WO2006036816A2 - Chemical compounds - Google Patents

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Publication number
WO2006036816A2
WO2006036816A2 PCT/US2005/034218 US2005034218W WO2006036816A2 WO 2006036816 A2 WO2006036816 A2 WO 2006036816A2 US 2005034218 W US2005034218 W US 2005034218W WO 2006036816 A2 WO2006036816 A2 WO 2006036816A2
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Prior art keywords
methyl
compound
alkyl
tetrahydro
pyridin
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PCT/US2005/034218
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French (fr)
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WO2006036816A3 (en
Inventor
Kristjan Gudmundsson
Sharon Davis Boggs
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Smithkline Beecham Corporation
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Priority to EP05817347A priority Critical patent/EP1793825A4/en
Priority to JP2007533667A priority patent/JP2008514622A/en
Priority to US11/575,869 priority patent/US20080171740A1/en
Publication of WO2006036816A2 publication Critical patent/WO2006036816A2/en
Publication of WO2006036816A3 publication Critical patent/WO2006036816A3/en

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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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P11/02—Nasal agents, e.g. decongestants
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 and/or CCR5 of a target cell.
  • HIV gains entry into host cells by means of the CD4 receptor and at least one co-receptor expressed on the surface of the cell membrane.
  • M-tropic strains of HIV utilize the chemokine receptor CCR5
  • T-tropic strains of HIV mainly use CXCR4 as the co-receptor.
  • HIV co-receptor usage largely depends on hyper- variable regions of the V3 loop located on the viral envelope protein gp120. Binding of gp120 with CD4 and the appropriate co-receptor results in a conformational change and unmasking of a second viral envelope protein called gp41. The protein gp41 subsequently interacts with the host cell membrane resulting in fusion of the viral envelop with the cell.
  • CCR5/CD4 or CXCR4/CD4 would be a useful therapeutic in the treatment of a disease, disorder, or condition characterized by infection with M-tropic or T-tropic strains, respectively, either alone or in combination therapy.
  • the direct interaction of the HIV viral protein gp120 with CXCR4 could be a possible cause of CD8 + T-cell apoptosis and AIDS-related dementia via induction of neuronal cell apoptosis.
  • the signal provided by SDF-1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth; the known angiogenic growth factors VEG-F and bFGF up- regulate levels of CXCR4 in endothelial cells and SDF-1 can induce neovascularization in vivo.
  • leukemia cells that express CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-1.
  • chemokine receptors include, but are not limited to, CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR1 , CXCR2, CXCR3, CXCR4, and CXCR5.
  • the present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor, such as CXCR4 and/or CCR5 of a target cell.
  • each R 1 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -OR 10 , -OAy, -OHet, -R 8 OR 10 , -NR 6 R 7 , -R 3 NR 6 R 7 , -R 8 C(O)R 10 , -C(O)R 10 , -CO 2 R 10 , -R 8 CO 2 R 10 , -C(O)NR 6 R 7 , -C(O)Ay,
  • n is O, 1 , or 2; each R 2 independently is H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, -R 3 Ay,
  • R 3 is selected from a group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, alkenyl, alkynyl, -R 3 Ay, -, R 3 OR 11 , R 3 S(0) q R 11 , wherein R 3 is not substituted with amine or alkylamine; each R 4 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -HetN(R 10 ) 2 , -OR 10 , -OAy, -OHet, -R 3 OR 10 , -
  • Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene;
  • Z is -N(R 10 J 2 , -AyN(R 10 ) 2 , -AyR a N(R 10 ) 2 , -Het, -HetN(R 10 ) 2 , -HetR 3 N(R 10 ) 2 , -HetR a Ay, or -HetR 3 Het; each R 10 independently is H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,
  • each of R 6 and R 7 independently are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R a cycloalkyl, -R 3 OH, -R 3 OR 10 , -R 3 NR 8 R 9 , -Ay, -Het, -R 3 Ay,
  • each R a independently is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo,
  • cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo,
  • alkenylene, cycloalkenylene, or alkynylene each of R 8 and R 9 independently are selected from H or alkyl;
  • each q independently is O, 1 , or 2;
  • each R 11 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, or -Ay;
  • each Ay independently represents an optionally substituted aryl group;
  • each Het independently represents an optionally substituted 4-, 5-, 6- or 7-membered heterocyclyl or heteroaryl group.
  • -Het is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • -Het is optionally substituted with one or more of C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • -Ay is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • -Ay is optionally substituted with one or more of C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • t is 1.
  • t is 2.
  • t is 1.
  • R 2 is H, alkyl, haloalkyl or cycloalkyl.
  • R 2 is H.
  • n 0.
  • n is 1 and R 1 is halogen, haloalkyl, alkyl, OR 10 , NR 6 R 7 , CO 2 R 10 , C(O)NR 6 R 7 , or cyano.
  • R 3 is H, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl.
  • R 3 is H, alkyl, haloalkyl, or cycloalkyl. More preferably R 3 is H or alkyl. More preferably R 3 is H.
  • R 3 is R a OR 11
  • n is 0. In one embodiment m is 1 or 2. Preferably m is 1.
  • R 4 preferably is one or more of halogen, haloalkyl, alkyl, OR 10 , NR 6 R 7 , CO 2 R 10 , C(O)NR 6 R 7 , or cyano.
  • m is 1 and R 4 is -Het, -HetN(R 10 ) 2 and R 10 is H or alkyl, or -NHHet, where Het is optionally substituted with CrC 8 alkyl or C 3 - C f jcycloalkyl.
  • Z is -N(R 10 J 2 , -AyR a N(R 10 ) 2 , -Het, -HetN(R 10 ) 2 , - HetR a N(R 10 ) 2 , or -HetR ⁇ et; more preferentially Z is -N(R 10 J 2 , -Het or -HetN(R 10 ) 2 .
  • Y is alkylene, cycloalkylene, alkenylene, cycloalkenylene, or alkynylene; more preferentially Y is alkylene or cycloalkylene.
  • n is 0, t is 1 or 2
  • Y is alkylene
  • Z is N(R 10 ) 2 , where R 10 is
  • R 2 is H
  • R 3 is H, alkyl or R 3 OR 11 and R 11 is H or alkyl
  • m is 0.
  • n 0, t is 1 or 2
  • Y is alkylene
  • Z is N(R 10 J 2 , where R 10 is H, alkyl or cycloalkyl
  • R 2 is H
  • R 3 is H, alkyl or R 3 OR 11 and m is 1
  • R 4 is -Het, - HetN(R 10 ) 2 and R 10 is H or alkyl, or -NHHet where Het is optionally substituted with C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • n 0, t is 1 or 2, Y is alkylene, Z is N(R 10 ) 2 , where R 10 is H, alkyl or cycloalkyl; R 2 is H, R 3 is H, alkyl or R 3 OR 11 and m is 1 , and R 4 is -Het where Het is piperazine optionally substituted with C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • n is O 1 1 is 1 or 2
  • Y is alkylene
  • Z is -AyR a N(R 10 ) 2 ,
  • R 10 is H, alkyl or cycloalkyl
  • R 2 is H
  • R 3 is H, alkyl or R a OR 11 and m is O.
  • n 0, t is 1 or 2
  • Y is alkylene
  • Z is -AyR a N(R 10 ) 2 , -AyN(R 10 J 2 , -Het or -HetN(R 10 ) 2 , where R 10 is H, alkyl or cycloalkyl
  • R 2 is H
  • R 3 is H, alkyl or R a OR 11 and m is 1
  • R 4 is -Het or -NHHet where Het is optionally substituted with C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • n O 1 1 is 1 or 2
  • Y is alkylene
  • Z is -AyR a N(R 10 ) 2
  • R 10 is H, alkyl or cycloalkyl
  • R 2 is H
  • R 3 is H, alkyl or R a OR 11 and m is 1
  • R 4 is -Het where Het is piperazine optionally substituted with C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • Compounds of the present invention include:
  • Preferred compounds of the present invention include:
  • More preferred compounds of the present invention include: ⁇ /-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)- ⁇ /-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; ⁇ /-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]- ⁇ /-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
  • Still more preferred compounds of the present invention include: ⁇ /-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)- ⁇ /-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
  • One aspect of the invention includes the following compounds:
  • One aspect of the invention includes the following compounds:
  • One aspect of the invention includes the following compounds:
  • One aspect of the present invention includes the compounds substantially as hereinbefore defined with reference to any one of the Examples.
  • One aspect of the present invention includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention includes one or more compounds of the present invention for use as an active therapeutic substance.
  • One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of diseases and conditions caused by inappropriate activity of CXCR4.
  • One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of diseases and conditions caused by inappropriate activity of CCR5.
  • One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus
  • One aspect of the present invention includes the use of one or more compounds of the present invention in the manufacture of a medicament for use in the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor.
  • a chemokine receptor is CXCR4 or CCR5.
  • One aspect of the present invention includes use of one or more compounds of the present invention in the manufacture of a medicament for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic l
  • One aspect of the present invention includes a method for the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor comprising the administration of one or more compounds of the present invention.
  • a chemokine receptor is CXCR4 or CCR5.
  • One aspect of the present invention includes a method for the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia grav
  • One aspect of the present invention includes a method for the treatment or prophylaxis of HIV infection, rheumatoid arthritis, inflammation, or cancer comprising the administration of one or more compounds of the present invention.
  • alkyl refers to a straight or branched chain hydrocarbon, preferably having from one to twelve carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl.
  • C x- C y alkyl refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, and the like.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynyl and the like.
  • alkylene refers to an optionally substituted straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms.
  • alkylene as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like. Preferred substituents include alkyl, hydroxyl, or oxo.
  • alkenylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinylene, allylene or 2-propenylene, and the like.
  • alkynylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynylene and the like.
  • cycloalkyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring.
  • exemplary “cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkyl includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non-cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein “aryl,” such as a benzene ring) to form, for example, groups such as indane.
  • Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • cycloalkenyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached.
  • exemplary "cycloalkenyl” groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • cycloalkylene refers to a divalent, optionally substituted non-aromatic cyclic hydrocarbon ring.
  • Exemplary "cycloalkylene” groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.
  • Preferred substituents include alkyl, hydroxyl, or oxo.
  • cycloalkenylene refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds.
  • exemplary "cycloalkenylene” groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, and cycloheptenylene.
  • heterocycle or “heterocyclyl” refers to an optionally substituted mono- or polycyclic ring system containing one or more degrees of unsaturation and also containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. More preferably, the heteroatom is N.
  • heterocyclyl ring is three to twelve-membered and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4- dioxane, 1 ,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrothiopyran, aziridine, azetidine and tetrahydrothiophene.
  • Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • aryl refers to an optionally substituted benzene ring or to an optionally substituted fused benzene ring system, for example anthracene, phenanthrene, or naphthalene ring systems.
  • aryl groups include, but are not limited to, phenyl, 2-naphthyl, and 1-naphthyl.
  • Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • heteroaryl refers to an optionally substituted monocyclic five to seven membered aromatic ring, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings.
  • These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N- oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroatom is N.
  • heteroaryl groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted with at least one halogen.
  • branched or straight chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl groups and the like.
  • alkoxy refers to a group -OR', where R' is alkyl as defined.
  • cycloalkoxy refers to a group -OR', where R' is cycloalkyl as defined.
  • alkoxycarbonyl refers to groups such as:
  • R' represents an alkyl group as herein defined.
  • aryloxycarbonyl refers to groups such as:
  • Ay represents an aryl group as herein defined.
  • nitro refers to a group -NO 2 .
  • cyano refers to a group -CN.
  • zido refers to a group -N 3 .
  • amino refers to a group -NR 1 R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • alkylamino includes an alkylene linker through which the amino group is attached. Examples of “alkylamino” as used herein include groups such as -(CH 2 ) X NH 2 , where x is preferably 1 to 6.
  • amide refers to a group -C(O)NR 1 R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R' and R independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • Examples of "amide” as used herein include groups such as -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 J 2 , and the like.
  • the compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of formula (I).
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures.
  • Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts.
  • Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives for example, esters and amides, will be clear to those skilled in the art, without undue experimentation.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • modulators as used herein is intended to encompass antagonist, agonist, inverse agonist, partial agonist or partial antagonist, inhibitors and activators.
  • the compounds demonstrate protective effects against HIV infection by inhibiting binding of HIV to a chemokine receptor such as CXCR4 and/or CCR5 of a target cell.
  • the invention includes a method that comprises contacting the target cell with an amount of the compound that is effective at inhibiting the binding of the virus to the chemokine receptor.
  • CXCR4 modulators may also have a therapeutic role in the treatment of diseases associated with hematopoiesis, including but not limited to, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
  • compounds may also have a therapeutic role in diseases associated with inflammation, including but not limited to inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g.
  • idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune throiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn 1 s disease and ulcerative colitus; spondyloarthropathies; scleroderma; psoriasis (including T-cell-mediated psoriasis) and inflammatory derma
  • therapeutically effective amounts of a compound of formula (I), as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • the invention further provides pharmaceutical compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as herein described.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of formula (I) for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal one example of an actual amount per day would usually be from 7 to 700 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • the carrier(s) or excipient(s) By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • Flavorings, preservatives, dispersing agents, and coloring agents can also be present.
  • Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • binders examples include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl- aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
  • compositions adapted for nasal administration where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns.
  • the powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question.
  • formulations suitable for oral administration may include flavoring or coloring agents.
  • the compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • the compounds may be used in combination with any other pharmaceutical composition where such combined therapy may be useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and/or immunoregulatory diseases.
  • the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • agents useful in the prevention or treatment of HIV include:
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors include an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • nevirapine such as delavirdine, efavirenz, loviride, immunocal, oltipraz, and similar agents
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, palinavir, lasinavir, and similar agents;
  • Entry inhibitors such as T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS- 806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,180 and similar agents;
  • Budding inhibitors such as PA-344 and PA-457, and similar agents.
  • CXCR4 and/or CCR5 inhibitors such as Sch-C, Sch-D, TAK779, UK 427,857, TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
  • combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).
  • RT room temperature
  • h hours
  • min minutes
  • TLC thin layer chromatography
  • mp melting point
  • RP reverse phase
  • T r retention time
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • THF tetrahydrofuran
  • TFAA trifluoroacetic anhydride
  • CD 3 OD deuterated methanol
  • CDCI 3 deuterated chloroform
  • DMSO dimethylsulfoxide
  • SiO 2 (silica); atm (atmosphere);
  • MeOH methanol
  • P-TsOH p-toluenesulfonic acid
  • MP-TsOH polystyrene resin bound equivalent of p-TsOH from Argonaut Technologies
  • Mass spectra were obtained on Micromass Platform or ZMD mass spectrometers from Micromass Ltd., Altricham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI).
  • APCI Atmospheric Chemical Ionization
  • ESI Electrospray Ionization
  • VCD Ab lnitio Vibrational Circular Dichroism
  • the experimental VCD spectra were acquired in CDCI 3 using a Bomem Chiral RTM VCD spectrometer operating between 2000 and 800 cm "1 .
  • the Gaussian 98 Suite of computational programs was used to calculate model VCD spectrums.
  • the stereochemical assignments were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R)- or (S)-configuration. Incorporated by reference with regard to such spectroscopy are: J.R. Chesseman, M.J. Frisch, F.J. Devlin and P.J. Stephens, Chem. Phys. Lett.
  • compounds of formula (I) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) under reductive amination conditions.
  • the reductive amination can be carried out by treating the compound of formula (IV) with a compound of formula (V) in an inert solvent in the presence of a reducing agent.
  • the reaction may be heated to 50-150 0 C or performed at ambient temperature.
  • Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like.
  • the reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction can be run in presence of acid, such as acetic acid and the like.
  • Compounds of formula (II) can be prepared as described in the literature (J. Org. Chem., 2002, 67, 2197-2205, herein incorporated by reference with regard to such synthesis).
  • Compounds of formula (IV) can be prepared by reductive amination of compounds of formula (II) using processes well known to those skilled in the art of organic synthesis.
  • Compounds of formula (V) can be prepared by methods similar to those described in the literature ⁇ J. Heterocyclic Chemistry, 1992, 29, 691-697, incorporated by reference with regard to such synthesis).
  • Compound of formula (I) can be prepared by reacting a compound of formula (IV) with a compound of formula (Vl) where LV is a leaving group (e.g., halogen, mesylate, tosylate, or the like). This condensation is typically carried out in a suitable solvent optionally in the presence of base, optionally with heating. Suitable solvents include tetrahydrofuran, dioxane, acetonitrile, nitromethane, ⁇ /, ⁇ /-dimethylformamide, and the like.
  • a leaving group e.g., halogen, mesylate, tosylate, or the like.
  • Suitable bases include triethylamine, pyridine, dimethylaminopyridine, ⁇ /, ⁇ /-diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate and the like.
  • the reaction can be carried out at room temperature or optionally heated to 30-200 0 C. Optionally the reaction can be carried out in a microwave.
  • a catalyst such as potassium iodide, tertbutylammonium iodide, or the like, can optionally be added to the reaction mixture.
  • Compounds of formula (Vl) can be prepared by methods similar to those described in the literature (Chem. Pharm. Bull. 2000, 48, 935; Tetrahedron, 1991 , 47, 5173; Tetrahedron Lett.
  • a compound of formula (I-A) where R 4 is selected from a group containing -Het, -NHHet, -OR 10 , -OHet, -NR 6 R 7 can be synthesized from compound of formula (Vl-A) where R 4 is halogen ("Hal") by treatment with a nucleophile.
  • the reaction can be carried out by treating the compound of formula (Vl-A) with a suitable nucleophile, neat, or optionally in the presence of an inert solvent.
  • the reaction may be heated to 50-200 0 C or performed at ambient temperature.
  • the reaction may be carried out in a microwave.
  • a compound of formula (I-B) can be prepared from compound of formula (IX) by reductive amination.
  • the reductive amination can be carried out by treating the compound of formula (IX) with an aldehyde in an inert solvent in the presence of a reducing agent.
  • the reaction may be heated to 50-150 0 C or performed at ambient temperature.
  • Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like.
  • the reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction can be run in presence of acid, such as acetic acid and the like.
  • a compound of formula (IX) can be prepared by deprotection of compound of formula (VIII).
  • Deprotection method would depend on the choice of the protecting group.
  • the protecting group is ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine or ⁇ 1-[4-(methyloxy)phenyl]ethyl ⁇ amine
  • a suitable deprotection method includes treatment with an acid.
  • Treatment of compound of formula (VIII) with a stong acid in a suitable solvent is an appropriate method for removing the protecting group.
  • Suitable acids include trifluoroacetic acid and the like.
  • Suitable solvents include dichloromethane, dichloroethane and the like. The reaction can optionally be heated.
  • Alternative methods for removing these protecting groups include use of Lewis acids (e.g. BCI 3 , AICI 3 , BBr 3 and the like) or removal of the protecting group under reductive conditions (e.g. Pd on charcoal or PtO 2 under H 2 atmosphere).
  • Lewis acids e.g. BCI 3 , AICI 3 , BBr 3 and the like
  • removal of the protecting group under reductive conditions e.g. Pd on charcoal or PtO 2 under H 2 atmosphere.
  • a compound of formula (VIII) can be prepared from compound of formula (VII) and compound of formula (V) by reductive amination using conditions similar to those described in connection with previous Schemes.
  • a compound of formula (I-C) where m is 1 , R 4 is Het, R 2 is H, R 3 is H, t is 1 and all other variables are as defined in connection with compound of formula (I) can be synthesized in a chiral fashion as outlined in Scheme 5.
  • a compound of formula (I-C) can be prepared from a compound of formula
  • Treatment of compound of formula (XVIII) with a stong acid in a suitable solvent is an appropriate method for removing [4-(Methyloxy)phenyl]ethyl group.
  • Suitable acids include trifluoroacetic acid and the like.
  • Suitable solvents include dichloromethane, dichloroethane and the like.
  • the reaction can optionally be heated.
  • Alternative methods for removing [4-(Methyloxy)phenyl]ethyl group include use of Lewis acids (e.g. BCI 3 , AICI 3 , BBr 3 and the like) or removal of the protecting group under reductive conditions (e.g. Pd on charcoal or PtO 2 under H 2 atmosphere).
  • the resulting amine can then be treated with a suitable aldehyde under reductive amination conditions to give a compound of formula (I-C).
  • the reductive amination can be carried out by treating the amine with the aldehyde in an inert solvent in the presence of a reducing agent.
  • the reaction may be heated to 50-150 0 C or performed at ambient temperature.
  • Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like.
  • the reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction can be run in presence of acid, such as acetic acid and the like.
  • a compound of formula (XVIII) can be prepared from a compound of formula (XVII) and compound of formula (XVI).
  • Reductive amination of compound of formula (XVI) with a compound of formula (XVII) gives compounds of formula (XVIII).
  • the reductive amination can be carried out in an inert solvent in the presence of a reducing agent.
  • the reaction may be heated to 50-150 0 C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like.
  • the reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction can be run in presence of acid, such as acetic acid and the like.
  • Compound of formula (XVII) can be prepared form (S)-(-)-1-(4-methoxyphenyl)ethylamine and 6,7- dihydro-8(5H)-quinolinone ⁇ J. Org. Chem., 2002, 67, 2197-2205 incorporated by reference with regard to such synthesis) by reductive amination.
  • a compound of formula (XVI) can be prepared from a compound of formula (XV).
  • XV XVI Oxidation of compound of formula (XV) gives a compound of formula (XVI).
  • a suitable oxidation method is to treat compound of formula (XV) with MnO 2 in a suitable solvent.
  • suitable solvents include dichloromethane, chloroform, dichloroethane and the like.
  • a compound of formula (XV) can be prepared from a compound of formula (XIV).
  • a compound of formula (I-C) where m is 1 , R 4 is Het, R 2 is H, R 3 is H, t is 1 and all other variables are as defined in connection with compound of formula (I) can be synthesized in a chiral fashion as outlined in Scheme 6.
