WO2014063199A1

WO2014063199A1 - Organic compounds

Info

Publication number: WO2014063199A1
Application number: PCT/AU2013/001235
Authority: WO
Inventors: Damian W Grobelny; Gurmit S Gill
Original assignee: Akaal Pharma Pty Ltd
Priority date: 2012-10-26
Filing date: 2013-10-25
Publication date: 2014-05-01

Abstract

Novel benzofuran derivatives are disclosed. The derivatives have S1P1 receptor activity and/or disease modifying activity and find use in the treatment of conditions or diseases associated with the immune, vascular and nervous systems in animals and/or humans

Description

ORGANIC COMPOUNDS

FIELD OF DISCLOSURE

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.

BACKGROUND TO THE DISCLOSURE

Sphingosine 1 -phosphate (S1 P) 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. 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. , 2005, 1044, 84 - 89; Kimura, et al, Blood, 2004, 103, 4478-86) and are potential therapeutics where the regeneration is required. 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. et al, Cellular Signalling, 2005, 17, pp 131 -39). 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. Physiol Heart Circ Physiol, 2009, 296, H33-H42). It also reduces a vascular leakage in models of acute lung injury (McVerry, B. J. , et al, Am J of Respiratory and Critical Care Medicine, 2004, 170, 987-93). The S1 P vasculo-protection effect, mediated by nitric oxide and prostacyclin (Rodriguez C et al, Thromb Haemost, 2009, 101 , 66-73), prevents the development of atherosclerotic lesions (Nofer, J. R. et al, Circulation, 2007, 1 15, 501 -8; Tolle, M., et al, European J Clin Inv, 2007, 37, 17-9; Keul, P., et al, Arterioscler.Thromb.Vasc. Biol, 2007, 27, 607-13). 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. K., et al, Cardiovascular Research; 2009, 82, 193-200; Hofmann, U., et al, Cardiovascular Research, 2009, 83, 285-93; Tao, R., et al, J Cardiovasc Pharmacol, 2009, 53, 486-94) and the signalling axis of S1 P are important in the treatment of myocardial infarction (Yeh, C. C, et al, Am J Physiol Heart Circ Physiol; 2009, 296, H1 193-9). Thus S1 P like molecular modulators have a great developmental potential in wide range of cardiovascular medicines. 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. The discovery and approval of 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

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. Pharmacology and Experimental Therapeutics, 2007, 323, 626-35; Miron, V. E. et al, Ann Neurol, 2008, 63, 61 -71 ). Phosphorylated form of FTY-720 is speculated to be an anti- metastasis drug (Meeteren, et al, Cancer Lett., 2008, 266, 203-8). FTY-720 inhibits vascular endothelial cell growth factor induced vascular permeability (Sanchez, T., et al, J. Biological Chem., 2003, 278, 47281 -90), linked to an anticancer and anti-metastatic effect in animal models (Azuma, H., et al, Cancer Res, 2002, 1410-19; Chua, C-W., at al, Int. J Cancer, 2005, 1 17, 1039-48; LaMontange, K. et al, 2006, 66, 221 -31 ). The anti- angiogenic effect of FTY-720 through its interaction with S1 P receptor subtype - 1 , has been described (Schmid, G., et al, J Cellular Biochem, 2007, 101 , 259-70). 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). Of the classical mimics of S1 P, 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. While an in vivo phosporylation of the hydroxyl group of FTY 720 appears to be necessary for the most effective extracellular signalling and agonistic effect upon binding to S1 P1 -5, the apoptotic effect is limited to its non-phosphorylated form.

It is desirable to provide alternatives to FTY-720 and in particular alternative compounds with improved properties and/or activity. For example, this could include compounds with greater range of activity, altered or enhanced specificity, improved pharmacological properties or reduction in side effects.

