9' is H; R10 is selected from the group consisting of H, methyl, -C(=O)CF3, -C(=0)NR8-C6-10aryl, whrein said C6- ioaryl is optionally substituted with at least 1-3 subsitutents selected from the group consisting of fluoro, difluoromethoxy, and phenoxy; R14 and R15 are H; and R16, and R16 are independently H or alkyl.
In another embodiment, the compound of formula III' is selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a compound of the formula IHA
Figure imgf000043_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R4, R9 , R10, R14, R15, R16 and R16' have the previously defined meanings. In another embodiment, in formula IHA, R4 is selected from the group consisting of phenyl, naphthyl, indanyl, isoxazolyl, and
Figure imgf000043_0002
each of which is optionally substituted with 1 -3 substituents independently selected from the group consisting of dimethylamino, phenyl, and trifluoromethyl.
In another embodiment, in formula IHA, R9', R10, R14, R15, R16, and R16> are all H.
In another embodiment, the compound of formula MIA is selected from the group consisting of:
Figure imgf000043_0003
Figure imgf000043_0004
and
Figure imgf000044_0001
or a pharmaceutically acceptable salt or solvate thereof.
In a further embodiment, the present invention provides a compound of formula IV,
Figure imgf000044_0002
for or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R4, R9 , R10, R14, R15, R18 and b have the previously defined meanings.
In another embodiment, in formula IV, b is 1 or 2. In another embodiment, in formula IV, R4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro, methoxy, and fluoro.
In another embodiment, in formula IV, R9>, R10, R14, R15, and R18 are all H. In another embodiment, the compound of formula IV is selected from the group consisting of:
Figure imgf000044_0003
Figure imgf000045_0001
Figure imgf000045_0002
or a pharmaceutically acceptable salt or solvate thereof.
In a further embodiment, the present invention provides a compound of formula V,
Figure imgf000045_0003
V wherein R4, R9 , R10, R14, R15, R17 and b have the previously defined meanings.
In another embodiment, in formula V, b is 0 or 1. In another embodiment, in formula V, R4 is phenyl which is optionally substituted with 1 -3 substituents selected from the group consisting of chloro and trifluorom ethyl.
In another embodiment, in formula V, R9' , R1 0 , R14, and R1 5 are all H; and
R1' is H or methyl. In another embodiment, the compound of formula V, from the group consisting of:
Figure imgf000046_0001
thereof.
In another embodiment, the present invention provides a compound of formula Vl,
Figure imgf000046_0002
formula Vl wherein R4, R9', R10, R14, R15, R21 and b have the previously defined meanings. In another embodiment, in formula Vl, b is 0.
In another embodiment, in formula Vl, R4 is phenyl, naphthyl, or quinolinyl, each of which is independently optionally substituted with 1 -3 substituents selected from the group consisting of: trifluoromethyl, methyl, ethyl, -NH-C(=O)-CH3, -CH2NH2, trifluoromethoxy, methoxy, t-butyl, isopropoxy, acetyl, fluoro, isopropyl, phenyl, n-propyl, and phenoxy.
In another embodiment, in formula Vl, R9', R10 , R14, R15, and R21 are all
H. In another embodiment, the compound of formula Vl is selected from the group consisting of:
Figure imgf000047_0001
Figure imgf000047_0003
Figure imgf000047_0002
Figure imgf000047_0004
Figure imgf000048_0001
Figure imgf000048_0002
or a pharmaceutically acceptable salt or solvate thereof.
In a further embodiment, the present invention provides a compound of formula VII,
Figure imgf000048_0003
wherein R4, R9 , R1U, R14, R15, R^ and b have the previously defined meanings. In a further embodiment, the present invention provides a compound of formula VIII
Figure imgf000049_0001
formula VIII wherein R4, R9 , R10, R14, R15, R22 and b have the previously defined meanings. In another embodiment, in formula VIII, b is 0. In another embodiment, in formula VIII, R4 is selected from the group consisting of phenyl and naphthyl, each of which independently is optionally substituted with 1 -3 substituents selected from the group consisting of: trifluoromethyl, chloro, bromo, and methyl.
In another embodiment, in formula VIII, R9', R10, R14, and R15 are all H and R22 is H or methyl.
In another embodiment, the compound of formula VIII is selected from the group consisting of:
Figure imgf000049_0002
Figure imgf000050_0001
pharmaceutically acceptable salt or solvate thereof.
In another embodiment, In another embodiment, in formula I, R1 is
Figure imgf000050_0002
and wherein d, X1, and R9a have the previously defined meanings. In another embodiment, in formula I, R1 is
Figure imgf000050_0003
wherein X1 is NR10.
In another embodiment, in formula I, R1 is
Figure imgf000050_0004
wherein d is 1.
In another embodiment, in formula I, R1 is
Figure imgf000050_0005
wherein Raa is H.
In another embodiment, in formula I, R1 is
Figure imgf000050_0006
wherein R9b ; is H.
In another embodiment, the present invention provides a compound of the formula X
Figure imgf000051_0001
wherein R4, R16, and R16 have the previously defined meanings.
In another embodiment, in Formula X, R4 is selected from the group consisting of phenyl, indolyl, naphthyl, each of which independently is optionally substituted with 1-3 substituents selectd from the group consisting of trifluoromethyl, chloro, methoxy, isopropyl, bromo, and methyl.
In another embodiment, in Formula X, R16 and R16 are both H. In another embodiment, the compound of Formula X is selected from the group
consisting of
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000052_0003
and
Figure imgf000052_0002
or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a compound of formula Xl
Figure imgf000052_0004
Formula Xl wherein R4 and R22 have the previously defined meanings. In another embodiment, in Formula Xl, R4 is selected from the group phenyl and napthyl each of which is independently optionally substituted with 1- 3 substituents selected from the group consisting of: bromo, methyl, trifluoromethyl, methoxy, and chloro.
In another embodiment, in Formula Xl, R22 is H. In another embodiment, the compound of Formula Xl is selected from the group consisting of:
Figure imgf000053_0001
thereof. In another embodiment, the present invention provides a compound of the formula Xl
Figure imgf000053_0002
Formula XI wherein R4 and R22 have the previously defined meanings. In another embodiment, in Formula Xl, R4 is selected from the group phenyl and napthyl each of which is independently optionally substituted with 1- 3 substituents selected from the group consisting of: bromo, methyl, trifluoromethyl, methoxy, and chloro.
In another embodiment, in Formula Xl, R22 is H. In another embodiment, the compound of Formula Xl is selected from the group consisting of:
Figure imgf000054_0001
thereof.
In another embodiment, in Formula I, R1 is
Figure imgf000054_0002
wherein d, X3, R9a, and R9b have the previously defined meanings. In another embodiment, R1 is
Figure imgf000054_0003
wherein X is N.
In another embodiment, R1 is
Figure imgf000055_0001
wherein d is 1.
In another embodiment, R1 is
Figure imgf000055_0002
wherein F ir9aa :is H.
In another embodiment, R1 is
Figure imgf000055_0003
wherein R9b is H.
In another embodiment, the present invention provides a compound of the formula XI
Figure imgf000055_0004
whrein a, R2, R2 , R5, R16, and R16 have the previously defined meanings.
In another embodiment, in Formula Xl, a is 2, and R2 and R2 are independently H and methyl.
In another embodiment, in Formula Xl, R5 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro and trifluoromethyl. In another embodiment, the compound of Formula Xl is selected from the group consisting of:
Figure imgf000056_0001
or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, in Formula I, R1 is
Figure imgf000056_0002
wherein d, R9a, and R9b have the previously defined meanings. In another embodiment, in Formula I, R1 is
Figure imgf000056_0003
wherein d is 1.
In another embodiment, in Formula I, R1 is
Figure imgf000056_0004
wherein R9a and R9b are both H.
In another embodiment, the present invention provides a compound of the formula XII:
Figure imgf000057_0001
Formula XIl wherein R4, R16, and R16 have the previously defined meanings.
In another embodiment, in Formula XII, R4 is phenyl which is optionally substituted with a trifluoromethyl.
In another embodiment, in Formula XII, R16 and R16 are both H. In another embodiment, the compound of Formula XII is
Figure imgf000057_0002
or a a pharmaceutically acceptable salt or solvate thereof. In another embodiment, in Formula I or IA, R1 is
Figure imgf000057_0003
wherein d is 0, R9' is H, X1 is CR11R11', X2 is CH2, Y1 is CR12, Y3 is CR14, and Y4 is CR15. In another embodiment, the present invention provides a compound of
Formula XIII:
Figure imgf000058_0001
F or a pharmaceutically acceptable salt or solvate thereof, wherein R4, R16 and R16 have the previously defined meanings. In another embodiment, in Formula XIII, R4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of trifluoromethyl and chloro.
In another embodiment, in Formula XIII, R16 and R16 are both H. In another embodiment, the compound of Formula XIII is selected from the group consisting of:
Figure imgf000058_0002
or a a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, in Formula I, R1 is
Figure imgf000058_0003
wherein the variables Y1 -Y4 have the previously defined meanings. In another embodiment, in Formula I, R1 is
Figure imgf000058_0004
wherein Y1 is CR12, Y2 is CR13, Y3 is CR14, and Y4 is CR15. In another embodiment, the present invention provides a compound of the formula XIV
Figure imgf000059_0001
wherein b, R3, R3 , R4, R16, and R16 have the previously defined meanings. In another embodiment, in Formula XIV, b is 1. In another embodiment, in Formula XIV, R3 and R3 are both H. In another embodiment, in Formula XIV, R16 and R16 are both H. In another embodiment, in Formula XIV, R4 is phenyl which is optionally substituted with 1-3 chloro substituents.
