WO2014063199A1 - Composés organiques - Google Patents

Composés organiques Download PDF

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Publication number
WO2014063199A1
WO2014063199A1 PCT/AU2013/001235 AU2013001235W WO2014063199A1 WO 2014063199 A1 WO2014063199 A1 WO 2014063199A1 AU 2013001235 W AU2013001235 W AU 2013001235W WO 2014063199 A1 WO2014063199 A1 WO 2014063199A1
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WO
WIPO (PCT)
Prior art keywords
oxadiazol
benzofuran
amino
diol
propane
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PCT/AU2013/001235
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English (en)
Inventor
Damian W Grobelny
Gurmit S Gill
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Akaal Pharma Pty Ltd
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Filing date
Publication date
Priority claimed from AU2012904703A external-priority patent/AU2012904703A0/en
Application filed by Akaal Pharma Pty Ltd filed Critical Akaal Pharma Pty Ltd
Publication of WO2014063199A1 publication Critical patent/WO2014063199A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • This disclosure relates to novel compounds having S1 P1 receptor activity and/or disease modifying activity and to the use of such compounds to treat conditions or diseases associated with the immune, vascular and nervous systems in animals and/or humans.
  • Sphingosine 1 -phosphate is a natural sphingolipid that functions as an intramolecular messenger in many types of cells and as an extracellular signalling molecule (for a recent review see Cooke et al, Annual Reports in Medicinal Chemistry, 2007, 42, pp 245 - 263 and references therein).
  • the cellular effects induced by S1 P are associated with platelet aggregation, cell morphology and proliferation, tumour cell invasion, endothelial cell chemotaxis and in vitro angiogenesis.
  • the extracellular signalling occurs through interaction of S1 P with G-protein-coupled receptors S1 P1 -5.
  • S1 P The intracellular activity of S1 P affects the HDAC activity (Hait NC et al, Science, 2009, 4, 325, 1254-7).
  • S1 P and its target have an essential role in lymphocyte migration through secondary lymphoid organs such the spleen, lymph nodes and mucosa- associated tissues such as the tonsils and Peyer's patches. T and B lymphocytes are effectively sequestered to the secondary lymphoid tissue and the receptor subtype -1 (S1 P1 ) is responsible for this action.
  • S1 P type molecular modulators have been shown to be effective in multiple animal disease models.
  • the S1 P mediated trans-activation of insulin receptor has been reported to help treat insulin resistance and type 2 diabetes (Rapizzi E. et al, Cell Mol Life Sci, 2009, 66, 3207-18).
  • S1 P1 receptor axis has a role in the migration of neural stem cells toward the site of spinal cord injury (Kimura, A., et al, Stem Cells, 2007, 25, 1 15-24).
  • the S1 P and its modulators supports the trafficking of hematopoietic progenitor cells and are helpful in tissue repair in myocardial infarction (Seitz, G., et al, Ann. N. Y. Acad. Sci.
  • S1 P receptors play a critical role in endothelial barrier enhancement and vasculature maturation (McVerry, B. J. , et al, Journal of Cellular Biochemistry, 2004, 1075 -85; Allende, M. L, et al, Blood, 2003, 102, pp 3665-7; Paik, J., et al, Genes and Development, 2004, 18, 2392-2403; Brinkmann, et al, American J. of transplantation, 2004, 4, 1019-25; McVerry B. J.
  • S1 P type modulation reduces ischemia reperfusion injuries (Lein, Y. H., et al, Kidney International, 2006, 69, 1601 - 8; Tsukada, Y. T. et al, J Cardiovascular Pharmocol, 2007, 50, 660-9).
  • S1 P1 signalling is critical in preventing inflammation induced vascular leakage (Niessen, F. et al; Blood, 2009, 1 13, 2859-66; Wang L et al, Microvascular Research, 2009, 77, 39 -45; Lee, J. F., et al, Am.J.
  • S1 P prevents tumour necrosis factor alpha mediated monocyte adhesion to endothelial cells, implicated in the pathology of arthrosclerosis and inflammatory diseases (Bolick, D. T. et al, Arterioscler. Thromb. Vase. Biol, 2005, 25, 976-81 ). Additionally, the S1 P and its modulators have cardio protective effects (Means, C.
  • S1 P receptor subtype - 1 The role of S1 P receptor subtype - 1 in modulating nociception has recently been described (Selley S M J et al, Journal of Neurochemistry, 2009, 1 10, pp 1 191 - 1202).
  • the S1 P1 mechanism in adjuvant with immunotherapy has proven to be able to, on the one hand, eradicate autoimmunity (Yoshida Y et al, Biol Pharm Bull, 201 1 , 34(6), 933-36) and, on the other hand, enhance the immunotherapy against cancer (Marcus A and Eshar Z, Expert opinion Biol Ther, 201 1 , 1 1 (12), 1551 -54).
  • Fingolimod (2-amino-2-(2-[4-octylphenyl] ethyl)-1 ,3-propanediol) (FTY-720) is metabolised to a structural analogue of S1 P and has been found to effect S1 P receptors.
  • FTY-720 as a multiple sclerosis drug, including its efficiency in animal models, related to many autoimmune and other diseases, has resulted in research efforts into S1 P receptors.
  • FTY-720 decreases peripheral blood lymphocyte counts (lymphopenia) reversibly, without impairing the effector function of the immune cells (Pinschewer, D. et al, J. Immunology, 2000, 164, 5761 -70).
  • FTY-720 is an novel drug for Multiple Sclerosis (MS) (Kieseier, B. C , et al, Pharmacological Research, 2009, 60, 207-1 1 ; Brown, B. A., The Annals of Pharmacotherapy, 2007, 41 , 1660-8) and has a direct cyto-protective and process extension effect in oligodendrocyte progenitors (Coelho, R. P. et al, J.
  • FTY-720 inhibits vascular endothelial cell growth factor induced vascular permeability (Sanchez, T., et al, J.
  • FTY-720 helps favourable central nervous system (CNS) gene expression and improves the blood brain barrier function (Foster, C. A., et al, Brain Pathology, 2009, 19, 254-66). Its anti- fibrotic activity was reported recently (Brunati, A. M., et al, Biochem Biophys Acta, 2008, 1783, 347-59; Delbridge, M. S., et al, Transplantation Proceedings, 2007, 39, 2992-6). FTY 720 inhibits development of atherosclerosis in low density lipoprotein receptor deficient mice (Nofer, J. R., et al, Circulation, 2007, 1 15, 501 -8; Tolle, M. et al, European J Clinical Investigation, 2007, 37, 171 -79).
  • FTY720 was effective in the treatment of cerebral ischemia in the mouse model (Czech, B. , et al, Biochem Biophys Res Comm, 2009, online), indicating the great potential of S1 P receptors modulators in the wide range of cardiovascular medicine.
  • the derivatives of FTY-720 were reported as pulmonary barrier enhancers and thus potential agents for the development of critical care medicines (Camp, S. M., et al, J Pharmacol Experimental Therapeutics, 2009, online).
  • the amino alcohols and their respective monophosphates, amino phosphonates, amino acids, alkoxyamino alcohols, alkyl carboxylates appear to be the most effective S1 P receptors modulators.
  • FTY-720 FTY-720 and in particular alternative compounds with improved properties and/or activity.
  • this could include compounds with greater range of activity, altered or enhanced specificity, improved pharmacological properties or reduction in side effects.
  • L is selected from H, deuterium, F, CI, Br, alkyl (C 1-3 );
  • G is a group selected from one of the following:
  • R is selected from H, COOH, alkyl (d-4) and hydroxy-alkyl (Ci- 4 );
  • R' and R" are independently selected from H, alkyl (d-4) and acyl;
  • R' is selected from OH, -OP0 3 H 2 and physiologically acceptable salts
  • the compound of formula (I) has the structure (II)
  • R ⁇ R 2 , R 3 , R 4 , A, L, R, R' and R" are as hereinbefore defined.
  • the compound of formula (I) has the structure (II)
  • R is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- iissooppeennttyyll,, OO--ccyyccllooppeennttyyll,, OO--aallllyyll,, OO--bbeennzzyyll aanndd ;;
  • RR 22 iiss sseelleecctteedd ffrroomm HH,, ddeeuutteerriiuumm,, FF,, CCII,, BBrr,, CCNN,, CCFF 33 ,, MMee,, OOMMee,, OOEEtt,, OOPPrr,, OO--iiPPrr,,
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • R is selected from H, Me or -CH 2 OH
  • R' is selected from H and Me
  • R" is selected from H and Me
  • L is selected from H, deuterium, Me and CI;
  • the compound of formula (I) has the structure (II) wherein R y is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 2 is H
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • R is selected from H, Me or -CH 2 OH
  • R' is selected from H and Me
  • R" is selected from H and Me
  • R 2 , R 3 , R 4 , A, L and m are as defined for the structure of formula (I); and wherein X is selected from H, Me, -CH 2 or -CH 2 CH 2 -.
  • the compound of formula (I) has the structure (III):
  • R is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and I/ ;
  • R 2 is selected from H, deuterium, F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr,
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • L is selected from H, deuterium, Me and CI; wherein X is selected from H, Me, -CH 2 or -CH 2 CH 2
  • the compound of formula (I) has the structure (III) wherein R, is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and ;
  • R 2 is H
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • L is H
  • the compound of formula (I) has the structure (IV):
  • the compound of formula (I) has the structure (IV):
  • R is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 2 is selected from H, deuterium, F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr,
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • R is selected from H, Me or -CH 2 OH
  • R' is selected from H and Me
  • L is selected from H, deuterium, Me and CI;
  • the compound of formula (I) has the structure (IV) wherein R, is selected from F, CI, Br, CN, CF 3 , Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 2 is H
  • R 3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O- isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and
  • R 4 is selected from H, deuterium, Me and Et;
  • R is selected from H, Me or -CH 2 OH
  • R' is selected from H and Me
  • L is H
  • a compound having S1 P receptor modulating activity and/or expression against target cells and /or having immune modulator activity in another aspect there is provided a compound having S1 P receptor modulating activity and/or expression against target cells and /or having immune modulator activity.
  • a pharmaceutical comprising at least one compound as herein described in any of its stereo isomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio together with a pharmaceutically acceptable carrier(s) and/or excipient(s).
  • a method of treating a disease and/or condition caused by or associated either directly or indirectly with inappropriate S1 P receptor modulating activity and/or expression and or immune activity by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of cell mobilization including immune cell, progenitor and/or stem cells by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating cancer, solid tumours, haematological disorders, infections, immunological and immune mediated disorders, pain, blood vessel disease, liver disease/injury, lung pathologies/injury, hypoxia and/or allograft or autograft rejection by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating immunological and/or, vascular and/or nervous system disorders by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating inflammation and/or inflammatory disorders by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating autoimmune disorders by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • the autoimmune disorder includes eczema, acne, skin cancer, dermatitis, vitiligo or psoriasis.
  • a method of treating nervous system diseases or neurodegenerative diseases including Multiple Sclerosis by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating infection including sepsis by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a method of treating epileptic conditions including seizures, convulsions and epilepsy neurodegeneration by the administration of an effective amount of a compound as herein disclosed or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.
  • a pharmaceutical comprising at least one compound as herein described in any of its stereo isomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the treatment of diseases and/or conditions caused by or associated with inappropriate immune response, central nervous system response or vascular system response for example, autoimmune disease and/or central nervous system disease and/or vascular disease in animals and humans.
  • a pharmaceutical comprising at least one compound as herein described in any of its stereo isomeric or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated either direct or indirect inappropriate S1 P receptor modulating activity or expression such as autoimmune disease and/or central nervous system disease and/or vascular disease in animals and/or humans.
  • the compounds as herein described may be used for the prevention and/or prophylaxis and/or treatment and/or immunotherapy of infectious diseases including any infection caused by viruses, bacteria, fungi, parasites, prions and/or any other pathogens.
  • the compounds as herein described may be used for the prevention and/or prophylaxis and/or treatment and/or immunotherapy of cancer and immune mediated diseases which include immune related and inflammatory diseases; autoimmune diseases; allergic conditions; pain; central nervous system diseases; neurodegenerative diseases, cardiovascular diseases; haematological pathologies.
  • immune related and inflammatory diseases include immune related and inflammatory diseases; autoimmune diseases; allergic conditions; pain; central nervous system diseases; neurodegenerative diseases, cardiovascular diseases; haematological pathologies.
  • the compounds as herein described may be used for prevention and/or treatment of vascular diseases including, but not limited to, hypoxia, atherosclerosis, diabetic blood vessel disease like inflammation, hyper vascularisation related disorders such as cancer and neoplasm, metastasis, ischemia, reperfusion injury, angina pectoris, coronary artery disease, stroke, thrombosis, artery/vein blockage or obstruction, diabetic retinopathy, sepsis and kidney failure, reperfusion or injury, fibrosis.