SUMMARY OF THE EMBODIMENTS

There is provided a compound of formula (I)

wherein P is selected from H, deuterium, halogen, CN, CF₃, -COOH, amide, sulphonamide, an alkyl chain (d-₅) said alkyl chain optionally comprising one or more of deuterium, O, S, NFT (FT = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl, cycloalkyl (C₃.₇) or carbocycle;

wherein R₂ is selected from H, deuterium, halogen, CN, CF₃, an alkyl chain (d-₄) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl or cycloalkyl (C₃-₇) or carbocycle; wherein R₃ is selected from H, deuterium, halogen, an alkyl chain (d-₇) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl or cycloalkyl (C₃.₇) or carbocycle;

wherein R₄ is selected from H, deuterium, halogen, CN, CF₃, an alkyl chain (d-₄) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl or cycloalkyl (C₃.₇); wherein A is optional and when present is selected to replace one or more ring carbon atoms by N;

wherein L is selected from H, deuterium, F, CI, Br, alkyl (C_1-3);

wherein G is a group selected from one of the following:

wherein R is selected from H, COOH, alkyl (d-4) and hydroxy-alkyl (Ci-₄);

wherein R' and R" are independently selected from H, alkyl (d-4) and acyl;

wherein R'" is selected from OH, -OP0₃H₂ and physiologically acceptable salts;

X = H, Me, -CH₂-, -CH₂CH₂- m = 0, 1 , 2

wherein '^' represents an optional bridging group;

wherein represents an optional bond, the asterisks indicating the attachment of group G within formula (I).

In one embodiment the compound of formula (I) has the structure (II)

wherein R^ R₂, R₃, R₄, A, L, R, R' and R" are as hereinbefore defined.

In another embodiment the compound of formula (I) has the structure (II)

wherein R is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- iissooppeennttyyll,, OO--ccyyccllooppeennttyyll,, OO--aallllyyll,, OO--bbeennzzyyll aanndd

;;

wwhheerreeiinn RR₂₂ iiss sseelleecctteedd ffrroomm HH,, ddeeuutteerriiuumm,, FF,, CCII,, BBrr,, CCNN,, CCFF₃₃,, MMee,, OOMMee,, OOEEtt,, OOPPrr,, OO--iiPPrr,,

O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

wherein R₃ 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

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein R" is selected from H and Me;

wherein L is selected from H, deuterium, Me and CI; and

wherein A is as hereinbefore defined.

In another embodiment the compound of formula (I) has the structure (II) wherein R_y is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

wherein R₂ is H;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein R" is selected from H and Me;

wherein L is H; and wherein A is not present.

In another embodiment the compound of formula (I) has the structure

wherein R₂, R₃, R₄, A, L and m are as defined for the structure of formula (I); and wherein X is selected from H, Me, -CH₂ or -CH₂CH₂-.

In another embodiment the compound of formula (I) has the structure (III):

wherein R, is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and I/ ;

wherein R₂ is selected from H, deuterium, F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr,

O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and V ;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein L is selected from H, deuterium, Me and CI; wherein X is selected from H, Me, -CH₂ or -CH₂CH₂

wherein A and m are as hereinbefore defined.

In another embodiment the compound of formula (I) has the structure (III) wherein R, is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

;

wherein R₂ is H;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein L is H; and

wherein A is not present and m is as hereinbefore defined.

In another embodiment the compound of formula (I) has the structure (IV):

(IV) wherein R^ , R₂, R₃, R₄, A, L, R and R' are as defined for the compound of formula (I).

In another embodiment the compound of formula (I) has the structure (IV):

(IV) wherein R is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

^■

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein L is selected from H, deuterium, Me and CI; and

wherein A is as hereinbefore defined.

In another embodiment the compound of formula (I) has the structure (IV) wherein R, is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

wherein R₂ is H;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein L is H; and

wherein A is not present.

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.

In a further aspect there is provided 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).