  • Compound of formula (I-C) can be prepared from compounds of formula (XVI) and (XX) via reductive amination.
  • the reductive amination can be carried out in an inert solvent in the presence of a reducing agent.
  • the reaction may be heated to 50-150 0 C or performed at ambient temperature.
  • Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like.
  • the reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction can be run in presence of acid, such as acetic acid and the like.
  • Compounds of formula (XX) and of formula (XVI) can be prepared in a similar fashion as described in connection with previous Schemes. As is evident to one skilled in the art the other enantiomer can be made in a similar fashion.
  • Example 1 ⁇ /-(lmidazoM ,2-alpyridin-2-ylmethyl)- ⁇ /-(5.6.7.8-tetrahvdro-8-quinolinyl)- 1.4-butanediamine
  • Example 2 ⁇ /-r(8-MethylimidazoM .2-alpyridin-2-yl)methyll- ⁇ /-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
  • Example 3 ⁇ /-r(7-Methylimidazo ⁇ ,2-alpyridin-2-yl)methvn- ⁇ /-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
  • Example 6 ⁇ /-(5,6,7,8-Tetrahvdro-8-quinolinyl)- ⁇ /-(r7-(trifluoromethyl)imidazof 1 ,2- alpyridin-2-yl1methyl)-1 ,4-butanediamine
  • Example 7 ⁇ /-(5.6 J,8-Tetrahvdro-8-quinolinyl)- ⁇ /-(f6-(trifluoromethyl)imidazori ,2- alpyridin-2-yllmethyl)-1.4-butanediamine
  • Example 8 ⁇ /-(5.6.7.8-Tetrahvdro-8-quinolinyl)- ⁇ /-(r5-(trifluoromethyl)imidazo ⁇ .2- alpvridin-2-vl1methvl ⁇ -1.4-butanediamine
  • Example 10 ⁇ /-r(6-Chloroimidazo ⁇ ⁇ 2-a1pyridin-2-vnmethyl1- ⁇ /-(5.6,7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
  • Example 11 /V-f(6-FluoroimidazoH ,2-alpyridin-2-yl)methyll- ⁇ /-(5,6.7,8-tetrahvdro-8- quinolinvD-1 ,4-butanediamine
  • Example 12 ⁇ /-r(5-BromoimidazoM .2-alpyridin-2-v0methv ⁇ - ⁇ /-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
  • Example 13 A/-f(5-Chloroimidazon .2-a1pyridin-2-vnmethyll-A/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1.4-butanediamine
  • Example 14 ⁇ /-r(5-FluoroimidazoH ,2-alpyridin-2-yl)methyll- ⁇ /-(5,6,7.8-tetrahvdro-8- quinolinyl)-1 , 4-butanediamine
  • Example 15 ⁇ /-rf5.7-Dimethylimidazo ⁇ ,2-alpyridin-2-yl)methyll- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
  • Example 16 ⁇ /-r(6.8-Dichloroimidazo ⁇ .2-alpyhdin-2-vnmethyl1- ⁇ /-(5.6.7.8-tetrahvdro- 8-quinolinyl)-1 ,4-butanediamine
  • Example 17 /V-(r8-Chloro-6-(trifluoromethyl)imidazoM ⁇ 2-a1pyridin-2-yllmethyl>- ⁇ /- (5,6.7,8-tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
  • Example 18 ⁇ /-r(6-Bromo-5-methylimidazoH ,2-alpyridin-2-yl)methyll- ⁇ /-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine
  • Example 19 ⁇ /-r(6-Bromo-8-methylimidazo ⁇ .2-alpyridin-2-yl)methyll- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
  • Example 20 /V-r(8-Bromo-6-methylimidazoH ,2-alpyridin-2-yl)methyll- ⁇ /-(5,6,7,8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
  • Example 21 ⁇ /- ⁇ r5-H-Pyrrolidinyl)imidazoH .2-alpyridin-2-yllmethyl)- ⁇ /-(5.6.7.8- tetrahvdro-8- ⁇ uinolinyl)-1.4-butanediamine
  • Example 22 ⁇ /-fr5-(1-Piperazinyl)imidazori .2-alpyridin-2-yllmethyl)- ⁇ /-(5,6.7.8- tetrahydro-8-quinolinyl)-1.4-butanediamine
  • Example 23 ⁇ /-fr5-(4-Morpholinyl)imidazo ⁇ .2-a1pyridin-2-yllmethyl)- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
  • the mixture was stirred at room temperature for 15 hours, filtered through a silica plug, rinsed with 10% 2 M ammonia in methanol-ethyl acetate, concentrated, and purified by preparative chromatography (0-70% acetonitrile-water; 0.1 % trifluoroacetic acid).
  • the purified intermediate was dissolved in dichloromethane (0.30 mL) and trifluoroacetic acid (0.30 mL) was added.
  • the resulting mixture was stirred for 1 1/2 h, concentrated in vacuo, and then the residue was dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate.
  • Example 24 ⁇ /-(r5-(4-Methyl-1-piperazinyl)imidazoH ,2-alpyridin-2-yl1methyl)- ⁇ /- (5,6,7,8-tetrahvdro-8- ⁇ uinolinvl)-1.4-butanediamine
  • Example 25 ⁇ /- ⁇ f5-(Methyloxy)imidazoH .2-a1pyridin-2-yllmethyl>- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
  • Example 26 ⁇ /-r(5-AminoimidazoM .2-a1pyridin-2-yl)methyll- ⁇ /-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
  • the mixture was stirred at room temperature for 30 minutes, filtered through a silica plug, rinsed with 10% ammonium hydroxide-acetonitrile, and concentrated. The residue was dissolved in tetrahydrofuran (10 ml_), treated with 4N hydrochloric acid (2 ml_), and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and extracted with aqueous sodium carbonate.
  • the reaction mixture was stirred at room temperature for 15 hours and treated with sodium carbonate (106 g, 996 mmol) and stirred for 30 minutes.
  • the mixture was diluted with dichloromethane, the organic layer separated, and the aqueous extracted with more dichloromethane.
  • reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, separated, and extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, concentrated, and purified by flash chromatography (0-4% ammonium hydroxide in acetonitrile).
  • Example 37 /V-dmidazoM ⁇ 2-alPyridin-2-ylmethyl)- ⁇ /-(5.6.7.8-tetrahvdro-8-quinolinvO- 1.4-cvclohexanediamine
  • Example 38 /V-HmidazoM .2-alpyridin-2-ylmethyl)- ⁇ /'. ⁇ /'-dimethyl- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinv0-1.4-cvclohexanediamine 63
  • (8S)-/V- ⁇ [2-(Dimethylamino)phenyl]rriethyl ⁇ - ⁇ /- ⁇ [5-(4-methyl-1-piperazinyl)imidazo[1 ,2- a]pyridin-2-yl]methyl ⁇ -5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)-N- ⁇ (1 S)- 1 -[4-(methyloxy)phenyl]ethyl ⁇ - ⁇ /- ⁇ [5-(4-methyl-1 -piperazinyl)imidazo[1 ,2- a]pyridin-2-yl]methyl ⁇ -5,6,7,8-tetrahydro-8-quinolinamine and 2- dimethylaminobenzaldehyde via deprotection and reductive amination in a similar manner as described herein to give an off-white solid (60% yield, 2 steps).
  • Example 32 (8S)- ⁇ /-(r5-(4-Methyl-1-piperazinyl)imidazoH .2-a1Pyridin-2-yllmethyl)- ⁇ /- (4-pyridinylmethv ⁇ -5.6.7.8-tetrahvdro-8-quinolinamine
  • (8S)- ⁇ /- ⁇ [5-(4-Methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl ⁇ - ⁇ /-(4- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)- ⁇ /- ⁇ (1 S)- 1 -[4-(methyloxy)phenyl]ethyl ⁇ - ⁇ /- ⁇ [5-(4-methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2- yl]methyl ⁇ -5,6,7,8-tetrahydro-8-quinolinamine and 4-pyridinecarboxaldehyde via deprotection and reductive amination in a similar manner as described herein to give a tan oil (96% yield, 2 steps).
  • Example 33 r2-(((r2-(Dimethylamino)phenyllmethyl)r(8S)-5.6.7.8-tetrahvdro-8- quinolinv ⁇ amino)methyl)-5-(4-methyl-1-piperazinyl)imidazo ⁇ ,2-aipyridin-3- yllmethanol 67
  • Example 36 r5-(4-Methyl-1 -piperazinv ⁇ -2-(f (4-pyridinylmethyl)r(8S)-5.6.7.8- tetrahvdro-8-quinolinvnamino)methyl)imidazof1 ,2-alpyridin-3-yllmethanol
  • Example 39 ⁇ /-(lmidazon .2-alpyridin-2-ylmethyl)-/ ⁇ /-r2-(1-methyl-3-piperidinvnethyll- 5,6,7.8-tetrahvdro-8-quinolinamine
  • Example 40 ⁇ /-(lmidazoM ⁇ 2-a1pyridin-2-ylmethvn-/V-(4-piperidinylmethvn-5.6.7.8- tetrahvdro-8-quinolinamine
  • ⁇ /-(lmida2 ⁇ [1 ,2-a]pyridin-2-ylmethyl)- ⁇ /-(4-piperidinylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine was prepared from ⁇ /-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-5,6,7,8- tetrahydro-8-quinolinamine and 1 ,1-dimethylethyl 4-formyl-1-piperidinecarboxylate in a similar manner as described above to give a tan oil (20% yield).
  • Example 41 ⁇ /-(lmidazoH .2-a1pyridin-2-ylmethyl)- ⁇ /-r(1-methyl-4-piperidinyl)methvn- 5,6,7,8-tetrahvdro-8- ⁇ uinolinamine
  • ⁇ /-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-A/-[(1-methyl-4-piperidinyl)methyl]-5, 6,7,8- tetrahydro-8-quinolinamine trifluoroacetic acid salt was prepared from ⁇ /- (imidazo[1 ,2-a]pyridin-2-ylmethyl)- ⁇ /-(4-piperidinylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine and paraformaldehyde in a similar manner as described above to give a tan oil (38% yield).
  • Example 42 ⁇ /-(lmidazoM .2-alPyridin-2-ylmethyl)- ⁇ /-(5.6.7.8-tetrahydroquinolin-8- yl)ethane-1 ,2-diamine
  • Acetic acid 0.039 ml_, 0.686 mmol
  • sodium triacetoxyborohydride (0.145g, 0.686 mmol) were added and the mixture was stirred at room temperature overnight.
  • 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes.
  • the organic layer was washed with saturated brine.
  • Acetic acid 0.034 mL, 0.60 mmol
  • sodium triacetoxyborohydride (0.127g, 0.60 mmol) were added and the mixture was stirred at room temperature overnight.
  • 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes.
  • the organic layer was washed with saturated brine.
  • Example 45 ⁇ /-r(3-Chloroimidazo ⁇ ⁇ 2-alpyridin-2-vnnrtethyll- ⁇ /-(5.6.7.8-tetrahydro-8- ⁇ uinolinyl)-1.4-butanediamine
  • Example 46 ⁇ /-r(3-BromoimidazoM .2-alpyridin-2-yl)methv ⁇ - ⁇ /-(5.6.7.8-tetrahvdro-8- ⁇ uinolinyl)-1 ,4-butanediamine
  • Example 47 ⁇ /-(lmidazo ⁇ ,2-alpyridin-2-ylmethyl)- ⁇ /'. ⁇ /'-dimethyl- ⁇ /-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
  • HIV-1 tat GenBank Accession No. X07861
  • rev GeneBank Accession No. M343728
  • the complete coding sequence of the HIV-1 (HXB2 strain) gp160 envelope gene was cloned into plasmid pCRII-TOPO.
  • the three HIV genes were additionally inserted into the baculovirus shuttle vector, pFastBacMami , under the transcriptional control of the CMV promoter.
  • a construction of the pHIV-l LTR containing mutated NFkB sequences linked to the luciferase reporter gene was prepared by digesting pcDNA3.1 , containing the G418 resistance gene, with Nm I and Bam HI to remove the CMV promoter. LTR-luc was then cloned into the Nru I/Bam HI sites of the plasmid vector. Plasmid preparations were performed after the plasmids were amplified in Escherichia coli strain DH5-alpha. The fidelity of the inserted sequences was confirmed by double-strand nucleotide sequencing using an ABI Prism Model 377 automated sequencer.
  • BacMam Baculovirus Generation Recombinant BacMam baculoviruses were constructed from pFastBacMam shuttle plasmids by using the bacterial cell-based Bac-to-Bac system. Viruses were propagated in Sf9 (Spodoptera frugiperda) cells cultured in Hink's TNM-FH Insect media supplemented with 10% (v/v) fetal bovine serum and 0.1 % (v/v) pluronic F-68 according to established protocols. Cell Culture
  • HOS Human osteosarcoma
  • the cells were maintained in Dulbeccos modified Eagles media supplemented with 10% fetal calf serum (FCS), G418 (400ug/ml), puromycin (1 ug/ml), mycophenolic acid (40ug/ml), xanthine (250ug/ml) and hypoxanthine (13.5ug/ml) to maintain a selection pressure for cells expressing the LTR-luciferase, hCCR5 and hCD4, respectively.
  • Human embryonic kidney (HEK- 293) cells stably transfected to express the human macrophage scavenging receptor (Class A 1 type 1 ; GenBank Accession No.
  • HEK-293 cells were maintained in DMEM/F-12 media (1 :1 ) supplemented with 10% FCS and 1.5ug/ml puromycin.
  • the expression of this receptor by the HEK-293 cells enhances their ability to stick to tissue culture treated plasticware. Transduction of HEK-293 cells
  • HEK-293 cells were harvested using enzyme-free cell dissociation buffer. The cells were resuspended in DMEM/F-12 media supplemented with 10% FCS and 1.5ug/ml and counted. Tranductions were performed by direct addition of BacMam baculovirus containing insect cell media to cells. The cells were simultaneously transduced with BacMam baculovirus expressing HIV-1 tat, HIV-1 rev and HIV-1 gp160 (from the HXB2 HIV strain). Routinely an MOI of 10 of each virus was added to the media containing the cells. 2mM butyric acid was also added to the cells at this stage to increase protein expression in transduced cells. The cells were subsequently mixed and seeded into a flask at 30 million cells per T225. The cells were incubated at 37 0 C, 5% CO 2 , 95% humidity for 24h to allow for protein expression. Cell/cell fusion assay format
  • HEK and HOS cells were harvested in DMEM/F-12 media containing 2% FCS and DMEM media containing 2% FCS, respectively, with no selection agents added. Compounds were plated as 1ul spots in 100% DMSO on a 96-well CulturPlate plates. HOS cells (5OuI) were added first to the wells, followed immediately by the HEK cells (5OuI). The final concentration of each cell type was 20,000 cells per well. Following these additions, the cells were returned to a tissue culture incubator (37 0 C; 5%CO 2 /95% air) for an additional 24h. Measurement of Luciferase Production
  • HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase) were harvested and diluted in Dulbeccos modified Eagles media supplemented with 2% FCS and non-essential amino acid to a concentration of 60,000 cells/ml. The cells were plated into 96-well plates (10OuI per well) and the plates were placed in a tissue culture incubator (37 0 C; 5%CO 2 /95% air) for a period of 24h.
  • B indicates an activity level of between 10OnM to 50OnM in the HOS HIV anti-infectivity assay.
  • C indicates an activity level of between 50OnM and 10 ⁇ M in the HOS
  • Compounds of the present invention demonstrate desired potency. Compounds of the present invention demonstrate anti-HIV activity in the range of IC 50 of about 1 nM to about 50 ⁇ M. In one aspect of the invention, compounds of the present invention have anti-HIV activity in the range of up to about 10OnM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 10OnM to about 500 nM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 50OnM to 10 ⁇ M. In another aspect of the invention, compounds have anti-HIV activity in the range of from about 10 ⁇ M to about 50 ⁇ M. Antiviral activity is separated from cytotoxicity. Moreover, compounds of the present invention are believed to provide a desired pharmacokinetic profile. Also, compounds of the present invention are believed to provide a desired secondary biological profile. Test compounds were employed in free or salt form.

Abstract

The present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 and/or CCR5 of a target cell.

Description

CHEMICAL COMPOUNDS Field of the Invention
The present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 and/or CCR5 of a target cell.
Background of the Invention
HIV gains entry into host cells by means of the CD4 receptor and at least one co-receptor expressed on the surface of the cell membrane. M-tropic strains of HIV utilize the chemokine receptor CCR5, whereas T-tropic strains of HIV mainly use CXCR4 as the co-receptor. HIV co-receptor usage largely depends on hyper- variable regions of the V3 loop located on the viral envelope protein gp120. Binding of gp120 with CD4 and the appropriate co-receptor results in a conformational change and unmasking of a second viral envelope protein called gp41. The protein gp41 subsequently interacts with the host cell membrane resulting in fusion of the viral envelop with the cell. Subsequent transfer of viral genetic information into the host cell allows for the continuation of viral replication. Thus infection of host cells with HIV is usually associated with the virus gaining entry into the cell via the formation of the ternary complex of CCR5 or CXCR4, CD4, and gp120. A pharmacological agent that would inhibit the interaction of gp120 with either
CCR5/CD4 or CXCR4/CD4 would be a useful therapeutic in the treatment of a disease, disorder, or condition characterized by infection with M-tropic or T-tropic strains, respectively, either alone or in combination therapy.
Evidence that administration of a selective CXCR4 antagonist could result in an effective therapy comes from in vitro studies that have demonstrated that addition of ligands selective for CXCR4 as well as CXCR4-neutralizing antibodies to cells can block HIV viral/host cell fusion. In addition, human studies with the selective CXCR4 antagonist AMD-3100, have demonstrated that such compounds can significantly reduce T-tropic HIV viral load in those patients that are either dual tropic or those where only the T-tropic form of the virus is present.
In addition to serving as a co-factor for HIV entry, it has been recently suggested that the direct interaction of the HIV viral protein gp120 with CXCR4 could be a possible cause of CD8+ T-cell apoptosis and AIDS-related dementia via induction of neuronal cell apoptosis. The signal provided by SDF-1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth; the known angiogenic growth factors VEG-F and bFGF up- regulate levels of CXCR4 in endothelial cells and SDF-1 can induce neovascularization in vivo. In addition, leukemia cells that express CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-1.
The binding of SDF-1 to CXCR4 has also been implicated in the pathogenesis of atherosclerosis, renal allograft rejection, asthma and allergic airway inflammation, Alzheimer's disease, and arthritis. The present invention is directed to compounds that can act as agents that modulate chemokine receptor activity. Such chemokine receptors include, but are not limited to, CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR1 , CXCR2, CXCR3, CXCR4, and CXCR5.
The present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor, such as CXCR4 and/or CCR5 of a target cell.
Summary of the Invention The present invention includes compounds of formula (I):
Figure imgf000003_0001
including salts, solvates, and physiologically functional derivatives thereof, wherein: t is O, 1, or 2; each R1 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -OR10, -OAy, -OHet, -R8OR10, -NR6R7, -R3NR6R7, -R8C(O)R10, -C(O)R10, -CO2R10, -R8CO2R10, -C(O)NR6R7, -C(O)Ay,
-C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; n is O, 1 , or 2; each R2 independently is H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, -R3Ay,
-R3OR10, or -RaS(O)qR10;
R3 is selected from a group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, alkenyl, alkynyl, -R3Ay, -, R3OR11, R3S(0)qR11, wherein R3 is not substituted with amine or alkylamine; each R4 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -HetN(R10)2, -OR10, -OAy, -OHet, -R3OR10, -
NR6R7, -R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7, -C(O)Ay, -C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; m is O, 1 , or 2;
Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene; Z is -N(R10J2, -AyN(R10)2, -AyRaN(R10)2, -Het, -HetN(R10)2, -HetR3N(R10)2, -HetRaAy, or -HetR3Het; each R10 independently is H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,
-Racycloalkyl, -RaOR11, , -R3NR8R9 or -RaHet; each of R6 and R7 independently are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -R3OH, -R3OR10, -R3NR8R9, -Ay, -Het, -R3Ay,
-RaHet, or -S(O)qR10; each Ra independently is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo,, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo,, alkenylene, cycloalkenylene, or alkynylene; each of R8 and R9 independently are selected from H or alkyl; each q independently is O, 1 , or 2; each R11 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, or -Ay; each Ay independently represents an optionally substituted aryl group; and each Het independently represents an optionally substituted 4-, 5-, 6- or 7-membered heterocyclyl or heteroaryl group.
In one embodiment -Het is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino. Preferably, -Het is optionally substituted with one or more of C1-C8 alkyl or C3-C8 cycloalkyl. In one embodiment -Ay is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino. Preferably, -Ay is optionally substituted with one or more of C1-C8 alkyl or C3-C8 cycloalkyl. In one embodiment t is 1. In another embodiment t is 2. Preferably t is 1.
In one embodiment R2 is H, alkyl, haloalkyl or cycloalkyl. Preferably R2 is H.
In one embodiment n is 0.
In one embodiment n is 1 and R1 is halogen, haloalkyl, alkyl, OR10, NR6R7, CO2R10, C(O)NR6R7, or cyano. In one embodiment R3 is H, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl. Preferably R3 is H, alkyl, haloalkyl, or cycloalkyl. More preferably R3 is H or alkyl. More preferably R3 is H.
In another embodiment R3 is RaOR11
In one embodiment m is 0. In one embodiment m is 1 or 2. Preferably m is 1.
When m is not 0, R4 preferably is one or more of halogen, haloalkyl, alkyl, OR10, NR6R7, CO2R10, C(O)NR6R7, or cyano.
In another embodiment m is 1 and R4 is -Het, -HetN(R10)2 and R10 is H or alkyl, or -NHHet, where Het is optionally substituted with CrC8 alkyl or C3- Cfjcycloalkyl.