  • vascular diseases including, but not limited to, hypoxia, atherosclerosis, diabetic blood vessel disease like inflammation, hyper vascularisation related disorders such as cancer and neoplasm, metastasis, ischemia, reperfusion injury, angina pectoris, coronary artery disease, stroke, thrombosis, artery/vein blockage or obstruction, diabetic retinopathy, sepsis and kidney failure, reperfusion or injury, fibrosis.
  • the compounds as herein described may be used for prevention and/or treatment and/or immunotherapy of pain including chronic pain, which could either be somatogenic (organic) or psychogenic.
  • the somatogenic pain may be of nociceptive, inflammatory and or neuropathic origin.
  • the pain may be related to nociceptive pain, peripheral neuropathy, central neuropathy, neuralgia, migraine, psychotic, inflammatory and or neurological disorders.
  • the compounds as herein described may be used for organ transplant and/or allograft and/or autograft, for example, kidney, liver, lung, heart, skin, stem cell or bone marrow transplant and in the treatment of graft versus host disease.
  • the compounds as herein described may be used for prevention and/or treatment and/or immunotherapy for the pathologies caused by bioterrorism agents.
  • the compounds as herein described may be used as a vaccine adjuvant to boost and/or enhance the action of a vaccine and/or immune agent and/or for immunization.
  • the compounds as herein described may be used to mobilize the progenitor/ stem cells preferably towards the site of injury, ischemia, stroke etc.
  • the compounds as herein described may be used for regeneration purpose, for example, in wound healing.
  • the compounds as herein described may be used for any of the above indications and in any of the above methods in humans and/or animals.
  • treatment includes any effect such as lessening, reducing, modulating and/or eliminating, resulting in the improvement of the condition, disease or disorder to be treated in humans and/or animals.
  • An appropriate concentration level in treatment is from 0.01 nM to 1 Molar.
  • compositions as herein described may be administered via any route for example oral, intra tracheal, topical, intravenous and in any combination with a variety of pharmaceutical agents, pharmaceutical excipients, including stabilizing agents carriers and/or encapsulation formulations known in the art.
  • the compounds as herein described may be used alone or in combination with any suitable adjuvant, non limiting examples of which include, known immunosuppressants such as cyclosporine, tecrolimus, rapamycin, azathioprine, cyclophosphamide, dexamethasone, flunisolide, prednisolone, prednisone, amcinomide desonide, methylprednisolone, triamcinolone, alclometasone and TGFp.
  • immunosuppressants such as cyclosporine, tecrolimus, rapamycin, azathioprine, cyclophosphamide, dexamethasone, flunisolide, prednisolone, prednisone, amcinomide desonide, methylprednisolone, triamcinolone, alclometasone and TGFp.
  • the compounds as herein described may be administered alone or in any combination with any suitable adjuvant, non limiting examples of which include, other anticancer, antiviral, antibacterial, antifungal, and/or any anti-pathogen agent, a immune stimulating or activating compound which could make a delayed type hypersensitivity response.
  • suitable adjuvant non limiting examples of which include, other anticancer, antiviral, antibacterial, antifungal, and/or any anti-pathogen agent, a immune stimulating or activating compound which could make a delayed type hypersensitivity response.
  • the molecule/s or compounds as herein described may be used with T cell, B cell, dendritic cell, antigen, protein, protein conjugate and or like which could be used for such immunization purpose.
  • Figure 1 illustrates the results of autoimmune encephalomyelitis assay in relation to a compound as disclosed herein
  • Figure 2 illustrates the results of cytokine inhibition assay in relation to a compound as disclosed herein
  • Figure 3 illustrates the results of contact hypersensitivity assay in relation to a compound as disclosed herein
  • Figure 4 illustrates the results of inflammatory inhibition in relation to a compound as disclosed herein
  • Figure 5 illustrates the results of excitotoxic and inflammatory neurodegeneration in relation to a compound as disclosed herein
  • Figure 6 illustrates the results of the inhibition of seizures in relation to a compound as disclosed herein
  • Figure 7 illustrates the results of the inhibition of infarct size with a compound as disclosed herein
  • Figure 8 illustrates the effects on sensory motor function in relation to a compound as disclosed herein
  • Figure 9 illustrates the effect of a compound as disclosed herein on body temperature and weight.
  • pharmaceutically active agent “medicament”, “active”, “molecule” and “drug” are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect.
  • the terms also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those active agents/compounds specifically mentioned herein and compounds of the invention including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like.
  • ⁇ ективное amount and "therapeutically effective amount” of a compound as used herein mean a sufficient amount of the compound to provide the desired therapeutic or physiological effect or outcome.
  • a practitioner balances the potential benefits against the potential risks in determining what an appropriate "effective amount” is. The exact amount required will vary from subject to subject, depending on factors including the age and general condition of the subject, mode of administration and the like.
  • the term 'subject' means a human or animal.
  • a "pharmaceutically acceptable" carrier, excipient or diluent may include a pharmaceutical vehicle comprised of a material that may not be biologically active or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any and/or a substantial adverse reaction.
  • Carriers may include excipients and other additives such as diluents, detergents, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
  • compositions and combination therapies as disclosed herein may be administered in combination with a variety of pharmaceutical agents, pharmaceutical excipients, including stabilizing agents, carriers or encapsulation formulations.
  • Effective combinations are those which provide favourable synergistic effect which assist in treatment and/or prevention and/or immunotherapy better than the agents alone.
  • alkyl or "alkyl chain” includes within its meaning straight and branched chain alkyl groups. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethyl-propyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1 , 1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethylpropyl, 1 ,1 ,2-trimethylpropyl, heptyl, 5-methylhexyl, 1 -methyl
  • cycloalkyl or “carbocyle” refers to mono- or polycyclic alkyl groups, or alkyl substituted cyclic alkyl groups. Examples of such groups include cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, ethylcyclopentyl, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, decahydronaphthyl, bicyclo[2.2.1 ]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.2]decyl, bicycleo4.4.3]dodecyl, bicyclo[
  • aryl refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems.
  • groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquino
  • heterocyclic refers to any 3- to 16-membered monocyclic, bicyclic or polycyclic ring containing, for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 1 1 -membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur.
  • heterocyclic includes any group in which a heterocyclic ring is fused to a benzene ring.
  • heterocyclics are pyrryl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, piperidinyl, pyridinyl, furyl, thiophenyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolyl, pyrenyl, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, furfuryl, thienyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl,
  • alkoxy refers to a group of the formula alkyl-O-, wherein the alkyl group is as defined above.
  • the compound preparations illustrated can be carried out by generally known methods as exemplified hereinafter.
  • the starting materials and intermediates used in the synthesis of compounds of this invention are generally commercially available or may be prepared by conventional methods of organic chemistry. Suitable methods for the synthesis of compounds of this invention and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991 ); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O.
  • Step A 4-Hydroxy-3-iodobenzonitrile: To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH 4 OH (22 ml) a solution of l 2 (1 .06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H 2 0 (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H 2 0 (3 ml).
  • Step B 2-(Hydroxymethyl)benzofuran-5-carbonitrile: Propargyl alcohol (0.24 ml; 5.2 mmol) was added drop wise during 30 min to a refluxed suspension of the product of Step A (0.48 g; 1 .96 mmol) and Cu 2 0 (0.28 g; 1 .96 mmol) in anhydrous pyridine ( 4 ml) with stirring under N 2 . After additional reflux for 15 min, the mixture was cooled to room temperature, diluted to 20 ml with ethyl acetate (EtOAc) and insoluble material was removed by filtration.
  • EtOAc ethyl acetate
  • Step C N-Hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide: A mixture of the product of Step B (0.22 g; 1 ,27 mmol) and HCI x NH 2 OH (0.18 g; 2.59 mmol) and ⁇ , ⁇ -diisopropylethylamine (DI PEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at ⁇ 71 °C. The solvents were removed in vacuo and the residue was treated with H 2 0 (3 ml) and the product was taken up by EtOAc (3 x 15 ml). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and filtrate evaporated to dryness to give the title compound (0.2 g; 76%), as colourless solid, which was used in the next step without further purification.
  • DI PEA ⁇ , ⁇ -diis
  • Step D (5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yljmethanol: A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (0.22 g; 1 .15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at ⁇ 40°C under N 2 .
  • DMSO dimethylsulfoxide
  • Step E 5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- carbaldehyde: A suspension of the product of Step D (0.13 g; 0.34 mmol) and Mn0 2 (0.15 g; 1 .7 mmol) in dioxane (4 ml) was refluxed for 1 h with stirring. After cooling to room temperature, the insoluble material was removed by filtration, washed with EtOAc (20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.13 g; 100%), as greyish solid.
  • Step F 5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid;
  • EtOH 0.2 ml
  • H 2 0 0.1 ml
  • KOH 10% KOH
  • Step A Methyl 1-((5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzo furan-2- yl)methyl)azetidine-3-carboxylate: A mixture the product of Example 1 , Step E (0.07 g; 0.85 mmol), azetidine-3-methylcarboxylate hydrochloride (0.03 g; 0.199 mmol) and DIPEA (0.035 ml, 0.2 mmol) in 1 ,2-dichloroethane (1 ml) and methanol (MeOH) (3 ml) was sonicated for 30 min at room temperature, then evaporated to dryness.
  • Methyl 1-((5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzo furan-2- yl)methyl)azetidine-3-carboxylate A mixture the product of Example 1 , Step E (0.
  • Step B 1-((5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)methyl)azetidine-3-carboxylic acid: A mixture of the product of Step A (0.06 g; 0.126 mmol) and 10 % KOH (0.1 ml) in dioxane (2 ml) was refluxed for 1 h and solvents were evaporated to dryness. The residue was treated with AcOH (0.5 ml) and evaporated to dryness in vacuo.
  • Step A N-Hydroxy-3-iodo-4-isopropoxybenzimidamide: A suspension of 3-iodo-4- isopropoxybenzonitrile (0.576 g; 2 mmol), HCI x NH 2 OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50 S C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H 2 0. The organic layer was separated, dried over MgS0 4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid.
  • Step B 5-(3-Chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- o adiazole: A mixture of 3-chloro-4-propoxybenzoic acid (0.298 g, 0.93 mmol), the product of Step A (0.2 g, 0.93 mmol) and EDC (0.214 g, 1 .1 mmol) in anhydrous DMF (3 ml) was stirred overnight at 45 S C . 1 M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 1 10 S C. The reaction mixture was diluted to 20 ml with H 2 0 and extracted with EtOAc (2 x 15 ml).
  • Step C 4-(5-(3-Chloro-4-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol: To a solution of the product of Step B (0.2 g, 0.4 mmol) in anhydrous CH 2 CI 2 (2 ml) 1 M BCI 3 in CH 2 CI 2 (3 ml) was added drop wise at rt. After 1 h, more of 1 M BCI 3 in CH 2 CI 2 (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH 4 CI solution and extracted with CH 2 CI 2 (20 ml). The organic layer was separated, dried over MgS0 4 and filtered.
  • Step D tert-Butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DI PEA (3 ml: 0.3 ml) was degassed with N 2 and CI 2 Pd(PPh 3 ) 4 (0.025 g) was added, followed by catalytic amount of Cul.
  • Step E 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: To a stirred solution of product of Step D (0.1 g, 0.17 mmol) in CH 2 CI 2 (0.5 ml) TFA (1 ml) was added. After stirring for 1 h at room temperature, EtOH (2 ml) was added and stirring was continued for additional 1 h.
  • Step A (E)-3-(3-lodo-4-isopropoxyphenyl)-5-(4-methylstyryl)- 1 ,2,4-oxadiazole: When 3-chloro-4-propoxybenzoic acid was replaced with (E)-3-p-tolylacrylic acid the similar procedure as described in Example 3, Step B gave the title compound (0.23 g, 52%) as white solid.
  • Step B (E)-2-lodo-4-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)phenol: When 5-(3- chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1 ,2,4-oxadiazole was replaced with the product of step A the similar procedure as in Example 3, Step C gave the title compound (0.105 g, 53%) as white solid.
  • Step C (E)-Tert-butyl 2,2-dimethyl-5-(5-(5-(4-methylstyryl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)- 1,3-dioxan-5-ylcarbamate: When 4-(5-(3-Chloro-4-propoxy phenyl)- 1 ,2,4- oxadiazol-3-yl)- 2-iodophenol was replaced with the product of Step B the similar procedure as in Example 3, Step D gave the title compound (0.08 g, 68%) as pale paste.
  • Step D (E)-2-Amino-2-(5-(5-(4-methylstyryl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane- 1,3-diol: When tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-yl carbamate was replaced with the product of Step C the similar procedure as in Example 3, Step E gave the title compound (0.025 g, 48%) as white solid.
  • Step A 5-(4-Bromo-3-chlorophenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 4-bromo-3-chlorobenzoic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 72% yield, as creamy solid.
  • Step B 4-(5-(4-Bromo-3-chlorophenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 86% yield, as creamy solid.