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In some embodiments the autoimmune disorder includes eczema, acne, skin cancer, dermatitis, vitiligo or psoriasis.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In a further aspect there is provided 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.

In yet a further aspect there is provided the use of a compound as described herein in any one 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 production of a pharmaceutical for modulation of S1 P receptor activity and/or expression against target cells.

In a still further aspect there is provided the use of 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.

In a still yet further aspect there is provided the use of 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.

In a further aspect 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.

In a further aspect 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. For example, Multiple Sclerosis, Alzheimer's, dementia, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, Coeliac, inflammatory bowel, Crohn's, ulcerative colitis, Lupus Erythematosus, Lupus Nehritis, osteoarthritis, psoriasis, eczema, pruritus, arthritis, rheumatoid arthritis, osteoporosis, Sjogren Syndrome, uveitis, asthma, hay fever, COPD, sleep disorders, macular degeneration, glaucoma, typel and 2 diabetes, myasthenia gravis, non-glomerular nephrosis, autoimmune hepatitis, Behcet's, glomerulonephritis, chronic thrombocytopenia purpure, haemolytic anaemia, Wegner's granuloma and fibrosis, nervous system (spasticity), spinal cord injury, spinocerebellar ataxia, tardive dyskinesia, cognitive disorders, neuropathy, nephropathy, epilepsy, migraine, neuromuscular disorders, bipolar disorders, atopic dermatitis, acne.

In a further aspect 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.

In a further aspect 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.

In a further aspect 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.

In a further aspect the compounds as herein described may be used for prevention and/or treatment and/or immunotherapy for the pathologies caused by bioterrorism agents.

In a further aspect 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.

In a further aspect the compounds as herein described may be used to mobilize the progenitor/ stem cells preferably towards the site of injury, ischemia, stroke etc. In a further aspect the compounds as herein described may be used for regeneration purpose, for example, in wound healing.

In a further aspect 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.

As used herein, "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.

The compounds and 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.

In case of treatment of autoimmune and inflammatory diseases, 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.

In case of treatment of infection and or cancer 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.

During vaccination/s and or immunization/s 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.

Throughout this specification, use of the terms "comprises" or "comprising" or grammatical variations thereon shall be taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof not specifically mentioned.

BRIEF DESCRIPTION OF THE FIGURES

The present disclosure will now be described with reference to the accompanying Figures where: 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.

DETAILED DESCRIPTION OF THE EMBODIMENTS The terms "compound", "agent", "active agent", "chemical agent",

"pharmacologically 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. When the terms "molecule", "compound", "agent", "active agent", "chemical agent" "pharmacologically active agent", "medicament", "active" and "drug" are used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable and/or, pharmacologically active salt/s, esters, amides, prodrug/s, metabolites, analogs and the like.

The terms "effective 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.

The 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.

As used herein, the term "optionally substituted" or "optionally containing" means that one or more hydrogen or carbon atoms may be replaced by a group or groups selected from : -D, -F, -CI, -Br, -I, amide, sulphonamide, -COOH, -CF3, -OH, -OR7, -NH2, -NHR7, -NR7R8, -CN, -N02, -SH, -SR7, -SOR7, -S02R7, =0, =S, =NOH, =NOR7, - NHOH, -NHOR7, -CHO, alkyl, cycloalkyl, carbocyle, or any other specified group; where R7 and R8 are independently (C1 -C18)alkyl, typically (C1 -C12)alkyl; (C3-C18)cycloalkyl, typically (C3-C12)cycloalkyl; (C3-C18)cycloalkyl(C1 -C18)alkyl, typically (C3-C12)cyclo- alkyl(C1 -C6)alkyl; (C6-C24)aryl, typically (C6-C16)aryl; (C7-C25)aralkyl, typically (C7-C16)aralkyl; (C2-C18)alkenyl, typically (C2-C12)alkenyl; (C8-C26)aralkenyl, typically (C8-C16)aralkenyl; (C2-C18)alkynyl, typically (C2-C12)alkynyl; (C8-C26)aralkynyl, typically (C8-C16)aralkynyl; or heterocyclic.