In one embodiment Z is -N(R10J2, -AyRaN(R10)2, -Het, -HetN(R10)2, - HetRaN(R10)2, or -HetRΗet; more preferentially Z is -N(R10J2, -Het or -HetN(R10)2.
In one embodiment Y is alkylene, cycloalkylene, alkenylene, cycloalkenylene, or alkynylene; more preferentially Y is alkylene or cycloalkylene. In one embodiment n is 0, t is 1 or 2, Y is alkylene, Z is N(R10)2, where R10 is
H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or R3OR11 and R11 is H or alkyl, and m is 0.
In one embodiment n is 0, t is 1 or 2, Y is alkylene, Z is N(R10J2, where R10 is H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or R3OR11 and m is 1 , and R4 is -Het, - HetN(R10)2 and R10 is H or alkyl, or -NHHet where Het is optionally substituted with C1-C8 alkyl or C3-C8cycloalkyl.
In one embodiment n is 0, t is 1 or 2, Y is alkylene, Z is N(R10)2, where R10 is H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or R3OR11 and m is 1 , and R4 is -Het where Het is piperazine optionally substituted with C1-C8 alkyl or C3-C8cycloalkyl. In another emobodiment n is O1 1 is 1 or 2, Y is alkylene, Z is -AyRaN(R10)2,
-AyN(R10J2, -Het or -HetN(R10)2, where R10 is H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or RaOR11 and m is O.
In another emobodiment n is 0, t is 1 or 2, Y is alkylene, Z is -AyRaN(R10)2, -AyN(R10J2, -Het or -HetN(R10)2, where R10 is H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or RaOR11 and m is 1 and R4 is -Het or -NHHet where Het is optionally substituted with C1-C8 alkyl or C3-C8cycloalkyl.
In another emobodiment n is O1 1 is 1 or 2, Y is alkylene, Z is -AyRaN(R10)2,
-AyN(R10J2, -Het or -HetN(R10)2, where R10 is H, alkyl or cycloalkyl; R2 is H, R3 is H, alkyl or RaOR11 and m is 1 and R4 is -Het where Het is piperazine optionally substituted with C1-C8 alkyl or C3-C8cycloalkyl.
Compounds of the present invention include:
Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(7-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[7-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine; Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
2-{[(4-Aminobutyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]methyl}imidazo [1 ,2- a]pyridine-6-carbonitrile;
Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Chloroimidazo[1,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5,7-Dimethylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-
1 ,4-butanediamine;
Λ/-[(6,8-Dichloroimidazo[1 )2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)- 1 ,4-butanediamine;
Λ/-{[8-Chloro-6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-[(6-Bromo-8-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(8-Bromo-6-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Morpholinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(4-Methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-
8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and
Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine, including salts solvates, and pharmaceutically functional derivatives thereof.
Preferred compounds of the present invention include:
Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(7-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
2-{[(4-Aminobutyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]methyl}imidazo [1 ,2- a]pyridine-6-carbonitrile; Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7>8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
^-[(S-FluoroimidazoII ^-aJpyridin^-yOmethyll-A/^S.ej.e-tetrahydro-e-quinolinyO-i ^- butanediamine; Λ/-[(5,7-Dimethylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-
1,4-butanediamine;
Λ/-[(6,8-Dichloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-
1 ,4-butanediamine;
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Bromo-8-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Morpholinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(4-Methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine, including salts solvates, and pharmaceutically functional derivatives thereof.
More preferred compounds of the present invention include: Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; A/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-A/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Pipera2inyl)imidazo[1 I2-a]pyridin-2-yl]methyl}-Λ/-'(5,6,7I8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(4-Morpholinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and
Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine, including salts solvates, and pharmaceutically functional derivatives thereof.
Still more preferred compounds of the present invention include: Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine;
Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine; Λ/-[(5-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7l8-tetrahydro- 8-quinolinyl)-1,4-butanediamine;
Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5)6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine, including salts solvates, and pharmaceutically functional derivatives thereof.
One aspect of the invention includes the following compounds:
Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2- a]pyridin-2-yl]methyl}-1 ,4-butanediamine;
Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-[(5-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(4-Morpholinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine; Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
(8S)-Λ/-{[2-(Dimethylamino)phenyl]methyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine; Λ/-[(3-bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and pharmaceutically acceptable salts or esters thereof.
One aspect of the invention includes the following compounds:
(8S)-Λ/-{[2-(Dimethylamino)phenyl]methyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(2- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine; (8S)-Λ/-{[5-(4-Methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(4- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine; and pharmaceutically acceptable salts and esters thereof.
One aspect of the invention includes the following compounds:
[2-({{[2-(Dimethylamino)phenyl]methyl}[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)-5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-3- yl]methanol;
[5-(4-Methyl-1-piperazinyl)-2-({(2-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol;
[5-(4-Methyl-1-piperazinyl)-2-({(3-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol; [5-(4-Methyl-1-piperazinyl)-2-({(4-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol; and pharmaceutically acceptable salts and esters thereof.
One aspect of the present invention includes the compounds substantially as hereinbefore defined with reference to any one of the Examples.
One aspect of the present invention includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention includes one or more compounds of the present invention for use as an active therapeutic substance.
One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of diseases and conditions caused by inappropriate activity of CXCR4.
One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of diseases and conditions caused by inappropriate activity of CCR5.
One aspect of the present invention includes one or more compounds of the present invention for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondyloarthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers. Preferably the condition or disease is HIV infection, rheumatoid arthritis, inflammation, or cancer.
One aspect of the present invention includes the use of one or more compounds of the present invention in the manufacture of a medicament for use in the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor. Preferably the chemokine receptor is CXCR4 or CCR5.
One aspect of the present invention includes use of one or more compounds of the present invention in the manufacture of a medicament for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondylo¬ arthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers. Preferably the use relates to a medicament wherein the condition or disorder is HIV infection, rheumatoid arthritis, inflammation, or cancer.
One aspect of the present invention includes a method for the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor comprising the administration of one or more compounds of the present invention. Preferably the chemokine receptor is CXCR4 or CCR5.
One aspect of the present invention includes a method for the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondylo¬ arthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers comprising the administration of one or more compounds of the present invention.
One aspect of the present invention includes a method for the treatment or prophylaxis of HIV infection, rheumatoid arthritis, inflammation, or cancer comprising the administration of one or more compounds of the present invention. Detailed Description of the Invention
Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.
As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon, preferably having from one to twelve carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl.
As used throughout this specification, the preferred number of atoms, such as carbon atoms, will be represented by, for example, the phrase "Cx-Cy alkyl," which refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well.
As used herein the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, and the like. As used herein the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynyl and the like.
As used herein, the term "alkylene" refers to an optionally substituted straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like. Preferred substituents include alkyl, hydroxyl, or oxo.
As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinylene, allylene or 2-propenylene, and the like.
As used herein, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynylene and the like.
As used herein, the term "cycloalkyl" refers to an optionally substituted non- aromatic cyclic hydrocarbon ring. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, the term "cycloalkyl" includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non-cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein "aryl," such as a benzene ring) to form, for example, groups such as indane. Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
As used herein, the term "cycloalkenyl" refers to an optionally substituted non- aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached. Exemplary "cycloalkenyl" groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino. As used herein, the term "cycloalkylene" refers to a divalent, optionally substituted non-aromatic cyclic hydrocarbon ring. Exemplary "cycloalkylene" groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene. Preferred substituents include alkyl, hydroxyl, or oxo.
As used herein, the term "cycloalkenylene" refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds. Exemplary "cycloalkenylene" groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, and cycloheptenylene.
As used herein, the term "heterocycle" or "heterocyclyl" refers to an optionally substituted mono- or polycyclic ring system containing one or more degrees of unsaturation and also containing one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. More preferably, the heteroatom is N.
Preferably the heterocyclyl ring is three to twelve-membered and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4- dioxane, 1 ,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrothiopyran, aziridine, azetidine and tetrahydrothiophene. Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
As used herein, the term "aryl" refers to an optionally substituted benzene ring or to an optionally substituted fused benzene ring system, for example anthracene, phenanthrene, or naphthalene ring systems. Examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, and 1-naphthyl. Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino. As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic five to seven membered aromatic ring, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N- oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Preferably, the heteroatom is N. Examples of "heteroaryl" groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Preferred substituent groups include alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted with at least one halogen. Examples of branched or straight chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include such substituents as perfluoroalkyl groups and the like.
As used herein the term "alkoxy" refers to a group -OR', where R' is alkyl as defined.
As used herein the term "cycloalkoxy" refers to a group -OR', where R' is cycloalkyl as defined.
As used herein the term "alkoxycarbonyl" refers to groups such as:
Figure imgf000018_0001
where the R' represents an alkyl group as herein defined.
As used herein the term "aryloxycarbonyl" refers to groups such as:
Figure imgf000018_0002
where the Ay represents an aryl group as herein defined.
As used herein the term "nitro" refers to a group -NO2. As used herein the term "cyano" refers to a group -CN. As used herein the term "azido" refers to a group -N3. As used herein the term amino refers to a group -NR1R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Similarly, the term "alkylamino" includes an alkylene linker through which the amino group is attached. Examples of "alkylamino" as used herein include groups such as -(CH2)XNH2, where x is preferably 1 to 6.
As used herein the term "amide" refers to a group -C(O)NR1R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Examples of "amide" as used herein include groups such as -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3J2, and the like.
As used herein throughout the present specification, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substituent group. The phrase should not be interpreted so as to be imprecise or duplicative of substitution patterns herein described or depicted specifically. Rather, those of ordinary skill in the art will appreciate that the phrase is included to provide for obvious modifications, which are encompassed within the scope of the appended claims.
The compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives, for example, esters and amides, will be clear to those skilled in the art, without undue experimentation. Reference may be made to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, VoI 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
The term "modulators" as used herein is intended to encompass antagonist, agonist, inverse agonist, partial agonist or partial antagonist, inhibitors and activators. In one preferred embodiment of the present invention, the compounds demonstrate protective effects against HIV infection by inhibiting binding of HIV to a chemokine receptor such as CXCR4 and/or CCR5 of a target cell. The invention includes a method that comprises contacting the target cell with an amount of the compound that is effective at inhibiting the binding of the virus to the chemokine receptor.
In addition to the role chemokine receptors play in HIV infection this receptor class has also been implicated in a wide variety of diseases. Thus CXCR4 modulators may also have a therapeutic role in the treatment of diseases associated with hematopoiesis, including but not limited to, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia. In addition, compounds may also have a therapeutic role in diseases associated with inflammation, including but not limited to inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g. idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune throiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn1 s disease and ulcerative colitus; spondyloarthropathies; scleroderma; psoriasis (including T-cell-mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis (e.g. necrotizing, cutaneous, and hypersensitivity vasculitis); eoosinophilic myotis, eosinophilic fasciitis; and cancers.
For use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
Accordingly, the invention further provides pharmaceutical compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as herein described. The carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
A therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of formula (I) for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal one example of an actual amount per day would usually be from 7 to 700 mg. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others.
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Generally, powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents can also be present. Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above. Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl- aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
Pharmaceutical formulations adapted for nasal administration, where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question. For example, formulations suitable for oral administration may include flavoring or coloring agents. The compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. The compounds may be used in combination with any other pharmaceutical composition where such combined therapy may be useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and/or immunoregulatory diseases.
The present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV. Examples of such agents include:
Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, and similar agents;
Non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, and similar agents;
Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, palinavir, lasinavir, and similar agents;
Entry inhibitors such as T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS- 806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,180 and similar agents;
Budding inhibitors such as PA-344 and PA-457, and similar agents; and
Other CXCR4 and/or CCR5 inhibitors such as Sch-C, Sch-D, TAK779, UK 427,857, TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
The scope of combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
In all of the examples described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).
Those skilled in the art will recognize if a stereocenter exists in compounds of formula (I). Accordingly, the scope of the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry. EXPERIMENTAL SECTION Abbreviations:
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);
L (liters); ml_ (milliliters); μL (microliters); psi (pounds per square inch);
M (molar); mM (millimolar);
Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles);
RT (room temperature); h (hours); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase);
Tr (retention time); TFA (trifluoroacetic acid);
TEA (triethylamine); THF (tetrahydrofuran);
TFAA (trifluoroacetic anhydride); CD3OD (deuterated methanol);
CDCI3 (deuterated chloroform); DMSO (dimethylsulfoxide);
SiO2 (silica); atm (atmosphere);
EtOAc (ethyl acetate); CHCI3 (chloroform);
HCI (hydrochloric acid); Ac (acetyl);
DMF (N,N-dimethylformamide); Me (methyl);
CS2CO3 (cesium carbonate); EtOH (ethanol);
Et (ethyl); tBu (tert-butyl);
MeOH (methanol) P-TsOH (p-toluenesulfonic acid); MP-TsOH (polystyrene resin bound equivalent of p-TsOH from Argonaut Technologies).
Unless otherwise indicated, all temperatures are expressed in 0C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted.
1H-NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad).
Mass spectra were obtained on Micromass Platform or ZMD mass spectrometers from Micromass Ltd., Altricham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI).
Analytical thin layer chromatography was used to verify the purity of intermediate(s) which could not be isolated or which were too unstable for full characterization as well as to follow the progress of reaction(s).
The absolute configuration of compounds was assigned by Ab lnitio Vibrational Circular Dichroism (VCD) Spectroscopy. The experimental VCD spectra were acquired in CDCI3 using a Bomem Chiral RTM VCD spectrometer operating between 2000 and 800 cm"1. The Gaussian 98 Suite of computational programs was used to calculate model VCD spectrums. The stereochemical assignments were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R)- or (S)-configuration. Incorporated by reference with regard to such spectroscopy are: J.R. Chesseman, M.J. Frisch, F.J. Devlin and P.J. Stephens, Chem. Phys. Lett. 252 (1996) 211 ; P.J. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.11.4, M.J. Frisch et al., Gaussian, Inc., Pittsburgh PA, 2002. Compounds of formula (I) where all variables are as defined herein can be prepared according to Scheme 1 :
Scheme 1
Figure imgf000031_0001
More specifically, compounds of formula (I) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) under reductive amination conditions. The reductive amination can be carried out by treating the compound of formula (IV) with a compound of formula (V) in an inert solvent in the presence of a reducing agent. The reaction may be heated to 50-150 0C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like. The reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Optionally the reaction can be run in presence of acid, such as acetic acid and the like.
Compounds of formula (II) can be prepared as described in the literature (J. Org. Chem., 2002, 67, 2197-2205, herein incorporated by reference with regard to such synthesis). Compounds of formula (IV) can be prepared by reductive amination of compounds of formula (II) using processes well known to those skilled in the art of organic synthesis. Compounds of formula (V) can be prepared by methods similar to those described in the literature {J. Heterocyclic Chemistry, 1992, 29, 691-697, incorporated by reference with regard to such synthesis).
The sequence of the reductive amination steps can be changed as is evident to those skilled in the art of organic synthesis. Also evident is the fact that where Z in a compound of formula (IV) is a primary or secondary amine a suitable protecting group may be required for selective reductive amination. Any commonly used amine protecting group can be employed and means of removing the protecting groups at the end of the synthesis are well known to those skilled in the art of organic synthesis.
Scheme 2
Figure imgf000032_0001
Compound of formula (I) can be prepared by reacting a compound of formula (IV) with a compound of formula (Vl) where LV is a leaving group (e.g., halogen, mesylate, tosylate, or the like). This condensation is typically carried out in a suitable solvent optionally in the presence of base, optionally with heating. Suitable solvents include tetrahydrofuran, dioxane, acetonitrile, nitromethane, Λ/,Λ/-dimethylformamide, and the like. Suitable bases include triethylamine, pyridine, dimethylaminopyridine, Λ/,Λ/-diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate and the like. The reaction can be carried out at room temperature or optionally heated to 30-200 0C. Optionally the reaction can be carried out in a microwave. A catalyst, such as potassium iodide, tertbutylammonium iodide, or the like, can optionally be added to the reaction mixture. Compounds of formula (Vl) can be prepared by methods similar to those described in the literature (Chem. Pharm. Bull. 2000, 48, 935; Tetrahedron, 1991 , 47, 5173; Tetrahedron Lett. 1990, 31 , 3013; J. Heterocyclic Chemistry, 1988, 25, 129; Chemistry of Heterocyclic Compounds, 2002, 38, 590; each incorporated by reference with regard to such synthesis). Also evident is the fact that where Z in a compound of formula (IV) is a primary or secondary amine a suitable protecting group may be required for selective reaction. Any commonly used amine protecting group can be employed and means of removing the protecting groups at the end of the synthesis are well known to those skilled in the art of organic synthesis. Scheme 3
Figure imgf000033_0001
Alternatively a compound of formula (I-A) where R4 is selected from a group containing -Het, -NHHet, -OR10, -OHet, -NR6R7, can be synthesized from compound of formula (Vl-A) where R4 is halogen ("Hal") by treatment with a nucleophile.
The reaction can be carried out by treating the compound of formula (Vl-A) with a suitable nucleophile, neat, or optionally in the presence of an inert solvent. The reaction may be heated to 50-200 0C or performed at ambient temperature. Optionally the reaction may be carried out in a microwave.
A compound of formula (I-B) where Pr is a suitable protecting group (such as {[4-(methyloxy)phenyl]methyl}amine, {1-[4-(methyloxy)phenyl]ethyl}amine and related benzyl protecing groups), R2 is H and all other variables are as defined in connection with compound of formula (I) can be prepared as outlined in Scheme 4.
Scheme 4
Figure imgf000034_0001
V
Reductive amination
Figure imgf000034_0002
A compound of formula (I-B) can be prepared from compound of formula (IX) by reductive amination. The reductive amination can be carried out by treating the compound of formula (IX) with an aldehyde in an inert solvent in the presence of a reducing agent. The reaction may be heated to 50-150 0C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like. The reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Optionally the reaction can be run in presence of acid, such as acetic acid and the like.
A compound of formula (IX) can be prepared by deprotection of compound of formula (VIII). Deprotection method would depend on the choice of the protecting group. In the case where the protecting group is {[4-(methyloxy)phenyl]methyl}amine or {1-[4-(methyloxy)phenyl]ethyl}amine, a suitable deprotection method includes treatment with an acid. Treatment of compound of formula (VIII) with a stong acid in a suitable solvent is an appropriate method for removing the protecting group. Suitable acids include trifluoroacetic acid and the like. Suitable solvents include dichloromethane, dichloroethane and the like. The reaction can optionally be heated. Alternative methods for removing these protecting groups include use of Lewis acids (e.g. BCI3, AICI3, BBr3 and the like) or removal of the protecting group under reductive conditions (e.g. Pd on charcoal or PtO2 under H2 atmosphere).
A compound of formula (VIII) can be prepared from compound of formula (VII) and compound of formula (V) by reductive amination using conditions similar to those described in connection with previous Schemes.
A compound of formula (I-C) where m is 1 , R4 is Het, R2 is H, R3 is H, t is 1 and all other variables are as defined in connection with compound of formula (I) can be synthesized in a chiral fashion as outlined in Scheme 5.
Scheme 5
Figure imgf000036_0001
Oxidation
Figure imgf000036_0002
XIV
Figure imgf000036_0003
XVI
Figure imgf000036_0004
XVIII
Figure imgf000036_0005
I-C
A compound of formula (I-C) can be prepared from a compound of formula
(XVIII)
ination
Figure imgf000036_0006
Figure imgf000036_0007
XVIII I-C
Treatment of compound of formula (XVIII) with a stong acid in a suitable solvent is an appropriate method for removing [4-(Methyloxy)phenyl]ethyl group. Suitable acids include trifluoroacetic acid and the like. Suitable solvents include dichloromethane, dichloroethane and the like. The reaction can optionally be heated. Alternative methods for removing [4-(Methyloxy)phenyl]ethyl group include use of Lewis acids (e.g. BCI3, AICI3, BBr3 and the like) or removal of the protecting group under reductive conditions (e.g. Pd on charcoal or PtO2 under H2 atmosphere). The resulting amine can then be treated with a suitable aldehyde under reductive amination conditions to give a compound of formula (I-C). The reductive amination can be carried out by treating the amine with the aldehyde in an inert solvent in the presence of a reducing agent. The reaction may be heated to 50-150 0C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like. The reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Optionally the reaction can be run in presence of acid, such as acetic acid and the like.
A compound of formula (XVIII) can be prepared from a compound of formula (XVII) and compound of formula (XVI).
Figure imgf000037_0001
XVI
Figure imgf000037_0002
Reductive amination of compound of formula (XVI) with a compound of formula (XVII) gives compounds of formula (XVIII). The reductive amination can be carried out in an inert solvent in the presence of a reducing agent. The reaction may be heated to 50-150 0C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like. The reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Optionally the reaction can be run in presence of acid, such as acetic acid and the like. Compound of formula (XVII) can be prepared form (S)-(-)-1-(4-methoxyphenyl)ethylamine and 6,7- dihydro-8(5H)-quinolinone {J. Org. Chem., 2002, 67, 2197-2205 incorporated by reference with regard to such synthesis) by reductive amination. A compound of formula (XVI) can be prepared from a compound of formula (XV).
Figure imgf000038_0001
XV XVI Oxidation of compound of formula (XV) gives a compound of formula (XVI). A suitable oxidation method is to treat compound of formula (XV) with MnO2 in a suitable solvent. Suitable solvents include dichloromethane, chloroform, dichloroethane and the like.
Several additional oxidation methods known to those skilled in the art are also suitable for this oxidation.
A compound of formula (XV) can be prepared from a compound of formula (XIV).
Figure imgf000038_0002
XIV XV
Treatment of compound of formula (XIV) with a nucleophilic heterocycle optionally in a suitable solvent optionally with heating or in a microwave can be used to give compound of formula (XV). Compound of formula (XIV) can be prepared as outlined in connection with Scheme 5. As is evident to one skilled in the art other regioisomers of compound of formula (I-C) can be prepared in a similar fashion.