In another embodiment, the compound of Formula XIV is
Figure imgf000059_0002
or a a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a compound of the formula XV
Figure imgf000059_0003
F wherein b, R3, R3 , R4, R16, and R16 have the previously defined meanings. In another embodiment, in formula XV, b is 1. In another embodiment, in formula XV, R3 and R3 are both H. In another embodiment, in formula XV, R and R are both H. In another embodiment, in formula XV, R4 is phenyl which is optionally substituted with 1-3 chloro substituents.
In another embodiment, the compound of formula XV is
Figure imgf000060_0001
or a pharmaceutically acceptable salt or solvate thereof.
The compounds of Formula I are prepared by methods well known in the art of organic chemistry, see for example, J. March, 'Advanced Organic Chemistry' 4th Edition, John Wiley and Sons. Specific synthetic routes are described in the generalized Schemes 1-6 depicted below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P. G. M. Wutts 'Protective Groups in Organic Synthesis' 3rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art of organic chemistry.
Compounds of formula I, wherein L is a urea, thiourea or aminourea may be prepared according to the general route shown in Scheme 1 or Scheme 2 below, wherein R1, R2, R2', R3, R3', R4, R16, R16', a and b have the previously defined meanings. The method of Scheme 1 involves coupling an isocyanate (or alternatively a thioisocyanate or an aminoisocyanate) with a suitably functionalized amine in a suitable solvent, for example N,N-dimethylformamide (DMF) to provide the desired urea (or thiourea or aminourea) product. The amine, isocyanate, thioisocyanate or aminoisocyantae starting materials are either commercially available or prepared using methods well known in the art of organic chemistry. For example, isocyanates can be conveniently prepared in situ by reaction of a suitably functionalised carboxylic acid with, for example, diphenylphosphoryl azide (DPPA) in the presence of a suitable base, for example di-isopropylethylamine (DIPEA).
Figure imgf000061_0001
Z is O, S, NR Scheme 1
According to the method of Scheme 2, a resin bound amine (prepared by coupling a resin bound aldehyde with a suitable amine in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride and in a suitable solvent system, for example acetic acid and dichloroethane) is reacted with an isocyanate to form a resin bound urea which is subsequently cleaved under acidic conditions (for example, using trifluoroacetic acid) to provide the desired urea product. Again the isocyanate may be prepared in situ by reaction of a suitably functionalised carboxylic acid with diphenylphosphoryl azide (DPPA) in the presence of a suitable base, for example di-isopropylethylamine (DIPEA).
Figure imgf000062_0001
Scheme 2
Compounds of formula I, wherein L is an amide may be prepared according to the general route shown in Scheme 3, wherein R1, R2, R2", R3, R3 ', R4, R18, R18 , a, b and e have the previously defined meanings. A suitably functionalised carboxylic acid is coupled with a suitably functionalised amine in the prersence of a suitable coupling agent, for example, O-(7- Azabenzotriazole-1 -yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate (HATU) and in the presence of a suitable base, for example, di- isopropylethylamine (DIPEA) and solvent, for example N,N-dimethylformamide (DMF). The carboxylic acid and amine starting materials are either commercially available or prepared using methods well known in the art of organic chemistry.
Figure imgf000063_0001
Scheme 3
Compounds of formula I, wherein L is a sulfonamide may be prepared according to the general route shown in Scheme 4, wherein R1, R2, R2 , R3, R3 , R4, R21, R21 , a, b and f have the previously defined meanings. A suitably functionalized sulfonyl chloride is coupled with a suitably functionalized amine in the presence of a suitable base, for example, triethylamine and solvent, for example, N,N-dimethylformamide (DMF). The sulphonyl chloride and amine starting materials are either commercially available or prepared using methods well known in the art of organic chemistry. For example, sulfonyl chlorides are readily obtained by treatment of suitably functionalized sulphonic acids with, for example, thionyl chloride.
Figure imgf000063_0002
Scheme 4
Compounds of formula I, wherein L is a carbamate may be prepared according to the general route shown in Scheme 5, wherein R1, R2, R2, R3, R3 , R4, R22, a and b have the previously defined meanings. A suitably functionalized amine is coupled with a suitably functionalized chloroformate in the presence of a suitable base, for example, triethylamine and solvent, for example, N,N-dimethylformamide (DMF). The amine and chloroformate starting materials are either commercially available or prepared using methods well known in the art of organic chemistry.
Figure imgf000064_0001
Scheme 5
The present invention also includes within its scope all stereoisomeric forms of the compounds of Formula I resulting, for example, because of configurational isomerism. Such stereoisomeric forms are enantiomers, or diastereoisomers.
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.
For example, in the case where R2 is methyl and R2 is H, the compound exists as a pair of enantiomers. In the case of the individual enantiomers of the compounds of Formula I or salts or solvates thereof, the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other enantiomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present 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.
For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g., synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art. 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. In one embodiment, the compound is at least 90% pure, in another embodiment at least 95% pure, and in another embodiment, at least 99% pure.
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 (1991), 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. CS. 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 (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. 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, (C1-C8)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-(CrC2)alkyl, N,N-di (C1- C2)alkylcarbamoyl-(C1-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-C6)alkanoyloxymethyl, 1-((CrC6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (Cr C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl,(C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α- aminoacyl-u-aminoacyl, where each α-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 α-aminoacyl or natural α- aminoacyl, -C(OH)C(O)OY1 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- C6)alkyl, amino(C1-C4)alkyl or mono-N — or di-N,N-(C1-C6)alkylaminoalkyl, — C(Y4) Y5 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 H20.
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 a!, J. Pharmaceutical Sci., 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, 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 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, bisulfates, 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. 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) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), 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 quartemized 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, C1-4alkyl, or C1-4alkoxy 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) 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.
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, 32P1 35S, 18F1 36CI 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 11C 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-life 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, lsotopically 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.
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 a/., 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, 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. 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 parent- eral administration, 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.
In a further aspect, 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. 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 Anti retroviral 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, NJ 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Welicome Research Triangle, NC 27709; abacavir (1592U89) 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-10619) under development by Biochem Pharma, 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 06511 ; 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" ("NNRTI"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 furopyridine-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., LaJoIIa CA 92037-1020; MKC-442 (1-(ethoxy- methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1 H,3H)-pyrimidinedione) 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" ("Pl") 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., LaJoIIa CA 92037-1020; amprenavir (141W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, MA 02139-4211 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 Pl; ABT-378 under development by Abbott , Abbott Park, IL 60064; and AG- 1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc., LaJoIIa 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, 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 IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, NJ 071 10-1199 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. 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-β-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. 4,211 ,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-HIV-1 drugs selected from two NRTIs, one Pl, a second Pl, 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 Pl ; or (b) two NRTIs and one NNRTI ; and (c) quadruple combination therapies such as two NRTIs , one Pl and a second Pl 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 Pl is preferred unless there is intolerance to PIs. Drug compliance is essential. The CD4+ and HIV-1 -RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one Pl or one NNRTI could be added. See the table below wherein typical therapies are further described: ANTI-HIV-1 MULTI DRUG COMBINATION THERAPIES A. Triple Combination Therapies
1. Two NRTIs1 + one Pl2
2. Two NRTIs1 + one NNRTI3
B. Quadruple Combination Therapies
Two NRTIs + one Pl + a second Pl or one NNRTI
C. ALTERNATIVES 5 Two NRTI1
One NRTI5 + one Pl2
Two PIs6 ± one NRTI7 or NNRTI3
One Pl2 + one NRTI7 + one NNRTI3
FOOTNOTES TO TABLE
1. One of the following: zidovudine + lamivudine; zidovudine + didanosine; stavudine + lamivudine; stavudine + didanosine; zidovudine + zalcitabine
2. Indinavir, nelfinavir, 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 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.
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. 11607 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 NMR 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-10A LC column: Altech platinum C18, 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 1100 series LC/MSD mass spectrometer.
Purification of Final Products
Final compounds were purified by PrepLC using the column of Varian Pursuit XRs C18 10 μm 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 CH3CN (95%) / H2O (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 C18 5μm 15O 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%) / H2O (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 C18 5μm 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 H2O and the mobile phase B is composed of CH3CN (95%) / H2O (5%) / TFA (0.1 %). The column was eluted at a flow rate of 3 mL/min 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 (DPPA), ethanol (EtOH), ethyl acetate (EtOAc), 0-(7-Azabenzotriazole-1- yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate (HATU), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (TEA), trifluoroacetic acid (TFA), water (H2O) and Stratospheres™ 4-formyl-3,5-dimethoxyphenoxy resin (PL-FDMP) Preparation of Examples 1-1 - 1-124.