  • Step C tert-Butyl 5-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 58% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step A tert-Butyl 5-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3-thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H 2 0 (5 ml:1 ml), Pd(PPh 3 ) 4 (0.03 g) was added at 80 S C, followed by the NaHC0 3 solution (0.065 g in 1 ml H20) and this was stirred for 2 h.
  • Step B 2-Amino-2-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: Vl ⁇ ren the product of Step A was substituted for tert- butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 3, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid.
  • Step A 5-(3,4-Diethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole: When 3,4-diethoxy benzoic acid was substituted for 3-chloro-4-propoxybenzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 60% yield, as colourless solid.
  • Step B 4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 84% yield, as a creamy solid.
  • Step C tert-Butyl 5-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yl)-2,2-dimethyl- 1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 66% yield, as creamy paste.
  • Step D 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane- 1,3-diol:
  • Step C 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane- 1,3-diol:
  • Step E the similar procedure afforded the title compound in 61 % yield, as creamy solid.
  • Step A 5-(4-Propoxy-3-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 4-propoxy-3-methoxybenzoic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 58% yield, as creamy solid.
  • Step B 4-(5-(4-Propoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-
  • Step C tert-Butyl 5-(5-(5-(4-propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 68% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-Propoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: Vl ⁇ ren the product of Step C was substituted for tert- butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 3, Step E, the similar procedure afforded the title compound in 57% yield, as colourless solid.
  • Step A 2-methylbenzofuran-5-carbonitrile: 2-iodo-4-cynophenol (0.25 g, 1 mmol) was added hexamethyldisilazine (2 ml) and saccharin (0.1 gm) and refluxed under N 2 gas for 2 hrs when the solution became clear. The solvent was distilled and the crude was dried under high vacuum, dissolved in dry THF (2 ml) and was added to a solution of 1 - propynyl Zn [made by the treating 0.5 M solution of 1 -propynyl magnesium bromide (7.8 ml) with dry ZnCI 2 (0.3 gm] under nitrogen].
  • Step B 5-(3,4-diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)- 1,2,4-oxadiazole: When 3-chloro-4-propoxy benzoic acid and A/-Hydroxy-3-iodo-4-isopropoxybenzimidamide were replaced with 3,4-diethoxybenzoic acid and A/-hydroxy-2-methylbenzofuran-5- carboximidamide respectively the similar procedure as described in Example 3, Step B gave the title compound (0.01 1 g, 6%) as white solid.
  • Step A 6-Methoxybenzofuran-2-carboxylic acid: Methyl 6-methoxybenzofuran-2- carboxylate (0.25 g, 1 .21 mmol) was dissolved in a mixture of solvents (THF: CH 3 OH: H 2 0; 5 ml: 2 ml: 1 ml) and to the stirred solution was added a solution of LiOH (0.145 g, 6 mmol) in H 2 0 (0.5 ml) and the mixture was stirred at room temp for 3 hrs. The solvent was distilled and the crude was portioned in EtOAc (20 ml) and 1 M HCI (2 ml). The organic layer was washed with water and dried over magnesium sulphate.
  • solvents CH 3 OH: H 2 0; 5 ml: 2 ml: 1 ml
  • Step B 3-(3-lodo-4-isopropoxyphenyl)-5-(6-methoxybenzofuran-2-yl)-1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was replaced with product of Step A the similar procedure as described in Example 3, Step B gave the title compound (0.17 g, 67%) as white solid.
  • Step C 2-lodo-4-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)phenol: When 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1 ,2,4-oxadiazole was replaced with the product of Step A the similar procedure as in Example 3, Step C gave the title compound (0.09 g, 65%) as white solid.
  • Step D Tert-butyl 5-(5-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When 4-(5-(3-Chloro-4- propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol was replaced with the product of Step C the similar procedure as in Example 3, Step D gave the title compound (0.075 g) as pale paste and was used in the next step.
  • Step E 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate was replaced with the product of Step D the similar procedure as in Example 3, Step E gave the title compound (0.012 g, 26%) as creamy green solid.
  • Step A 3-(3-lodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1 ,2,4-oxadiazole:
  • 4-propylbenzoic acid was substituted for 3-chloro-4-propoxy benzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 82% yield, as colourless solid.
  • Step B 2-lodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)phenol: l ⁇ ren the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 82% yield, as colourless solid.
  • Step C tert-Butyl 2,2-dimethyl-5-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl) benzo- furan-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 35% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol:
  • Step E the similar procedure afforded the title compound in 28% yield, as creamy solid.
  • Step A 5-(4-Ethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4-oxadiazole: When 4-ethoxybenzoic acid was substituted for 3-chloro-4-propoxy benzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 53% yield, as white solid.
  • Step B 4-(5-(4-Ethoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 87% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)- 2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 60% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol:
  • Step E the similar procedure afforded the title compound in 32% yield, as light yellow solid.
  • Step A 2-Chloro-N-hydroxy-5-iodo-4-isopropoxybenzimidamide: To a stirred solution of 2-chloro-4-isopropoxybenzonitrile (0.8 g, 4.1 mmol) and CF 3 C0 2 Ag (1 .3 g, 5.1 mmol) in CH 2 CI 2 (50 ml) l 2 (1 g, 4 mmol) was added and the mixture was stirred for 6 h at reflux. This was filtered through the Celite bead and the washed with CH 2 CI 2 .
  • Step B 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1,2,4- oxadiazole:
  • Step B 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1,2,4- oxadiazole:
  • Step C 5-Chloro-2-iodo-4-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)phenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 55% yield, as creamy solid.
  • Step D 2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4- oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate was replaced with the tert-butyl 5-(6-chloro-5-(5-(4-propylphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 3, Step D) the similar procedure as in Example 36, Step E gave the title compound
  • Step A 1 -Butyl- 1 H-pyrazole-4-carboxylic acid: To a stirred suspension of 4- iodopyrazole (0.3 g, 1 .55 mmol) and 60% NaH (0.08 g, 2 mmol) in anhydrous THF (1 ml) butyl bromide (0.5 ml) was added and the mixture was stirred overnight at 70 S C. The mixture was quenched with saturated NH 4 CI and extracted with EtOAc (50 ml). The organic layer was washed with H 2 0, dried over MgS0 4 and filtered.
  • Step B 5-( 1-Butyl-1H-pyrazol-4-yl)-3-(3-iodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazole: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 3, Step B the similar procedure afforded the title compound in 17% yield, as creamy gum.
  • Step C 4-(5-(1-Butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C 4-(5-(1-Butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 72% yield, as creamy solid.
  • Step D tert-Butyl 5-(5-(5-(1-butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: ⁇ Nher the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol in Example 3, Step D, the similar procedure afforded the title compound in 68% yield, as pale paste.
  • Step E 2-Amino-2-(5-(5-(1 -butyl-1 H-pyrazol-4-yl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step D 2-Amino-2-(5-(5-(1 -butyl-1 H-pyrazol-4-yl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step B 3-(3-lodo-4-isopropoxyphenyl)-5-(3-nitro-4-propoxyphenyl)- 1,2,4- oxadiazole:
  • Step B 3-(3-lodo-4-isopropoxyphenyl)-5-(3-nitro-4-propoxyphenyl)- 1,2,4- oxadiazole:
  • Step C 2-lodo-4-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 77% yield, as creamy solid.
  • Step D tert-Butyl 2,2-dimethyl-5-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)- 1,3-dioxan-5-ylcarbamate:
  • Step C tert-Butyl 2,2-dimethyl-5-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)- 1,3-dioxan-5-ylcarbamate:
  • Step E 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step D 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol:
  • Step B 5-(3-(3-lodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile:
  • Step B the similar procedure afforded the title compound in 57% yield, as creamy solid.
  • Step C 5-(3-(4-Hydroxy-3-iodophenyl)- 1 ,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile:
  • Step C the similar procedure afforded the title compound in 74% yield, as creamy solid.
  • Step D tert-Butyl 5-(5-(5-(3-cyano-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol in Example 3, Step D, the similar procedure afforded the title compound in 44% yield, as pale paste.
  • Step E 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)benzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-propoxy benzonitrile:
  • product of Step D was substituted for tert- butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) in Example 3, Step E, the similar procedure afforded the title compound in 29% yield, as off white solid.
  • Step A 3-Bromo-4-propoxybenzoic acid: 3-Bromo-4-propoxybenzaldehyde was oxidized by KMn0 4 , according to the procedure as described in Example 14, Step A, to give the title compound in 96%, as white solid.
  • Step B 4-(5-(3-Bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 70% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(3-bromo-4-propoxy-phenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl-carbamate: ⁇ Nher with the product of
  • Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenol in Example 3, Step D, the similar procedure afforded the title compound in 98% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1 ,3-diol:
  • Step C 2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1 ,3-diol:
  • Step B 2-lodo-4-octylbenzenethiol: To a stirred mixture of the product of Step A (0.4 g, 1 .21 mmol) in 35% HCI (0.2 ml) at 0 S C was added ice cold solution of NaN0 2 (100 mg, 1.3 mmol) and this solution was added to a stirred solution of K-ethylxhanthate solution [prepared by rapid stirring of a mixture of KOH (85 mg, 1 .5 mmol) and CS 2 (173 mg, 1 .5 mmol)in a mixture of solvent EtOH: H20; 1 ml: 1 .5 ml for 2.5 hr at room temperature ref.
  • K-ethylxhanthate solution prepared by rapid stirring of a mixture of KOH (85 mg, 1 .5 mmol) and CS 2 (173 mg, 1 .5 mmol)in a mixture of solvent EtOH: H20; 1 ml: 1 .5
  • Step C Tert-butyl 2,2-dimethyl-5-(5-octylbenzo[b]thiophen-2-yl)-1,3-dioxan-5- ylcarbamate: When 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxy-phenyl)-1 ,2,4- oxadiazole was replaced with the product of Step - B the similar procedure as described in Example 3, Step C gave the title compound (0.03 g, 24%) as white solid.
  • Step D 2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1,3-diol:
  • tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl- 1 ,3-dioxan -5-ylcarbamate was replaced with the product of Step C the similar procedure as described in Example 3, Step E gave the title compound (0.008 g, 38%) as light yellow solid.
  • Step B Tert-butyl 2,2-dimethyl-5-(5-octylbenzofuran-2-yl)-1,3-dioxan-5- ylcarbamate: When 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxy-phenyl)-1 ,2,4- oxadiazole was replaced with the product of Step A the similar procedure as in Example 3, Step C gave the title compound (0.13 g, 53%) as a light yellow paste.
  • Step C 2-Amino-2-(5-octylbenzofuran-2-yl)propane-1,3-diol:
  • tert-butyl 5-(5- (5-(3-chloro-4-propoxy phenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3- dioxan -5-ylcarbamate was replaced with the product of Step B the similar procedure as in Example 3, Step E gave the title compound (0.065 g, 51 %) as off white solid.
  • Step A 5-(2-Cyclopropylbenzofuran-5-yl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 2- cyclopropylbenzofuran-5-carboxlic acid in Example 3, Step B, the similar process afforded the title compound in 47% yield, as brown gum.
  • Step B 4-(5-(2-Cyclopropylbenzofuran-5-yl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 69% yield, as white solid.
  • Step C 2-Amino-2-(5-(5-(2-cyclopropylbenzofuran-5-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: When tert-butyl 5-(5-(5-(2-cyclopropylbenzofuran-5- yl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate
  • Step D obtained via a similar procedure as described in Example 3, Step D when the product of above Step B was replaced with 4-(5-(3-Chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenol) tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran- 2-yl)-2,2-dimethyl-1 ,3-dioxan-5-yl carbamate in Example 3, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid.
  • Step B 2-lodo-4-(5-(4-isobutoxyphenyl)-1,2,4-oxadiazol-3-yl)phenol : When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 84% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(4-isobutoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl)- 2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 61 % yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-isobutoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol:
  • Step D 2-Amino-2-(5-(5-(4-isobutoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol:
  • Step A 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(3,4-diethoxyphenyl)-1,2,4- oxadiazole: When 3-propylbenzoic acid was substituted for 3,4-diethoxybenzoic acid and in Example 13, Step B, the similar process afforded the title compound in 35% yield, as creamy solid.
  • Step B 5-Chloro-4-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 64% yield, as white solid.
  • Step C tert-Butyl 5-(6-chloro-5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 57% yield, as creamy solid.
  • Step D 2-Amino-2-(6-chloro-5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step C 2-Amino-2-(6-chloro-5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step A 5-(3-Chloro-4-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3-chloro-4- methoxybenzoic acid in Example 3, Step B, the similar process afforded the title compound in 59% yield, as pale paste.
  • Step B 4-(5-(3-Chloro-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 62% yield, as white solid.
  • Step C 2-Amino-2-(5-(5-(3-chloro-4-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • tert-butyl-5-(5-(5-(3-chloro-4-methoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan -5-ylcarbamate (obtained via a similar procedure as described in Example 3, Step D when the product of above Step B was replaced with 4-(5-(3-Chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenol) was replaced with tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4- o
  • Step A 5-(3,4-Dimethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3,4-dimethoxybenzoic acid in Example 3, Step B, the similar process afforded the title compound in 78% yield, as crude pale solid.