A compound of formula (I-C) where m is 1 , R4 is Het, R2 is H, R3 is H, t is 1 and all other variables are as defined in connection with compound of formula (I) can be synthesized in a chiral fashion as outlined in Scheme 6.
Scheme 6
Figure imgf000039_0001
XIII
Reductive amination
Figure imgf000039_0003
Figure imgf000039_0002
Re
Figure imgf000039_0004
4-(Methyloxy)phenyl]ethyl group XX
Figure imgf000039_0005
I-C
Compound of formula (I-C) can be prepared from compounds of formula (XVI) and (XX) via reductive amination.
Figure imgf000039_0006
XVI I-C
The reductive amination can be carried out in an inert solvent in the presence of a reducing agent. The reaction may be heated to 50-150 0C or performed at ambient temperature. Suitable solvents include dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, and the like. The reducing agent is typically sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Optionally the reaction can be run in presence of acid, such as acetic acid and the like. Compounds of formula (XX) and of formula (XVI) can be prepared in a similar fashion as described in connection with previous Schemes. As is evident to one skilled in the art the other enantiomer can be made in a similar fashion.
EXAMPLES
Example 1 : Λ/-(lmidazoM ,2-alpyridin-2-ylmethyl)-Λ/-(5.6.7.8-tetrahvdro-8-quinolinyl)- 1.4-butanediamine
Figure imgf000040_0001
A) 1.1 -Dimethylethyl F4-(5,6 J,8-tetrahvdro-8-quinolinylamino)butvπcarbanrιate To a solution of 6,7-dihydro-8(5H)-quinolinone (J. Org. Chem. 2002, 67, 2197) (7.0 g, 47 mmol) in dichloroethane (235 mL) was added fe/t-butyl-N-(4- aminobutyl)carbamate (9 mL, 47 mmol), acetic acid (2.7 mL, 47 mmol), and sodium triacetoxyborohydride (30 g, 141 mmol). The mixture was stirred at room temperature for 2 hours and then filtered through a silica plug and rinsed with 10% 2 M ammonia in methanol-ethyl acetate. The solvent was removed and the residue purified by flash chromatography (0-10% 2 M ammonia in methanol-ethyl acetate) to give 12 g (80% yield) 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate as a tan solid. 1H-NMR (CDCI3): δ 8.37 (d, 1 H), 7.36 (d, 1 H), 7.05 (m, 1 H), 4.85 (s, 1 H), 3.75 (t, 1 H), 3.13 (m, 2H), 2.74 (m, 4H), 2.13 (m, 1 H), 1.97 (m, 1 H), 1.75 (m, 2H), 1.58 (m, 4H), 1.41 (s, 9H); MS m/z 320 (M+1 ).
B) 1.1 -Dimethylethyl M-ffimidazoH ■2-a1pyridin-2-ylmethyl)(5.6.7.8-tetrahvdro-8- αuinolinvDaminolbutvDcarbamate
To a solution of 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8-quinolinylamino)butyl] carbamate (972 mg, 3 mmol) and imidazo[1 ,2-a]pyridine-2-carbaldehyde (J.
Heterocyclic Chem. 1992, 29, 691 ; 450 mg, 3 mmol) in dichloroethane (15 mL) was added acetic acid (0.36 mL, 6 mmol) and sodium triacetoxyborohydride (1.3 g, 6 mmol). The mixture was stirred at room temperature for 8 hours and then aqueous sodium bicarbonate was added and the resulting mixture stirred for 15 minutes. The organic phase was separated, dried with magnesium sulfate and concentrated to a syrup that was purified by silica gel chromatography (0-15 % methanol in dichloromethane) to give 1.3 g of 1 ,1-dimethylethyl {4-[(imidazo[1 ,2-a]pyridin-2- ylmethyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]butyl}carbamate as a yellow syrup: 1H-NMR (CDCI3): δ 8.42 (d, 1 H), 8.00 (d, 1 H), 7.67 (s, 1 H), 7.47 (d, 1 H), 7.25 (d, 1 H), 7.04 (t, 1 H), 6.96 (q, 1 H), 6.64 (t, 1 H), 4.98 (s, 1 H), 4.11 (m, 1 H), 3.94 (d, 1H), 3.80 (d, 1 H), 2.97 (m, 2H), 2.50-2.70 (m, 4H), 1.4-2.1 (multiplets, 7H)1.40 (s, 9H); MS m/z 450 (M+1 ).
C) Λ/-(lmidazoπ .2-a1pyridin-2-ylmethvn-Λ/-(5.6.7.8-tetrahvdro-8-αuinolinvn-1 A- butanediamine
1 ,1-Dimethylethyl {4-[(imidazo[1 ,2-a]pyridin-2-ylmethyl)(5,6,7,8-tetrahydro-8- quinolinyl)amino]butyl}carbamate (280 mg, 0.62 mmol) was dissolved in dichloromethane (4 ml.) and trifluoroacetic acid (1 ml_) was added. The resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane and extracted with aqueous sodium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the product (190 mg, 90% yield) as a yellow foam: 1H-NMR (CDCI3): δ 8.60 (d, 1H), 8.09 (d, 1 H), 7.67 (d, 1 H), 7.57 (s, 1 H), 7.38 (d, 1 H), 7.21 (t, 1 H), 7.11 (q, 1 H), 6.80 (t, 1 H), 4.02 (m, 1 H), 3.89 (d, 1 H), 3.78 (d, 1H), 3.33 (m, 1 H), 2.96 (m, 1 H), 2.82-2.64 (m, 3H), 2.40 (m, 1H), 2.24 (m, 1 H), 2.05 (m, 1 H), 2.0-1.4 (m, 6H); MS m/z 350 (M+1).
Example 2: Λ/-r(8-MethylimidazoM .2-alpyridin-2-yl)methyll-Λ/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
Figure imgf000042_0001
Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 8-methylimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a pale orange oil (74% yield). 1H-NMR (CDCI3): δ 8.68 (d, 1 H), 7.95 (d, 1 H), 7.51 (m, 1 H), 7.41 (d, 1 H), 7.15 (m, 1 H), 7.01 (d, 1 H), 6.72 (t, 1 H), 4.05 (m, 1 H), 3.80 (m, 2H), 3.42 (m, 1 H), 3.00 (m, 1 H), 2.80-2.69 (m, 3H), 2.59 (s, 3H), 2.40 (m, 1 H), 2.25 (m, 1 H), 2.07 (m, 1 H), 1.93-1.83 (m, 2H), 1.69-1.54 (m, 4H); MS m/z 364 (M+1 ).
Example 3: Λ/-r(7-Methylimidazoπ ,2-alpyridin-2-yl)methvn-Λ/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
Λ/-[(7-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 , 1 -dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 7-methylimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a pale orange oil (59% yield). 1H-NMR (CDCI3): δ 8.65 (d, 1 H), 8.15 (m, 1 H), 7.77 (m, 1 H), 7.56 (m, 1 H), 7.48 (m, 1 H), 7.20 (m, 1 H), 6.79 (m, 1 H), 4.13 (m, 1 H), 3.93 (m, 2H), 3.18 (m, 1 H), 2.94 (m, 1 H), 2.84-2.71 (m, 3H), 2.53 (m, 1 H), 2.43 (s, 3H), 2.29 (m, 1 H), 2.10 (m, 1 H), 1.92- 1.80 (m, 2H), 1.75-1.58 (m, 4H); MS m/z 364 (M+1 ).
Example 4: Λ/-r(6-MethylimidazoH ■2-a1pyridin-2-vnmethyll-Λ/-(5,6.7.8-tetrahvdro-8- guinolinyl)-1.4-butanediamine
Figure imgf000043_0001
Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 6-methylimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a pale orange oil (43% yield). 1H-NMR (CDCI3): δ 8.60 (d, 1H), 7.87 (s, 1 H), 7.59 (d, 1 H), 7.46 (m, 1 H), 7.39 (d, 1 H), 7.11 (m, 2H), 4.02 (m, 1 H), 3.88-3.72 (m, 2H), 3.31 (m, 1 H), 2.94 (m, 1 H), 2.83- 2.66 (m, 3H), 2.40 (m, 1 H), 2.29 (s, 3H), 2.22 (m, 1 H), 2.05 (m, 1 H), 1.93-1.76 (m, 2H), 1.70-1.44 (m, 4H); MS m/z 364 (M+1 ).
Example 5: Λ/-r(5-Methylimidazoπ .2-alpyridin-2-vnmethvn-Λ/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1.4-butanediamine
Figure imgf000044_0001
Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 5-methylimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a yellow solid (50% yield). 1H- NMR (CDCI3): δ 8.60 (d, 1 H), 7.55 (d, 1 H), 7.36 (m, 2H), 7.16 (m, 1 H), 7.09 (m, 1 H), 6.61 (d, 1 H), 3.99 (m, 1 H), 3.88-3.76 (m, 2H), 3.37 (m, 1 H), 2.95 (m, 1 H), 2.82-2.64 (m, 3H), 2.53 (s, 3H), 2.34 (m, 1 H), 2.23 (m, 1 H), 2.02 (m, 1 H), 1.92-1.77 (m, 2H), 1.65-1.41 (m, 4H); MS m/z 364 (M+1 ).
Example 6: Λ/-(5,6,7,8-Tetrahvdro-8-quinolinyl)-Λ/-(r7-(trifluoromethyl)imidazof 1 ,2- alpyridin-2-yl1methyl)-1 ,4-butanediamine
Figure imgf000044_0002
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[7-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 7-(trifluoromethyl)imidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give an off-white solid (49% yield).1H-NMR (CDCI3): δ 8.52 (d, 1H), 8.25 (d, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.36 (d, 1H), 7.06 (m, IH), 6.89 (dd, 1H), 4.03 (m, 1H), 3.89-3.73 (m, 2H), 3.13 (m, 1H), 2.90 (m, 1H), 2.82-2.66 (m, 3H), 2.46 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.88-1.77 (m, 2H), 1.66-1.48 (m, 4H); MS m/z418 (M+1).
Example 7: Λ/-(5.6 J,8-Tetrahvdro-8-quinolinyl)-Λ/-(f6-(trifluoromethyl)imidazori ,2- alpyridin-2-yllmethyl)-1.4-butanediamine
Figure imgf000045_0001
Λ/-(5,6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine was prepared from 1 , 1 -dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 6-(trifluoromethyl)imidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give an off-white solid (34% yield).1H-NMR (CDCI3): δ 8.52 (d, 1H), 8.50 (s, 1H), 7.76 (d, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.30 (dd, 1H), 7.09 (m, 1H), 4.04 (m, 1H), 3.90-3.76 (m, 2H), 3.18 (m, 1H), 2.92 (m, 1H), 2.83-2.67 (m, 3H), 2.44 (m, 1H), 2.23 (m, 1H), 2.03 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.49 (m, 4H); MS /r?/z418 (M+1).
Example 8: Λ/-(5.6.7.8-Tetrahvdro-8-quinolinyl)-Λ/-(r5-(trifluoromethyl)imidazoπ .2- alpvridin-2-vl1methvl}-1.4-butanediamine
Figure imgf000046_0001
Λ/-(5l6,7,8-Tetrahydro-8-quinolinyl)-Λ/-{[5-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 5-(trifluoromethyl)imidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a white solid (64% yield). 1H-NMR (CDCI3): δ 8.52 (d, 1 H), 7.95 (d, 1 H), 7.63 (s, 1 H), 7.37 (d, 1H), 7.25 (m, 2H), 7.09 (m, 1 H), 4.00 (m, 1 H), 3.87-3.78 (m, 2H), 3.34 (m, 1 H), 2.95 (m, 1 H), 2.81-2.66 (m, 3H), 2.36 (m, 1H), 2.21 (m, 1 H), 2.02 (m, 1 H), 1.92- 1.76 (m, 2H), 1.65-1.47 (m, 4H); MS m/z 418 (M+1 ).
Example 9: 2-(f(4-Aminobutyl)(5.6J.8-tetrahvdro-8-quinolinyl)aminolmethyl)imidazo H ,2-aipyridine-6-carbonitrile
Figure imgf000046_0002
2-{[(4-Aminobutyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]methyl}imidazo [1 ,2- a]pyridine-6-carbonitrile was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro- 8-quinolinylamino)butyl]carbamate and 2-formylimidazo[1 ,2-a]pyridine-6-carbonitrile in a similar manner as described in Example 1 to give a tan solid (22% yield). 1H- NMR (CDCI3): δ 8.61 (s, 1H), 8.55 (m, 1H), 7.78 (m, 2H), 7.42 (d, 1H), 7.28 (dd, 1H), 7.13 (m, 1H), 4.06 (m, 1H), 3.92-3.77 (m, 2H), 3.31 (m, 1H), 2.94 (m, 1H), 2.85-2.70 (m, 3H), 2.46 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.96-1.79 (m, 2H), 1.72-1.49 (m, 4H); MSm/z375(M+1).
Example 10: Λ/-r(6-Chloroimidazoπ ■2-a1pyridin-2-vnmethyl1-Λ/-(5.6,7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
Figure imgf000047_0001
Λ/-[(6-Chloroimidazo[1,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- butanediamine was prepared from 1,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 6-chloroimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a yellow solid (41% yield).1H- NMR (CDCI3): δ 8.55 (m, 1H), 8.12 (m, 1H), 7.64 (d, 1H), 7.51 (s, 1H), 7.37 (d, 1H), 7.14 (dd, 1H), 7.09 (m, 1H), 3.98 (m, 1H), 3.83-3.70 (m, 2H), 3.28 (m, 1H), 2.93 (m, 1H), 2.82-2.66 (m, 3H), 2.36 (m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.93-1.75 (m, 2H), 1.69-1.41 (m, 4H); MS m/z 384 (M+1 ).
Example 11 : /V-f(6-FluoroimidazoH ,2-alpyridin-2-yl)methyll-Λ/-(5,6.7,8-tetrahvdro-8- quinolinvD-1 ,4-butanediamine
Figure imgf000048_0001
Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7>8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 6-fluoroimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give an off-white solid (48% yield). 1H-NMR (CDCI3): δ 8.53 (d, 1 H), 8.03 (m, 1 H), 7.64 (m, 1H), 7.55 (s, 1 H), 7.36 (d, 1H), 7.07 (m, 2H), 3.98 (m, 1 H), 3.83-3.69 (m, 2H), 3.24 (m, 1 H), 2.91 (m, 1 H), 2.81- 2.65 (m, 3H), 2.37 (m, 1 H), 2.21 (m, 1 H), 2.03 (m, 1 H), 1.90-1.74 (m, 2H), 1.66-1.41 (m, 4H); MS m/z 368 (M+1 ).
Example 12: Λ/-r(5-BromoimidazoM .2-alpyridin-2-v0methvπ-Λ/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
Figure imgf000048_0002
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 5-bromoimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give an off-white solid (63% yield). 1H-NMR (CDCI3): δ 8.55 (d, 1 H), 7.70 (d, 1 H), 7.65 (s, 1 H), 7.37 (d, 1 H), 7.10 (m, 2H), 7.01 (d, 1H), 3.99 (m, 1H), 3.87-3.76 (m, 2H), 3.36 (m, 1H), 2.95 (m, 1H), 2.82- 2.65 (m, 3H), 2.33 (m, 1H), 2.22 (m, 1H), 2.02 (m, 1H), 1.92-1.76 (m, 2H), 1.65-1.44 (in, 4H); MS m/z 428 (M+1).
Example 13: A/-f(5-Chloroimidazon .2-a1pyridin-2-vnmethyll-A/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1.4-butanediamine
Figure imgf000049_0001
Λ/-[(5-Chloroimidazo[1,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- butanediamine was prepared from 1,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 5-chloroimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a white solid (51% yield).1H- NMR (CDCI3): δ 8.54 (d, 1H), 7.66 (d, 1H), 7.63 (s, 1H), 7.37 (d, 1H), 7.19 (m, 1H), 7.09 (m, 1H), 6.86 (m, 1H), 3.97 (m, 1H), 3.87-3.75 (m, 2H), 3.35 (m, 1H), 2.95 (m, 1H), 2.81-2.64 (m, 3H), 2.33 (m, 1H), 2.22 (m, 1H), 2.02 (m, 1H), 1.92-1.76 (m, 2H), 1.68-1.41 (m, 4H); MS m/z 384 (M+1).
Example 14: Λ/-r(5-FluoroimidazoH ,2-alpyridin-2-yl)methyll-Λ/-(5,6,7.8-tetrahvdro-8- quinolinyl)-1 , 4-butanediamine
Figure imgf000049_0002
Λ/-[(5-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6l7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 5-fluoroimidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a white solid (45% yield). 1H- NMR (CDCI3): δ 8.58 (d, 1 H), 7.53 (m, 2H)1 7.38 (d, 1 H), 7.26 (m, 1 H), 7.11 (m, 1 H), 6.47 (m, 1 H), 3.98 (m, 1H), 3.88-3.76 (m, 2H), 3.39 (m, 1 H), 2.96 (m, 1 H), 2.83-2.65 (m, 3H), 2.34 (m, 1 H), 2.23 (m, 1 H), 2.04 (m, 1 H), 1.95-1.76 (m, 2H), 1.70-1.42 (m, 4H); MS m/z 368 (M+1 ).
Example 15: Λ/-rf5.7-Dimethylimidazoπ ,2-alpyridin-2-yl)methyll-Λ/-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
Figure imgf000050_0001
Λ/-[(5,7-Dimethylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)- 1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 5,7-dimethylimidazo[1 ,2-a]pyridine-2- carbaldehyde in a similar manner as described in Example 1 to give a yellow solid (26% yield). 1H-NMR (CDCI3): δ 8.61 (d, 1 H), 7.36 (d, 1 H), 7.31 (s, 1 H), 7.25 (m, 1 H), 7.10 (m, 1 H), 6.45 (s, 1 H), 3.99 (m, 1 H), 3.85-3.72 (m, 2H), 3.40 (m, 1 H), 2.95 (m, 1 H)1 2.82-2.63 (m, 3H), 2.49 (s, 3H), 2.33 (m, 4H), 2.22 (m, 1 H), 2.03 (m, 1H), 1.92- 1.76 (m, 2H), 1.68-1.40 (m, 4H); MS m/z 378 (M+1 ).
Example 16: Λ/-r(6.8-Dichloroimidazoπ .2-alpyhdin-2-vnmethyl1-Λ/-(5.6.7.8-tetrahvdro- 8-quinolinyl)-1 ,4-butanediamine
Figure imgf000051_0001
Λ/-[(6,8-Dichloroimida2θ[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)- 1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate and 6,8-dichloroimidazo[1 ,2-a]pyridine-2- carbaldehyde in a similar manner as described in Example 1 to give a yellow solid (76% yield). 1H-NMR (CDCI3): δ 8.62 (d, 1 H), 8.16 (d, 1 H), 7.64 (s, 1 H), 7.36 (d, 1 H), 7.19 (d, 1H), 7.08 (m, 1 H), 4.04 (m, 1 H), 3.73 (s, 2H), 3.27 (m, 1 H), 2.96 (m, 1 H), * 2.83-2.67 (m, 3H), 2.41 (m, 1 H), 2.21 (m, 1 H), 2.03 (m, 1 H), 1.96-1.79 (m, 2H), 1.71- 1.49 (m, 4H); MS m/z 418 (M+1 ).
Example 17: /V-(r8-Chloro-6-(trifluoromethyl)imidazoM ■2-a1pyridin-2-yllmethyl>-Λ/- (5,6.7,8-tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
Figure imgf000051_0002
Λ/-{[8-Chloro-6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4- (S.ey.δ-tetrahydro-δ-quinolinylaminojbutyllcarbamate and δ-chloro-e- (trifluoromethyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a clear oil (16% yield). 1H-NMR (CDCI3): δ 8.67 (m, 1H), 8.64 (d, 1 H), 8.54 (s, 1 H), 7.98 (d, 1H), 7.61 (m, 1 H), 7.59 (m, 1 H), 4.43 (m, 2H), 4.19 (m, 1 H), 2.95 (m, 5H), 2.61 (m, 1H)1 2.46 (m, 1 H), 2.25 (m, 1 H), 1.98-1.63 (m, 6H); MS m/z 452 (M+1 ).
Example 18: Λ/-r(6-Bromo-5-methylimidazoH ,2-alpyridin-2-yl)methyll-Λ/-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine
Figure imgf000052_0001
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 6-bromo-5-methylimidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give an off-white solid (33% yield). 1H-NMR (CDCI3): δ 8.55 (d, 1 H), 7.46 (d, 1 H), 7.39 (s, 1 H), 7.36 (d, 1 H), 7.31 (d, 1 H), 7.08 (m, 1 H), 3.97 (m, 1 H), 3.85-3.74 (m, 2H), 3.34 (m, 1 H), 2.93 (m, 1 H), 2.81-2.68 (m, 3H), 2.65 (s, 3H), 2.33 (m, 1 H), 2.22 (m, 1 H), 2.01 (m, 1 H), 1.92-1.76 (m, 2H), 1.67-1.39 (m, 4H); MS m/z 442 (M+1 ).
Example 19: Λ/-r(6-Bromo-8-methylimidazoπ .2-alpyridin-2-yl)methyll-Λ/-(5.6.7.8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
Figure imgf000053_0001
Λ/-[(6-Bromo-8-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 6-bromo-8-methylimidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a yellow solid (93% yield). 1H-NMR (CDCI3): δ 8.53 (d, 1 H), 8.10 (s, 1 H), 7.51 (s, 1 H), 7.34 (d, 1 H), 7.04 (m, 1 H), 6.96 (m, 1 H), 3.96 (m, 1 H), 3.77-3.68 (m, 2H), 3.30 (m, 1 H), 2.92 (m, 1 H), 2.79-2.63 (m, 3H), 2.48 (s, 3H), 2.33 (m, 1 H), 2.18 (m, 1H), 2.02 (m, 1 H), 1.90-1.73 (m, 2H), 1.66-1.41 (m, 4H); MS m/z 442 (M+1 ).