Procedure 1 - Synthesis of Compounds of Formula I, wherein L is a Urea or Thiourea by Solution Phase (Method A)
Figure imgf000086_0002
The amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine for Example 1.1) was weighed into a 4 mt_ scintillation vial and then dissolved in 0.5 mt_ 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 mt_ 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 mt_ 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 mt_ of DMSO/acetonitrile (3:1 )) and further purified by HPLC using the general purification conditions descriobed above to provide the desired products. Preparations of Examples 1-125 - 1-259 Alternative Method 1A: General Method 1A: Preparation of 1-(3,4-dichlorobenzyl)-3-(2-(5,6,7,8- tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (1 -127)
Figure imgf000086_0001
A solution of 3,4-dichlorobenzyl isocyanate (202 mg, 1.0 mmol) in anhydrous methylene chloride (1 mL) was added to a suspension of 2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2-yl)ethanamine hydrochloride (177 mg, 1.0 mmol) and resin- bound diisopropylethylamine (1.0 g, 4.0 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen, and the mixture was stirred for 1 h. The solids were removed by filtration and the solvents were removed from the filtrate under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 1 -(3,4-dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethyl)urea (161 mg, 42%) as an off-white solid: 1H NMR (300 MHz, CDCI3) δ 7.39-7.28 (m, 4H), 7.14 (d, 1H), 6,45 (d, 1H), 6.05 (t, 2H), 4.29 (d, 2H), 3.60 (t, 2H), 3.44-3.40 (m, 2H), 2.84 (t, 2H), 2.74 (t, 2H), 1.97-1.91 (m, 2H) ppm; ESI MS m/z 379 .
Alternative Method 1 B:
General Method 1B: Preparation of 1-(benzo[cQoxazol-4-yl)-3-(2-(5,6,7,8- tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (1 -170)
Figure imgf000087_0001
Step 1. A solution of diphenylphosphoryl azide (1.1O g, 4.0 mmol) in anhydrous methylene chloride (5 mL) was added dropwise to a solution of 3-(8-(tert- butoxycarbonyl)-5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)propanoic acid (1.22 g, 4.0 mmol) and diisopropylethylamine (0.86 mL, 4.0 mmol) in anhydrous methylene chloride (10 mL) at 0 °C under nitrogen, after which the mixture was slowly warmed to room temperature, stirring for a total of 2 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1 :1 ), to provide tert-butyl 7-(3-azido-3-oxopropyl)-3,4-di hydro- 1 ,8-naphthyridine-1 (2H)- carboxylate (740 mg, 56%) as a yellow oil. Step 2. A solution of tert-butyl 7-(3-azido-3-oxopropyl)-3,4-dihydro-1 ,8- naphthyridine-1(2H)-carboxylate (133 mg, 0.40 mmol) in anhydrous toluene (1 mL) was heated at 100 °C under nitrogen in a sealed vial for 10 min. A solution of benzo[d]oxazol-4-amine (53 mg, 0.40 mmol) in anhydrous toluene (2 mL) was added and heating at 100 °C was continued for an additional 30 min. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :19), to provide tert-butyl 7-(2-(3- benzo[cf]oxazol-4-ylureido)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)- carboxylate (65 mg, 37%) as a yellow oil: ESI MS m/z 437 .
Step 3. Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 7-(2-(3- benzo[d]oxazol-4-ylureido)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)- carboxylate (65 mg, 0.15 mmol) in anhydrous methylene chloride (1 mL) at room temperature under nitrogen, and the mixture was stirred for 3 h. The solvents were removed under reduced pressure and the residue was dissolved in anhydrous methanol at room temperature under nitrogen. Macroporous triethylammonium methylpolystyrene carbonate (1 g) was added and the mixture was stirred for 30 min. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 1 -(benzo[φxazol-4-yl)-3-(2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)urea (20 mg, 40%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 8.03-7.98 (m, 2H), 7.64 (s, 1H), 7.32 (t, 1H), 7.18 (d, 1H), 7.05 (d, 1 H), 6.36 (d, 1 H), 6.09 (br s, 1 H), 5.03 (br s, 1 H), 3.67-3.63 (m, 2H), 3.38-3.34 (m, 2H), 2.80 (t, 2H), 2.67 (t, 2H), 1.90-1.86 (m, 2H) ppm; ESI MS m/z 338 . Alternative Method 1C:
General Method 1C: Preparation of 1-(3,4-dichlorobenzyl)-3-(2-(5,6,7,8- tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)thiourea (1-238)
Figure imgf000089_0002
z
Figure imgf000089_0001
3,4-Dichlorobenzyl isothiocyanate (123 mg, 0.56 mmol) was added to a solution of 2-(5,6,7)8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine (100 mg, 0.56 mmol) and diisopropylethylamine (0.12 mL, 0.68 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen, and the mixture was stirred for 5 h. Silica gel (5 g) was added to the mixture and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :9), to provide 1-(3,4-dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)thiourea (92 mg, 42%) as an off-white solid: 1H NMR (300 MHz, CDCI3) δ 7.33 (t, 2H), 7.12 (d, 1 H), 7.05 (d, 1 H), 6.31 (d, 1 H), 4.69 (s, 2H), 3.74 (s, 2H), 3.22 (s, 2H), 2.78 (t, 2H), 2.61 (t, 2H), 1.72-1.68 (m, 2H) ppm; ESI MS m/z 395 . Alternative Method 1 D:
Preparation of 1-(3,4-dichlorobenzyl)-1 ,3-dimethyl-3-(2-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)ethyl)urea hydrochloride (1-255)
Figure imgf000089_0003
Step 1. A solution of carbonyl diimidazole (380 mg, 3.4 mmol) in anhydrous methylene chloride (2 mL) was added to a solution of 1-(3,4-dichlorophenyl)-N- methylmethanamine (560 mg, 2.0 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen and the mixture was stirred for 1 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to provide A/-(3,4-dichlorobenzyl)-A/-methyl-1 H-imidazole-1-carboxamide (417 mg, 73%) as a colorless oil: 1H NMR (400 MHz, CDCI3) δ 7.93 (s, 1 H), 7.48-7.44 (m, 2H), 7.23 (s, 1H), 7.16 (d, 1H), 7.10 (s, 1 H), 4.60 (s, 2H), 3.05 (s, 3H) ppm.
Step 2. lodomethane (0.19 mL, 3.04 mmol) was added dropwise to a solution of N-(3,4-dichlorobenzyl)-A/-methyl-1 H-imidazole-1-carboxamide (205 mg, 0.76 mmol) in anhydrous acetonitrile at room temperature under nitrogen and the mixture was stirred for 20 h. The solvent was removed under reduced pressure to provide 1-((3,4-dichlorobenzyl)(methyl)carbamoyl)-3-methyl-1 H-imidazol-3- ium iodide as a yellow oil (201 mg, 63%) that was used in the next step without further purification.
Step 3. A mixture of 1-((3,4-dichlorobenzyl)(methyl)carbamoyl)-3-methyl-1 H- imidazol-3-ium iodide (160 mg, 0.38 mmol), N-methyl-2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine (40 mg, 0.21 mmol) and resin-bound diisopropylethylamine (200 mg, 0.80 mmol) in anhydrous dichloroethane was stirred at room temperature under nitrogen for 12 h. The solids were removed by 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 (1:9), to provide a yellow solid. This material was dissolved in acetonitrile (1 mL), treated with 1 N HCl (1 mL) and the solvents were removed under high vacuum to provide 1 -(3,4-dichlorobenzyl)- 1 ,3-dimethyl-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea hydrochloride (7 mg, 8%) as a dark yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.56 (d, 1 H), 7.49 (d, 1 H), 7.40 (S, 1 H), 7.17 (d, 1 H), 6.58 (d, 1 H), 4.41 (s, 2H), 3.55 (t, 2H), 3.49 (t, 2H), 2.99-2.90 (m, 5H), 2.80 (t, 2H), 3.74 (s, 3H), 1.93-1.88 (m, 2H) ppm; ESI MS m/z 407 . Compounds of the invention prepared according to this procedure are shown in Table 1 below.
Preparation of Examples 2-1 - 2-14
Procedure 2 - Synthesis of Compounds of Formula I, wherein L is a Urea by Solution Phase (Method B)
Figure imgf000091_0001
The amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethanamine for Example 2.1) 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 the amine dissolved. Triethylamine (0.36 mmol) was then added. The isocyanate component (0.05 mmol) (4-trifluoromethylphenylisocyanate for Example 2.1) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF. All of the isocyanate 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). To each vial was added 1.5 mL of 95% TFA/DCM at rt over 2h. Acetonitrile (1 mL) was then added and the reaction mixture was savanted to dryness. The samples were then resolubilised (1.5 mL of DMSO/acetonitrile (3:1)) and allowed to shake 1 h at rt. They were then reanalysed by LC-MS. Further purification by HPLC using the general purification conditions descriobed above provided the desired products. Compounds of the invention prepared according to this procedure are shown in Table 2 below. Preparation of Examples 3-1 - 3-17 Procedure 3 - Synthesis of Compounds of Formula I, wherein L is a Urea by Solid Phase- Step 1 - Linking the Amine to the Resin
Figure imgf000092_0001
3
To resin (Stratospheres PL-FDMP) (0.08 mmol) was added the amine component (0.4 mmol, 5 equiv.) in 5% AcOH/DCE (1 mL). Sodium triacetoxyborohydride was then added to the reaction mixture (0.4 mmol, 85 mg per reaction). The reactions were shaken at rt for 36h. Methanol (1.0 mL) was added to each vessel and the reaction mixtures were filtered. The filtered resin was washed with methanol (3X), DMF 93x), isopropanol (3x), DCM (3x) and the resin was dried in a vacuum oven for at least 2h. Step B - Formation of The Resin Bound Urea
Figure imgf000092_0002
In a 4 mL scintillation vial was added the acid component (0.15 mmol per reaction), DPPA (0.188 mmol) and DIEA (0.18 mmol). Toluene (1 mL) was added and the reaction mixture was shaken at rt for 30 mins and then at 90 °C overnight. The acid mixture was combined with resin bound amine (0.036 mmol per reaction) and the resulting mixture shaken for 5h at 90 °C. The reaction mixtures were then filtered and the filtered resin was washed with DMF (3X), with AcOH/DCM (1 :1) (3X), with water (3X), with IPA (3X), with DCM (3X) and the resin was dried in a vacuum oven for at least 2h. Step C - Cleavage of the Urea Product from the Resin. To each resin in a Bohdan tube was added 1.5 mL of 95% TFA/H2O at rt for 2 h. The resin was filtered and washed with acetonitrile (1 mL). Water (1 mL) was added and the filtrate was savanted to dryness. The residue was dissolved in acetonitrile (1 mL), followed by the addition of water (1 mL) and the mixture was shaken at rt for 2 h and then lyophilized. 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)), allowed to shake for 1 h at rt and further purified by HPLC using the general purification conditions descriobed above to provide the desired products.