  • Step B 4-(5-(3,4-Dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 55% yield, as white solid.
  • Step C 2-Amino-2-(5-(5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol:
  • tert-butyl 5-(5-(5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained via a similar procedure as described in Example 3, Step D when the product of above Step B was replaced with 4-(5-(3-Chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol) was replaced with tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl
  • Step A 5-(3-Chloro-4-ethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4propoxybenzoic acid was substituted for 3-chloro-4- methoxybenzoic acid in Example 3, Step B, the similar process afforded the title compound in 64% yield, as pale paste.
  • Step B 4-(5-(3-Chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 68% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(3-chloro-4-ethoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 55% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step C 2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step A 2-Ethoxy-5-(3-(3-iodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-5- yl)benzonitrile: When 3-chloro-4-propoxybenzoic acid was substituted for 3-cyno-4- ethoxybenzoic acid [ 1 H-NMR (DMSO-d 6 ) 7.13 (b, 1 H), 6.26 (b, 1 H), 5.9 (b, 1 H), 3.13 (b, 2H), 0.41 (b, 3H)] in Example 3, Step B, the similar process afforded the title compound in 78% yield, as creamy paste.
  • Step B 2-ethoxy-5-(3-(4-hydroxy-3-iodophenyl)-1 ,2,4-oxadiazol-5-yl)benzonitrile:
  • Step C When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 56% yield, as white solid.
  • Step C 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)benzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-ethoxybenzonitrile:
  • tert-butyl 5-(5-(5-(3-cyano-4-ethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained via a similar procedure as described in Example 3, Step D when the product of above Step B was replaced with 4-(5-(3-Chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenol) was replaced with tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4- oxadiazol-3-yl
  • Step A N-Hydroxy-3-iodo-4-isopropoxy-5-methylbenzimidamide:
  • 4-Bromo-2- methylphenol To a stirred solution of 2-methylphenol (1 gm, 9.3 mmol) in DCM (20 mL) at 0 S C was added bromine (500 ⁇ , 9.3 mmol) drop wise. The solution was stirred for 1 hr, quenched with sodium bicarbonate solution and was diluted with DCM (30 mL). The organic layer was washed with sodium thiosulphate solution and dried over magnesium sulphate. The solvent was distilled to gave the product (1 .62 gm, 93%) as creamy solid.
  • Step B 5-(3-Chloro-4-ethoxyphenyl)-3-(3-iodo-4-isopropoxy-5-methylphenyl)- 1,2,4- oxadiazole:
  • 3-chloro-4-propoxybenzoic acid was substituted for 3-chloro-4- ethoxybenzoic acid and A/-hydroxy-3-iodo-4-isopropoxybenzimidamide with the product of Step A in Example 3, Step B, the similar process afforded the title compound in 37% yield, as creamy paste
  • Step C 4-(5-(3-Chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodo-6- methylphenol: When the product of Step B was substituted for
  • Step D tert-Butyl 5-(5-(5-(3-chloro-4-ethoxyphenyl)- 1,2,4-oxadiazol-3-yl)-7- methylbenzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 57% yield, as pale paste.
  • Step E 2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-7- methylbenzofuran-2-yl)propane-1 ,3-diol:
  • Step D 2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-7- methylbenzofuran-2-yl)propane-1 ,3-diol:
  • Step A 5-(3,4-Diethoxyphenyl)-3-(3-iodo-4-isopropoxy-5-methylphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-ethoxybenzoic acid was substituted for 3,5- diethoxybenzoic acid in Example 27, Step B, the similar process afforded the title compound in 59% yield, as colourless paste.
  • Step B 4-(5-(3,4-Diet oxy phenyl)- 1,2,4-oxadiazol-3-yl)-2-iodo-6-methylphenol:
  • Step C the similar procedure afforded the title compound in 54% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-7- methylbenzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 47% yield, as creamy paste.
  • Step D 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-7- methylbenzofuran-2-yl)propane-1,3-diol: WJher the product of Step C was substituted for tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-yl carbamate in Example 3, Step E, the similar procedure afforded the title compound in 59% yield, as creamy solid.
  • Step A 5-(3-(3-lodo-4-isopropoxy-5-methylphenyl)-1,2,4-oxadiazol-5-yl)-2- propoxybenzonitrile: When 3-chloro-4-ethoxybenzoic acid was substituted for 3,5- diethoxybenzoic acid in Example 27, Step B, the similar process afforded the title compound in 75% yield, as yellow brown paste.
  • Step B 5-(3-(4-Hydroxy-3-iodo-5-methylphenyl)- 1 ,2,4-oxadiazol-5-yl)-2- propoxybenzonitrile:
  • Step C the similar procedure afforded the title compound in 54.4% yield, as creamy white solid.
  • Step C 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)-7-methylbenzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-propoxybenzonitrile:
  • tert-butyl 5-(5-(5-(3-cyano-4- propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-7-methylbenzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan- 5-ylcarbamate (obtained via a similar procedure as described in Example 3, Step D when the product of above Step B was replaced with 4-(5-(3-Chloro-4-propoxyphenyl)-1 ,2,4- oxadiazol-3-yl)-2-iodophenol) was replaced with tert-butyl5-(5-(5-(3-chloro-4- propoxyphenyl)-1 ,2,4-oxadiazol-3-
  • Step A 4-Ethoxy-3-nitrobenzoic acid: A mixture of 4-hydroxy-3-nitrobenzoic acid (0.22 g, 1 .2 mmol), K 2 C0 3 (0.17 g, 1 .23 mmol) and Etl (0.29 ml, 3.69 mmol) in anhydrous DMF (5 ml) was stirred at ⁇ 50°C for three days under N 2 .
  • Step B 4-Ethoxy-3-(methylsulfonamido)benzoic acid: A mixture of the product of Step A (0.22 g, 1 .05 mmol), 10% Pd/C (0.2 g) in EtOH (20 ml) was vigorously stirred for 1 h at room temperature under H2 (balloon). The catalyst was removed by filtration, washed with CH 2 CI 2 , and combined filtrates were evaporated to dryness to give 3-amino- 4-ethoxybenzoic acid (0.19 g, 100%), as colourless solid, which was used in the next step without further purification.
  • Step C N-(2-Ethoxy-5-(3-(3-iodo-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide: A mixture of the product of Step B (0.12 g, 0.46 mmol), the product of Example 36, Step A (0.15 g, 0.47 mmol) and EDC (0.13 g, 0.7 mmol) in anhydrous DMSO (3 ml) was stirred for 2 h at -40 °C under N 2 .
  • Step D N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)- 1,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide: To a solution of the product of Step C (0.08 g, 0.147 mmol) in anhydrous CH 2 CI 2 (0.5 ml) 1 M BCI 3 in CH 2 CI 2 (0.44 ml, 0.44 mmol) was added at 0°C. The mixture was allowed to warm up to room temperature, with stirring for 1 h.
  • Step E tert-Butyl 5-(5-(5-(4-ethoxy-3-(methylsulfonamido)phenyl)- 1,2,4- oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A suspension of the product of Step D (0.07 g, 0.14 mmol), tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5- yl carbamate (0.04 g, 0.16 mmol) and anhydrous Cu 2 0 (0.02 g, 0.14 mmol) in anhydrous pyridine (1 ml) was degassed under reduced pressure and saturated with N 2 .
  • Step F N-(5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)benzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-ethoxyphenyl)methanesulfonamide: To a solution of the product of Step E (0.03 g, 0.048 mmol), Nal (0.032 g, 0.216 mmol) in anhydrous CH 3 CN (1 ml) Me 3 SiCI (0.1 ml) was added and the mixture was stirred for 1 h at room temperature under N 2 . After evaporation of solvents under reduced pressure, the residue was diluted to 2 ml with EtOH, and re evaporated to dryness.
  • Step A 4-Amino-3-iodobenzonitrile: To a solution of 4-aminobenzonitrile (2.4 g 20 mmol) and -30% H 2 0 2 (not titrated before use) in MeOH (30 ml) a solution of l 2 (5.05 g, 12 mmol) in MeOH (50 ml) was added at room temperature and the resulting mixture was stirred for 48 h, while a fresh H 2 0 2 (2 ml) was added every day. The mixture was concentrated under reduced pressure and treated with saturated solution of Na 2 S 2 0 3 until most of the colour disappeared.
  • Step B N-(4-Cyano-2-iodophenyl)acetamide: A solution of the product of Step A (0.32 g, 1 .31 mmol) and 1 M NaN(SiMe 3 ) 2 in THF (2.62 ml) in anhydrous THF (2 ml) was stirred at ⁇ -5°C for 30 min under N 2 . To it acetyl chloride (0.1 1 ml, 1 .44 mmol) was and the mixture was stirred overnight at room temperature, than evaporated to dryness under reduced pressure.
  • Step C N-(4-(N-(Hydroxymethyl)carbamirnidoyl)-2-iodophenyl) acetamide: A mixture of the product of Step B (0.26 g, 0.91 mmol), HCIxH 2 NOH (0.13 g, 1 .87 mmol) and DIPEA (0.47 ml; 2.7 mmol) in EtOH (3 ml) was stirred at room temperature for 6 h under N 2 . The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 ml) and H 2 0 (5 ml).
  • Step D N-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2- iodophenyljacetamide: To a mixture of the product of Step C (0.24 g, 0.74 mmol) and 3,4- diethoxybenzoyl chloride (0.17 g, 0.74 mmol) in 50%solution of EtOAc in CH 2 CI 2 (5 ml) DIPEA (0.14 ml, 0.81 mmol) was added at room temperature.
  • Step E tert-Butyl 5-((2-acetamido-5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)phenyl)ethynyl)-2,2-dimethyl- 1,3-dioxan-5-ylcarbamate: A mixture of the product of Step D (0.24 g, 0.49 mmol) tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5-yl carbamate (0.15 g, 0.59 mmol), PdCI 2 (PPh 3 ) 2 (0.02 g) and Cul (0.01 g) in anhydrous DMF (2ml) was degassed in vacuo, and saturated with N 2 .
  • Step F N-(5-(5-(5-(5-(3,4-Diethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)- 1 H-indol-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-yl)acetamide: A mixture of the product of Step E (0.09 g, 0.145 mmol) and 1 M TBAF in THF in anhydrous THF (3 ml) was refluxed under N2 for 30 h. After cooling to room temperature the solven was removed under reduced pressure and the residue was diluted to 30 ml with EtOAc.
  • Step G 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)- 1 H-indol-2- yl)propane-1 ,3-diol:
  • a mixture of the product of Step F (0.02 g, 0.038 mmol) and TFA (0.1 ml) in EtOH (2 ml) was stirred for 15 min at room temperature and solvent were removed under reduced pressure and the residue kept in vacuo for 1 h. This was diluted to 2 ml with iPrOH and solid KOH (0.1 g was added. The resulting mixture was refluxed for 6 h and solvent was removed under reduced pressure.
  • Step B 2-Amino-4-cyanopyridine: A suspension of the product of Step A (4 g, 18.2 mmol) and anhydrous CuCN (1 .82 g, 20.3 mmol) in anhydrous pyridine (5 ml) was refluxed for 30 min. The solvent was removed in vacuo and the residue was partitioned between EtOAc (150 ml) and 10% NH4CI (pH ⁇ 9, adjusted with NH40H; 50 ml). The organic phase was washed with brine, dried over anhydrous MgS04, filtered and the filtrate evaporated to dryness to give the title compound (1 .8 g, 82%), as yellowish solid.
  • Step C 2-Hydroxy-4-cyanopyridine: NaN0 2 (0.99 g, 14.3 mmol) was added in small portions to a well stirred solution of the product of Step B (0.96 g, 8.1 mmol) in a premixed solution of concentrated H 2 S0 4 (1 .2 ml) and H 2 0 (1 1 .5 ml) while the temperature of the reaction mixture was kept at ) 0 - 5°C. The clear solution became heterogenous with evolution of N 2 . The mixture was allowed to warm up to room temperature with stirring, than heated on the water bath (reflux) for 30 min and cooled to room temperature.
  • Step D 2-Hydroxy-3-iodo-4-iodopyridine: A solution of the product of Step C
  • Step E N,6-dihydroxy-5-iodonicotinimidamide: A mixture of the product of Step D (0.3 g, 1 .22 mmol), HCI x H 2 NOH (0.18 g, 2.5 mmol) and DIPEA (1 ml) in EtOH (1 ml) was stirred overnight at room temperature and solvents were removed in vacuo. The residue was treated with H 2 0 (2 ml). The precipitate formed was filtered off, washed with fresh cold H 2 0 and dried in vacuo to give the title compound (0.31 g, 92%) as colourless solid, which was used in the next step without further purification.