Example 20: /V-r(8-Bromo-6-methylimidazoH ,2-alpyridin-2-yl)methyll-Λ/-(5,6,7,8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
Figure imgf000053_0002
Λ/-[(8-Bromo-6-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5,6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 8-bromo-6-methylimidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described in Example 1 to give a tan solid (58% yield). 1H-NMR (CDCI3): δ 8.63 (d, 1 H), 7.87 (s, 1 H), 7.53 (s, 1 H), 7.36 (d, 1 H), 7.21 (S, 1 H), 7.08 (m, 1 H), 4.03 (m, 1 H), 3.70 (s, 2H), 3.34 (m, 1 H), 2.96 (m, 1 H), 2.81-2.66 (m, 3H), 2.34 (m, 1H), 2.23 (s, 3H), 2.19 (m, 1 H), 2.04 (m, 1H), 1.89- 1.77 (m, 2H), 1.69-1.49 (m, 4H); MS m/z 442 (M+1 ).
Example 21 : Λ/-{r5-H-Pyrrolidinyl)imidazoH .2-alpyridin-2-yllmethyl)-Λ/-(5.6.7.8- tetrahvdro-8-αuinolinyl)-1.4-butanediamine
Figure imgf000054_0001
A) 1.1 -Dimethylethyl {4-Kr5-(1 -PyrrolidinvDimidazoH .2-alpyridin-2-vnmethyl)(5.6.7.8- tetrahvdro-δ-quinolinvDaminolbutyllcarbamate
A solution of 1 ,1-dimethylethyl {4-[[(5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl](5,6,7,8- tetrahydro-8-quinolinyl)amino]butyl}carbamate (100 mg, 0.21 mmol) in pyrrolidine (500 μL) was subjected to microwave irradiation at 100°C for 10 minutes. Reaction mixture was concentrated and purified by preparative chromatography (0-5% ammonium hydroxide-acetonitrile) to give 63 mg (58% yield) of a yellow oil: 1H-NMR (CDCI3): δ 8.44 (m, 1 H), 7.77 (s, 1 H), 7.29 (d, 1 H), 7.10 (m, 1 H), 7.05 (d, 1 H), 6.99 (m, 1 H), 6.05 (d, 1 H), 4.15 (m, 1 H), 3.98-3.81 (m, 2H), 3.35 (m, 4H), 2.98 (m, 2H), 2.81-2.61 (m, 5H), 2.51 (m, 1 H), 2.44 (m, 1 H), 2.08 (m, 1 H), 2.01 (m, 5H), 1.90-1.84 (m, 1 H), 1.67 (m, 2H), 1.38 (s, 9H); MS m/z 519 (M+1 ).
B) Λ/-(r5-(1-Pyrrolidinyl)imidazori .2-alPyridin-2-yllmethyl)-Λ/-(5,6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
1 ,1-Dimethylethyl {4-[{[5-(1-pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}(5,6,7,8- tetrahydro-8-quinolinyl)amino]butyl}carbamate (63 mg, 0.12 mmol) was dissolved in dichloromethane (0.60 ml_) and trifluoroacetic acid (0.60 mL) was added. The resulting mixture was stirred for 2 1/2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the product (21 mg, 42% yield) as an off-white foam: 1H-NMR (CDCI3): δ 8.60 (d, 1 H), 7.65 (s, 1 H), 7.42 (d, 1 H), 7.29 (m, 2H), 7.15 (m, 1 H), 6.23 (m, 1 H), 4.08 (m, 1 H), 3.98-3.84 (m, 2H), 3.42 (m, 4H), 3.23 (m, 1 H), 2.93 (m, 1 H), 2.81 (m, 1 H), 2.70 (m, 2H), 2.48 (m, 1 H), 2.26 (m, 1 H), 2.04 (m, 5H), 1.90-1.78 (m, 2H), 1.72-1.51 (m, 4H); MS m/z 419 (M+1 ).
Example 22: Λ/-fr5-(1-Piperazinyl)imidazori .2-alpyridin-2-yllmethyl)-Λ/-(5,6.7.8- tetrahydro-8-quinolinyl)-1.4-butanediamine
Figure imgf000055_0001
Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl {4-[[(5- fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl](5,6,7,8-tetrahydro-8-quinolinyl)amino]butyl} carbamate and terf-butyl piperazine-1-carboxylate in a similar manner as described in Example 21 to give a tan solid (44% yield): 1H-NMR (CDCI3): δ 8.58 (m, 1H), 7.39 (m, 3H), 7.21 (m, 1 H), 7.12 (m, 1 H), 6.32 (m, 1 H), 4.02 (m, 1 H), 3.80 (m, 2H), 3.37 (m, 1 H), 3.23-3.16 (m, 6H), 3.08 (m, 2H), 2.96 (m, 1 H), 2.84-2.67 (m, 3H), 2.30 (m, 2H), 2.07 (m, 1 H), 1.95-1.80 (m, 2H), 1.71-1.42 (m, 4H); MS m/z 434 (M+1 ).
Example 23: Λ/-fr5-(4-Morpholinyl)imidazoπ .2-a1pyridin-2-yllmethyl)-Λ/-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
Figure imgf000056_0001
A) 5-BromoimidazoH ,2-a1pyridine-2-carbaldehyde
To a solution of 2-amino-6-bromopyridine (10 g, 58 mmol) in ethylene glycol dimethyl ether (66 mL) was added trichloroacetone (18 mL, 173 mmol). The mixture was stirred at 7O0C for 15 hours and the resulting precipitate was collected by filtration and refluxed in ethyl alcohol (50 mL) for 7 hours. The reaction mixture was cooled to room temperature, concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was isolated, dried with magnesium sulfate, and concentrated. The resulting solid was refluxed in aqueous calcium carbonate for 1.5 hours, cooled to room temperature, and extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated to give 6.6 g (50% yield) 5-bromoimidazo[1 ,2-a]pyridine-2- carbaldehyde as an orange solid. 1H-NMR (CDCI3): δ 10.16 (s, 1 H), 8.37 (s, 1 H), 7.69 (d, 1 H), 7.22 (m, 1 H), 7.16 (m, 1 H); TLC (10% ammonium hydroxide- acetonitrile) R^ = 0.44.
B) (5-BromoimidazoH .2-alpyridin-2-yl)methanol
To a stirred solution of 5-bromoimidazo[1 ,2-a]pyridine-2-carbaldehyde (1.42 g, 6.31 mmol) in methyl alcohol (30 mL) cooled to O0C was added sodium borohydride (286 mg, 7.57 mmol). The mixture was stirred at room temperature for 4 hours, quenched with water, and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to give 0.6 g (42% yield) 5-bromoimidazo[1 ,2- a]pyridin-2-yl)methanol as an orange solid. 1H-NMR (CDCI3): δ 7.76 (s, 1 H), 7.55 (d, 1 H), 7.09 (m, 1 H), 7.03 (dd, 1 H), 4.87 (s, 2H); MS m/z 227 (M+1 ).
C) 5-(4-Morpholinyl)imidazoπ .2-aipyridine-2-carbaldehvde A solution of (5-bromoimidazo[1 ,2-a]pyridin-2-yl)methanol (150 mg, 0.66 mmol) in morpholine (500 μL) was subjected to microwave irradiation at 200°C for 20 minutes. Reaction mixture was concentrated and purified by preparative chromatography (0- 5% ammonium hydroxide-acetonitrile) to give [5-(4-morpholinyl)imidazo[1 ,2-a]pyridin- 2-yl]methanol. To this alcohol in chloroform (6.6 mL) was added manganese dioxide (574 mg, 6.6 mmol). The reaction mixture was stirred at room temperature overnight, filtered through celite, rinsed with dichloromethane, and concentratred to give 150 mg (98% yield) 5-(4-morpholinyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde. 1H-NMR (CDCI3): δ 10.16 (s, 1 H), 8.16 (s, 1 H), 7.46 (d, 1 H), 7.30 (m, 1 H), 6.40 (d, 1 H), 3.94 (m, 4H), 3.13 (m, 4H); MS m/z 232 (M+1 ).
D) Λ/-fr5-(4-Morpholinvnimidazoπ .2-a1pyridin-2-yllmethyl>-Λ/-(5.6.7,8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
To a solution of ) 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8- quinolinylamino)butyl]carbamate (86 mg, 0.27 mmol) and 5-(4- morpholinyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde (69 mg, 0.30 mmol) in dichloroethane (1.4 mL) was added acetic acid (15 μL, 0.27 mmol) and sodium triacetoxyborohydride (172 mg, 0.81 mmol). The mixture was stirred at room temperature for 15 hours, filtered through a silica plug, rinsed with 10% 2 M ammonia in methanol-ethyl acetate, concentrated, and purified by preparative chromatography (0-70% acetonitrile-water; 0.1 % trifluoroacetic acid). The purified intermediate was dissolved in dichloromethane (0.30 mL) and trifluoroacetic acid (0.30 mL) was added. The resulting mixture was stirred for 1 1/2 h, concentrated in vacuo, and then the residue was dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the product (12 mg, 10% yield) as a tan solid: 1H-NMR (CDCI3): δ 8.62 (d, 1 H), 7.46 (d, 1H), 7.41 (s, 1 H), 7.39 (d, 1 H), 7.25 (m, 1 H), 7.13 (m, 1 H), 6.33 (d, 1 H), 4.02 (m, 1 H), 3.92 (m, 4H), 3.87-3.77 (m, 2H), 3.40 (m, 1 H), 3.16-3.02 (m, 4H), 2.95 (m, 1 H), 2.79-2.66 (m, 3H), 2.36 (m, 1 H), 2.24 (m, 1 H), 2.04 (m, 1 H), 1.93-1.79 (m, 2H), 1.69-1.43 (m, 4H); MS m/z 435 (M+1 ).
Example 24: Λ/-(r5-(4-Methyl-1-piperazinyl)imidazoH ,2-alpyridin-2-yl1methyl)-Λ/- (5,6,7,8-tetrahvdro-8-αuinolinvl)-1.4-butanediamine
Figure imgf000058_0001
Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5, 6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde in a similar manner as described in Example 23 to give a tan solid (11% yield): 1H-NMR 5 8.61 (d, 1 H), 7.41 (d, 1 H), 7.37 (m, 2H), 7.22 (m, 1H), 7.12 (m, 1 H), 6.31 (d, 1 H), 4.00 (m, 1 H), 3.85-3.75 (m, 2H), 3.40 (m, 1 H), 3.19-3.06 (m, 4H), 2.95 (m, 1 H), 2.83-2.65 (m, 7H), 2.42 (s, 3H), 2.35 (m, 1 H), 2.23 (m, 1H), 2.06 (m, 1 H), 1.93-1.79 (m, 2H), 1.71-1.42 (m, 4H); MS m/z 448 (M+ 1 ).
Example 25: Λ/-{f5-(Methyloxy)imidazoH .2-a1pyridin-2-yllmethyl>-Λ/-(5.6.7.8- tetrahvdro-8-quinolinyl)-1 ,4-butanediamine
Figure imgf000058_0002
Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from 1 ,1-dimethylethyl [4-(5, 6,7,8- tetrahydro-8-quinolinylamino)butyl]carbamate and 5-(methyloxy)imidazo[1 ,2- a]pyridine-2-carbaldehyde in a similar manner as described above to give a tan solid (96% yield): 1H-NMR δ 8.55 (d, 1 H), 7.59 (s, 2H), 7.39 (d, 1 H), 7.26 (m, 1 H), 7.10 (m, 1 H), 6.10 (m, 1 H), 4.05 (m, 4H), 3.94-3.80 (m, 2H), 3.24 (m, 1 H), 2.92 (m, 1 H), 2.82- 2.66 (m, 3H), 2.40 (m, 1H), 2.23 (m, 1 H), 2.02 (m, 1 H), 1.86-1.76 (m, 2H), 1.68-1.48 (m, 4H); MS m/z 380 (M+1 ).
Example 26: Λ/-r(5-AminoimidazoM .2-a1pyridin-2-yl)methyll-Λ/-(5.6.7.8-tetrahvdro-8- quinolinyl)-1 ,4-butanediamine
Figure imgf000059_0001
A) (5-r(Diphenylmethylidene)aminolimidazori ,2-a1pyridin-2-yl)methanol
To a solution of (5-bromoimidazo[1 ,2-a]pyridin-2-yl)methanol (1.00 g, 4.40 mmol), 2,2'-bis(diphenylphosphino)-1 ,1'-binapthyl (986 mg, 1.58 mmol), and cesium carbonate (4.30 g, 13.2 mmol) in toluene (20 mL) was added benzophenone imine (2.22 mL, 13.2 mmol) and palladium(ll) acetate (119 mg, 0.53 mmol). The reaction mixture was heated at 1000C for 15 hours, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate. The organic layer was isolated, dried with magnesium sulfate, and filtered. The solvent was removed and the residue purified by flash chromatography (0-7.5% ammonium hydroxide-acetonitrile) to give 0.80 g (56% yield) {5- [(diphenylmethylidene)amino] imidazo[1 ,2-a]pyridin-2-yl}methanol. 1H- NMR (CDCI3): δ 7.88 (m, 2H), 7.69 (m, 1 H), 7.57 (m, 1 H), 7.47 (m, 2H), 7.38 (m, 1 H), 7.30 (m, 2H), 7.23 (m, 1H), 7.09 (m, 2H), 6.92 (m, 1 H), 5.67 (m, 1 H), 4.90 (s, 2H); MS m/z 328 (M+1 ).
B) 5-r(Diphenylmethylidene)aminolimidazof1.2-aipyridine-2-carbaldehvde To a solution of {5-[(diphenylmethylidene)amino]imidazo[1 ,2-a]pyridin-2-yl}methanol (300 mg, 0.92 mmol) in chloroform (9 mL) was added manganese dioxide (797 mg, 9.2 mmol). The reaction mixture was stirred at room temperature overnight, filtered through celite, rinsed with dichloromethane, and concentratred to give 299 mg (100% yield) 5-[(diphenylmethylidene)amino]imidazo[1 ,2-a]pyridine-2-carbaldehyde. 1H- NMR (CDCI3): δ 10.17 (s, 1 H), 8.34 (s, 1 H), 7.86 (m, 2H), 7.58 (m, 1 H), 7.47 (m, 2H), 7.40 (m, 1 H), 7.32 (m, 3H), 7.09 (m, 2H), 7.02 (m, 1 H), 5.74 (dd, 1 H).
C) Λ/-r(5-Aminoimidazof1.2-alpyridin-2-yl)methvn-Λ/-(5,6,7.8-tetrahvdro-8-quinolinyl)- 1.4-butanediamine
To a solution of 1 ,1-dimethylethyl [4-(5,6,7,8-tetrahydro-8-quinolinylamino)butyl] carbamate (96 mg, 0.30 mmol) and 5-[(diphenylmethylidene)amino]imidazo[1 ,2- a]pyridine-2-carbaldehyde (99 mg, 0.30 mmol) in dichloroethane (1.5 ml.) was added acetic acid (17 μl_, 0.30 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes, filtered through a silica plug, rinsed with 10% ammonium hydroxide-acetonitrile, and concentrated. The residue was dissolved in tetrahydrofuran (10 ml_), treated with 4N hydrochloric acid (2 ml_), and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and extracted with aqueous sodium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1 ,1-dimethylethyl {4-[[(5-aminoimidazo[1 ,2-a]pyridin-2-yl)methyl](5,6,7,8-tetrahydro-8- quinolinyl)amino]butyl} carbamate (110 mg, 79% yield). This intermediate was dissolved in dichloromethane (1.0 mL) and trifluoroacetic acid (1.0 ml_) was added. The resulting mixture was stirred for 1 1/2 h, concentrated in vacuo, and then the residue was dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (10% ammonium hydroxide-acetonitrile) to give Λ/-[(5-aminoimidazo[1 ,2-a]pyridin-2- yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 , 4-butanediamine (2 mg, 2% yield) as a tan solid: 1H-NMR (CDCI3): δ 8.69 (d, 1 H), 7.74 (s, 1 H), 7.32 (d, 1 H), 7.02 (m, 2H), 6.97 (m, 1 H), 5.95 (dd, 1H), 5.28 (m, 2H), 4.14 (m, 1 H), 3.88-3.69 (m, 2H), 2.93-2.61 (m, 6H), 2.35 (m, 1 H), 2.06 (m, 1H), 1.91-1.81 (m, 2H), 1.72-1.49 (m, 4H); MS m/z 365 (M+1 ).
Example 27: (8S)-Λ/-((1 S)-1-r4-(Methyloxy)phenyllethyl)-Λ/-(r5-(4-methyl-1- piperazinyl)imidazof1.2-alpyridin-2-yllmethyl>-5.6.7.8-tetrahvdro-8-quinolinamine
(Intermediate)
Figure imgf000061_0001
A) 6-Fluoro-2-pyridinannine:
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H), 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
B) 2-(Dichloromethyl)-5-fluoroimidazoH ,2-aipyridine:
A solution of 6-fluoro-2-pyridinamine (67 g, 0.60 mol) in ethylene glycol dimethyl ether (570 mL) was treated with 1 ,1 ,3-trichloroacetone (190 mL, 1.80 mol) and heated at 850C for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with hexanes, and dried to yield 2-(dichloromethyl)-5- fluoroimidazo[1 ,2-a]pyridine (85 g, 65% yield) as an olive green solid. 1H-NMR (CDCI3): δ 8.18 (s, 1 H), 7.60 (s, 1 H), 7.54-7.46 (m, 2H), 6.93 (m, 1 H).
C) 5-FluoroimidazoH ,2-alpyridine-2-carbaldehyde:
A solution of 2-(dichloromethyl)-5-fluoroimidazo[1 ,2-a]pyridine (103 g, 470 mmol) in ethanol (300 mL) and water (600 mL) was treated with sodium acetate (96 g, 1.17 mol) and heated at 6O0C for 2 hours. The reaction was cooled, filtered though celite, and concentrated in vacuo to remove the ethanol. The aqueous was extracted twice with chloroform and the organics were combined, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was filtered through a pad of silica, rinsed with dichloromethane and ethyl acetate, concentrated, triturated with hexanes, filtered, and dried to yield 5-fluoroimidazo[1 ,2-a]pyridine-2-carbaldehyde (40 g, 52% yield) as a tan solid. 1H-NMR (CDCI3): δ 10.17 (s, 1 H), 8.22 (s, 1 H), 7.57 (d, 1 H)1 7.38-7.32 (m, 1H), 6.60 (m, 1H); TLC (10% 2 M ammonia in methy alcohol- ethyl acetate) Rf = 0.60.
D) (5-Fluoroimidazoπ .2-a1Pyridin-2-yl)methanol: A solution of 5-fluoroimidazo[1 ,2-a]pyridine-2-carbaldehyde (80 g, 490 mmol) in methanol (1 L) at O0C was treated with sodium borohydride (24 g, 640 mmol) in portions. The reaction was slowly brought to room temperature, stirred for 2 hours, quenched with water, concentrated, dissolved in 3:1 dichloromethane to isopropyl alcohol, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous extracted four times with 3:1 dichloromethane to isopropyl alcohol. The organic layers were combined, dried over sodium sulfate, concentrated, triturated with hexanes, and filtered to yield (5-fluoroimidazo[1 ,2- a]pyridin-2-yl)methanol (76 g, 93% yield) as a brown solid. 1H-NMR (CDCI3): δ 7.59 (s, 1 H), 7.38 (d, 1 H), 7.21-7.15 (m, 1 H), 6.43 (m, 1 H), 4.85 (s, 2H), 4.45 (s, 1 H).
E) r5-(4-Methyl-1 -piperazinvDimidazoH ,2-alpyridin-2-yllmethanol:
A solution of (5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methanol (76 g, 460 mmol) in 1- methyl piperazine (150 mL) was heated at 7O0C for 15 hours. The reaction mixture was cooled, poured into 1.3 L brine, and extracted into 3:1 chloroform to isopropyl alcohol. The combined extracts were dried over sodium sulfate, concentrated in vacuo, azeotroped with hexanes, and triturated with diethyl ether to yield [5-(4- methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methanol (101 g, 90% yield) as a tan solid. 1H-NMR (CDCI3): δ 7.51 (s, 1 H), 7.33 (d, 1 H), 7.21-7.17 (m, 1 H), 6.31 (m, 1 H), 4.87 (S, 2H), 3.17 (s, 4H), 2.68 (s, 4H), 2.42 (s, 3H).
F) 5-(4-Methyl-1-piperazinyl)imidazoπ .2-aipyridine-2-carbaldehvde: A solution of [5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methanol (101 g, 410 mmol) in chloroform (1650 mL) was treated with manganese dioxide (360 g, 4100 mmol) and stirred at room temperature for 72 hours. The reaction mixture was filtered through celite, rinsed with chloroform, and concentrated to yield 5-(4-methyl- 1-piperazinyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde (82 g, 82% yield) as gold solid. 1H-NMR (CDCI3): δ 10.17 (s, 1 H), 8.15 (s, 1 H), 7.44 (d, 1H), 7.31-7.27 (m, 1 H), 6.40 (m, 1H), 3.16 (s, 4H), 2.68 (s, 4H), 2.42 (s, 3H).