Compounds of the invention prepared according to this procedure are shown in Table 3 below. Preparation of Examples 4-1 - 4-13 Procedure 4 - Synthesis of Compounds of Formula I, wherein L is an amide
mmol
Figure imgf000093_0001
Figure imgf000093_0002
The amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine for Example 4.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then placed in a 4mL scintillation vial and added to 0.36 mmol of DIPEA. The vial was stirred until dissolved. The acid component (0.1 mmol) (3,4-dichlorophenylacetic acid for Example 4.1) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF. HATU (0.18 mmol) was then was added and the mixture stirred until the acid was activated. All of the amine solution was added to the appropriate 4 mL vial containing the activated acid and the reactions were shaken overnight at room temperature. The samples were analysed by LC-MS and the solvent removed under reduced pressure (Genevac). Further purification by HPLC provided the desired products. Preparation of Examples 4-14 - 4-23
Alternative the following examples can be synthesized by the following methods: Method 4A:
Preparation of N-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)-2-(3- (trifluoromethyl)phenyl)acetamide (4-17)
Figure imgf000094_0001
2-(3-(Trifluoromethyl)phenyl)acetyl chloride (138 mg, 0.62 mmol) was added slowly to a suspension of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethanamine (100 mg, 0.56 mmol) and sodium carbonate (27 mg, 0.26 mmol) in anhydrous methylene chloride (2 mL) and the mixture was stirred for 8 h. The solids were removed by filtration and the solvents were removed from the filtrate under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1 :4), to provide N-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyπdin-2-yl)ethyl)-2-(3- (trifluoromethyl)phenyl)acetamide (49 mg, 24%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.60-7.52 (m, 2H), 7.52-7.45 (m, 2H), 7.28 (d, 1 H), 6.37 (d, 1 H), 3.52 (s, 2H), 3.50 (t, 2H), 3.45 (t, 2H), 2.85-2.72 (m, 4H), 1.92-1.88 (m, 2H) ppm; ESI MS m/z365 . Method 4B:
Preparation of 2-(3-f luorophenylamino)-N-(2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)acetamide (4-21 )
Figure imgf000095_0001
Carbonyldiimidazole (96 mg, 0.59 mmol) was added in one portion to a suspension of 2-(3-fluorophenylamino)acetic acid (100 mg, 0.59 mmol) in anhydrous methylene chloride (2 mL) at 0 °C under nitrogen and the resulting mixture was stirred for 30 min. A solution of 2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethanamine (104 mg, 0.59 mmol) in anhydrous methylene chloride (1 mL) was added and the resulting mixture was slowly warmed to room temperature, stirring for a total of 8 h. The mixture was directly purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :4), to provide 2-(3-fluorophenylamino)-N-(2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)acetamide (73 mg, 37%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.13-6.98 (m, 2H), 6.45-6.29 (m, 2H), 6.29-6.17 (m, 2H), 3.66 (s, 2H), 3.47 (t, 2H), 3.31 (t, 2H), 2.67-2.59 (m, 4H), 1.85-1.74 (m, 2H) ppm; ESI MS m/z 329 . Method 4C:
Preparation of N-(3,4-dichlorobenzyI)-2-(2-(5,6,7,8-tetrahydro-1 ,8- na phthy r id i n-2-y l)et hy lam i no)acetam ide (4-22)
Figure imgf000095_0002
A mixture of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine (100 mg, 0.56 mmol), 2-bromo-N-(3,4-dichlorobenzyl)acetamide (166 mg, 0.56 mmol), sodium carbonate (20 mg, 0.19 mmol) and lithium iodide (5 mg, 0.04 mmol) in anhydrous acetonitrile (4 mL) was heated at 65 °C under nitrogen for 18 h. The solids were removed from the cooled mixture by vacuum filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :4), to produce a white residue that was triturated with diethyl ether to provide N-(3,4-dichlorobenzyl)-2-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethylamino)acetamide (28 mg, 13%) as a light brown solid: 1H NMR (400 MHz, CDCI3) δ 7.37 (d, 2H), 7.18-7.08 (m, 2H), 6.32 (d, 1H), 4.40 (d, 2H), 3.41 (S, 2H), 3.38 (t, 2H), 2.97 (t, 2H), 2.78 (t, 2H), 2.65 (t, 2H), 1.90-1.86 (m, 2H) ppm; ESI MS m/z 393 .
Compounds of the invention prepared according to this procedure are shown in Table 4 below.
Preparation of Examples 5-1 - 5-29
Procedure 5.- Synthesis of Compounds of Formula I, wherein L is a
Sulfonamide
Figure imgf000096_0001
The amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethanamine for Example 5.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then added to triethylamine (0.36 mmol) cooled at 0 °C in an ice bath. The sulfonyl chloride component (0.05 mmol) (4- trifluorophenylsulfonyl chloride for Example 5.1) was then weighed into a 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF. All of the sulfonyl chloride solution was added dropwise to the appropriate 4mL 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). Further purification by HPLC provided the desired products. Compounds of the invention prepared according to this procedure are shown in
Table 5 below.
Preparation of Examples 6-1 - 6-17
Procedure 6 - Synthesis of Compounds of Formula I1 wherein L is a Carbamate
Figure imgf000097_0001
The amine component (0.14 mmol) (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethanamine for Example 6.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. This was then added to triethylamine (0.36 mmol) cooled at 0 °C in an ice bath. The chloroformate component (0.05 mmol) (3-trifluorophenyl chloroformate for Example 6.1) was then weighed into a 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF. All of the carbamate solution was added dropwise to the appropriate 4mL vial containing the amine and the reactions were shaken 3h at room temperature. The samples were analysed by LC-MS and the solvent removed under reduced pressure (Genevac). Further purification by HPLC provided the desired products. Method 6B:
Preparation of Examples 6-18 - 6-22 Preparation of 3,4-dichlorobenzyl 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethylcarbamate (6-22)
Figure imgf000097_0002
A solution of carbonyl diimidazole (53 mg, 0.30 mmol) in anhydrous methylene chloride (1 mL) was added slowly to a solution of 3,4-dichlorobenzyl alcohol (49 mg, 0.30 mmol) in anhydrous methylene chloride (1 mL) at 0 °C under nitrogen. The mixture was warmed to room temperature after which a suspension of 2- (5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine hydrochloride (64 mg, 0.30 mmol) and resin-bound diisopropylethylamine (225 mg, 0.90 mmol) in anhydrous methylene chloride (2 mL) was added. The mixture was stirred for 2 h after which the solids were removed by filtration and the solvents were removed from the filtrate under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :19), to provide 3,4-dichlorobenzyl 2-(5,6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethylcarbamate (39 mg, 34%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 7.48-7.38 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.34 (d, 1H), 5.65 (br s, 1 H), 5.06 (S1 2H), 4.78 (br s, 1 H), 3.57-3.45 (m, 2H), 3.45-3.36 (m, 2H), 2.78-2.65 (m, 4H), 1.97-1.86 (m, 2H) ppm; ESI MS m/z 380 . Method 6C:
Preparation of Examples 6-23 Preparation of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yI)ethyl 3- fluorophenylcarbamate (6-23)
Figure imgf000098_0001
Step 1. A solution of fe/t-butyl 7-(2-methoxy-2-oxoethyl)-3,4-dihydro-1 ,8- naphthyridine-1 (2H)-carboxylate (150 mg, 0.50 mmol) in anhydrous THF (3 mL) was added dropwise to a suspension of sodium borohydride (38 mg, 1.0 mmol) and lithium chloride (43 mg, 1.0 mmol) in ethanol (4.5 mL) at 0 °C under nitrogen after which the mixture was slowly warmed to room temperature, stirring for a total of 14 h. The solids were removed by vacuum filtration, washing with ethanol. The filtrate solvents were removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL), washed with brine (50 mL) dried (Na2SO4), filtered and the solvent was removed under reduced pressure to provide fe/t-butyl 7-(2-hydroxyethyl)-3,4-dihydro-1 ,8- naphthyridine-1(2H)-carboxylate (135 mg, 99%) as a white solid that was suitable for use without further purification: 1H NMR (300 MHz, CDCI3) δ 7.30 (d, 1 H), 6.76 (d, 1 H), 3.99-3.95 (m, 2H), 3.80-3.75 (m, 2H), 2.94-2.89 (m, 2H), 2.72 (t, 2H), 1.95-1.89 (m, 2H), 1.54 (s, 9H) ppm.