As used herein, the term "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 -methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4-dimethyl-pentyl, 1 ,2,3-trimethylbutyl, 1 , 1 ,2- trimethylbutyl, 1 ,1 ,3-trimethylbutyl, octyl, 6-methylheptyl, 1 -methylheptyl, 1 ,1 ,3,3- tetramethylbutyl, nonyl, 1 -, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1 -, 2-, 3-, 4- or 5-ethylheptyl,

1 - , 2- or 3-propylhexyl, decyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1 -, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1 -, 2-, 3- or 4-propylheptyl, undecyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9- methyldecyl, 1 -, 2-, 3-, 4-, 5, 6- or 7-ethylnonyl, 1 -, 2-, 3-, 4- or 5-propyloctyl, 1 -, 2- or 3- butylheptyl, 1 -pentylhexyl, dodecyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1 -,

2- , 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1 -, 2-, 3-, 4-, 5- or 6-propylnonyl, 1 -, 2-, 3- or 4-butyloctyl, 1 - or 2-pentylheptyl, and the like.

A used herein, the term "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[4.4.0]octyl and the like.

As used herein, the term "aryl" refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of such 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, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula (I).

As used herein, the term "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. The term "heterocyclic" includes any group in which a heterocyclic ring is fused to a benzene ring. Examples of 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, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, azanorbornyl, isoquinuclidinyl and the like. Nitrogen-containing heterocyclics may be substituted at nitrogen with an oxygen atom. Sulfur-containing heterocyclics may be substituted at sulfur with one or two oxygen atoms.

As used herein, the term "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. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc. , Menlo Park, 1972); N. S. Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. H. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988).

GENERAL METHOD OF PREPARATIONS

The molecules described herein may be prepared by the use of following Schemes:

G^p = protected G X = OH or CI

(i) H₂NOH/EtOH; (ii) a) when X = OH; dehydrating agend (eg EDC)/DMSO; TBAF/DMSO/ ~120°C b) when X = CI; DIPEA, THF; TBAF/DMSO/- ~120°C; (iii) removal of protective group(s) of G

X = OH or CI Op = protected OH G^p = protected G

(i) a) when X = OH; dehydrating agend (eg EDC)/DMSO; TBAF/DMSO/ ~120°C b) when X = CI; DIPEA, THF; TBAF/DMSO/ ~120°C; (iii) removal of protective group of OH; (iii) Cu^(l) or Pd mediated coupling; (iv) removal of protective group(s) of G.

Representative compounds in accordance with the present disclosure are

illustrated below.

0110319

EXAMPLES

The following Examples describe the preparation of compounds according to the present disclosure and are intended to be illustrative. The Examples are not to be construed as limiting in any way the scope of the present disclosure. Proton NMR spectra were recorded at 300MHz on a Bruker EM 300 spectrometer in CDCI₃ unless otherwise stated. Chemical shifts for proton NMR are ppm downfield from tetramethylsilane.



Example 1

5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid

Step A: Step A: 4-Hydroxy-3-iodobenzonitrile: To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH₄OH (22 ml) a solution of l₂ (1 .06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H₂0 (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 H₂0 (3 ml). The precipitate formed was filtered off, washed with cold H₂0 (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. ¹ H-NMR (CDCI₃) 7.96 (d, 1 H, 1 .9 Hz) ; 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz) ; 7.03 (d, 1 H, J = 8.5 Hz); 6.03 (s, 1 H) ;