  • Step F 5-(5-(3,4-Diethoxyphenyl)-1,2 -oxadiazol-3-yl)-3-iodopyridin-2-ol:
  • a mixture of the product of Step E (0.31 g, 1 .1 mol) 3,4-dietoxybenzoic acid (0.24 g, 1 .1 mmol) and EDC (0.32 g, 1 .67 mmol) in anhydrous DMSO (1 .5 ml) was stirred for 2 h at ⁇ 40°C.
  • 1 M TBAF in THF 0.5 ml
  • the mixture was degassed in vacuo and saturated with N2, than stirred for 1 h at ⁇ 1 10oC.
  • Step G tert-Butyl 5-(5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)furo[2,3- b]pyridin-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate: A mixture of the product of Step F (0.1076 g, 0.24 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5-yl carbamate (0.07 g, 0.27 mmol) and anhydrous Cu 2 0 (0.04 g, 0.28 mmol) in anhydrous pyridine (1 ml) was degassed under reduced pressure and saturated with N 2 and stirred for 1 .5 h at ⁇ 1 10°C.
  • Step H 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)furo[2,3- b]pyridin-2-yl)propane-1,3-diol: To a solution of the product of Step G (0.09 g, 0.155 mmol) and Nal (0.09 g, 0.62 mmol) in anhydrous CH 3 CN (3 ml) Me3SiCI (0.3 ml) was added at room temperature under N2. After stirring for 30 min solvents were removed under reduced pressure and the residue was diluted to 5 ml with MeOH and re evaporated to dryness.
  • Step A 5-(4-Ethoxy-3-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-propoxy benzoic acid was substituted for 3-methoxy-4- ethoxy benzoic acid in Example 3, Step B, the similar procedure afforded the title compound (220 mg, 49%) as a pale solid.
  • Step B 4-(5-(4-Ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step B 4-(5-(4-Ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C tert-Butyl 5-(5-(5-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step C tert-Butyl 5-(5-(5-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D 2-amino-2-(5-(5-(4-Ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.HCI: When the product of above Step C was substituted for the product of Example 3, Step D, the similar procedure as described in Example 36, Step E afforded the title compound as a free base which was turned to HCI salt (30 mg, 44%) by TMSCI to afford a white solid.
  • Step A 5-(1-Admantyl-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4-oxadiazole: When 3- chloro-4-propoxy benzoic acid was substituted for 1 -admananylchloride similar procedure as described in Example 3, Step B without using the EDC.HCI afforded the title compound (290 mg, crude 55%).
  • Step B 4-(5-1 -Admantyl -1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure as described in Example 3, Step C afforded the title compound (1 10 mg, 42%) as off white solid.
  • Step C tert-Butyl 5-(5-(5-(1 -Admantyl) -1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step C tert-Butyl 5-(5-(5-(1 -Admantyl) -1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D 2-Amino-2-(5-(5-(1-Admantyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.
  • HCI When the product of above Step C was substituted for the product of Example 3, Step D, the similar procedure as described in Example 36, Step E afforded the title compound (25 mg, 63%) which was turned to HCI salt (15 mg) as a white solid.
  • Step A N-((5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)- 2,2-dimethyl-1,3-dioxan-5-amine:
  • azetidine-3-methyl carboxylate was substituted with 2,2-dimethyl-1 ,3-dioxo-5-aminocyclohexane the similar procedure as described in Example 2, Step A, afforded the title compound (35 mg, 55 %) as colourless paste.
  • Step B 2-((5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)methylamino)propane-1,3-diol.HCI: To a stirred solution of product of above Step A in ordinary wet methanol (2 mL) and TMSCI (200 ⁇ _, excess) was added and the solution was stirred at room temperature for 2 hours. The solution was clear when the solvent was distilled and the residue was dried in oven at 60 S C for 2 hours to afford the title compound (34 mg, quantitative) as white solid.
  • Step B tert-Butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,3,4-oxadiazol-2- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step F the similar procedure as described in Example 32, Step G afforded the title compound (30 mg, 34%) as a white solid.
  • Step C 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1,3,4-oxadiazol-2- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step G the similar procedure as described in Example 32, Step H to afford the title compound (15 mg, quantitative) as a white solid.
  • Step A 2-(3-Chloro-4-propoxyphenyl)-5-(3-iodo-4-isopropoxyphenyl)- 1,3,4- thiadiazole: The 3-chloro-A/-(3-iodo-4-isopropoxybenzoyl)-4-propoxy benzohydrazide obtained as in Example 36, Step A and the product (310 mg, 0.6 mmol) in dry toluene (5 imL) was added Lawssen's reagent (240 mg, 0.6 mmol) and the mixture was stirred at reflux for 2 hours. The solvent was distilled and the crude was taken in ethyl acetate (50 imL) and washed with sodium bicarbonate solution.
  • Step B 4-(5-(3-Chloro-4-propoxyphenyl)- 1,3,4-thiadiazol-2-yl)-2-iodophenol:
  • Step B the similar procedure as described in Example 3, Step C afforded the title compound (40 mg, 44%) as white solid.
  • Step C tert-Butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,3,4-t iadiazol-2- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step F the similar procedure as described in Example 32, Step G afforded the title compound (35 mg, 89%) as white solid.
  • Step D 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)- 1 ,3,4-thiadiazol-2- yl)benzofuran-2-yl)propane- 1,3-diol:
  • Step G the similar procedure as described in Example 32, Step H afforded the title compound (23 mg, quantitative) as a white solid.
  • Step A 3-Chloro-4-(2,2,2-trifluroethoxy)benzoic acid: The 4 (2,2,2- trifluroethoxy)benzoic acid (1 gm, 4.55 mmol) was dissolved in dry methanol (70 ml.) and TMSCI (2 ml.) was added. The mixture was stirred at room temperature for overnight and solvent was distilled. The crude was taken in ethyl acetate (50 imL) and washed with water (10 mL). The organic layer was dried on magnesium sulphate and solvent was distilled to gave the creamy solid (1 .1 gm, 95%).
  • Step B 5-(3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-(3-iodo-4- isopropoxyphenyl)-1,2,4-oxadiazole:
  • 3-chloro-4-propoxy benzoic acid was substituted for the product of Step A the similar procedure as described in Example 3, Step B by using the EDC.HCI afforded the title compound (75 mg, crude, 53.4%) as off white solid.
  • Step C 4-(5-(3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol:
  • Step C 4-(5-(3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol:
  • Step D tert-Butyl 5-(5-(5-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1 ,2,4- oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl- 1 ,3-dioxan-5-ylcarbamate:
  • Step C tert-Butyl 5-(5-(5-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1 ,2,4- oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl- 1 ,3-dioxan-5-ylcarbamate:
  • Step E 2-Amino-2-(5-(5-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1,2,4- oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol:
  • Step G the similar procedure as described in Example 32, Step H afforded the title compound (10 mg, 96%) as a pale solid.
  • Step A 5- (4-Butoxy-3-chlorophenyl) -3- (3-iodo-4-isopropoxyphenyl) -1,2,4- oxadiazole: When 3-chloro-4-propoxy benzoic acid was substituted for 3-chloro-4-butoxy benzoic acid the similar procedure as described in Example 3, Step B by using the EDC. HCI afforded the title compound (210 mg, 62%) as white solid.
  • Step B 4-(5-(4-Butoxy-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step B the similar procedure as described in Example 3, Step C afforded the title compound (120 mg, 66%) as creamy solid.
  • Step C tert-Butyl 5-(5-(5-(4-butoxy-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step F the similar procedure as described in Example 32, Step G afforded the title compound (1 10 mg, 87%) as a light yellow paste which solidified on standing.
  • Step D 2-Amino-2-(5-(5-(4-butoxy-3-chlorophenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1 ,3-diol:
  • Step G the similar procedure as described in Example 32, Step H afforded the title compound (55 mg, 79%) as a creamy solid.
  • Step A tert-Butyl 4-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yl)-2,2-dimethyloxazolidine-3-carboxylate:
  • Example 3 was treated with tert-butyl 4-ethynyl-2,2-dimethyloxazolidine-3-carboxylate [ 1 H-NMR (CDCI 3 ) 4.52 (bd, 1 H), 4.01 - 3.96 (b, 2H), 2.25 (s, 1 H), 1 .47 (s, 15H)] the similar procedure as described in Example 32, Step G afforded the title compound (380 mg, 73%) as pale thick oil.
  • Step B 2-amino-2-(5-(5-(3-chloro-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)ethanol.
  • HCI The product (170 mg, 0.3 mmol) was taken in EtOH (10 imL), concentrated HCI (0.3 ml.) was added and the mixture was stirred gently at 68 S C for 5 minutes. The solvent was distilled and co-distilled with ethanol and dried under high vacuum.
  • Step B tert-Butyl 5-(5-iodobenzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5- ylcarbamate; Vl ⁇ ren the product of Step A was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- hydroxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)methanesulfonamide in Example 30, Step E, the identical process afforded the title compound in 70% yield., as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step C 3-Chloro-4-propoxybenzaldehyde: A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmol), 1 -bromopropane (0.3 ml) and K 2 C0 3 (0.69 g, 5 mmol) in anhydrous DMF (5 ml) was stirred for 1 h at reflux. This was diluted to 100 ml with EtOAc and washed with H 2 0. The organic layer was separated, dried over MgS0 4 and filtered.
  • Step D 2-Chloro-4-ethynyl- 1-propoxybenzene: A mixture of the product of Step C (0.1 1 g, 0.554 mmol), dimethyl(1 -diazo-2-oxoprpyl)phosphonate (0.215 g) and K 2 C0 3 (0.19 g, 1 .38 mmol) in anhydrous MeOH (1 .5 ml) was stirred for 1 h at room temperature. The solvent was evaporated and the residue was taken in Et 2 0 (25 ml), washed with H 2 0 (2 x 10 ml) and dried over MgS0 4 and filtered.
  • Step D When the product of Step D was substituted for tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5-yl carbamate and the product of Step B was substituted for N-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenyl)acetamide in Example 31 , Step E, the identical process afforded the title compound in 17% yield., as colourless solid, after purification by FCC (Si0 2 , hexane/EtOAc 8 ; 2).
  • Step F 2-Amino-2-(5-((3-chloro-4-propoxyphenyl)ethynyl) benzofuran-2- yl)propane-1 ,3-diol:
  • Step E 2-Amino-2-(5-((3-chloro-4-propoxyphenyl)ethynyl) benzofuran-2- yl)propane-1 ,3-diol:
  • Step A tert-Butyl 5-(5-(3-chloro-4-propoxyphenethyl) benzofuran-2-yl)-2,2- dimethyl-1,3-dioxan-5-ylcarbamate;
  • a suspension of the product of Example 86, Step E (0.032 g; 0.058 mmol) and 10% Pd/C (0.03 g) in EtOAc (10 ml) was vigorously stirred under H2 (balloon) for 30 min at room temperature. The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure.
  • Step B 2-Amino-2-(5-(3-chloro-4-propoxyphenethyl)benzofuran-2-yl)propane-
  • Step B 5-Chloro-2-lodo-4-propylphenol: To a solution of the product of Step A (0.12 g; 0.46 mmol) and NCS (0.07 g; 0.52 mmol) in CH 2 CI 2 (3 ml), TiCI 4 (0.01 ml) was added at room temperature and the mixture was stirred for 30 min then poured onto ice (5 ml). This was diluted to 15 ml with fresh CH 2 CI 2 , the organic phase was washed with brine, dried over anhydrous MgS0 4 , filtered and evaporated to dryness.
  • Step C (7-Chloro-5-propylbenzofuran-2-yl)methanol: When propargyl alcohol was substituted for tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5-yl carbamate and the product of Step B was substituted for N-(2-ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4- oxadiazol-5-yl)phenyl)methanesulfonamide in Example 30, Step E, the identical process afforded the title compound in 62% yield., as colourless syrup, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step D 7-Chloro-5-propylbenzofuran-2-carbaldehyde: A suspension of the product of Step C (0.03 g; 0.13 mmol) and Mn0 2 (0.06 g) in dioxane (1 .5 ml) was refluxed for 1 h, cooled to room temperature and filtered. The solids were washed with fresh dioxane (2 x 2 ml), and combined organic filtrates were evaporated to dryness to give title compound (0.0286 g; 99%), which was used in the next step without further purification.
  • Step E 7-Chloro-2-ethynyl-5-propylbenzofuran;
  • Step D the identical process afforded the title compound in 65% yield as yellowish syrup, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step F tert-Butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran- 2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 1 1 % yield., as deep reddish solid , after purification by FCC (Si0 2 , hexane/EtOAc 9 : 1 ).
  • Step G 2-Amino-2-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl)benzofuran-
  • Step A tert-Butyl 2-(5-(5-(3-chloro-4-propoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)- 1,3-dihydroxypropan-2-ylcarbamate;
  • a mixture of hydrochloride salt of Example 36 (0.15 g; 0.31 mmol), di-tert-butyl dicarbonate (0.082 g; 0.37 mmol); and DIPEA (0.07 ml) in anhydrous DMF was stirred overnight at room temperature.