Step 2. A solution of 3-fluorophenyl isocyanate (353 mg, 0.25 mmol) in anhydrous methylene chloride (1 mL) was added to a solution of fe/t-butyl 7-(2- hydroxyethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)-carboxylate (65 mg, 0.23 mmol) and pyridine (20 mg, 0.25 mmol) in anhydrous methylene chloride (5 mL) at 0 °C under nitrogen after which the mixture was slowly warmed to room temperature, stirring for a total of 28 h. The mixture was diluted with water (100 mL) and extracted with methylene chloride (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide fe/t-butyl 7-(2-(3- fluorophenylcarbamoyloxy)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1 (2H)- carboxylate (81 mg, 82%) as an amber oil.
Step 3. Trifluoroacetic acid (1 mL) was added to a solution of fe/t-butyl 7-(2-(3- fluorophenylcarbamoyloxy)ethyl)-3,4-dihydro-1 ,8-naphthyridine-1(2H)- carboxylate (80 mg, 0.19 mmol) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen and the mixture was stirred for 16 h. The solvent was removed under reduced pressure and the residue was diluted with anhydrous methanol (10 mL), macroporous triethylammonium methylpolystyrene carbonate (1 g) was added and the mixture was stirred for 10 min. The solids were removed by vacuum filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :19), to provide 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl 3- fluorophenylcarbamate (59 mg, 98%) as a white solid: 1H NMR (500 MHz, DMSO-Cf6) δ 9.87 (s, 1H), 8.12 (brs, 1H), 7.57 (d, 1H), 7.36-7.27 (m, 2H), 7.19 (d, 1H), 6.81 (t, 1H), 6.67 (d, 1H), 4.40 (t, 2H), 3.40 (t, 2H), 3.02 (t, 2H), 2.73 (t, 2H), 1.82 (q, 2H) ppm; ESI MS m/z 393 .
Compounds of the invention prepared according to this procedure are shown in Table 6 below. Example 7:
Example 7.1 3-(2-(5,6,7,8-Tetrahvdro-1 ,8-naphthyridin-2-yl)ethylamino)-4-(4- (trifluoromethyl)phenylamino)cyclobut-3-ene-1 ,2-dione.
Figure imgf000100_0001
Figure imgf000100_0002
The method of J. Med. Chem. 2006, 49, 7603 was employed. To a solution of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine 7.1.1 (100 mg, 0.56 mmol) in EtOH (2 mL) at rt was added diethoxysquarate 7.1.2 (143 mg, 0.84 mmol) dropwise at 0 °C over 2h. The resulting mixture was stirred for 48 h and was recooled to 0 °C. The mixture was filtered and the resultant solid was washed with cold EtOH (2 x 1 mL). The solid was dried under high vacuum to afford a solid which then was dissolved up in minimum amount of DCM and purified in Biotage instrument 50% EtOAc/Hex to afford 7.1.3.
Figure imgf000101_0001
To a solution of 4-( trifluoromethyl)aniline 7.1.4 (32 mg, 0.2 mmol) in
EtOH (2 mL) at rt was added adduct 7.1.3 (50 mg, 0.16 mmol ) in one portion.
The resulting mixture was refluxed overnight (until TLC analysis and LCMS revealed reaction complete) and was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography to afford the title compound 7.1. RT 3.38; [M+H], 417.1462, calculated mass, 416.14617.
Example 7.2 3-(3,4-Dichlorobenzylamino)-4-(2-(5.6,7.8-tetrahvdro-1 ,8- naphthyridin-2-yl)ethylamino)cvcloput-3-ene-1 ,2-dione.
Figure imgf000101_0002
Figure imgf000102_0001
To a solution of 3,4-dichlorobenzylamine 7.2.1 (98 mg, 0.56 mmol) in EtOH (2 mL) at rt was added diethoxysquarate 7.1.2 (143 mg, 0.84 mmol) dropwise at 0 °C over 2h. The resulting mixture was stirred for 48 h and was recooled to 0 °C. The mixture was filtered and the solid was washed cold EtOH (2 x 1 mL). The solid was dried under high vacuum to afford a solid which then was dissolved in minimum amount of DCM and purified in Biotage instrument 50% EtOAc/Hexane to afford 7.2.2.
Figure imgf000102_0002
To a solution of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine 7.1.1 (50 mg , 0.28 mmol) in EtOH (2 mL) at rt was added adduct 7.2.2 (50 mg; 0.16 mmol) dropwise at 0 °C over 2h. The resulting mixture was stirred for 48 h and was recooled to 0 °C. The mixture was filtered and the resultant solid was washed cold EtOH (2 x 1 mL). The solid was dried under high vacuum to afford a solid 7.2.3. The title compound was purified by reverse phase chromatography, RT 3.38; [M+H], 431.0966, calculated mass, 430.0966. Example 8:
Preparation of Examples 8-1 - 8-3
Method 8A:
Preparation of 1 -(2-(8-acetyl-5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethyl)-3-(3,4-dichlorobenzyl)urea (8-2)
Figure imgf000103_0001
Acetic anhydride (0.06 mL, 0.6 mmol) was added to a mixture of 1-(3,4- dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (115 mg, 0.30 mmol) and triethylamine (0.12 mL, 0.90 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen and the mixture was heated at reflux for 48 h. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to provide 1-(2-(8-acetyl-5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethyl)-3-(3,4-dichlorobenzyl)urea (96 mg, 76%) as a white solid: 1H NMR (500 MHz, DMSO-Cf6) δ 7.57 (d, 1H), 7.49 (d, 1H)1 7.45 (s, 1H), 7.22 (d, 1H), 6.93 (d, 1H), 6.43 (s, 1 H), 6.02 (s, 1H), 4.15 (d, 2H), 3.76 (t, 2H), 3.37-3.33 (m, 2H), 2.78 (t, 2H), 2.72 (t, 2H), 2.37 (s, 3H), 1.82 (t, 2H) ppm; ESI MS m/z 421 . Example 9:
Preparation of Examples 9-1 - 9-3
Method 9: Preparation of 1-(3,4-dichIorobenzyI)-3-(2-(8-methyl-5,6,7,8- tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (9-3)
Figure imgf000103_0002
Sodium cyanoborohydride (190 mg, 3.0 mmol) was added to a mixture of 1- (3,4-dichlorobenzyl)-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (115 mg, 0.30 mmol), formalin (1.23 g, 15 mmol, 37% solution of formaldehyde in water) and acetic acid (0.86 mL, 15 mmol) in methanol (5 ml.) at room temperature under nitrogen and the mixture was stirred for 3 h. The solvents were removed under reduced pressure and the residue was neutralized with saturated Na2CO3 solution (20 mL), extracted with ethyl acetate (3 x 50 mL), dried (Na2SO4) filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 1 -(3,4-dichlorobenzyl)-3-(2-(8-methyl-5)6,7,8-tetrahydro-1 ,8- naphthyridin-2-yl)ethyl)urea (84 mg, 71%) as a white solid: 1H NMR (500 MHz, DMSO-ofe) δ 7.57 (d, 1 H), 7.43 (s, 1 H), 7.25-7.21 (m, 1H), 7.04 (d, 1 H), 6.47 (t, 1H), 6.37 (d, 1H), 5.95 (t, 1H), 4.18 (d, 2H), 3.38-3.28 (m, 4H), 3.01 (s, 3H), 2.68-2.58 (m, 4H), 1.85-1.81 (m, 2H) ppm; ESI MS m/z 393 . Example 10: Preparation of Examples 10-1 - 10-2
Method R: Preparation of 1-(3,4-dichlorobenzyl)-3-(2-(8-(methylsulfonyl)- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)urea (10-1)
Figure imgf000104_0001
A solution of methanesulfonyl chloride (42 mg, 0.36 mmol) in anhydrous methylene chloride (1 mL) was added to a mixture of 1 -(3,4-dichlorobenzyl)-3- (2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (115 mg, 0.30 mmol) and triethylamine (0.06 mL, 0.45 mmol) in anhydrous methylene chloride (5 mL) at room temperature under nitrogen and the mixture was heated at reflux for 36 h. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to produce a colorless oil. This residue was diluted with anhydrous methylene chloride (0.5 mL) and a solution of HCl in diethyl ether was added until precipitation was complete. The solids were collected by filtration to provide 1-(3,4-dichlorobenzyl)-3-(2-(8- (methylsulfonyl)-5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)urea (70 mg, 51%) as a white solid: 1H NMR (500 MHz, DMSO-Of6) δ 7.58 (d, 1 H), 7.48-7.42 (m, 2H)1 7.21 (d, 1 H), 6.86 (d, 1 H), 4.18 (s, 2H), 3.79 (t, 2H), 3.49 (s, 3H), 3.37 (t, 2H), 2.80-2.72 (m, 4H), 1.92-1.85 (m, 2H) ppm; ESI MS m/z 457 . Example 11 :
Preparation of Examples 11-1 - 11-2 Method L: Preparation of 2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2- yl)ethylsulfamic acid N-(3,4-dichlorobenzyl) amide (11-1)
Figure imgf000105_0001
Step 1. A solution of 2-bromoethanol (0.64 mL, 9.0 mmol) in anhydrous methylene chloride (5 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (0.78 mL, 9.0 mmol) in anhydrous methylene chloride (18 mL) at 0 °C under nitrogen and the mixture was stirred for 30 min. To the mixture was added dropwise a solution of (3,4-dichlorophenyl)methanamine (1.33 mL, 10.0 mmol) and triethylamine (2.73 mL, 20.0 mmol) in anhydrous methylene chloride (10 mL) and the resulting mixture was slowly warmed to room temperature, stirring for a total of 30 min. The mixture was washed with 2N HCl (3 x 15 mL) and water (30 mL) and the solvent was removed under reduced pressure. The resulting solids were collected by vacuum filtration and washed with water to produce a solid that was recrystallized from ethyl acetate/hexanes to provide 2- bromoethyl A/-(3,4-dichlorobenzyl)sulfamoylcarbamate (2.73 g, 93%) as an off- white solid: 1H NMR (300 MHz, CD3OD) δ 7.53 (s, 1 H), 7.46 (d, 1 H), 7.28 (d, 1 H), 4.34 (t, 2H), 4.21 (d, 2H), 3.54 (t, 2H) ppm; ESI MS m/z 406 . Step 2. A mixture of 2-bromoethyl N-(3,4-dichlorobenzyl)sulfamoylcarbamate (560 mg, 1.4 mmol) and resin-bound diisopropylethylamine (1.02 g, 4.1 mmol) in 1 ,2-dichloroethane (10 mL) was heated at 60 °C under nitrogen for 3 h. The solids were removed from the cooled mixture by vacuum filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1 :2), to provide N-(3,4-dichlorobenzyl)-2-oxooxazolidine-3- sulfonamide (382 mg, 85%) as a white solid: 1H NMR (300 MHz, DMSO-Cf6) δ 9.04 (s, 1 H), 7.64 (s, 1H), 7.60 (s, 1H), 7.33 (d, 1H), 4.30-4.20 (m, 4H), 3.88 (t, 2H) ppm; ESI MS m/z 323 [M - H]-.