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 Cu₂0 (0.28 g; 1 .96 mmol) in anhydrous pyridine ( 4 ml) with stirring under N₂. 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. The filtrate was evaporated to dryness under reduced pressure and the residue was diluted to 20 ml with EtOAc, washed with diluted HCI (10 ml). The insoluble material formed was filtered off and the organic phase was washed with H₂0 (5 ml), brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness. The residue was purified by flash column chromatography (FCC) (Si0₂, CH₂CI₂ and EtOAc, 9 : 1 ) to give the title compound (0.23 g; 67%) as a colourless solid. ¹ H-NMR (CDCI₃) 7.86 (m, 1 H); 7.49 - 7.55 (m, 2H); 6.72 (d, 1 H, J = 3 Hz) ; 4.8 (d, 2H, J = 3 Hz) ; 2.18 (broad s, 1 H);

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 NH₂OH (0.18 g; 2.59 mmol) and Ν,Ν-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 H₂0 (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.

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 N₂. To it 1 M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at ~ 120 °C, then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H₂0 (5 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄ and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (Si0₂; CH₂CI₂) to give the title compound (0.13 g; 34%), as greyish solid. ¹ H- NMR (CDCI₃ ) 8.36 (d, 1 H, J = 3 Hz); 8.09 (dd, 1 H, J = 3, 9 Hz); 7.79 (dd, 1 H, J = 3, 9 Hz); 7.68 (d, 1 H, J = 3 Hz) ; 7.55 (d, 1 H, J = 9 Hz); 6.98 (d, 1 H, J = 9 Hz) ; 6.73 (s, 1 H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1 H); 1 .51 (m, 6H) ;

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 Mn0₂ (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. ¹ H-NMR (CDCI₃ ) 9.91 (s, 1 H); 8.59 (s, 1 H) ; 8.33 (dd, 1 H, J = 2, 9 Hz) ; 7.63 - 7.82 (m, 4H); 6.99 (d, 1 H, J = 9 Hz); 4.14 - 4.26 (m, 4H); 1 .4 - 1 .57 (m, 6H + H₂0).

Step F: 5-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid; To a suspension of the product of Step E (0.009 g; 0.024 mmol) and AgN0₃ (0.06 g; 0.14 mmol) in EtOH (0.2 ml) H₂0 (0.1 ml) was added at room temperature, followed by 10% KOH (0.1 ml). The resulting black suspension was stirred for 1 h at ~ 50 °C and cooled to room temperature and filtered. The insoluble material was washed with H₂0 (2 x 0.2 ml). The combined filtrates were acidified to pH = 1 with HCI and the product was taken up by extraction with EtOAc (2 x 5 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si0₂, CH₂CI₂/ acetic acid (AcOH) 98/2) to give the title compound (0.00012 g; 12.8 %), as a creamy solid. ¹ H-NMR (CDCI₃ + CD₃OD) 8.48 (s, 1 H); 8.22 (m, 1 H); 7.77 (m, 1 H); 7.64 - 7.66 (m, 2H); 7.58 (s, 1 H); 6.96 (d, 1 H, J = 6 Hz) ; 4.19 (m, 4H); 1 .4 - 1 .54 (m, 6H). Example 2

1- ((5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)azetidine- 3-carboxylic acid

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. The yellowish residue was suspended in 1 ,2-dichloroethane (1 ml) and NaBH(OAc)₃ (0.12 g; 0.57 mmol) was added, followed by AcOH (0.01 ml). This was stirred for 1 h at room temperature and diluted to 15 ml with EtOAc, washed with 10% KOH (2 x 3 ml); brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (Si0₂, EtOAc) to give the title compound (0.06 g; 68%), as creamy syrup. ¹ H-NMR (CDCI₃) 8.33 (d, 1 H, J = 3 Hz); 8.06 (dd, 1 H, 3, 9 Hz); 7.78 (dd, 1 H, J = 3, 9 Hz) ; 6.87 (d, 1 H, J = 2 Hz) ; 6.63 (s, 1 H); 4.14 - 4.22 (m, 4H) ; 3.6 - 3.7 (m, 5H); 3.48 - 3.34 (m, 2H); 1 .49 (m, 6H).