  • the solvents were removed in vacuo and the residue was purified by FCC (Si0 2 , CH 2 CI 2 saturated with NH 4 OH, MeOH 95 : 5).
  • Step B 5-tert-Butoxycarbonylamino-5-[5-(5-(3-chloro-4-propoxyphenyl)- 1,2,4- oxadiazol-3-yl)benzofuran -2-yl]-1,3,2-dioxaphosphinan-2-ol 2-oxide;
  • a suspension of the product of Step A (0.07 g; 0.13 mmol) and DI PEA (0.05 ml; 0.28 mmol) in anhydrous CH 2 CI 2 (1 ml) was added dropwise at 0°C under N 2 with stirring.
  • Step C 5-Amino-5-[5-(5-(3-chloro-4-propoxyphenyl)- 1,2,4-oxadiazol-3- yljbenzofuran -2-yl]- 1, 3, 2-dioxaphosphinan-2-ol 2-oxide;
  • Step B When the product of Step B was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43 Step G, the similar process afforded the title compound in 60.6%, as creamy solid (zwitterion), poorly soluble in most solvents, including DMSO, soluble in basic mixtures (eg MeOH + NH 4 OH).
  • Step A Methyl 4-hydroxy-3-iodobenzoate: To a suspension of methyl 4- hydroxybenzoate (1 .52 g; 10 mmol) and N-iodosuccinimide (2.25 g; 10 mmol) in anhydrous CH 2 CI 2 (15 ml) TiCL 4 (0.1 ml; 0.098 mmol) was added at 0°C with stirring. The resulting dark solution was stirred for 1 h at room temperature, then evaporated to dryness under reduced pressure.
  • Step B Methyl 3-iodo-4-propoxybenzoate: A suspension of the product of Step A (1 .14 g; 4.1 mmol), 1 -bromopropane (1 ml) and K 2 C0 3 (0.57 g; 4.1 mmol) in anhydrous DMF (2.5 ml) was stirred for 2 h at ⁇ 55°C under N 2 . This was partitioned between hexane (30 ml) and water.
  • Step C Methyl 4-propoxy-3-(trifluoromethyl)benzoate: Methyl 2,2-difluoro-2-
  • Step D 4-Propoxy-3-(trifluoromethyl)benzoic acid: The mixture of the product Step C (0.28 g; 1 .07 mmol), KOH (0.2 g; 3.56 mmol), H 2 0 (3 ml) in dioxane (3 ml) was refluxed for 5 min, allowed to cool to room temperature, concentrated to about 3 ml under reduced pressure and acidified to pH ⁇ 2 with concentrated HCI. The product was taken up with EtOAc (30 ml). The organic phase was washed with brine, dried over anhydrous MgS0 4 , filtered and filtrate evaporated to dryness to give the title compound (0.26 g; 98%), as colourless solid, which was used in next step without further purification.
  • Step E 3-(3-lodo-4-isopropoxyphenyl)-5-(4-propoxy-3-(trifluoromethyl)- phenyl)- 1 ,2,4-oxadiazole: A mixture of the product of Step D (0.26 g; 1 .05 mmol), the product of Example 3, Step A (0.34 g, 1 .05 mmol) and EDC (0.3 g, 1 .56 mmol) in anhydrous DMSO (2 ml) was stirred for 15 min at ⁇ 45°C under N 2 .
  • Step F 2-lodo-4-(5-(4-propoxy-3-(trifluoromethyl)phenyl)- 1,2,4-oxadiazol-3- yljphenol:
  • the product of Step E was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield., as colourless solid.
  • Step G tert-Butyl 2,2-dimethyl-5-(5-(5-(4-propoxy-3-(trifluoromethyl)phenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate: When the product of Step F was substituted for N-(2-ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide in Example 30, Step E, the identical process afforded the title compound in 85% yield.
  • Step H 2-Amino-2-(5-(5-(4-propoxy-3-(trifluoromethyl)phenyl)- 1 ,2,4-oxadiazol- 3-yl)benzofuran-2-yl)propane- 1,3-diol, HCI salt:
  • Step G 2-Amino-2-(5-(5-(4-propoxy-3-(trifluoromethyl)phenyl)- 1 ,2,4-oxadiazol- 3-yl)benzofuran-2-yl)propane- 1,3-diol, HCI salt:
  • Step A 3-Chloro 4-hydroxybenzoic acid: To a solution of 4-hydroxybenzoic acid
  • Step B 3-Chloro-4-hydroxybenzoyl chloride: To a suspension of the product of Step A (0.61 g; 3.53 mmol) in anhydrous CH 2 CI 2 (15 ml) oxalyl chloride (0.45 ml; 5.32 mmol) was added at room temperature with stirring, followed by anhydrous DMF (0.1 ml). This was stirred for 2 h at room temperature and solvents were removed under reduced pressure. The residue was kept in vacuo for 1 h to give the title compound (0.68g; 100%), as creamy solid, which was used in next step without further purification.
  • Step C N-(3-Chloro-4-hydroxybenzoyloxy)-3-iodo-4-isopropoxybenzimidamide:
  • Step A To a suspension of the product of Step B (0.68 g; 3.53 mmol) and the product of Example 3, Step A (1 .13 g, 3.53 mmol) in anhydrous THF, DIPEA (0.74 ml; 4.25 mmol) was added at -5°C under N 2 , with stirring. The mixture was allowed to warm up to room temperature and stirred for 1 h, than evaporated to dryness under reduced pressure. The residue was partitioned between 10% NH 4 CI (20 ml) and EtOAc (80 ml). The organic phase was washed with brine, dried over anhydrous MgS0 4 , filtered and filtrate evaporated to dryness to give the title compound (1.6 g; 95%), as greyish solid, which was used in the next step without further purification.
  • Step D 2-Chloro-4-(3-(3-iodo-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5 yl)phenol: To a solution of the product of Step C (1 .6 g; 3.37 mmol) in anhydrous DMSO (3 ml) 1 M TBAF in THF (0.6 ml)was added and the resulting mixture was degassed in vacuo and saturated with N2. This was stirred for 1 h at -1 10 °C, cooled to room temperature and poured on ice (5 g)The solid formed was filtered off, washed with water (2 x 5 ml) and dried.
  • Step E 2-Chloro-4-(3-(4-hydroxy-3-iodophenyl)- 1,2,4-oxadiazol-5-yl)phenol: To a solution of the product of Step D (1 .03 g; 2.26 mmol) in CH 2 CI 2 (5 ml) 1 M BCI 3 in CH 2 CI 2 (5 ml)was added. The resulting mixture was stirred overnight at room temperature, tham poured onto ice (50 g). The solid formed was filtered off, washed with water (5 ml), and CH2CI2 (10 ml) and dried in vacuo. The combined filtrates were separated and organic phase was dried over anhydrous MgS0 4 , filtered and filtrate evaporated to dryness.
  • Step F tert-Butyl 5-(5-(5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A suspension of the product of Step E (0.94 g; 2.26 mmol), tert-butyl 5-ethynyl-2,2-dimethyl-1 ,3dioxan-5-yl carbamate (0.58 g, 2.27 mmol) and Cu 2 0 (0.3 g, 2.1 mmol) in anhydrous pyridine (4 ml) was degassed under reduced pressure and saturated with N 2 .
  • Step G tert-Butyl 5-(5-(5-(3-chloro-4-isoproproxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A suspension of the product of Step F (0.26 g; 0.48 mmol), 2-bromopropane (0.1 ml; 1 .06 mmol) and anhydrous K 2 C0 3 (0.07 g; 0.51 mmol) in anhydrous DMF (1 .5 ml) was stirred overnight at ⁇ 55 °C under N 2 .
  • Step H 2-Amino-2-(5-(5-(3-chloro 4-isopropoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol:
  • a mixture of the product of Step G (0.24 g; 0.41 mmol) and MeS0 3 H (0.067 ml; 1 .03 mmol) in EtOH (3 ml) was refluxed for 30 min and cooled to room temperature, than solvent was removed under reduced pressure. The residue was kept in vacuo for 30 min and gummy residue was diluted to 5 ml with H 2 0 and to it 25% NH 4 OH (0.3 ml) was added.
  • Step A tert-Butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A suspension of the product of Example 46, Step F (0.1019 g; 0.419 mmol), benzyl bromide (0.044 ml; 0.37 mmol) and anhydrous K 2 C0 3 (0.026 g; 0.19 mmol) in anhydrous DMF (1 ml) was stirred at room temperature for 3 h under N 2 .
  • Step B 2-Amino-2-(5-(5-(4-benzyloxy-3-chlorophenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI Salt: To a suspension of the product of Step A (0.1 g; 0.16 mmol) in EtOH (2 ml) 30% HCI (0.5 ml) was added and the mixture was gently refluxed until became homogenous (-10 min). The solvents were removed under reduced pressure and the residue was kept in vacuo for 1 h. than purified by crystallization from EtOH, to give the title compound (0.07 g; 82%), as colourless solid.
  • Step A tert-Butyl 5-(5-(5-(4-(allyloxy)-3-chlorophenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step A tert-Butyl 5-(5-(5-(4-(allyloxy)-3-chlorophenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step B 2-Amino-2-(5-(5-(4-allyloxy-3-chlorophenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI Salt:
  • Step B the identical process afforded the title compound in 85% yield., as colourless solid, after purification by crystallization from acetonitrile/EtOH.
  • Step A tert-Butyl 5-(5-(5-(3-chloro-4-(isopentyloxy)phenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: To a flame dried tube a product of Example 91 , Step F (0.141 g; 0.26 mmol) was added followed by PPh3 (0.071 g; 0.27 mmol), isoamyl alcohol (0.03 ml, 0.28 mmol) and anhydrous THF (1 ml) under N 2 .
  • the reaction mixture was cooled to 0°C and to it DIPEA (0.046 ml; 0.26 mmol) was added followed by diethylazodicarboxylate (0.049 ml; 0.32 mmol), with stirring under N 2 .
  • the resulting mixture was stirred at room temperature until all starting materials were converted (-2.5 h).
  • the mixture was diluted to 70 ml with Et 2 0, washed with 1 M NaOH (2 x 10 ml), H 2 0 (2 x 15 ml), brine, dried over anhydrous MgS0 4 , filtered and filtrate evaporated to dryness under reduced pressure.
  • Step B 2-Amino-2-(5-(5-(3-chloro-4-isopentyloxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI salt:
  • Step B 2-Amino-2-(5-(5-(3-chloro-4-isopentyloxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI salt:
  • Step B the identical process afforded the title compound in 69% yield as colourless solid, after purification by crystallization from acetonitrile/EtOH.
  • Step A 3-(3-iodo-4-isopropoxyphenyl)-5-(3-isobutoxy-4-methoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3-isobutoxy-4- methylbenzoic acid in Example 3, Step B, the similar process afforded the title compound (0.63 g; 80%), as colorless solid.
  • Step B 2-iodo-4-(5-(3-isobutoxy-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenol:
  • Step C When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound (0.36 g; 77%), as off white solid.
  • Step C tert-butyl 5-(5-(5-(3-isobutoxy-4-methoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide
  • Step E the similar procedure afforded the title compound (0.34 g; 78%), as pale solid.
  • Step D 2-amino-2-(5-(5-(3-isobutoxy-4-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: W ⁇ ren the product of Step C was substituted for tert- butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 48, Step B, the identical process afforded the solid which was dissolved in water (2 imL) and aqueous ammonium hydroxide (2 ml_) was added to it.
  • Step A 5-(3-ethoxy-4-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3-ethoxy-4- methylbenzoic acid in Example 3, Step B, the similar process afforded the title compound (0.21 g; 36%), as off white solid.
  • Step B 4-(5-(3-ethoxy-4-methoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound (0.14 g; 80%), as off white solid.
  • Step C tert-butyl 5-(5-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide
  • Step E the similar procedure afforded the title compound (85 mg; 52%), as pale solid.
  • Step D 2-amino-2-(5-(5-(3-ethoxy-4-methoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: W ⁇ ren the product of Step C was substituted for tert- butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 48, Step B, the identical process afforded the solid which was dissolved in water (2 ml_) and aqueous ammonium hydroxide was added to it.
  • Step A 2-iodo-4-(5-(4-isobutoxy-3-methylphenyl)- 1 ,2,4-oxadiazol-3-yl)phenol: When the 5-(3-methyl-4-isobutoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1 ,2,4- oxadiazole was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title (105 mg; 88%), as off white solid.
  • Step B tert-butyl 5-(5-(5-(4-isobutoxy-3-methylphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide
  • Step E the similar procedure afforded the title compound (0.1 1 g; 87%), as pale solid.
  • Step C 2-amino-2-(5-(5-(4-isobutoxy-3-methylphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI: When the product of Step C was substituted for tert-butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)- 2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 48, Step B, the identical process afforded the title compound (60 mg; 73%), as off white solid.