Step 3. Triethylamine (0.04 mL, 0.2 mmol) was added to a mixture of provide N-(3,4-dichlorobenzyl)-2-oxooxazolidine-3-sulfonamide (33 mg, 0.10 mmol), 2- (5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethanamine hydrochloride (21 mg, 0.10 mmol) and resin-bound diisopropylethylamine (50 mg, 0.20 mmol) in anhydrous acetonitrile (2 mL) at room temperature under nitrogen and the mixture was heated at 75 °C for 12 h. The solids were removed from the cooled mixture by vacuum filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1 :19), to produce a colorless residue. The compound was triturated with water (3 mL) and the resulting solids were collected by vacuum filtration and washed with water to provide 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethylsulfamic acid N-(3,4- dichlorobenzyl) amide (9 mg, 21%) as a white solid: 1H NMR (400 MHz, CDCI3) δ 7.41-7.37 (m, 2H), 7.15 (d, 1 H), 7.08 (d, 1H), 6.33 (d, 1 H)1 6.10 (br s, 1 H), 4.73 (br s, 1 H), 4.57 (br S, 1 H), 4.09 (s, 2H), 3.39-3.31 (m, 4H), 2.75 (t, 2H), 2.67 (t, 2H), 1.91-1.85 (m, 2H) ppm; ESI MS m/z 415 . Example 12: Preparation of Examples 12-1 - 12-51 Method 12: Preparation of 1-(3,4-dichlorobenzyl)-3-(2-(6- (methylamino)pyridin-2-yl)ethyl)urea (12-1 )
1 atm H2, 10% Pd/C EtOH, rt
Figure imgf000107_0001
Figure imgf000107_0002
Step 1. A solution of 9-BBN dimmer (8.0 mL, 4.0 mmoi, 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 PdCI2(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 NaHCCb solution (75 mL), extracted with ethyl acetate (3 x 100 mL), dried (Na2SO4), 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: 1H NMR (CDCI3, 300 MHz) δ 7.36-7.28 (m, 6H), 6.40 (d, 1 H), 6.21 (d, 1 H), 5.86 (brs, 1 H), 5.09 (s, 2H), 4.56 (brs, 1 H), 3.55 (q, 2H), 2.86 (d, 3H), 2.79 (t, 2H); ESI MS m/z 286 . 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 .
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 warmed 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: 1H NMR (300 MHz, DMSO-d6) δ 7.56 (d, 1 H), 7.45 (s, 1 H), 7.31-7.20 (m, 2H), 6.49 (t, 1 H), 6.34-6.23 (m, 3H), 6.03 (t, 1 H), 4.18 (d, 2H), 3.37-3.31 (m, 2H), 2.75 (d, 3H), 2.63 (t, 2H) ppm; ESI MS m/z 353 . Example 15- Biological Assays
15.1 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 ligand 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 μM in this assay, whilst several others exhibited Kd values ranging from 3 μM 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. 15.2 HIV Replication Assay Virus Stocks and Reagents
Luciferase reporter viruses (ADA, YU-2) were generated as described by Connor et al. (J. Virol., 1996, 70, 5206-5311). Primary H IV-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 GIo Lysis buffer (Promega) and the Brightlite reagent (PerkinElmer).
1. Ogert, R. A., L. Ba, Y. Hou, C. Buontempo, P. Qiu, J. Duca, N. Murgolo,
P. Buontempo, R. Ralston, and J. A. Howe. 2009. Structure-function analysis of HIV-1 gp120 amino acid mutations associated with resistance to the CCR5 co-receptor antagonist vicriviroc. J Virol, e- published.
2. Ogert, R. A., L Wojcik, C. Buontempo, L Ba, P. Buontempo, R. Ralston, J. Strizki, and J. A. Howe. 2008. Mapping resistance to the CCR5 co- receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key determinants in the C2-V5 domain of gp120. Virology 373:387-99.
3. Pontow, S., and L. Ratner. 2001. Evidence for common structural determinants of human immunodeficiency virus type 1 coreceptor activity provided through functional analysis of CCR5/CXCR4 chimeric coreceptors. J Virol 75:11503-14.
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 1h at 37 °C and infected in triplicate with 25-100 tissue culture 50% ineffective dose (TCID50) per well of an HIV-1 primary isolate for 3-4 h. The cells were washed twice in PBS to remove residual virus and cultured in the presence of inhibitor for 4-6 days. HIV-1 replication was quantitatied by measurement of extracellular p24 antigen by ELISA. 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-well 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 1 h. 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 μM 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. In one embodiment, the compounds of the present invention have IC50 values of less than 5 uM (< 5 μM), in another embodiment, they range from 5 uM to 20 μM, in another embodiment from 20 μM to 50 uM, and in another embodiment, more than 50 μM (>50 μM). The compounds in table 1 below were prepared according to the experimental procedures set forth above.
Table 1 Compounds of Formula I, wherein L is a Urea or Thiourea Prepared by Procedure 1.
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
4
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001

Claims

Claims
We claim:
1. A compound of Formula I
Figure imgf000198_0001
Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from the group consisting of:
Figure imgf000198_0002
and wherein: each R2 and R2 is independently H, C1-4alkyl or C3-7cycloalkyl, said d-4alkyl and C3-7cycloalkyl being optionally substituted with methyl, hydroxyl or halogen or R2 and R2 together with the carbon or carbons to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; a is an integer from 1-3; R3 and R3 are independently H, C1-4alkyl, C3-7cycloalkyl, or C6-10aryl, each of which is independently optionally substituted with methyl, hydroxyl or halogen or R3 and R3 together with the carbon to which they are shown bonded in formula I form a 3-6 membered carbocyclic ring optionally substituted with methyl, hydroxyl or halogen; b is 0, 1 or 2;
R4 is C6-10aryl, C3-7cycloalkyl or a 5-10 membered heteroaryl ring system comprising 1-3 heteroatoms independently selected from O, S and N, wherein said C6-10aryl and 5-10 membered heteroaryl ring system are optionally substituted with 1-3 R5 and wherein said C3-7cycloalkyl is optionally substituted with C1-4alkyl or OH; each R5 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkyloxy, SC1-4alkyl, SOC1-6alkyl, SO2C1-6alkyl, COC1-6alkyl, NR6R7, CO2R8 C6-10aryl, C6-10aryloxy, C6-10arylC1-2alkyl, C6-10arylC1-2alkyloxy, CN, halogen or a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms independently selected from O, S and N, said C1-6alkyl, C1-6alkyloxy, SC1- 6alkyl and C3-7cycloalkyl being optionally substituted with 1 or more halogens or two adjacent R5 together form -O-(CH2)C-O, wherein c is an integer from 1 to 3; R6 and R7 are independently H or C1-6alkyl, optionally substituted with methyl, hydroxyl or halogen or R6 and R7 together with the N to which they are bonded form a 5-7 membered heterocyclic ring optionally substituted with methyl, hydroxyl or halogen; each R8 independently is H, C1-6alkyl; R9 is H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl or a 5-10 membered heteroaryl ring system comprising 1 -2 heteroatoms independently selected from O, S and N, wherein each of said C1-6alkyl, C3-7CyClOaI kyl, C6-10aryl or 5-10 membered heteroaryl ring system independently is optionally substituted with 1-3 R5;
R9 is 1-2 substituents independently selected from H, C1-4alkyl and halogen or R9 and the carbon to which it is bonded form a carbonyl group; each R9a independently is 1 -2 substituents independently selected from the group consisting of H and C1-6alkyl; each R9b independently is 1-2 substituents independently selected from the group consisting of H and C1-6alkyl; each X1 independently is a covalent bond, NR10, CR11R11', O, S, SO or SO2;
X2 is NR10', O or CH2;
X3 is N or S; d is an integer from 0 to 2 ; each Y1 independently is N or CR12; each Y2 independently is N or CR13; each Y3 independently is N or CR14; each Y4 independently is N or CR15 with the proviso that one or two of Y1 -Y4 must be N;
R10 and R10' are independently H, C1-4alkyl, -C(=O) C1-6alkyl wherein said C1- 6alkyl is optionally substituted with a halogen, -C(=O)OC1-6alkyl, -C(=O)C6-
10aryl, -S(=O)2C1-6alkyl, -S(=O)2C6-10aryl, and -C(=O)NR8-C6-10aryl wherein said C6-10aryl is optionally substituted with at least 1-3 substituents selected from the group consisting of fluoro, difluoromethoxy, and phenoxy; R11 and R11 are independently H or C1-6alkyl; R12-R15 are independently H, C1-6alkyl, C1-6alkyloxy, halogen, hydroxyl or CN; L is a moiety selected from:
Figure imgf000201_0001
Figure imgf000201_0002
Z is O, S or NR24;
R16 and R16' are independently H, -C(=O)NR8C6-10aryl or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R16 and R16 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R17 and R17 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R17 and R17 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen;
R18 and R18 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R18 and R18 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; e is O or 1 ;
R19 and R19' are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R19 and R19' together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R20 and R20 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R20 and R20 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R21 and R21 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R21 and R21 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; f is O or 1 ;
R22 is H or C1-6alkyl; R23 and R23 are independently H or C1-6alkyl optionally substituted with methyl, hyrdroxyl or halogen or R23 and R23 together with the atoms to which they are bonded form a 5-7 membered ring, optionally substituted with methyl, hydroxyl or halogen; R24 is H, C1-6alkyl or COC1-6alkyl or a pharmaceutically acceptable salt or solvate thereof.