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. The residue was purified by FCC (Si0₂, CH₂CI₂ saturated with concentrated NH₄OH and MeOH, 85 : 15) to give the title compound (0.032 g; 55%), as a colourless solid. ¹ H-NMR (CD₃OD + CDCI₃) 8.37 (d, 1 H, J = 3 Hz) ; 8.09 (dd, 1 H, J = 3, 6 Hz) ; 7.77 (dd, 1 H, J = 3, 9 Hz); 7.68 (s, 1 H); 7.6 (d, 1 H, J = 9 Hz) ; 7.02 - 7.07 (m, 2H); 4.38 (s, 2H); 4.05 - 4.21 (m, 8H); 1 .44 - 1 .49 (m, 6H).

Example 3

2- Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

Step A: N-Hydroxy-3-iodo-4-isopropoxybenzimidamide: A suspension of 3-iodo-4- isopropoxybenzonitrile (0.576 g; 2 mmol), HCI x NH₂OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50 ^SC. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H₂0. The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. ¹ H-NMR (CDCI₃) 8.0 (d, 1 H, J = 2.22 Hz); 7.55 (dd, 1 H, J = 9.54, 2.28 Hz); 6.77 (d, 1 H, J = 8.7 Hz); 4.95 (b, 2H); 4.69 - 4.63 (m, 1 H); 1 .42 (d, 6H).

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 ^SC . 1 M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 1 10 ^SC. The reaction mixture was diluted to 20 ml with H₂0 and extracted with EtOAc (2 x 15 ml). The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was distilled off and the residue was purified by FCC (Si0₂, hexane/EtOAc) to give the title compound (0.22 g, 47.4%), as a colourless solid. ¹ H-NMR (CDCIg) 8.56 (d, 1 H, J = 2.04 Hz) ; 8.21 (d, 1 H, J = 2.37 Hz); 8.07 - 8.02 (m, 2H); 7.00 (d, 1 H, J = 8.73 Hz); 6.87 (d, 1 H, J = 8.67 Hz) ; 4.68 - 4.63 (m, 1 H); 4.08 (t, 2H, J = 6.45 Hz) ; 1 .93 - 1 .87 (m, 2H); 1 .36 (d, 6H, J = 6.06 Hz); 1.09 (t, 3H, J = 7.44 Hz).

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 CH₂CI₂ (2 ml) 1 M BCI₃ in CH₂CI₂ (3 ml) was added drop wise at rt. After 1 h, more of 1 M BCI₃ in CH₂CI₂ (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH₄CI solution and extracted with CH₂CI₂ (20 ml). The organic layer was separated, dried over MgS0₄ and filtered. The filtrates was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.145 g, 79%), as colourless solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .95 Hz) ; 8.21 (d, 1 H, J = 2.1 Hz); 8.06 - 8.04 (m, 1 H); 8.03 - 8.02 (m, 1 H); 7.07 (d, 1 H, J = 8.49 Hz); 7.00 (d, 1 H, J = 8.7 Hz); 4.08 (t, 2H, J = 6.45 Hz); 1.94 - 1 .87 (m, 2H); 1.09 (t, 3H, J = 7.44 Hz).

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 N₂ and CI₂Pd(PPh₃)₄ (0.025 g) was added, followed by catalytic amount of Cul. The mixture was stirred overnight at 45 ^SC under N₂, diluted to 20 ml with saturated NH₄CI and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was distilled off and the residue was purified by FCC (Si0₂, hexane/EtOAc) to give the title compound (0.1 1 g, 78%), as pale paste. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .29 Hz); 8.24 (d, 1 H, J = 2.13 Hz) ; 8.08 (t, 1 H, J = 1 .56 Hz) ; 8.05 (t, 1 H, J = 1 .56 Hz); 7.53 (d, 1 H, J = 8.67 Hz); 7.03 (d, 1 H, J = 8.67 Hz) ; 6.75 (s, 1 H); 4.26 - 4.19 (m, 4H) ; 4.06 (t, 2H, J = 5.49 Hz); 1 .94 - 1 .87 (m, 2H); 1 .41 (s, 9H); 1 .36 (s, 6H); 1 .1 (t, 3H, J = 7.44 Hz).