  • Step A 5-(3-chloro-4-isobutoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3-chloro-4- isobutoxybenzoic acid in Example 3, Step B, the similar process afforded the title compound (0.41 g; 46%), as pale solid.
  • Step B 4-(5-(3-chloro-4-isobutoxyphenyl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound (0.25 g; 68%), as off white solid.
  • Step C tert-butyl 5-(5-(5-(3-chloro-4-isobutoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step B was substituted for N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide
  • Step E the similar procedure afforded the title compound (0.27 g; 85%), as pale solid.
  • Step D 2-amino-2-(5-(5-(3-chloro-4-isobutoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol, HCI: When the product of Step C was substituted for tert-butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)- 2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 48, Step B, the identical process gave the title compound (0.2 g; 94%), as off white solid.
  • Step A 3-chloro-4-isopropoxy-5-cynobenzoic acid:
  • 3-chloro-4-isopropoxy-5- iodo-methylbenzoate To a stirred solution of 3-chloro-4-hydroxymethylbenzoate (2 gms, 10.8 mmol) in dry DCM (50 mL) was added NIS (2.5 gms, 1 1 mmol) followed by the addition of TiCI 4 (0.1 mL) and content was stirred at room temperature for overnight. The mixture was quenched with saturated sodium bicarbonate solution in water (20 mL) and the organic layer was separated, dried over magnesium sulphate. The solvent was distilled to gave an off white solid (2.35 gms; 70%).
  • This product (2.2 gms, 7 mmol) was dissolved in dry DMF (3 mL) and potassium carbonate (1.4 gms, 10 mmol) was added to it followed by the addition of the bromopropane (1 mL, excess). The content was stirred at 90 S C for 6 hrs (tic) and brought to room temperature, diluted with water (100 mL) and extracted with EtOAc (1 OOmL x 2). The organic layer was dried over magnesium sulphate and the solvent was distilled to gaive a pale oil (2.1 g, 84%).
  • Step B 5-(3-chloro-4-propoxy-5-cynophenyl)-3-(3-iodo-4-isopropoxy phenyl)- 1 ,2,4-oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 3-chloro-4- propoxy-5-cynobenzoic acid in Example 3, Step B, the similar process afforded the title compound (0.14 g; 43%), as pale solid.
  • Step C 4-(5-(3-chloro-4-isopropoxy-5-cynophenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol:
  • Step C the similar procedure afforded the title compound (0.08 g; 67%), as off white solid.
  • Step D tert-butyl 5-(5-(5-(3-chloro-4-isopropoxy-5-cynophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for N-(2-Ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide Example 30, Step E the similar procedure afforded the title compound (0.075 g; 74%), as off white solid.
  • Step E 2-amino-2-(5-(5-(3-chloro-4-isopropoxy-5-cynophenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: W ⁇ ren the product of Step D was substituted for tert- butyl 5-(5-(5-(4-(benzyloxy)-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2- dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 48, Step B, the identical process gave the title compound (0.02 g; 37%), as off white solid.
  • Step A Methyl 4-bromo-3-chlorobenzoate: To a suspension of 4-bromo-3- chlorobenzoic acid (1 .2 g; 5.18 mmol) in MeOH (HPLC grade; 10 ml) chlorotrimethylsilane (2 ml) was added and the resulting mixture was stirred over a weekend at room temperature. After evaporation of solvents under reduced pressure the residue was diluted to 60 ml with EtOAc, washed with 5% NaHC0 3 (2 x 10 ml), brine (20 ml), dried over anhydrous MgS04, filtered and filtrate evaporated to dryness to give a title compound (1 .2 g; 93%), as creamy solid.
  • Step B Methyl 4-n-butyl-3-chlorobenzoate: ZnBr 2 (0.56 g; 2.49 mmol) was kept in vacuo at 1 10°C for 1 h. After cooling to room temperature under N 2 , anhydrous THF (4 ml) was added to it with stirring and the resulting solution was cooled to -78°C. To it 2N nBuLi in cyclohexane was added and the resulting mixture was stirred at room temperature for 30 min, cooled back to -78°C. To it the product of Step A (0.75 g; 3 mmol) was added under N 2 with stirring, followed by CIPd(PPh 3 ) 2 (0.12 g) and Cul (0.05 g).
  • Step C 4-n-Butyl-3-chlorobenzoic acid: A mixture of the product of Step B (0.39 g; 1 .72 mmol), n-butyl 4-n-butyl-3-chlorobenzoate (0.17 g; 0.63 mmol), 3.76 M KOH (0.9 ml) and H 2 0 (2 ml) in dioxane (5 ml) was refluxed until become homogenous ( ⁇ 10 min).
  • Step D 3-(3-lodo-4-isopropoxyphenyl)-5-(4-n-butyl-3-chloro-phenyl)- 1,2,4- oxadiazole: To a solution of the product of Step C (0.16 g; 0.75 mmol) in CH 2 CI 2 (10 ml) oxalyl chloride (0.095 ml; 1 .12 mmol) was added, followed by anhydrous DMF (20 I) at room temperature. This was stirred for 1 h, than evaporated to dryness The residue was kept in vacuo to give 4-n-butyl-3-chloro benzoyl chloride ((0.2 g; 100%).
  • Step A (0.24 g, 0.75 mmol) in anhydrous THF (3 ml) DIPEA (0.4 ml; 2.3 mmol) was added at 0°C with stirring under N 2 . This was stirred for 2 h at room temperature, diluted to 50 ml with EtOAc, washed with H 2 0 (2 x 15 ml), brine (10 ml), dried over anhydrous MgS0 4 , filtered and filtrate evaporated to dryness, to give the creamy solid.
  • Step E 2-lodo-4-(5-(4-n-butyl-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenol:
  • the product of Step D was substituted for N-(2-ethoxy-5-(3-(3-iodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield., as colourless solid.
  • Step F tert-Butyl 2,2-dimethyl-5-(5-(5-(4-n-butyl-3-chlorophenyl)-1,2,4-oxadiazol- 3-yl)benzofuran-2-yl)- 1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 86% yield., as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /BOAc 95:5).
  • Step G 2-Amino-2-(5-(5-(4-butyl-3-chlorophenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step F was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 90 %, as colourless solid.
  • Step A Methyl 3,5-dichloro-4-hydroxybenzoate: To a mixture of 4-hydroxybenzoic acid (0.2 g; 1 .3 mmol) and N-chlorosuccinimide (0.37 g; 2.76 mmol) in dry CH 2 CI 2 (15 ml) TiCI_4 (0.1 ml; 0.9 mmol) was added at room temperature and the resulting mixture was stirred for 5h. To it ice (-10 g) was added and the resulting slurry was stirred for 30 min at room temperature, diluted to 100 ml with EtOAc.
  • Step B Methyl 3,5-dichloro-4-n-propoxybenzoate: When the product of Step A was substituted for tert-butyl 5-(5-(5-(3-chloro-4-hydroxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate and 1 -bromopropane was substituted for 2-bromopropane in Example 46, Step G, the similar process afforded the title compound in 74 %, as colourless solid.
  • 1 H-NMR (CDCI 3 ) 7.96 (s, 2H); 382 - 4.06 (m, 5H); 1.85 - 1 .92 (m, 2H); 1 .08 (tr, 3H, J 7.3 Hz).
  • Step C 3,5-dichloro-4-n-propoxybenzoic acid: When the product of Step B was substituted for the methyl 4-propoxy-3-(trifluoromethyl)benzoate of Example 45, Step C, the similar process afforded the title compound in 87% yield.
  • Step D 3-(3-lodo-4-isopropoxyphenyl)-5-(3,5-dichloro-4-propoxyphenyl)- 1,2,4- oxadiazole:
  • the product of Step C was substituted for the 4-n-butyl-3-chlorobenzoic acid oi Example 56, Step D, the similar process afforded the title compound in 45% yield.
  • Step E 2-lodo-4-(5-(3,5-dichloro-4-n-propoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)phenol:
  • the product of Step D was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield., as a creamy solid.
  • Step F tert-Butyl 2,2-dimethyl-5-(5-(5-(3,5-dichloro-4-n-propoxyphenyl)-1,2,4- oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate: When the product of Step E was substituted for N-(2-ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol-5- yl)phenyl)methanesulfonamide in Example 30, Step E, the identical process afforded the title compound in 71 % yield.
  • Step G 2-Amino-2-(5-(5-(3,5-dichloro-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step F was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 76 %, as colourless solid.
  • Step A 3-Chloro-4-hydroxy-5-methylbenzoic acid: T a mixture of 4-hydroxy-3- methyl benzoic acid (0.3 g; 1 .97 mmol) and N-chlorosuccinimide (0.26 g; 1 .97 mmol) in anhydrous EtOAc (5 ml) TiCI4 (0.04 ml; 0.36 mmol) was added at room temperature. After stirring for 2 h at room temperature an ice (-10 g) was added and stirring was continued for 15 min.
  • Step B Methyl 3-chloro-4-hydroxy-5-methylbenzoate:
  • the product of Step A was substituted for 4-bromo-3-chlorobenzoic acid in Example 56, Step A, the similar process afforded the title compound in 76 %, as a creamy solid., after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • 1 H-NMR (CDCI 3 ) 7.88 - 7.85 (m, 1 H); 7.74 - 7.73 (m, 1 H); 5.97 (s, 1 H); 3.87 (s, 3H): 2.31 (s, 3H).
  • Step C Methyl 3-chloro-5-methyl- 4-propoxy-benzoate:
  • the product of Step B was substituted for tert-butyl 5-(5-(5-(3-chloro-4-hydroxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate and 1 -bromopropane was substituted for 2-bromopropane in Example 46, Step G, the similar process afforded the title compound in 74 %, as colourless solid.
  • 1 H-NMR (CDCI 3 ) 7.88 (m, 1 H); 7.75 (m, 1 H);
  • Step D 3-Chloro-5-methyl- 4-propoxy-benzoic acid: When the product of Step C was substituted for the methyl 4-propoxy-3-(trifluoromethyl)benzoate of Example 45, Step C, the similar process afforded the title compound in 87% yield.
  • Step E 3-(3-lodo-4-isopropoxyphenyl)-5-(3-chloro-5-methyl-4-propoxyphenyl)- 1 ,2,4-oxadiazole:
  • the product of Step D was substituted for the 4-n-butyl-3- chlorobenzoic acid of Example 56, Step D, the similar process afforded the title compound in 55% yield.
  • Step F 2-lodo-4-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3- yljphenol:
  • Step E 2-lodo-4-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3- yljphenol:
  • Step G tert-Butyl 2,2-dimethyl-5-(5-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step F tert-Butyl 2,2-dimethyl-5-(5-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 86% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step H 2-Amino-2-(5-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4- oxadiazol-3-yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step G was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran- 2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 86 %, as colourless solid.
  • Step A 2-Chloro-6-propoxyisonicotinic acid: Sodium (0.5 g; 21.7 mmol) was added to anhydrous n-propanol (20 ml) and the mixture was gently refluxed until all sodium was consumed. After cooling to room temperature under N2, to it 2,6- dichloroisonicotinic acid (0.5 g; 2.6 mmol) was added and reaction mixture was gently refluxed until all acid was consumed ( ⁇ 1 .5 h; TLC; EtOAc). The solvent was removed under reduced pressure and the residue was diluted to 100 ml with H 2 0 and pH was adjusted to ⁇ 5 with citric acid.
  • Step B 5-(2-Chloro-6-propoxypyridin-4-yl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4- oxadiazole:
  • Step C the identical process afforded the title compound in 34% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step C 4-(5-(2-Chloro-6-propoxYpyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step B When the product of Step B was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield, as a creamy solid.
  • Step D tert-Butyl 5-(5-(5-(2-chloro-6-propoxypyridin-4-yl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 65% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step E 2-Amino-2-(5-(5-(2-chloro-6-propoxypyridin-4-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step D was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 89 %, as colourless solid.
  • Step B 3-Fluoro-4-n-propoxy-iodobenzene:
  • the product of Step A was substituted for tert-butyl 5-(5-(5-(3-chloro-4-hydroxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate and 1 -bromopropane was substituted for 2-bromopropane in Example 46, Step G, the similar process afforded the title compound in 74 %, as creamy solid.
  • Step C 3-Fluoro-4-n-propoxybenzoic acid: To a solution of the product of Step B (0.44 g; 1.57 mmol) in anhydrous THF (4 ml) 2 M n-butyllitium in cyclohexane (1 ml) was added at -78°C under N 2 , with stirring. After stirring for 30 min at -50 °C, the mixture was cooled to -78°C, degassed under reduced pressure and saturated with C0 2 ( balloon). This was stirred at room temperature for 30 min and evaporated to dryness under reduced pressure.
  • Step D 5-(3-Fluoro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole:
  • the product of Step C was substituted for 4-ethoxy-3- (methylsulfonamido)benzoic acid in Example 30, Step C, the identical process afforded the title compound in 46% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step E 4-(5-(3-Fluoro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step D When the product of Step D was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield, as a colourless solid.