2. The compound according to claim 1 , wherein R3 and R3 are both H and b is 1.
3. The compound according to claim 1 , wherein b is 0.
4. The compound according to claim 1 , wherein R2 and R2 are both H and a is 2.
5. The compound according claim 1 , wherein L is
Figure imgf000203_0001
and wherein Z, R16 and R16' have the previously defined meanings;
6. The compound according to claim 5, wherein L is
Figure imgf000203_0002
and wherein R16 is H, methyl, or -C(=O)NH-phenyl, wherein said phenyl is optionally substituted with a halogen.
7. The compound according to claim 1 , wherein R4 is phenyl or pyridyl, each of which is independently optionally substituted with 1-3 substituents independently selected from methyl, ethyl, isopropyl, thiomethyl, methoxy, dimethylamino, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, acetyl, phenyl or phenyloxy.
8. The compound according to claim 1 , wherein R is
Figure imgf000203_0003
and wherein d, X1, X2, Y1, Y3, Y4 and R9' have the previously defined meanings.
9. The compound according to claim 8, wherein d is 1 or 2, X1 is NR10, Y1 is N, X2 is CH2 or O; Y3 is CR14 and Y4 is CR15.
10. A compound according to claim 8 having the general formula HA
Figure imgf000204_0001
formula HA wherein b is 1 or 2, and R4, R9', R10, R14, R15, R16, and R16' have the previously defined meanings.
11. The compound according to claim 10, wherein R3 and R3 are independently H, C1-4alkyl, or C6-10aryl.
12. The compound according to claim 1 1 , wherein R3 and R3 are independently H, methyl, or phenyl.
13. The compound according to claim 10, wherein R is selected from the group consisting of phenyl, thiophenyl, and naphthyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
14. The compound according to claim 10, wherein R9' is H; R10 is selected from the group consisting of H, C1-6alkyl, -C(=O)Ci-6alkyl, -C(=0)C6-ioaryl, - S(=O)2C1-6alkyl, and -S(=O)2C6-10aryl; and R14, R15, R16, and R16' are all H.
15. The compound according to claim 10, wherein R9' is H; R10 is selected from the group consisting of H, methyl, 2-methylpropyl, , -C(=O)methyl, - C(=O)phenyl, -S(=O)2methyl, and -S(=O)2phenyl; and R14, R15, R16, and R16> are all H.
16. The compound according to claim 10, selected from the group consisting of:
Figure imgf000205_0001
Figure imgf000206_0001
pharmaceutically acceptable salt or solvate thereof. 17. A compound according to claim 8 having the formula IIB:
Figure imgf000207_0001
Formula HB wherein b is 1 or 2, and R4, R9', R10, R14, R15, R16, and R16> have the previously defined meanings.
18. The compound according to claim 17, wherein R3 and R3 are independently H.
19. The compound according to claim 17, wherein R4 is phenyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
20. The compound according to claim 17, wherein R9' is H, or R9' and the carbon to which it is bonded form a carbonyl group ; R10 is H; and R14, R15, R16, and R16' are all H.
21. The compound according to claim 17, selected from the group consisting
Figure imgf000207_0002
pharmaceutically acceptable salt or solvate thereof.
22. A compound according to claim 8 having the formula HC:
Figure imgf000208_0001
wherein b is 1 or 2, and R4, R9', R10, R14, R15, R16, and R16' have the previously defined meanings.
23. The compound according to claim 22, wherein R3 and R3 are independently H.
24. The compound according to claim 22, wherein R4 is phenyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, methoxy, chloro, fluoro, and bromo.
25. The compound according to claim 22, wherein R9' is H; R10 is H; and R14, R15, R16, and R16' are all H.
26. The compound according to claim 22, having the formula
Figure imgf000208_0002
or a pharmaceutically acceptable salt or solvate thereof.
27. A compound according to claim 8 having the formula III1
Figure imgf000209_0001
wherein R4, R9', R10, R14, R15, R16 and R16' have the previously defined meanings.
28. The compound according to claim 27, wherein R4 is selected from the group consisting of phenyl, naphthyl, indanyl, indolyl, isoxazolyl, cyclohexyl,
Figure imgf000209_0002
each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, ethoxy-C(=O)-, methoxy-C(=O)-, thiomethyl, methoxy, dimethylamino, trifluoromethyl, trifluoromethoxy, difluoromethoxy, chloro, fluoro, bromo, acetyl, phenyl and phenyloxy.
29. The compound according to claim 27, wherein R9' is H; R10 is selected from the group consisting of H, methyl, -C(=O)CF3, -C(=0)NR8-C6-10aryl, whrein said C6-10aryl is optionally substituted with at least 1-3 subsitutents selected from the group consisting of fluoro, difluoromethoxy, and phenoxy;
R14 and R15 are H; and R16, and R16' are independently H or alkyl.
30. The compound according to claim 27, selected from the group consisting of:
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
pharmaceutically acceptable salt or solvate thereof. 31. A compound according to claim 8 having the formula IHA
Figure imgf000215_0002
wherein R4, R9', R1ϋ, R14, R15, R16 and R160 have the previously defined meanings.
32. The compound according to claim 31 , wherein R4 is selected from the group consisting of phenyl, naphthyl, indanyl, isoxazolyl, and
Figure imgf000216_0001
each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of dimethylamino, phenyl, and trifluoromethyl.
33. The compound according to claim 31 , wherein R j9> , R o10 , D R14 , n R15 , D R16 , and R16' are all H.
34. The compound according to claim 31 , selected from the group consisting of:
Figure imgf000216_0002
thereof.
35. A compound according to claim 8 having the general formula IV
Figure imgf000217_0001
formula IV or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R4, R9 , R10, R14, R15, R18 and b have the previously defined meanings.
36. The compound of claim 35, wherein b is 1 or 2.
37. The compound of claim 35, wherein R4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro, methoxy, and fluoro.
38. The compound of claim 35, wherein R9', R10, R14, R15, and R18 are all H.
39. The compound of claim 35, selected from the group consisting of:
Figure imgf000217_0002
Figure imgf000218_0001
or a pharmaceutically acceptable salt or solvate thereof.
40. A compound according to claim 8 having the general formula V
Figure imgf000218_0002
formula V wherein R4, R9 , R10, R14, R15, R17 and b have the previously defined meanings.
41. The compound according to claim 40, wherein b is 0 or 1.
42. The compound according to claim 40, wherein R4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of chloro and trifluoromethyl.
43. The compound according to claim 40, wherein R9, R10, R14, and R15 are all H; and R17' is H or methyl.
44. The compound according to claim 40, selected from the group consisting of:
Figure imgf000219_0001
or a pharmaceutically acceptable salt or solvate
Figure imgf000219_0002
45. A compound according to claim 8 having the general formula VI
Figure imgf000219_0003
wherein R4 , R9' , R10 , R14 , R15 , R21 and b have the previously defined meanings.
46. The compound according to claim 45, wherein b is 0.
47. The compound according to claim 45, wherein R4 is phenyl, naphthyl, or quinolinyl, each of which is independently optionally substituted with 1-3 substituents selected from the group consisting of: trifluoromethyl, methyl, ethyl, -NH-C(=O)-CH3, -CH2NH2, trifluoromethoxy, methoxy, f-butyl, isopropoxy, acetyl, fluoro, isopropyl, phenyl, n-propyl, and phenoxy.