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 CH₂CI₂ (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. The mixture was evaporated to dryness and the residue was purified by FCC (Si0₂, CH₂CI₂ saturated with concentrated NH₄OH/MeOH ; 98:2) to give the title product (0.035 g, 46%) as colourless solid. ¹H-NMR (DMSO-d₆) 8.3 (d, 1 H, J = 1 .1 1 Hz) ; 8.15 (d, 1 H, J = 2.01 Hz); 8.09 (dd, 1 H, J = 8.67, 2.04 Hz) ; 7.94 (dd, 1 H, J = 8.58, 1 .53 Hz); 7.68 (d, 1 H, J = 8.61 Hz); 7.37 (d, 1 H, J = 8.76 Hz); 6.92 (s, 1 H) ; 4.91 (b, 2H) ; 4.14 (t, 2H, J = 6.36 Hz); 3.69 (d, 2H, J = 10.6 Hz) ; 3.59 (d, 2H, J = 10.6 Hz); 1 .83 - 1.72 (m, 2H); 0.97 (t, 3H, J = 7.41 Hz). Example 4

(E)-2-Amino-2-(5-(5-(4-methylstyryl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane- 1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.53 (d, 1 H, J = 2.07 Hz); 8.01 (dd, 1 H, J = 8.58, 2.1 Hz); 7.82 (d, 1 H, J = 16.35 Hz); 7.49 (d, 1 H, J = 8.1 Hz); 6.97 (d, 1 H, J = 16.38 Hz); 6.87 (d, 1 H, J = 8.76 Hz); 4.69 - 4.6 (m, 1 H); 1 .4 (d, 6H, J = 5.85 Hz).

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. ¹ H-NMR (CDCI₃) 8.44 (d, 1 H, J = 1 .95 Hz); 8.0 (dd, 1 H, J = 8.49, 2.01 Hz); 7.84 (d, 1 H, J = 16.35 Hz); 7.49 (d, 1 H, J = 8.16 Hz); 7.07 (d, 1 H, J = 8.49 Hz); 6.98 (d, 1 H, J = 16.83 Hz) ; 5.61 (s, 1 H).

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. ¹ H-NMR (CDCI₃) 8.30 (d, 1 H, J = 1 .32 Hz) ; 8.03 (dd, 1 H, J = 8.61 , 1 .68 Hz); 7.84 (d, 1 H, J = 16.38 Hz) ; 7.53 - 7.49 (m, 3H); 7.21 (d, 2H, J = 5.34 Hz) ; 7.0 (d, 1 H, J = 15.15 Hz) ; 5.28 (s, 1 H); 4.24 (b, 4H); 2.39 (s, 3H); 1.46 - 1 .39 (m, 15H).

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. ¹ H-NMR (DMSO-d₆) 8.23 (b, 1 H); 7.9 - 7.85 (m, 2H); 7.72 - 7.64 (m, 3H); 7.33 (d, 1 H, J = 16.2 Hz) ; 7.25 (d, 2H, J = 6.3 Hz); 6.87 (s, 1 H); 4.77 (b, 2H); 3.63 (b, 2H); 3.56 (b, 2H); 2.32 (s, 3H); 1 .95 (b, 2H).

Example 5

2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.55 (d, 1 H, J = 2.07 Hz) ; 8.27 (d, 1 H, J = 1 .89 Hz) ; 8.04 (dd, 1 H, J = 8.61 , 2.04 Hz); 7.91 (dd, 1 H, J = 8.34, 1 .95 Hz); 7.79 (d, 1 H, J = 8.37 Hz); 6.87 (d, 1 H, J = 8.67 Hz); 4.7 - 4.6 (m, 1 H); 1 .4 (d, 6H, J = 5.94 Hz).