  • Step F tert-Butyl 5-(5-(5-(3-fluoro-4-propoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 95% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step G 2-Amino-2-(5-(5-(3-fluoro-4-propoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step F was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 86 %, as colourless solid.
  • Step A 5-Chloro-6-propoxynicotinic acid: When 5,6-dichloronicotinic acid is substituted for 2,6-dichloroisonicotinic acid in Example 59, Step A, the identical process afforded the title compound in 100 % yield, as creamy solid.
  • Step B 5-(5-Chloro-6-propoxypyridin-3-yl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole:
  • Step C the identical process afforded the title compound in 46% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step C 4-(5-(5-chloro-6-propoxypyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step B When the product of Step B was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield, as a colourless solid.
  • Step D tert-Butyl 5-(5-(5-(5-chloro-6-propoxypyridin-3-yl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 74% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step E 2-Amino-2-(5-(5-(5-chloro-6-propoxypyridin-3-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step D was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 93 %, as colourless solid.
  • Step A 4-iodo-3-isopropoxybenzonitrile: When 3-hydroxy-4-iodobenzonitrile (Sagi et al, J Med Chem 2003, 46, 1853) was substituted for tert-butyl 5-(5-(5-(3-chloro-4- hydroxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5- ylcarbamate and 1 -bromopropane was substituted for 2-bromopropane in Example 46, Step G, the similar process afforded the title compound in 96 %, as creamy solid.
  • Step B N-Hydroxy-4-iodo-3-isopropoxybenzimidamide: A mixture of the product of Step A (0.48 g; 1 .67 mmol) HCI x NH 2 OH (0.23 g; 3.34 mmol) ans DIPEA (0876 ml;
  • Step C 5-(3-Chloro-4-propoxyphenyl)-3-(4-iodo-3-isopropoxyphenyl)- 1,2,4- oxadiazole:
  • 3-chloro-4-propoxybenzoic acid was substituted for 4-ethoxy-3- (methylsulfonamido)benzoic acid and the product of Step B was substituted for N- hydroxy-3-iodo-4-isopropoxybenzimidamide in Example 30, Step C, the identical process afforded the title compound in 41 % yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 ).
  • Step D 5-(5-(3-Chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step D When the product of Step C was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- isopropoxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-methanesulfonamide in Example 30, Step D, the identical process afforded the title compound in 100% yield, as a creamy solid.
  • Step E tert-Butyl 5-(6-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step E the identical process afforded the title compound in 53% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step F 2-Amino-2-(6-(5-(3-chloro-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step E was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 97 %, as colourless solid.
  • Step B tert-Butyl 5-(4-cyanobenzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5- ylcarbamate: Vl ⁇ ren the product of Step A was substituted for N-(2-ethoxy-5-(3-(3-iodo-4- hydroxyphenyl)-1 ,2,4-oxadiazol-5-yl)phenyl)methanesulfonamide in Example 30, Step E, the identical process afforded the title compound in 96% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step C tert-Butyl 5-(4-(N-hydroxycarbamimidoyl)benzofuran-2-yl)-2,2-dimethyl- 1 ,3-dioxan-5-ylcarbamate: A suspension of the product of Step B (0.15 g; 0.4 mmol), HCI x NH 2 OH (0.16 g; 2.3 mmol) and K 2 C0 3 (0.16 g; 1 .15 mmol) in anhydrous EtOH (3 ml) was stirred at -70 °C for 6 h under N 2 . After evaporation of solvent under reduced pressure the residue was treated with H 2 0 ( 5 ml).
  • Step D tert-Butyl 5-(4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • 3-chloro-4- propoxybenzoic acid was substituted for 4-ethoxy-3-(methylsulfonamido)benzoic acid and the product of Step C was substituted for N-hydroxy-3-iodo-4- isopropoxybenzimidamide in Example 30, Step C, the identical process afforded the title compound in 20% yield, as colourless solid, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step E 2-Amino-2-(4-(5-(3-chloro-4-propoxyphenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step E was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 98 %, as colourless solid.
  • Step A tert-Butyl 5-(4-(3-deutero-5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: ⁇ N er the product of Example 7, Step B was substituted for N-(2-ethoxy-5-(3-(3-iodo-4-hydroxyphenyl)-1 ,2,4-oxadiazol- 5-yl)phenyl)methanesulfonamide and 10% of 99% D 2 0 was added to anhydrous pyridine in Example 30, Step E, the identical process afforded the title compound in 100% yield, as colourless foam, after purification by FCC (Si0 2 , CH 2 CI 2 /EtOAc 95:5).
  • Step B 2-Amino-2-(3-deutero-5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol.
  • HCI salt When the product of Step A was substituted for tert-butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate in Example 43, Step G, the similar process afforded the title compound in 86 %, as colourless solid.
  • the S1 assay system was GTPgama-S35 binding in membranes from CHO K1 cells, expressing S1 ⁇ human receptor.
  • the S1 P 3 assay system was calcium mobilization in CHO K1 cells expressing S1 P 3 human receptor. There was no significant background response to S1 P in the CHO K1 cells with either assay.
  • Compounds were tested initially at a concentration of 10 ⁇ . Those compounds with significant efficacy (Emax > 0.15 relative to S1 P) at either receptor type were used to generate concentration-effect (dose response) curves at that receptor.
  • the objective of this study was to evaluate effects of the compound of example 3 on therapeutic EAE model which is a model of human Multiple Sclerosis.
  • the EAE was induced by MOG35-55 /CFA immunization and pertussis toxin injection in B57.BL/6 mice and was treated with the compound of example 3.
  • the compound was given once daily via oral dose to the animals for 2 weeks after the onset of disease.
  • AK refers to the compound of example 3.
  • the objective of this study was to evaluate effects of the compound of example 3 on inflammatory cytokine regulation.
  • the compound has a marked anti-inflammatory effect and has highly significant effect on inflammatory cytokine inhibition such as TNFa, IFNy, IL6, IL17 as shown in Figure 2.
  • Akaal refers to the compound of example 3
  • EAE refers to Experimental Autoimmune Encephalomyelitis
  • FTY refers to FTY720
  • MOG refers to an antigen.
  • the objective of this study was to evaluate effects of the compound of example 3 on cell mediated autoimmune response.
  • the contact hypersensitivity was induced by dinitroflurobenzene (DNFB) when the BALBc mice were senstitized to the agents twice before the challenge at right ear.
  • DNFB dinitroflurobenzene
  • the compound was given twice daily @ 3 mpk via oral dose to the animals.
  • There ear thickness, ear weight and MPO activity was inhibited as shown in Figure 3.
  • AK is the compound of example 3.
  • the objective of this study was to evaluate effects of the compound of example 3 on acute inflammation response.
  • the inflammation was induced by phorbol ester (PMA) when this agent was applied topically at the right ear of ICR mice.
  • PMA phorbol ester
  • the compound was applied topically before and after the challenge @ 10 mg per mice.
  • the ear thickness, ear weight and MPO activity was inhibited as shown in Figure 4.
  • AK is the compound of example 3.
  • the objective of this study was to evaluate effects of the compound of example 3 on excitotoxic and inflammatory neurodegeneration.
  • the Sprague Dawley rats were challenged with Kainic acid and treated with the compound @ 6 mpk once daily oral dose.
  • the histopathology of brain section was performed and stained with cresyl violet to check the level of neurodegeneration.
  • Control refers to not challenged and treated with vehicle
  • vehicle refers to challenged and treated with vehicle
  • AK refers to challenged and treated with the compound of example 3).
  • Kianic acid induces seizures in animals and mimics human epilepsy.
  • the objective of this study was to evaluate effects of the compound of example 3 on modulating seizures.
  • the Sprague Dawley rats were treated with the compound @ 6 mpk once as an oral dose and challenged with Kainic acid. There was marked inhibition in seizures as shown in Figure 6.
  • AK is the compound of example 3.
  • the middle cerebral artery occlusion (MCAO) in rats is a model of Stroke.
  • the objective of this study was to evaluate effects of the compound of example 3 on modulating the infarct size and volume including and neuronal functioning.
  • the rats were treated with the compound @ 1 , 3 and 5 mpk and the scores were measured at 72 hrs time. There was marked inhibition in infarct size and volume and highly significant impact on the sensory motor function as shown in Figures 7 and 8.
  • Figure 7 shows the effect of AK on infarct volume and infarct area in a rat model of transient cerebral ischemia for 60 min and reperfusion for 72 h. Sham refers to the control, IR refers to ischemic reperfusion and AK to the compound of example 3.
  • Figure 8 shoes the effect on sensory motor function (adhesive tape test) in a rat model of transient cerebral ischemia for 60 min and reperfusion for 72 h
  • LPS Lipopolysaccharide
  • the systemic dose of LPS induces sepsis like syndrome.
  • the objective of this study was to evaluate effects of the compound of example 3 on modulating the initial hyperthermia and latter hypothermia and the body weight including the organ pathology.
  • the rats were treated with the compound @ 3 mpk as a gavage fed to the animals after 1 hr challenge with LPS (5 mg/Kg) and every 24 hr cycle.
  • the disease scores were measured at 24 and 72 hrs time. There was marked inhibition in hyperthermia at 24 hrs and hypothermia at 72 hrs time and organ pathology.
  • the body weight loss was significantly halted in the treatment group as shown in Figure 9.
  • AK is the compound of example 3.
  • Figure 9 shows the effect of AK on body temperature and weight.

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Abstract

L'invention concerne des nouveaux dérivés de benzofurane. Lesdits dérivés ont une activité de récepteur S1P1 et/ou une activité de modification de maladie et sont utiles dans le traitement d'états ou de maladies associés aux systèmes immunitaire, vasculaire et nerveux chez les animaux et/ou les humains.
PCT/AU2013/001235 2012-10-26 2013-10-25 Composés organiques WO2014063199A1 (fr)

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JP2015057388A (ja) * 2008-10-17 2015-03-26 アカール ファーマ ピーティーワイ リミテッド Ｓ１ｐ受容体モジュレーターおよびそれらの使用
WO2017024355A1 (fr) * 2015-08-11 2017-02-16 Akaal Pharma Pty Ltd Compositions comprenant des modulateurs de récepteurs de s1p
CN110357773A (zh) * 2019-07-08 2019-10-22 南通嘉禾化工有限公司 3-氯-4-羟基苯甲酸的合成
US10676467B2 (en) * 2017-06-30 2020-06-09 Washington University Compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof
WO2021168518A1 (fr) * 2020-02-28 2021-09-02 Akaal Pharma Pty Ltd Modulateurs du récepteur s1p
CN113773247A (zh) * 2021-07-23 2021-12-10 无锡海伦生物科技有限公司 一种2-氨基-5-碘吡啶的制备方法
EP4025211A4 (fr) * 2019-09-05 2023-09-06 Trevena, Inc. Procédés de traitement de l'épilepsie à l'aide de ceux-ci

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US20080113961A1 (en) * 2005-04-22 2008-05-15 Daiichi Sankyo Company, Limited Heterocyclic compound
WO2010043000A1 (fr) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd Modulateurs des récepteurs s1p et leur utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080113961A1 (en) * 2005-04-22 2008-05-15 Daiichi Sankyo Company, Limited Heterocyclic compound
WO2010043000A1 (fr) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd Modulateurs des récepteurs s1p et leur utilisation

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015057388A (ja) * 2008-10-17 2015-03-26 アカール ファーマ ピーティーワイ リミテッド Ｓ１ｐ受容体モジュレーターおよびそれらの使用
US9707205B2 (en) 2008-10-17 2017-07-18 Akaal Pharma Pty Ltd. S1P receptors modulators and their use thereof
WO2017024355A1 (fr) * 2015-08-11 2017-02-16 Akaal Pharma Pty Ltd Compositions comprenant des modulateurs de récepteurs de s1p
CN108024998A (zh) * 2015-08-11 2018-05-11 阿卡制药有限公司 包含s1p受体调节剂的组合物
US20180228778A1 (en) * 2015-08-11 2018-08-16 Akaal Pharma Pty Ltd Compositions comprising s1p receptor modulators
EP3334428A4 (fr) * 2015-08-11 2019-07-17 Akaal Pharma Pty Ltd Compositions comprenant des modulateurs de récepteurs de s1p
US10676467B2 (en) * 2017-06-30 2020-06-09 Washington University Compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof
CN110357773A (zh) * 2019-07-08 2019-10-22 南通嘉禾化工有限公司 3-氯-4-羟基苯甲酸的合成
EP4025211A4 (fr) * 2019-09-05 2023-09-06 Trevena, Inc. Procédés de traitement de l'épilepsie à l'aide de ceux-ci
WO2021168518A1 (fr) * 2020-02-28 2021-09-02 Akaal Pharma Pty Ltd Modulateurs du récepteur s1p
CN113773247A (zh) * 2021-07-23 2021-12-10 无锡海伦生物科技有限公司 一种2-氨基-5-碘吡啶的制备方法

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