G) (8S)-Λ/-((1 S)-1 -r4-(Methyloxy)phenyl1ethyl)-5.67.8-tetrahvdro-8-αuinolinamine: A solution of (S)-(-)-1-(4-methoxyphenyl)ethylamine (25 g, 166 mmol) and 6,7- dihydro-8(5H)-quinolinone (24 g, 166 mmol) in dichloroethane was treated with glacial acetic acid (14 mL, 249 mmol) and sodium triacetoxyborohydride (53 g, 249 mmol). The reaction mixture was stirred at room temperature for 15 hours and treated with sodium carbonate (106 g, 996 mmol) and stirred for 30 minutes. The mixture was diluted with dichloromethane, the organic layer separated, and the aqueous extracted with more dichloromethane. The organic layers were combined, dried over magnesium sulfate, concentrated, and purified by column chromatography (0-3% 2 M ammonia in methanol/dichloromethane) to give a yellow oil which was crystallized from hexanes to yield (8S)-Λ/-{(1 S)-1-[4-(methyloxy)phenyl]ethyl}-5,6,7,8- tetrahydro-8-quinolinamine (33 g, 70% yield) as clear crystals. 1H-NMR (CDCI3): δ 8.40 (m, 1 H), 7.33 (m, 3H), 7.04 (m, 1 H), 6.84 (d, 2H), 4.02 (m, 1 H), 3.83-3.78 (m, 4H), 2.73-2.62 (m, 2H), 1.82 (m, 1 H), 1.72 (m, 1 H), 1.57 (m, 2H), 1.43 (d, 3H).
H) (8S)-Λ/4 (1 S)-1 -r4-(Methyloxy)phenyllethyl)-Λ/4r5-(4-methyl-1 - piperazinyl)imidazori .2-a1pyridin-2-yllmethyl)-5,6,7,8-tetrahvdro-8-quinolinamine: A solution of 5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridine-2-carbaldehyde (2.83 g, 11.6 mmol) and (8S)-Λ/-{(1 S)-1-[4-(methyloxy)phenyl]ethyl}-5,6,7,8-tetrahydro-8- quinolinamine (3.27 g, 11.6 mmol) in dichloroethane (40 mL) was treated with glacial acetic acid (1.0 mL, 17.4 mmol) and sodium triacetoxyborohydride (3.68 g, 17.4 mmol, added in portions) and stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, separated, and extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, concentrated, and purified by flash chromatography (0-4% ammonium hydroxide in acetonitrile). The residue was dissolved in dichloromethane and stirred with 2 M ammonia in methanol to yield (8S)-Λ/-{(1 S)-1-[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine (5.13 g, 87% yield) as pale yellow foam. 1H NMR (400 MHz, CDCI3) δ 8.48 (d, J = 4.6 Hz, 1 H), 7.78 (s, 1 H), 7.60-7.58 (m, 2 H), 7.24-7.18 (m, 2 H), 7.09-7.05 (m, 1 H), 6.97 (dd, J = 7.6, 4.7 Hz, 1 H)1 6.84-6.82 (m, 2 H), 6.21 (d, J = 7.2 Hz, 1 H), 4.82 (m, 1 H), 4.07 (m, 1 H), 3.91 (dd, J = 56.9, 17.1 Hz, 2 H), 3.77 (s, 3 H), 3.19-3.13 (m, 4 H), 2.74 (s, 4 H), 2.67-2.53 (m, 2 H), 2.47 (S, 3 H), 2.06 (m, 1 H), 1.85 (m, 2 H), 1.53 (m, 1 H), 1.34 (d, J = 6.4 Hz, 3 H); MS m/z 511 (M+1 ). 70
Example 37: /V-dmidazoM ■2-alPyridin-2-ylmethyl)-Λ/-(5.6.7.8-tetrahvdro-8-quinolinvO- 1.4-cvclohexanediamine
Figure imgf000064_0001
To a solution of Λ/-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine (0. 075g, 0.269mmol, prepared from 5,6,7,8-tetrahydro-8- quinolinaminen and imidazo[1 ,2-a]pyridine-2-carbaldehyde ), 1 ,1-dimethylethyl (4- oxocyclohexyl)carbamate (0.10Og, 0.269mmol) and acetic acid (0.023mL, 0.404mmol) in 1 ,2-dichloroethane (1.OmL) that had been stirring for 1 hour was added sodium triacetoxyborohydride (0.114mg, 0.539mmol). The mixture was stirred at room temperature for 18 hours. To this was added trifluoroacetic acid (1 mL) and stirring continued for 2 hours. The volatiles were removed by spin evaporation in vacuo and the residue was purified by reversed phase chromatography on Ce silica gel (0-100% gradient of acetonitrile in 1% aqueous TFA to afford 0.092g (57% yield) of Λ/-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- cyclohexanediamine as the trifluoroacetic acid salt as a tan oil. 1H NMR (DMSO-Cl6): δ 8.61-8.72 (m, 1 H), 8.48-8.61 (m, 1 H), 8.00-8.11 (m, 1 H), 7.79-7.86 (m, 1 H), 7.71- 7.78 (m, 2H), 7.39-7.60 (m, 1 H), 7.07-7.20 (m, 1 H), 4.49-4.65 (m, 2H), 4.34-4.40 (m, 1 H), 3.30-3.39 (m, 1 H), 2.90-3.08 (m, 2H), 2.21-2.33 (m, 2H), 2.10-2.21 (m, 2H), 1.91-2.07 (m, 3H), 1.73-1.85 (m, 3HO, 1.58-1.73 (m, 2H). MS m/z 376 (M+1 ).
Example 38: /V-HmidazoM .2-alpyridin-2-ylmethyl)-Λ/'.Λ/'-dimethyl-Λ/-(5.6.7.8- tetrahvdro-8-quinolinv0-1.4-cvclohexanediamine 63
Example 28: (8SVΛ/-fr5-(4-methvl-1-piperazinvl)imidazoM ,2-aipvridin-2-yllmethyl}- 5.6.7.8-tetrahydro-8-quinolinamine (Intermediate)
Figure imgf000065_0001
A solution of (8S)-Λ/-{(1S)-1-[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine (569 mg, 1.11 mmol) in dichloromethane (11.1 ml_) was treated with trifluoroacetic acid (1.11 ml_) and stirred at room temperature for 4 hours. The reaction was concentrated, diluted with dichloromethane, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield (8S)-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine as a yellow residue. 1H-NMR (CDCI3): δ 8.41 (d, 1 H), 7.65 (s, 1 H), 7.39 (d, 1 H), 7.31 (m, 1H), 7.16 (m, 1H), 7.09 (m, 1H), 6.27 (dd, 1H), 4.31-4.17 (m, 2H), 4.05 (m, 1H), 3.15 (m, 4H), 2.88-2.78 (m, 2H), 2.67 (m, 4H), 2.41 (s, 3H), 2.29 (m, 1 H), 2.08 (m, 1 H), 1.96 (m, 1 H), 1.77 (m, 1 H).
Example 29: (8S)-Λ/-(r2-(Dimethylamino)phenyllmethyl>-Λ/-(r5-(4-methyl-1 - piperazinvl)imidazof1 ,2-a1pvridin-2-yllmethvl)-5.6.7.8-tetrahvdro-8-quinolinamine 64
Figure imgf000066_0001
(8S)-/V-{[2-(Dimethylamino)phenyl]rriethyl}-Λ/-{[5-(4-methyl-1-piperazinyl)imidazo[1 ,2- a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)-N- {(1 S)- 1 -[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1 -piperazinyl)imidazo[1 ,2- a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine and 2- dimethylaminobenzaldehyde via deprotection and reductive amination in a similar manner as described herein to give an off-white solid (60% yield, 2 steps). 1H NMR (400 MHz, CDCI3) δ 8.50 (d, J = 4.6 Hz, 1 H), 8.10 (d, J = 7.5 Hz, 1 H), 7.80 (s, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 8.9 Hz, 1 H), 7.11-6.95 (m, 5 H), 6.17 (d, J = 7.0 Hz, 1 H), 4.16 (m, 1 H), 3.99-3.92 (m, 4 H), 3.09 (s, 4 H), 2.78 (m, 1 H), 2.67-2.57 (m, 11 H), 2.41 (s, 3 H), 2.19 (m, 1 H), 2.05-1.98 (m, 2 H), 1.63 (m, 1 H); MS m/z 510 (M+1).
Example 30: (8S)-Λ/-U5-(4-Methyl-1-piperazinvnimidazoπ .2-alpyridin-2-yllmethyl)-Λ/- (2-pyridinylmethvD-5,6,7,8-tetrahvdro-8-quinolinamine
Figure imgf000066_0002
65
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(2- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)-Λ/-{(1S)- 1 -[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine and 2-pyridinecarboxaldehyde via deprotection and reductive amination in a similar manner as described herein to give a tan oil (76% yield, 2 steps). 1H NMR (400 MHz, CDCI3) δ 8.50 (d, J = 4.5 Hz, 1 H), 8.38 (d, J = 4.7 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.68 (s, 1 H), 7.54 (m, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.26-7.24 (m, 1 H), 7.10-7.06 (m, 1 H), 7.03-6.97 (m, 2 H), 6.19 (d, J = 7.1 Hz, 1 H), 4.23 (m, 1 H), 4.05-3.88 (m, 4 H), 3.09 (s, 4 H), 2.82-2.74 (m, 2 H), 2.67 (s, 4 H), 2.42 (s, 3 H), 2.22 (m, 1 H), 2.01-1.94 (m, 2 H), 1.64 (m, 1 H); MS m/z 468 (M+ 1 ).
Example 31 : (8S)-Λ/-(r5-(4-Methyl-1-piperazinyl)imidazori .2-alpyridin-2-yllmethyl)-/V- (3-pyridinylmethyl)-5,6.7,8-tetrahvdro-8-quinolinamine
Figure imgf000067_0001
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)-Λ/-{(1 S)- 1 -[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine and 3-pyridinecarboxaldehyde via deprotection and reductive amination in a similar manner as described herein to give a tan oil (72% yield, 2 steps). 1H NMR (400 MHz, CDCI3) δ 8.63 (s, 1 H), 8.52 (d, J = 4.4 Hz, 1 H), 8.36 (m, 1 H), 7.88 (m, 1 H), 7.67 (s, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.15-7.07 (m, 2 H), 7.03 (dd, J = 7.6, 4.6 Hz, 1 H), 6.21 (d, J = 7.2 Hz, 1 H), 4.17 (m, 1 H), 4.05-3.99 (m, 3 H), 3.77 (d, J = 14.8 Hz, 1 H), 3.11 (s, 4 H), 2.82-2.74 (m, 2 H), 2.68 (s, 4 H), 2.43 (s, 3 H), 2.18 (m, 1 H), 2.01-1.96 (m, 2 H), 1.65 (m, 1 H); MS m/z 468 (M+1 ). 66
Example 32: (8S)-Λ/-(r5-(4-Methyl-1-piperazinyl)imidazoH .2-a1Pyridin-2-yllmethyl)-Λ/- (4-pyridinylmethvπ-5.6.7.8-tetrahvdro-8-quinolinamine
Figure imgf000068_0001
(8S)-Λ/-{[5-(4-Methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(4- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine was prepared from (8S)-Λ/-{(1 S)- 1 -[4-(methyloxy)phenyl]ethyl}-Λ/-{[5-(4-methyl-1 -piperazinyl)imidazo[1 ,2-a]pyridin-2- yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine and 4-pyridinecarboxaldehyde via deprotection and reductive amination in a similar manner as described herein to give a tan oil (96% yield, 2 steps). 1H NMR (400 MHz, CDCI3) δ 8.50 (d, J = 4.5 Hz, 1 H), 8.41 (d, J = 5.7 Hz, 2 H), 7.63 (s, 1 H), 7.45 (d, J = 5.6 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.24 (d, J = 9.4 Hz, 1 H), 7.11-7.07 (m, 1 H), 7.03 (dd, J = 7.6, 4.7 Hz, 1 H), 6.21 (d, J = 7.2 Hz, 1 H), 4.16-4.04 (m, 2 H), 4.01-3.95 (m, 2 H), 3.79 (d, J = 15.2 Hz, 1 H), 3.08 (s, 4 H), 2.81-2.73 (m, 2 H), 2.65 (s, 4 H), 2.42 (s, 3 H), 2.20 (m, 1 H), 2.02- 1.92 (m, 2 H), 1.65 (m, 1 H); MS m/z 468 (M+1 ).
Example 33: r2-(((r2-(Dimethylamino)phenyllmethyl)r(8S)-5.6.7.8-tetrahvdro-8- quinolinvπamino)methyl)-5-(4-methyl-1-piperazinyl)imidazoπ ,2-aipyridin-3- yllmethanol 67
Figure imgf000069_0001
A solution of (8S)-Λ/-{[2-(dimethylamino)phenyl]methyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine (29 mg, 0.057 mmol) in formaldehyde (1 ml_, 37 wt. % solution in water) and glacial acetic acid (100 μl_) was heated at 5O0C for 15 hours. The reaction mixture was cooled, diluted with dichloromethane, and washed with saturated aqueous sodium carbonate. The organic layer was isolated and the aqueous washed with dichloromethane/isopropyl alcohol. The organic layers were combined, concentrated, and purified by flash chromatography (0-10% ammonium hydroxide in acetonitrile) to give 17 mg (55% yield) [2-({{[2-(dimethylamino)phenyl]methyl}[(8S)- 5,6,7,8-tetrahydro-8-quinolinyl]amino}methyl)-5-(4-methyl-1-piperazinyl)imidazo[1 ,2- a]pyridin-3-yl]methanol as a white solid. 1H NMR (400 MHz, CDCI3) δ 8.50 (d, 1 H), 8.00 (m, 1 H), 7.30 (d, 2 H), 7.20 (m, 1 H), 7.07-6.99 (m, 3 H), 6.40 (d, 1 H), 5.39 (d, 1 H), 4.88 (d, 1 H), 4.03 (m, 1 H), 3.91-3.86 (m, 3 H), 3.75 (m, 1 H), 2.78 (m, 1 H), 3.17-3.04 (m, 2 H), 2.94-2.76 (m, 5 H), 2.65 (m, 2 H), 2.61 (s, 6 H), 2.47 (m, 2 H), 2.42 (s, 3 H), 2.08-2.00 (m, 2 H), 1.60 (m, 1 H); MS m/z 540 (M+1 ).
Example 34: r5-(4-Methyl-1 -piperazinvn-2-K(2-pyridinylmethyl)r(8S)-5.6.7.8- tetrahvdro-8-αuinolinyl1amino)methyl)imidazori .2-alpyridin-3-yl1methanol 68
Figure imgf000070_0001
[5-(4-Methyl-1-piperazinyl)-2-({(2-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol was prepared from (8S)- Λ/-{[5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]rnethyl}-Λ/-(2-pyridinylmethyl)- 5,6,7,8-tetrahydro-8-quinolinamine via hydroxymethylation in a similar manner as shown herein to give an off-white solid (61% yield). 1H NMR (400 MHz, CDCI3) δ 8.45 (m, 2 H), 7.84 (d, 1 H), 7.72 (t, 1 H), 7.30-7.27 (m, 2 H), 7.12 (m, 1 H), 7.05-6.99 (m, 2 H), 6.39 (d, 1 H), 5.38 (d, 1 H), 4.73 (d, 1 H), 3.97 (d, 2 H), 3.87 (m, 1 H), 3.72 (m, 1 H), 3.65 (dd, 2 H), 3.03 (s, 1 H), 2.93-2.88 (m, 2 H), 2.84-2.75 (m, 3 H), 2.63-2.52 (m, 2 H), 2.45-2.42 (m, 2 H), 2.38 (s, 3 H), 2.01-1.90 (m, 2 H), 1.59 (m, 1 H); MS m/z 498 (M+1 ).
Example 35: r5-(4-Methyl-1 -piperazinvn-2-f((3-pyridinylmethyl)r(8SV5,6.7.8- tetrahvdro-8-quinolinyllamino)methyl)imidazoπ ,2-alpyridin-3-yllmethanol
Figure imgf000070_0002
69
[5-(4-Methyl-1-piperazinyl)-2-({(3-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol was prepared from (8S)- Λ/-{[5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3-pyridinylmethyl)- 5,6,7,8-tetrahydro-8-quinolinamine via hydroxymethylation in a similar manner as shown herein to give an off-white solid (55% yield). 1H NMR (400 MHz, CDCI3) δ 8.57 (S, 1 H), 8.48 (m, 2 H), 7.99 (d, 1 H), 7.32-7.27 (m, 3 H), 7.06-7.01 (m, 2 H), 6.39 (d, 1 H), 5.33 (d, 1 H), 4.61 (d, 1 H), 3.97-3.83 (m, 3 H), 3.70 (m, 1 H), 3.54 (d, 1 H), 3.38 (d, 1 H), 3.02 (m, 1 H), 2.93-2.89 (m, 2 H), 2.84-2.76 (m, 3 H), 2.65-2.52 (m, 2 H), 2.45-2.41 (m, 2 H), 2.39 (s, 3 H), 2.01-1.90 (m, 2 H), 1.60 (m, 1 H); MS m/z 498 (M+1 ).
Example 36: r5-(4-Methyl-1 -piperazinvπ-2-(f (4-pyridinylmethyl)r(8S)-5.6.7.8- tetrahvdro-8-quinolinvnamino)methyl)imidazof1 ,2-alpyridin-3-yllmethanol
Figure imgf000071_0001
[5-(4-Methyl-1-piperazinyl)-2-({(4-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol was prepared from (8S)- Λ/-{[5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(4-pyridinylmethyl)- 5,6,7,8-tetrahydro-8-quinolinamine via hydroxymethylation in a similar manner as shown herein to give a pale yellow solid (50% yield). 1H NMR (400 MHz, CDCI3) δ 8.53 (d, 2 H), 8.49 (m, 1 H), 7.46 (d, 2 H), 7.31-7.25 (m, 2 H), 7.05-7.00 (m, 2 H), 6.39 (d, 1 H), 5.35 (d, 1 H), 4.71 (d, 1 H), 3.91-3.82 (m, 3 H), 3.68 (m, 1 H), 3.55 (d, 1 H), 3.36 (d, 1 H), 3.02 (m, 1 H), 2.91-2.74 (m, 5 H), 2.64-2.52 (m, 2 H), 2.44-2.35 (m, 5 H), 1.99-1.86 (m, 2 H), 1.60 (m, 1 H); MS m/z 498 (M+1 ).
To a solution of Λ/-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-cyclohexanediamine (0. 057g, 0.157mmol), paraformaldehyde (0.009g, 0.304mmol) and acetic acid (0.013ml_, 0.228mmol) in 1 ,2-dichloroethane (0.4mL) that had been stirring for 1 hour was added sodium triacetoxyborohydride (0.064mg, 0.304mmol). The mixture was stirred at room temperature for 18 hours. The volatiles were removed by spin evaporation in vacuo and the residue was purified by reversed phase chromatography on C8 silica gel (0-100% gradient of acetonitrile with 1 % TFA in water) to afford 0.022g (23% yield) of Λ/-(imidazo[1 ,2- a]pyridin-2-ylmethyl)-Λ/',Λ/'-dimethyl-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4 cyclohexanediamine as the trifluoroacetic acid salt as a tan oil. 1H NMR (DMSO-ck): δ 9.62 (bs, 1 H), 9.30 (bs, 1 H), 8.60-8.68 (m, 1 H), 8.53-8.60 (m, 1 H), 8.06-8.09 (m, 1 H), 7.69-7.81 (m, 2H), 7.48-7.63 (m, 1 H0, 7.36-7.48 (m, 1 H), 7.08-7.21 (m, 1 H), 4.45-4.59 (m, 2H), 4.22-4.36 (m, 1H), 3.10-3.21 (m, 1H), 2.95-3.10 (m, 2H), 2.79 (s, 3H), 2.66 (s, 3H)1 2.15-2.28 (m, 2H), 1.89-2.14 (m, 5H), 1.69-1.89 (m, 2H), 1.54-1.69 (m, 2H), 1.31-1.51 (m, 2H). MS m/z 404 (M+1 ).
Example 39: Λ/-(lmidazon .2-alpyridin-2-ylmethyl)-/\/-r2-(1-methyl-3-piperidinvnethyll- 5,6,7.8-tetrahvdro-8-quinolinamine
Figure imgf000073_0001
A) 2-(1-Methyl-3-piperidinyl)ethanol
Figure imgf000073_0002
To a solution of (1-methyl-3-piperidinyl)acetic acid (3.0Og, 15.5mmol) was added dropwise a stirring solution of 1 M lithium aluminum hydride in THF (15.5ml_, 15.5mmol) under a nitrogen atmosphere. After stirring for 2 hours, water (0.5ml_), 15% aqueous NaOH (0.5mL), and water (1.5ml_) were added successively with stirring. Extraction of the aqueous mixture with ethyl acetate followed by drying of the organic layers with magnesium sulfate and removal of the volatiles by spin evaporation in vacuo gave 2-(1-methyl-3-piperidinyl)ethanol (2.1g, 95%) as a clear oil. 1H NMR (DMSO-Of6): δ 4.33 (bs, 1 H), 3.36 - 3.43 (m, 2H), 2.57 - 2.67 (m, 2H), 2.09 (s, 3H), 1.70 - 1.78 (m, 1 H), 1.212 - 1.66 (m, 7H), 0.70 - 0.84 (m, 1 H).
B) (i-Methyl-3-piperidinvOacetaldehvde
Figure imgf000073_0003
To a stirring solution of oxalyl chloride in dichloromethane (1OmL) at -780C was added dimethyl sulfide. After 5 minutes a solution of 2-(1-methyl-3- piperidinyl)ethanol (0.20Og, 1.396mmol) in dichloromethane (1OmL) and the mixture was stirred for 15 minutes at -780C. To this was added diisopropylethylamine (1.216mL, 6.98mmol) and the solution was allowed to warm to room temperature. The reaction was diluted with water (2OmL) and extracted twice with dichloromethane (2OmL). The nonaqueous layers were combined and the volatiles were spin evaporated in vacuo. The residue was dissolved in ether, dried with magnesium sulfate and concentrated to give (1-methyl-3-piperidinyl)acetaldehyde as a yellow oil (0.178g, 90% yield). 1H NMR (DMSO-c/6): δ 9.63 (s, 1 H), 2.47-2.69 (m, 4H), 2.23- 2.37 (m, 2H), 2.09 (s, 3H), 1.96 - 2.07 (m, 2H), 1.73 - 1.85 (m, 1 H), 1.50 - 1.65 (m, 2H), 1.36 - 1.49 (m, 2H), 0.76 - 0.93 (m, 1 H). MS m/z 142 (M+1 ).