48. The compound according to claim 45, wherein R9', R10, R14, R15, and R21 are all H.
49. The compound according to claim 45, selected from the group consisting of:
Figure imgf000220_0001
Figure imgf000220_0003
Figure imgf000220_0002
Figure imgf000220_0004
Figure imgf000221_0001
Figure imgf000221_0002
or a pharmaceutically acceptable salt or solvate thereof. 50. A compound according to claim 8 having the general formula VIII
fo
Figure imgf000221_0003
wherein R4 , R9' , R10 , R14 , R15 , R22 and b have the previously defined meanings
51. The compound according to claim 50, wherein b is 0.
52. The compound according to claim 50, wherein R4 is selected from the group consisting of phenyl and naphthyl, each of which independently is optionally substituted with 1-3 substituents selected from the group consisting of: trifluoromethyl, chloro, bromo, and methyl.
53. The compound according to claim 50, wherein R , R , R , and R are all
H and R 22 is H or methyl.
54. . The compound according to claim 50, selected from the group consisting of:
Figure imgf000222_0001
pharmaceutically acceptable salt or solvate thereof.
55. The compound according to claim 1 , wherein R1 is
Figure imgf000223_0001
56. The heterocycylic derivative according to claim 55, wherein Y1 is N.
57, The heterocycyclic derivative according to claim 56, wherein Y2, Y3 and Y4 respectively are CR13, CR14, and CR15 .
58. The compound according to claim 56, wherein Y2 and Y3 respectively are CR13 and CR14 and Y4 is N.
59. The compound according to claim 56, wherein Y3 is N, and Y2 and Y4 respectively are CR13 and CR15.
60. The compound according to claim 55, wherein Y1 and Y3 respectivly are CR12 and CR14, and Y2 and Y4 are N.
61. The compound according to claim 55, wherein Y1 and Y2 are N, and Y3 and Y4 respectively are CR14 and CR15.
62. The compound according to claim 55, wherein Y1 and Y4 respectively are CR12 and CR15, and Y2 and Y3 are N.
63. The compound according to claim 55, wherein Y2 is N, and Y1, Y3, and Y4 respectively are CR12, CR14 and CR15.
64. The compound according to claim 57 having the formula IX O R3 R3'
R9
X1 "N
R 16 R16'
Figure imgf000224_0001
wherein b, X1, R3, R3', R4, R9, R14, R15, R16 and R16' have the previously defined meanings.
65. The compound according to claim 64, wherein X1 is selected from the group consisting of a covalent bond, O, and NR10 wherein R10 is selected from the group consisting of H and C1-6alkyl.
66. The compound according to claim 64, wherein R9 is selected from the group consisting of H, C1-6alkyl, -C(=O)-O-C1-6alkyl, -C(=O)-C1-6alkyl, and a 5- 10 membered heteroaryl ring sytem comprising 1-3 heteroatoms independently sleected from the group consisting of O, S and N, wherein said 5-10 membered heteroaryl ring sytem is optionally substituted with 1-3 C1-6alkyl substituents.
67. The compound according to claim 66, wherein said 5-10 membered heteroaryl ring sytem is selected from the group consisting of imidazolyl, pyrazolyl, benzimidazolyl, pyridopyrazolyl, each of which independently is optionally substituted with 1-3 C1-6alkyl substituents.
68. The compound according to claim 64, wherein b is 0, 1 or 2.
69. The compound according to claim 64, wherein wherein R3, R3 , R14, R15, R16 are all H, and R16' is H or -C(=O)-NH-C6-10aryl, wherein said said C6-10aryl is optionally substituted with a halogen.
70. The compound according to claim 64, whrein R4 is selected from the group consisting of cyclohexyl, phenyl and pyridyl, wherein said phenyl or said pyridyl is optionally substituted with 1-3 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, isopropyl, trifluorom ethyl, and trifluoromethoxy.
71. The compound according to claim 64, selected from the group consisting of:
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
thereof. . The compound according to claim 1 , wherein R1 is
Figure imgf000227_0002
and wherein d, X1, and R9a have the previously defined meanings.
73. The compound according to claim 72, wherein X1 is NR10.
74. The compound according to claim 72, wherein d is 1.
75. The compound according to claim 72, wherein R9a is H.
76. The compound according to claim 72, wherein R9bis H.
77. The compound according to claim 72 having the formula X
Figure imgf000228_0001
wherein R4, R16, and R16 have the previously defined meanings.
78. The compound according to claim 77, wherein R4 is selected from the group consisting of phenyl, indolyl, naphthyl, each of which independently is optionally substituted with 1-3 substituents selectd from the group consisting of trifluoromethyl, chloro, methoxy, isopropyl, bromo, and methyl.
79. The compound according to claim 77, wherein R16 and R16 are both H.
80. The compound according to claim 77 selected from the group consisting of:
Figure imgf000229_0001
Figure imgf000229_0003
and
Figure imgf000229_0002
or a pharmaceutically acceptable salt or solvate thereof. . The compound according to claim 72 having the formula Xl
Figure imgf000230_0001
wherein R and R ,22 have the previously defined meanings.
82. The compound according to claim 81 , wherein R4 is selected from the group phenyl and napthyl each of which is independently optionally substituted with 1-3 substituents selected from the group consisting of: bromo, methyl, trifluoromethyl, methoxy, and chloro.
83. The compound according to claim 81 , wherein R22 is H.
84. The compound according to claim 81 , selected from the group consisting of:
Figure imgf000230_0002
Figure imgf000231_0001
or a pharmaceutically acceptable salt or solvate thereof.
85. The compound according to claim 1 , wherein R1 is
Figure imgf000231_0002
wherein d, X3, R9a, and R9b have the previously defined meanings.
86. The compound according to claim 85, wherein X is N. 87. The compound according to claim 85, wherein d is 1.
88. The compound according to claim 85, wherein R9a is H.
89. The compound according to claim 85, wherein R 9b i;s H.
90. The compound according to claim 85 having the formula Xl
Figure imgf000231_0003
wherein a, R , R , R , R , and R have the previously defined meanings.
91. The compound according to claim 90, wherein a is 2, and R2 and R are independently H and methyl.
92. The compound according to claim 90, wherein R5 is phenyl which is optionally substituted with 1 -3 substituents selected from the group consisting of chloro and trifluoromethyl.
93. The compound according to claim 90, selected from the group consisting of:
Figure imgf000232_0001
or a pharmaceutically acceptable salt or solvate thereof.
94. The compound according to claim 1 , wherein R1 is
Figure imgf000232_0002
wherein d, R9a, and R9b have the previously defined meanings.
95. The compound according to claim 94, wherein d is 1.
96. The compound according to claim 94, wherein R9a and R9b are both H.
97. The compound according to claim 94, having the formula XII:
Figure imgf000233_0001
F wherein R , R , and R )16' have the previously defined meanings.
98. The compound according to claim 97, wherein R4 is phenyl which is optionally substituted with a trifluoromethyl.
99. The compound according to claim 97, wherein R and R are both H
100. The compound according to claim 97 having the structure
Figure imgf000233_0002
or a a pharmaceutically acceptable salt or solvate thereof.
101. The compound according to claim 8, wherein d is 0, R^ is H, X1 is CR11R11', X2 is CH2, Y1 is CR12, Y3 is CR14, and Y4 is CR15.
102. The compound according to claim 101 , represented by the formula XIII:
Figure imgf000233_0003
Formula XIII or a pharmaceutically acceptable salt or solvate thereof, wherein R4, R16 and R16 have the previously defined meanings.
103. The compound according to claim 102, wherein R4 is phenyl which is optionally substituted with 1-3 substituents selected from the group consisting of trifluoromethyl and chloro.
104. The compound according to claim 102, wherein R16 and R16 are both H.
105. The compound according to claim 102, selected from the group consisting of:
Figure imgf000234_0001
, and
Figure imgf000234_0002
or a a pharmaceutically acceptable salt or solvate thereof.
106. The compound according to claim 1, wherein R1 is
Figure imgf000234_0003
wherein the variables Y1-Y4 have the previously defined meanings.
107. The compound according to claim 106, wherein Y1 is CR12, Y2 is CR13, Y3 is CR14, and Y4 is CR15.
108. The compound according to claim 106, having the formula XIV
Figure imgf000235_0001
F wherein b, R3, R3 , R4, R16, and R16 have the previously defined meanings.
109. The compound according to claim 107, wherein b is 1.
110. The compound according to claim 107, wherein R3 and R3 are both H.
111. The compound according to claim 107, wherein R1b and R are both H
112. The compound according to claim 107, wherein R4 is phenyl which is optionally substituted with 1 -3 chloro substituents.
113. The compound according to claim 107 having the structure
Figure imgf000235_0002
or a a pharmaceutically acceptable salt or solvate thereof.
114. The compound according to claim 63, having the formula XV
Figure imgf000235_0003
wherein b, R3, R3 , R4, R16, and R16 have the previously defined meanings.
115. The compound according to claim 1 14, wherein b is 1.
116. The compound according to claim 1 14, wherein R3 and R3 are both H.
1 17. The compound according to claim 114, wherein R16 and R16 are both H.
118. The compound according to claim 1 14, wherein R4 is phenyl which is optionally substituted with 1 -3 chloro substituents.
119. The compound according to claim 114 having the structure
Figure imgf000236_0001
or a a pharmaceutically acceptable salt or solvate thereof.
120. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.
121. 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.
122. A method of claim 121 , wherein said disease is HIV.
123. The method of claim 122, further comprising administering one or more antiviral or other agents useful in the treatment of HIV.
124. The method of claim 123, 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.
125. The method of claim 121 , 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.
126. 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 of claims 1 in a pharmaceutically acceptable carrier, and in separate containers one or more pharmaceutical compositions comprising an effective amount of an antiviral agent or other agent useful in the treatment of HIV in a pharmaceutically acceptable carrier.
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