C) Λ/-(lmidazof1.2-aiPyridin-2-ylmethyl)-Λ/-r2-(1-methyl-3-piperidinvnethyll- 5.6.7.8-tetrahvdro-8-quinolinamine
To a solution of Λ/-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine (0. 075g, 0.269mmol), (1-methyl-3-piperidinyl)acetaldehyde (0.038g, 0.269mmol) and acetic acid (0.023mL, 0.404mmol) in 1 ,2-dichloroethane (1.OmL) that had been stirring for 1 hour was added sodium triacetoxyborohydride (0.086mg, 0.404mmol). The mixture was stirred at room temperature for 18 hours. The volatiles were removed by spin evaporation in vacuo and the residue was purified by reversed phase chromatography on C8 silica gel (0-100% gradient of acetonitrile in 1 % aqueous TFA to afford 0.082g (48% yield) of Λ/-(imidazo[1 ,2-a]pyridin-2- ylmethyl)-Λ/-[2-(1-methyl-3-piperidinyl)ethyl]-5,6,7,8-tetrahydro-8-quinolinamine as the trifluoroacetic acid salt as a tan oil. 1H NMR (DMSO-d6): δ 9.55 (bs, 1 ), 8.69- 8.74 (m, 1 H), 8.52-8.56 (m, 1 H), 8.17-8.21 (m, 1 H), 7.81-7.87 (m, 1 H), 7.70-7.76 (m, 1 H), 7.53-7.60 (m, 1 H), 7.45-7.52 (m, 1H), 7.14-7.21 (m, 1 H), 4.54-4.64 (m, 1 H), 4.30-4.40 (m, 2H), 3.44-3.51 (m, 1 H), 3.31-3.39 (m, 1 H), 3.21-3.30 (m, 1 H), 3.03- 3.13 (m, 1 H), 2.87-2.97 (m, 2H), 2.66-2.79 (m, 4H), 2.31-2.42 (m, 1 H), 1.92-2.07 (m, 2H), 1.71-1.80 (m, 2H), 1.41-1.69 (m, 4H), 0.87-0.97 (m, 1 H). MS m/z 404 (M+1 ).
Example 40: Λ/-(lmidazoM ■2-a1pyridin-2-ylmethvn-/V-(4-piperidinylmethvn-5.6.7.8- tetrahvdro-8-quinolinamine
Figure imgf000075_0001
Λ/-(lmida2θ[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(4-piperidinylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine was prepared from Λ/-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-5,6,7,8- tetrahydro-8-quinolinamine and 1 ,1-dimethylethyl 4-formyl-1-piperidinecarboxylate in a similar manner as described above to give a tan oil (20% yield). 1H-NMR (DMSO- dβ): δ 8.65-8.78 (m, 1 H), 8.48-8.57 (m, 1 H), 8.35-8.48 (m, 1 H), 8.15-8.20 (m, 1 H), 8.02-8.11 (m, 1 H), 7.74-7.82 (m, 1 H), 7.56-7.66 (m, 1 H), 7.39-7.49 (m, 1 H), 7.10- 7.24 (m, 1 H), 4.45-4.53 (m,1 H), 4.26-4.38 (m, 2H), 3.19-3.26 (m, 2H), 2.74-2.95 (m, 5H), 2.59-2.66 (m, 1 H), 2.27-2.37 (m, 1 H), 1.61-2.08 (m, 6H), 1.02-1.28 (m, 2H). MS /77/z 376 (M+1 ).
Example 41 : Λ/-(lmidazoH .2-a1pyridin-2-ylmethyl)-Λ/-r(1-methyl-4-piperidinyl)methvn- 5,6,7,8-tetrahvdro-8-αuinolinamine
Figure imgf000075_0002
Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-A/-[(1-methyl-4-piperidinyl)methyl]-5, 6,7,8- tetrahydro-8-quinolinamine trifluoroacetic acid salt was prepared from Λ/- (imidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(4-piperidinylmethyl)-5,6,7,8-tetrahydro-8- quinolinamine and paraformaldehyde in a similar manner as described above to give a tan oil (38% yield). 1H-NMR (DMSO-Cf6): δ 9.05 (bs, 1 H), 8.66-8.72 (m, 1 H), 8.46- 8.52 (m, 1 H), 8.12-8.15 (m, 1 H), 7.71-7.78 (m, 1 H), 7.63-7.70 (m, 1 H), 7.51-7.61 (m, 1 H), 7.29-7.40 (m, 1 H), 7.12-7.20 (m, 1 H), 4.35-4.48 (m, 12H), 4.18-4.28 (m, 1 H), 3.32-3.41 (m, 2H), 2.72-2.90 (m, 5H), 2.59-2.72 (m, 4H), 2.24-2.33 (m, 1H), 1.82- 2.12 (m, 5H), 1.63-1.77 (m, 1 H), 0.97-1.22 (m, 2H). MS m/z 376 (M+1 ).
Example 42: Λ/-(lmidazoM .2-alPyridin-2-ylmethyl)-Λ/-(5.6.7.8-tetrahydroquinolin-8- yl)ethane-1 ,2-diamine
Figure imgf000076_0001
A) terf-Butyl f2-(5.6.7.8-tetrahvdroquinolin-8-ylamino)ethyllcarbamate To a solution of terf-butyl (2-aminoethyl)carbamate (0.161 mL, 1.01 mmol) in anhydrous 1 ,2-dichloroethane (2.5 mL) was added 6,7-dihydroquinolin-8(5H)-one (0.1 g, 0.679 mmol), acetic acid (0.058 mL, 1.01 mmol) and stirred for 20 minutes. Sodium triacetoxyborohydride (0.216 g, 1.01 mmol) was added and mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine and then the combined aqueous layers were washed with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.16g (81% yield) of terf-butyl [2-(5,6,7,8-tetrahydroquinolin-8-ylamino)ethyl]carbamate as a yellow oil. 1H NMR (DMSO): δ 8.38 (d, 1 H), 7.55 (d, 1 H), 7.25 (q, 1 H), 6.85 (t, 1 H), 3.67 (t, 1 H), 3.20 (d, 2H), 3.07 (m, 2H), 2.73 (m, 3H), 1.97 (m, 2H), 1.67 (m, 2H), 1.41 (s, 9H). MS m/z 292 (M+1 ). B) te/t-Butyl ^-rdnnidazofi ^-alpyridin-Σ-ylmethvπfδ.e.y.δ-tetrahvdroquinolin-S- vDaminolethvDcarbamate tert-Butyl [2-(5,6,7,8-tetrahydroquinolin-8-ylamino)ethyl]carbamate (0.1Og , 0.343 mmol) and imidazo[1 ,2-a]pyridine-2-carbaldehyde (0.10 g, 0.686 mmol) , were dissolved in 1 ,2-dichloroethane (4 mL). Acetic acid (0.039 ml_, 0.686 mmol) and sodium triacetoxyborohydride (0.145g, 0.686 mmol) were added and the mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine. The combined organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.042 g (29% yield) of terf-butyl {2-[(imidazo[1 ,2-a]pyridin-2-ylmethyl)(5,6,7,8- tetrahydroquinolin-8-yl)amino]ethyl}carbamate as a yellow oil. 1H NMR (DMSO): δ 8.44 (d, 1 H), 8.41 (d, 1 H), 7.83 (s, 1 H), 7.43 (t, 1 H), 7.13 (m, 2H), 6.80 (t, 2H), 4.02 (m, 2H), 3.84 (d, 1 H), 2.95 (m, 3H), 2.61-2.77 (m, 4H), 2.07 (m, 1 H), 1.90 (m, 1 H), 1.76 (m, 1 H), 1.62 (m, 1 H), 1.34 (s, 9H). MS m/z 422 (M+1 ).
C) Λ/-(lmidazof1.2-alpyridin-2-ylmethyl)-Λ/-(5.6.7.8-tetrahvdroquinolin-8-vπethane- 1 ,2-diamine terf-Butyl {2-[(imidazo[1 ,2-a]pyridin-2-ylmethyl)(5,6,7,8-tetrahydroquinolin-8- yl)amino]ethyl}carbamate (0.042g, 0.100 mmol) was dissolved in methanol (2 ml), and trifluoroacetic acid (2 mL) was added. Reaction stirred overnight at room temperature. Concentrated solvent. Purified by reverse phase chromatography (1- 100% acetonitrile in water (0.1% TFA) to afford 0.27g (84% yield) of the trifluoroacetic acid salt which was free based by extraction with 1.0 N sodium hydroxide. 1H NMR (DMSO): δ 8.81 (d, 1 H), 8.64 (d, 1 H), 8.31 (s, 1 H), 8.07 (m, 1 H), 7.90 (m, 2H), 7.66 (t, 1 H), 7.44 (m, 1 H), 4.34 (m, 1 H), 4.08 (m, 2H), 3.07 (m, 1 H), 2.73-3.00 (m, 5H), 2.24 (m, 1 H), 2.02 (m, 1 H), 1.84 (m, 1 H), 1.71 (m, 1 H). MS m/z 322 (M+1).
Example 43: N-(lmidazoH ^-alpyridin^-ylmethvO-N-fS.ej.δ-tetrahvdro-δ-quinolinyl)- 1 ,5-pentanediamine
Figure imgf000078_0001
A) 1 ,1-Dimethylethyl r5-(5,6,7.8-tetrahvdro-8-quinolinylamino)pentyl1carbamate To a solution of 1 ,1-dimethylethyl (5-aminopentyl)carbamate (0.204 mL, 1.01 mmol) in anhydrous 1 ,2-dichloroethane (2.5 mL) was added 6,7-dihydroquinolin-8(5/-/)-one (0.1 g, 0.679 mmol), and acetic acid (0.058 mL, 1.01 mmol) and stirred for 20 minutes. Sodium triacetoxyborohydride (0.216 g, 1.01 mmol) was added and mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine and then the combined aqueous layers were washed with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.2Og (89% yield) of 1 ,1-dimethylethyl [5-(5,6,7,8-tetrahydro-8-quinolinylamino)pentyl] carbamate as a yellow oil. 1H NMR (DMSO): δ 8.39 (d, 1 H), 7.52 (d, 1 H), 7.25 (m, 1 H), 6.80 (t, 1 H), 4.13 (d, 1 H), 3.68 (t, 1 H), 3.20 (d, 1 H), 2.92 (m, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 2.04 (m, 1 H), 1.93 (m, 1 H), 1.67 (m, 2H), 1.24-1.53 (m, 13H). MS m/z 334 (M+1 ).
B) 1.1-Dimethylethyl f5-r(imidazoH .2-a1pyridin-2-ylmethvn(5.6.7.8-tetrahvdro-8- quinolinvDaminolpentvDcarbamate 1 ,1-dimethylethyl [5-(5,6,7,8-tetrahydro-8-quinolinylamino)pentyl]carbamate (0.10g, 0.30 mmol) and imidazo[1 ,2-a]pyridine-2-carbaldehyde (0.09 g, 0.60 mmol) were dissolved in 1 ,2-dichloroethane (4 mL). Acetic acid (0.034 mL, 0.60 mmol) and sodium triacetoxyborohydride (0.127g, 0.60 mmol) were added and the mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine. The organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0- 10% 2N methanolic ammonia in dichloromethane) to afford 0.062g (44% yield) of 1 ,1-dimethylethyl {5-[(imidazo[1 ,2-a]pyridin-2-ylmethyl)(5,6,7,8-tetrahydro-8- quinolinyl)amino]pentyl}carbamate as a yellow oil. 1H NMR (DMSO): δ 8.53 (d, 1H), 8.44 (d, 1 H), 7.86 (s, 1 H), 7.47 (t, 2H), 7.17 (m, 2H), 6.85 (t, 1 H), 6.76 (t, 1H), 4.10 (m, 3H), 3.20 (m, 4H), 2.79 (m, 4H), 1.93 (m, 2H), 1.64 (m, 2H), 1.15-1.45 (m, 13H). MS m/z 464 (M+1 ).
C) N-(lmidazori ,2-alpyridin-2-ylmethv0-N-(5.6J,8-tetrahydro-8-quinolinv0-1 ,5- pentanediamine 1 ,1-Dimethylethyl {5-[(imidazo[1 ,2-a]pyridin-2-ylmethyl)(5,6,7,8-tetrahydro-8- quinolinyl)amino]pentyl}carbamate (0.062g, 0.133 mmol) was dissolved in methanol (2 ml), and trifluoroacetic acid (2 mL) was added. Reaction stirred overnight at room temperature. Solvent was concentrated. Purified using silica gel chromatography (1- 10% ammonium hydroxide in acetonitrile) to afford 0.040 g (85% yield) of N- (imidazo[1 ,2-a]pyridin-2-ylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,5- pentanediamine as a yellow oil. 1H NMR (DMSO): δ 8.81 (d, 1 H), 8.64 (d, 1H), 8.31 (S, 1H), 8.07 (m, 1H), 7.90 (m, 2H), 7.66 (t, 1H), 7.44 (m, 1H), 4.34 (m, 1H), 4.08 (m, 2H), 3.07 (m, 1 H), 2.73-3.00 (m, 5H), 2.24 (m, 1 H), 2.02 (m, 1 H), 1.84 (m, 1H), 1.71 (m, 1 H). MS m/z 322 (M+1 ).
Example 44: N-(lmidazoH .2-a1pyridin-2-ylmethyl)-N-(5,6.7.8-tetrahvdro-8-quinolinyl)- 1 ,3-propanediamine
Figure imgf000079_0001
A) 1.1-Dimethylethyl r3-(5.6.7.8-tetrahvdro-8-quinolinylamino)propyπcarbamate To a solution of 1 ,1-dimethylethyl (3-aminopropyl)carbamate (0.176 mL, 1.01 mmol) in anhydrous 1 ,2-dichloroethane (2.5 mL) was added 6,7-dihydroquinolin-8(5H)-one (0.1 g, 0.679 mmol), and acetic acid (0.058 mL, 1.01 mmol) and stirred for 20 minutes. Sodium triacetoxyborohydride (0.216 g, 1.01 mmol) was added and mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine and then the combined aqueous layers were washed with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.171g (83% yield) of 1 ,1-dimethylethyl [3-(5,6,7,8-tetrahydro-8-quinolinylamino)propyl]carbamate as a yellow oil. 1H NMR (DMSO): δ 8.39 (d, 1H), 7.52 (d, 1H), 7.20 (m, 1 H), 6.86 (t, 1 H), 4.13 (d, 1H), 3.66 (t, 1H), 3.02 (q, 2H), 2.76 (m, 1H), 2.66 (t, 2H), 1.86-2.07 (m, 2H), 1.53-1.73 (m, 4H), 1.40 (s, 9H). MS m/z 306 (M+1).
B) Λ/-(lmidazori .2-a1pyridin-2-ylmethvn-Λ/-(5.6.7.8-tetrahvdro-8-quinolinvπ-1.3- propanediamine 1 ,1-Dimethylethyl [3-(5,6,7,8-tetrahydro-8-quinolinylamino)propyl]carbamate (0.048g, 0.157 mmol) and imidazo[1 ,2-a]pyridine-2-carbaldehyde (0.049 g, 0.33 mmol) were dissolved in 1 ,2-dichloroethane (4 ml). Acetic acid (0.037 mL, 0.65 mmol) and sodium triacetoxyborohydride (0.072g, 0.33 mmol) were added and the mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine. The organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0- 10% ammonium hydroxide in acetonitrile) to afford 1 ,1-dimethylethyl {3-[(imidazo[1 ,2- a]pyridin-2-ylmethyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]propyl}carbamate. The purified material was dissolved in anhydrous methanol (2 mL), and trifluoroacetic acid (2mL) was added then stirred at room temperature overnight. Solvent was evaporated and aqueous saturated sodium bicarbonate was added. Extracted with ethyl acetate, dried organics over magnesium sulfate and concentrated. Purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.017 g (32% yield) of the title compound. 1H NMR (DMSO): δ 8.49 (d, 1H), 8.39 (d, 1H), 7.90 (s, 1H), 7.52 (t, 2H), 7.22 (m, 2H), 6.88 (t, 1H), 3.77-4.06 (m, 3H), 2.97 (m, 2H), 2.75 (m, 3H), 2.59 (m, 2H), 2.21 (m, 1H), 1.94 (m, 2H)1 1.72 (m, 2H), 1.56 (m, 2H). MS m/z 336 (M+1). Example 45: Λ/-r(3-Chloroimidazoπ ■2-alpyridin-2-vnnrtethyll-Λ/-(5.6.7.8-tetrahydro-8- αuinolinyl)-1.4-butanediamine
Figure imgf000081_0001
Λ/-[(3-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl {4-[(imidazo[1 ,2-a]pyridin-2- ylmethyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]butyl}carbamate by treatment with N- chlorosuccinimide (1.2 equivalent in dichloromethane) followed by workup and subsequent treatment with trifluoroacetic acid in dichloromethane to give the title compound as a yellow syrup: 1H-NMR (CDCI3): δ 8.60 (d, 1H), 8.00 (d, 1 H), 7.73 (d, 1 H), 7.40 (d, 1 H), 7.29 (t, 1 H), 7.13 (q, 1 H), 6.95 (t, 1 H), 3.8-4.0 (m, 3H), 3.42 (m, 1 H), 2.96 (m, 1 H), 2.9-2.5 (m, 3H), 2.3-2.4 (m, 2H), 2.05 (m, 1 H), 2.0-1.4 (m, 6H); MS m/z 384 (M+1 ).
Example 46: Λ/-r(3-BromoimidazoM .2-alpyridin-2-yl)methvπ-Λ/-(5.6.7.8-tetrahvdro-8- αuinolinyl)-1 ,4-butanediamine
Figure imgf000081_0002
Λ/-[(3-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine was prepared from 1 ,1-dimethylethyl {4-[(imidazo[1 ,2-a]pyridin-2- ylmethyl)(5,6,7,8-tetrahydro-8-quinolinyl)amino]butyl}carbamate by treatment with N- bromosuccinimide (1.2 equivalent in dichloromethane) followed by workup and subsequent treatment with trifluoroacetic acid in dichloromethane to give the title compound as a syrup: 1H-NMR (CD3OD): δ 8.6 (d, 1 H), 8.4 (d, 1 H), 8.0 (d, 1 H), 7.74 (d, 1 H), 7.6 (m, 2H), 7.24 (t, 1 H), 4.6 (m, 1 H), 4.3 (m, 2H), 3.5 (m, 2H), 3.1 -1.5 (m, 12H); MS m/z 429 (M+1 ).
Example 47: Λ/-(lmidazoπ ,2-alpyridin-2-ylmethyl)-Λ/'.Λ/'-dimethyl-Λ/-(5.6.7.8- tetrahvdro-8-quinolinyl)-1.4-butanediamine
Figure imgf000082_0001
Λ/-(lmidazo[1 ,2-a)pyridin-2-ylmethyl)-Λ/',Λ/1-dimethyl-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine was prepared from Λ/-(imidazo[1 ,2-a]pyridin-2- ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4-butanediamine and formaldehyde via reductive amination in a similar fashion as described herein to give the title compound as a syrup: 1H-NMR (CDCI3): δ 8.46 (d, 1 H), 8.05 (d, 1 H), 7.72 (s, 1 H), 7.46 (d, 1H), 7.30 (d, 1 H), 7.06 (t, 1 H), 7.00 (q, 1 H), 6.68 (t, 1 H), 4.14 (m, 1H), 3.98 (d, 1 H), 3.81 (d, 1 H), 2.6-2.8 (m, 4H), 2.20 (s, 6H), 2.10 (m, 1 H), 1.8-2.0 (m, 2H), 1.65 (m, 1 H), 1.45 (m, 4H); MS m/z 378 (M+1 ).
BIOLOGICAL SECTION FUSION ASSAY
Plasmid Generation
The complete coding sequences of HIV-1 tat (GenBank Accession No. X07861 ) and rev (GenBank Accession No. M34378) were cloned into pcDNA3.1 expression vectors containing G418 and hygromycin resistance genes, respectively. The complete coding sequence of the HIV-1 (HXB2 strain) gp160 envelope gene (nucleotide bases 6225-8795 of GenBank Accession No. K03455) was cloned into plasmid pCRII-TOPO. The three HIV genes were additionally inserted into the baculovirus shuttle vector, pFastBacMami , under the transcriptional control of the CMV promoter. A construction of the pHIV-l LTR containing mutated NFkB sequences linked to the luciferase reporter gene was prepared by digesting pcDNA3.1 , containing the G418 resistance gene, with Nm I and Bam HI to remove the CMV promoter. LTR-luc was then cloned into the Nru I/Bam HI sites of the plasmid vector. Plasmid preparations were performed after the plasmids were amplified in Escherichia coli strain DH5-alpha. The fidelity of the inserted sequences was confirmed by double-strand nucleotide sequencing using an ABI Prism Model 377 automated sequencer. BacMam Baculovirus Generation Recombinant BacMam baculoviruses were constructed from pFastBacMam shuttle plasmids by using the bacterial cell-based Bac-to-Bac system. Viruses were propagated in Sf9 (Spodoptera frugiperda) cells cultured in Hink's TNM-FH Insect media supplemented with 10% (v/v) fetal bovine serum and 0.1 % (v/v) pluronic F-68 according to established protocols. Cell Culture
Human osteosarcoma (HOS) cells that naturally express human CXCR4 were transfected with human CCR5, human CD4 and the pHIV-LTR-luciferase plasmid using FuGENE 6 transfection reagent. Single cells were isolated and grown under selection condition in order to generate a stable HOS (hCXCR4/hCCR5/hCD4/pHIV- LTR-luciferase) clonal cell line. The cells were maintained in Dulbeccos modified Eagles media supplemented with 10% fetal calf serum (FCS), G418 (400ug/ml), puromycin (1 ug/ml), mycophenolic acid (40ug/ml), xanthine (250ug/ml) and hypoxanthine (13.5ug/ml) to maintain a selection pressure for cells expressing the LTR-luciferase, hCCR5 and hCD4, respectively. Human embryonic kidney (HEK- 293) cells stably transfected to express the human macrophage scavenging receptor (Class A1 type 1 ; GenBank Accession No. D90187), were maintained in DMEM/F-12 media (1 :1 ) supplemented with 10% FCS and 1.5ug/ml puromycin. The expression of this receptor by the HEK-293 cells enhances their ability to stick to tissue culture treated plasticware. Transduction of HEK-293 cells
HEK-293 cells were harvested using enzyme-free cell dissociation buffer. The cells were resuspended in DMEM/F-12 media supplemented with 10% FCS and 1.5ug/ml and counted. Tranductions were performed by direct addition of BacMam baculovirus containing insect cell media to cells. The cells were simultaneously transduced with BacMam baculovirus expressing HIV-1 tat, HIV-1 rev and HIV-1 gp160 (from the HXB2 HIV strain). Routinely an MOI of 10 of each virus was added to the media containing the cells. 2mM butyric acid was also added to the cells at this stage to increase protein expression in transduced cells. The cells were subsequently mixed and seeded into a flask at 30 million cells per T225. The cells were incubated at 370C, 5% CO2, 95% humidity for 24h to allow for protein expression. Cell/cell fusion assay format
HEK and HOS cells were harvested in DMEM/F-12 media containing 2% FCS and DMEM media containing 2% FCS, respectively, with no selection agents added. Compounds were plated as 1ul spots in 100% DMSO on a 96-well CulturPlate plates. HOS cells (5OuI) were added first to the wells, followed immediately by the HEK cells (5OuI). The final concentration of each cell type was 20,000 cells per well. Following these additions, the cells were returned to a tissue culture incubator (370C; 5%CO2/95% air) for an additional 24h. Measurement of Luciferase Production
Following the 24h incubation, total cellular luciferase activity was measured using the LucLite Plus assay kit (Packard, Meridien, CT). In brief, 100ul of this reagent was added to each well. The plates were sealed and mixed. The plates were dark adapted for approximately 10min prior to the luminescence being read on a Packard TopCount.
FUNCTIONAL ASSAY Cell Culture
Human embryonic kidney (HEK-293) cells were maintained and harvested as described above. Cells were plated in 96-well, black clear bottom, poly-lysine coated plates at a concentration of 40,000 cells per well in a final volume of 100ul containing human CXCR4 BacMam (MOI = 25) and Gqi5 BacMam (MOI = 12.5). The cells were incubated at 370C, 5% CO2, 95% humidity for 24h to allow for protein expression. Functional FLIPR Assay
After the required incubation time the cells were washed once with 5OuI of fresh serum-free DMEM/F12 media containing probenicid. 5OuI of dye solution was then added to the cells (Calcium Plus Assay Kit Dye; Molecular Devices) was dissolved in 200ml of the above probenicid/BSA containing media and incubated for 1h. Cell plates were transferred to a Fluorometric Imaging Plate Reader (FLIPR). Upon addition the effect of the compounds on the change in [Ca2+I1 was examined to determine if the compounds were agonists or antagonists (ability to block SDF-1 alpha activity) at the CXCR4 receptor. IC50 values are determined and pKb values are calculated using the Leff and Dougall equation: KB = IC50 / (( 2 + ( [agonist] / EC5O Λb)Λ1/b - 1 ) Where IC50 is that defined by the antagonist concentration-response curve [agonist] is the EC8O concentration of agonist used EC50 is that defined by the agonist concentration-response curve b is the slope of the agonist concentration- response curve.
HOS HIV-1 INFECTIVITY ASSAY HIV Virus Preparation
Compounds were profiled against two HIV-1 viruses, the M-tropic (CCR5 utilizing) Ba-L strain and the T-tropic (CXCR4 utilizing) IHB strain. Both viruses were propagated in human peripheral blood lymphocytes. Compounds were tested for there ability to block infection of the HOS cell line (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase) by either HIV-1 Ba-L or HIV-1 INB. Compound cytotoxicity was also examined in the absence of virus addition. HOS HIV-1 infectivity assay format
HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase) were harvested and diluted in Dulbeccos modified Eagles media supplemented with 2% FCS and non-essential amino acid to a concentration of 60,000 cells/ml. The cells were plated into 96-well plates (10OuI per well) and the plates were placed in a tissue culture incubator (370C; 5%CO2/95% air) for a period of 24h.
Subsequently, 5OuI of the desired drug solution (4 times the final concentration) was added to each well and the plates were returned to the tissue culture incubator (370C; 5%CO2/95% air) for 1h. Following this incubation 5OuI of diluted virus was added to each well (approximately 2 million RLU per well of virus). The plates were returned to the tissue culture incubator (370C; 5%CO2/95% air) and were incubated for a further 96h.
Following this incubation the endpoint for the virally infected cultures was quantified following addition of Steady-Glo Luciferase assay system reagent (Promega, Madison, Wl). Cell viability or non-infected cultures was measured using a CellTiter-Glo luminescent cell viability assay system (Promega, Madison, Wl). All luminescent readouts are performed on a Topcount luminescence detector (Packard, Meridien, CT).
The values given for the biological results should be interpreted with an appreciation for the amount of variability in the assays above-described, as will be accepted by those skilled in the art. The values provided should be considered predictive.
TABLE 1
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
TABLE 2
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
*
Figure imgf000102_0001
"A" indicates an activity level of less than 10OnM in the HOS HIV anti- infectivity assay.
"B" indicates an activity level of between 10OnM to 50OnM in the HOS HIV anti-infectivity assay.
"C" indicates an activity level of between 50OnM and 10μM in the HOS
HIV anti-infectivity assay..
Compounds of the present invention demonstrate desired potency. Compounds of the present invention demonstrate anti-HIV activity in the range of IC50 of about 1 nM to about 50μM. In one aspect of the invention, compounds of the present invention have anti-HIV activity in the range of up to about 10OnM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 10OnM to about 500 nM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 50OnM to 10μM. In another aspect of the invention, compounds have anti-HIV activity in the range of from about 10μM to about 50μM. Antiviral activity is separated from cytotoxicity. Moreover, compounds of the present invention are believed to provide a desired pharmacokinetic profile. Also, compounds of the present invention are believed to provide a desired secondary biological profile. Test compounds were employed in free or salt form.
All research complied with the principles of laboratory animal care (NIH publication No. 85-23, revised 1985) and GlaxoSmithKline policy on animal use.
Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000104_0001
wherein: t is O, 1 , or 2; each R1 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -OR10, -OAy, -OHet, -R3OR10, -NR6R7,
-R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7, -C(O)Ay,
-C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; n is O, 1 , or 2; each R2 independently is H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, -R3Ay,
-R3OR10, or -RaS(O)qR10;
R3 is selected from a group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, alkenyl, alkynyl, -R3Ay, -R3OR11, -RaS(0)qR11, wherein R3 is not substituted with amine or alkylamine; each R4 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -HetN(R10)2, -OR10, -OAy, -OHet, -R3OR10,
-NR6R7, -R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7,
-C(O)Ay, -C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; m is O, 1 , or 2;
Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene; Z is -N(R10)2, -AyN(R10J2, -AyR3N(R10J2, -Het, -HetN(R10)2, -HetRaN(R10)2, -HetRaAy, or -HetRaHet; each R10 independently is H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,
-Racycloalkyl, -R3OR11, -R3NR8R9, or -RaHet; each of R6 and R7 independently are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -R3OH, -R3OR10, -R3NR8R9, -Ay, -Het, -R3Ay,
-RaHet, or -S(O)qR10; each Ra independently is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene; each of R8 and R9 independently are selected from H or alkyl; each q independently is 0, 1 , or 2; each R11 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, or -Ay; each Ay independently represents an optionally substituted aryl group; and each Het independently represents an optionally substituted 4-, 5-, or 6-membered heterocyclyl or heteroaryl group; or pharmaceutically acceptable salts or esters thereof.
2. The compound of claim 1 wherein -Het is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
3. The compound of claim 1 wherein Ay is optionally substituted with one or more of alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkoxy, cyano, amide, amino, and alkylamino.
4. The compound of claim 1 wherein t is 1.
5. The compound of claim 1 wherein t is 2.
6. The compound of claim 1 wherein R2 is H, alkyl, haloalkyl or cycloalkyl.
7. The compound of claim 3 wherein R2 is H.
8. The compound of claim 1 wherein n is 0.
9. The compound of claim 1 wherein n is 1 and R1 is halogen, haloalkyl, alkyl, OR10, NR6R7, CO2R10, C(O)NR6R7, or cyano.
10. The compound of claim 1 wherein R3 is H, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl.
11. The compound of claim 1 wherein R3 is H, alkyl, haloalkyl, or cycloalkyl.
12. The compound of claim 1 wherein R3 is H.
13. The compound of claim 1 wherein R3 is RaOR11.
14. The compound of claim 13 wherein R3 is CH2OH.
15. The compound of claim 1 wherein m is 0.
16. The compound of claim 1 wherein m is 1 or 2.
17. The compound of claim 1 wherein m is 1.
18. The compound of claim 13 wherein each R4 independently is halogen, haloalkyl, alkyl, OR10, NR6R7, CO2R10, C(O)NR6R7, or cyano.
19. The compound of claim 13 wherein R4 is -Het, -HetN(R10)2 and R10 is H or alkyl, or -NHHet, and -Het is optionally substituted with at least one of d-C8alkyl or C3-C8 cycloalkyl.
20. The compound of claim 1 wherein Z is -N(R10)2) -AyRaN(R10)2, -Het, -HetN(R10)2, -HetRaN(R10)2, or -HetRaHet.
21. The compound of claim 17 wherein Z is -N(R10)2, -AyRaN(R10)2, -Het, or -HetN(R10)2.
22. The compound of claim 1 wherein Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo or cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo.
23. The compound of claim 1 wherein n is 0; t is 1 or 2; Y is alkylene; Z is -N(R10)2) -Het, or -HetN(R10)2; R2 is H; and R3 is H, alkyl or R3OR11.
24. The compound of claim 23 wherein m is 0.
25. The compound of claim 23 wherein m is 1 and R4 is -Het, -HetN(R10)2 and R10 is H or alkyl, or -NHHet and Het is optionally substituted with C1-C8 alkyl or C3-C8 cycloalkyl.
26. The compound of claim 25 wherein R3 is R3OR11.
27. The compound of claim 25 wherein R4 is -Het, optionally substituted with C1- C8 alkyl or C3-C8 cycloalkyl.
28. A compound selected from the group consisting of: Λ/-(lmidazo[1 ,2-a]pyridin-2-ylmethyl)-Λ/-(5,6,7,8-tetrahydro-8-quinolinyl)-1 ,4- butanediamine;
Λ/-[(8-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
A/-(5,6,7,8-Tetrahydro-8-quinolinyl)-/\/-{[5-(trifluoromethyl)imidazo[1 ,2- a]pyridin-2-yl]methyl}-1 ,4-butanediamine;
Λ/-[(6-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; Λ/-[(6-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
A/-[(5-Chloroimidazo[1 ,2-a]pyridin-2-yl)methyl]-/V-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(6-Bromo-5-methylimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Pyrrolidinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(1-Piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Morpholinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro- 8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8- tetrahydro-8-quinolinyl)-1 ,4-butanediamine;
Λ/-{[5-(Methyloxy)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
Λ/-[(5-Aminoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine;
(8S)-Λ/-{[2-(Dimethylamino)phenyl]methyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine;
Λ/-[(3-bromoimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-(5,6,7,8-tetrahydro-8- quinolinyl)-1 ,4-butanediamine; and pharmaceutically acceptable salts or esters thereof.
29. A compound selected from the group consisting of:
(8S)-Λ/-{[2-(Dimethylamino)phenyl]methyl}-Λ/-{[5-(4-methyl-1- piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-5,6,7,8-tetrahydro-8-quinolinamine; (8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)irπidazo[1 ,2-a]pyridin-2-yl]methyl}-/V-(2- pyridinylmethyO-S.βJ.δ-tetrahydro-δ-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(3- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine;
(8S)-Λ/-{[5-(4-Methyl-1-piperazinyl)irrιidazo[1 ,2-a]pyridin-2-yl]methyl}-Λ/-(4- pyridinylmethyl)-5,6,7,8-tetrahydro-8-quinolinamine; and pharmaceutically acceptable salts and esters thereof.
30. A compound selected from the group consisting of: [2-({{[2-(Dimethylamino)phenyl]methyl}[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)-5-(4-methyl-1-piperazinyl)imidazo[1 ,2-a]pyridin-3- yl]methanol;
[5-(4-Methyl-1-piperazinyl)-2-({(2-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol;
[5-(4-Methyl-1-piperazinyl)-2-({(3-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol;
[5-(4-Methyl-1-piperazinyl)-2-({(4-pyridinylmethyl)[(8S)-5,6,7,8-tetrahydro-8- quinolinyl]amino}methyl)imidazo[1 ,2-a]pyridin-3-yl]methanol; and pharmaceutically acceptable salts and esters thereof.
31. A compound substantially as hereinbefore defined with reference to any one of the Examples.
32. A pharmaceutical composition comprising a compound of claims 1-30 and a pharmaceutically acceptable carrier.
33. A pharmaceutical composition according to claim 32 in the form of a tablet or capsule.
34. A pharmaceutical composition according to claim 32 in the form of a liquid or suspension.
35. A composition according to claim 32, wherein said composition comprises at least one additional therapeutic agent selected from the group consisting of nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, and similar agents; non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, and similar agents; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, palinavir, lasinavir, and similar agents; entry inhibitors such as T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,180 and similar agents; budding inhibitors such as PA-344 and PA-457, and similar agents; and other CXCR4 and/or CCR5 inhibitors such as Sch-C, Sch-D, TAK779, UK 427,857, TAK449, and similar agents.
36. A compound of any of claims 1- 30 for use as an active therapeutic substance.
37. A compound of any of claims 1- 30 for use in the treatment or prophylaxis of diseases and conditions caused by inappropriate activity of CXCR4.
38. A compound of any of claims 1- 30 for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondylo¬ arthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers.
39. The compound of claim 38 wherein the condition or disease is HIV infection, rheumatoid arthritis, inflammation, or cancer.
40. The compound of claim 38 wherein the condition or disease is HIV infection.
41. The use of a compound of any of claims 1- 30 in the manufacture of a medicament for use in the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor.
42. The use of a compound of claim 41 wherein the chemokine receptor is CXCR4.
43. The use of a compound of any of claims 1- 30 in the manufacture of a medicament for use in the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondyloarthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers.
44. The use of claim 43 wherein the medicament is for the use in the treatment or prophylaxis of HIV infection, rheumatoid arthritis, inflammation, or cancer.
45. The use of claim 43 wherein the medicament is for the use in the treatment or prophylaxis of HIV infection.
46. A method for the treatment or prophylaxis of a condition or disease modulated by a chemokine receptor comprising the administration of a compound of any of claims 1- 30.
47. The method of claim 46 wherein the chemokine receptor is CXCR4.
48. A method for the treatment or prophylaxis of HIV infection, diseases associated with hematopoiesis, controlling the side effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, combating bacterial infections in leukemia, inflammation, inflammatory or allergic diseases, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, autoimmune diseases, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitus, spondyloarthropathies, scleroderma, psoriasis, T-cell-mediated psoriasis, inflammatory dermatoses, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, eoosinophilic myotis, eosinophilic fasciitis, and brain, breast, prostate, lung, or haematopoetic tissue cancers comprising the administration of a compound of any of claims 1- 30.
49. The method of claim 48 wherein the method is for the treatment or prophylaxis of HIV infection, rheumatoid arthritis, inflammation, or cancer.
50. A method for the treatment or prophylaxis of HIV infection comprising the administration of a compound of any of claims 1- 30.
51. A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound according to any one of claims 1 to 30 and another therapeutic agent.
52. A method according to claim 51 , wherein said therapeutic agent is selected from the group consisting of nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, and similar agents; non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, and similar agents; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, palinavir, lasinavir, and similar agents; entry inhibitors such as T-20, T-1249, PRO-542, PRO- 140, TNX-355, BMS-806, 5-Helix and similar agents; lntegrase inhibitors such as L- 870,180 and similar agents; budding inhibitors such as PA-344 and PA-457, and similar agents; and other CXCR4 and/or CCR5 inhibitors such as Sch-C, Sch-D, TAK779, UK 427,857, TAK449, and similar agents.
53. A process for the preparation of a compound of formula (I)
Figure imgf000113_0001
wherein t is O, 1 , or 2; each R1 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -OR10, -OAy, -OHet, -R3OR10, -NR6R7,
-R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7, -C(O)Ay,
-C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; n is O, 1 , or 2; each R2 independently is H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, -RaAy,
-R3OR10, or -RaS(O)qR10;
R3 is selected from a group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, alkenyl, alkynyl, -R3Ay, -R3OR11, -RaS(0)qR11, wherein R3 is not substituted with amine or alkylamine; each R4 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -HetN(R10)2, -OR10, -OAy, -OHet, -RaOR10,
-NR6R7, -R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7,
-C(O)Ay, -C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; m is O, 1 , or 2;
Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene;
Z is -N(R10)2, -AyN(R10)2> -AyR3N(R10J2, -Het, -HetN(R10)2) -HetR3N(R10)2, -HetRaAy, or -HetRΗet; each R10 independently is H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,
-R3cycloalkyl, -R3OR11, -R3NR8R9, or -RaHet; each of R6 and R7 independently are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -R3OH, -R3OR10, -R3NR8R9, -Ay, -Het, -R3Ay,
-RaHet, or -S(O)qR10; each Ra independently is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene; each of R8 and R9 independently are selected from H or alkyl; each q independently is O, 1 , or 2; each R11 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, or -Ay; each Ay independently represents an optionally substituted aryl group; and each Het independently represents an optionally substituted 4-, 5-, or 6-membered heterocyclyl or heteroaryl group; comprising the steps of treating a compound of formula (IV)
Figure imgf000115_0001
wherein R1, n, t, Y and Z are as defined with formula (I) with a compound of formula (V)
Figure imgf000115_0002
wherein R3, R4 and m are as defined with formula (I) under reductive amination conditions to form a compound of formula (I).
54. A process for the preparation of a compound of formula (I)
Figure imgf000115_0003
wherein t is O, 1 , or 2; each R1 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -OR10, -OAy, -OHet, -R3OR10, -NR6R7,
-R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7, -C(O)Ay,
-C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; n is O, 1 , or 2; each R2 independently is H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, -R3Ay,
-R3OR10, or -R3S(O)qR10; *
R3 is selected from a group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, alkenyl, alkynyl, -R3Ay, -RaOR11, -RaS(O)qR11, wherein R3 is not substituted with amine or alkylamine; each R4 independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Ay, -NHAy, -Het, -NHHet, -HetN(R10)2, -OR10, -OAy, -OHet, -R3OR10,
-NR6R7, -R3NR6R7, -R3C(O)R10, -C(O)R10, -CO2R10, -R3CO2R10, -C(O)NR6R7,
-C(O)Ay, -C(O)Het, -S(O)2NR6R7, -S(O)qR10, -S(O)qAy, cyano, nitro, or azido; m is O, 1 , or 2;
Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene;
Z is -N(R10J2, -AyN(R10J2, -AyR3N(R10J2, -Het, -HetN(R10)2, -HetR3N(R10)2, -HetR3Ay, or -HetRaHet; each R10 independently is H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,
-Racycloalkyl, -RaOR11, -R3NR8R9, or -RΗet; each of R6 and R7 independently are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -RaOH, -R3OR10, -R3NR8R9, -Ay, -Het, -R3Ay,
-RaHet, or -S(O)qR10; each Ra independently is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene; each of R8 and R9 independently are selected from H or alkyl; each q independently is O, 1 , or 2; each R11 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, or -Ay; each Ay independently represents an optionally substituted aryl group; and each Het independently represents an optionally substituted 4-, 5-, or 6-membered heterocyclyl or heteroaryl group;
comprising the steps of condensation of a compound of formula (IV)
Figure imgf000117_0001
wherein R1, n, t, Y and Z are as defined with formula (I) with a compound of formula (Vl)
Figure imgf000117_0002
(Vl) wherein R3, R4 and m are as defined with formula (I) and LV is a leaving group to form a compound of formula (I).
55. A process for the preparation of a compound of formula (I-C)
Figure imgf000117_0003
I-C wherein Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene and Z is -N(R10J2, -AyN(R10J2, -AyRaN(R10)2, -Het, -HetN(R10)2> -HetRaN(R10)2, -HetRaAy, or -HetRΗet;
comprising the steps of removal of a protecting group from a compound of formula (XVIII)
Figure imgf000118_0001
followed by reductive amination to form a compound of formula (I-C).
56. A process for the preparation of a compound of formula (I-C)
Figure imgf000118_0002
I-C wherein Y is alkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, cycloalkylene optionally substituted with one or more alkyl, hydroxyl, or oxo, alkenylene, cycloalkenylene, or alkynylene and Z is -N(R10)2, -AyN(R10J2, -AyRaN(R10)2, -Het, -HetN(R10)2, -HetRaN(R10)2, -HetRaAy, or -HetRaHet;
comprising the steps of treatment of compound formula (XVI)
Figure imgf000118_0003
XVI with a compound of formula (XX)
Figure imgf000118_0004
XX wherein Y and Z are as defined with formula (I-C) under reductive amination conditions to form a compound of formula (I-C).
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