Step B: 4-(5-(4-Bromo-3-chlorophenyl)- 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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 86% yield, as creamy solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1.98 Hz); 8.28 (d, 1 H, J = 1 .95 Hz); 8.03 (dd, 1 H, J = 8.49, 1.98 Hz); 7.92 (dd, 1 H, J = 8.37, 1 .98 Hz) ; 7.84 (d, 1 H, J = 8.37 Hz); 7.08 (d, 1 H, J = 8.52 Hz) ; 5.65 (b, 1 H).

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: When the product of Step B 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 58% yield, as pale paste. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .53 Hz); 8.31 (d, 1 H, J = 1 .95 Hz) ; 8.06 (dd, 1 H, J = 8.61 , 1 .68 Hz); 7.94 (dd, 1 H, J = 8.37, 1 .98 Hz) ; 7.8 (d, 1 H, J = 8.37 Hz); 7.54 (d, 1 H, J = 8.61 Hz) ; 6.76 (s, 1 H); 5.34 (bs, 1 H); 4.3 - 4.24 (m, 4H); 1 .55 (s, 9H); 1 .47(s, 6H). Step D: 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol: When 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 39% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.31 (b, 2H) ; 8.05 (d, 1 H, J = 8.52 Hz) ; 8.00 (d, 1 H, J = 8.49 Hz) ; 7.94 (d, 1 H, J = 8.58 Hz); 7.68 (d, 1 H, J = 8.46 Hz); 6.91 (s, 1 H) ; 4.88 (bs, 1 H) ; 3.66 (bs, 2H); 3.58 (bs, 2H).

Example 6

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

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 H₂0 (5 ml:1 ml), Pd(PPh₃)₄ (0.03 g) was added at 80 ^SC, followed by the NaHC0₃ solution (0.065 g in 1 ml H20) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H₂0, dried over MgS0₄ and filtered. The filtrate was evaporated and the residue was purified by FCC (Si0₂, hexane/EtOAc), to give the title compound (0.065 g, 71 %), as pale paste. ¹ H-NMR (CDCI₃) 8.45 (d, 1 H, J = 1 .53 Hz); 8.25 - 8.22 (m, 2H); 7.94 (dd, 1 H, J = 8.7, 1 .8 Hz) ; 7.55 - 7.42 (m, 3H); 7.38 - 7.37 (m, 2H); 6.78 (s, 1 H); 5.43 (bs, 1 H); 4.29 - 4.13 (m, 4H); 1 .46 (s, 9H); 1 .27 (b, 6H).

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. ¹ H-NMR (DMSO-d₆) 8.42 (s, 1 H); 8.28 (s, 1 H); 8.2 (d, 1 H, J = 8.41 Hz) ; 8.1 1 (d, 1 H, J = 8.1 Hz); 7.82 (s, 1 H); 7.64 - 7.61 (m, 3H); 7.4 (b, 1 H); 6.92 (s, 1 H); 4.9 (bs, 2H); 3.66 (b, 2H) ; 3.59 (b, 2H).

Example 7

2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.57 (d, 1 H, J = 2.05 Hz) ; 8.05 (dd, 1 H, J = 8.58, 2.03 Hz); 8.02 (d, 1 H, J = 2.07 Hz) ; 7.76 (dd, 1 H, J = 8.41 , 1 .94 Hz) ; 7.66 (d, 1 H, J = 1 .93 Hz) ; 6.96 (d, 1 H, J = 8.5 Hz); 6.87 (d, 1 H, J = 8.69 Hz); 4.67 - 4.63 (m, 1 H); 4.24 - 4.14 (m, 4H); 1.53 - 1 .4 (m, 6H); 1 .38 (d, 6H, J = 6.64 Hz).

Step B: 4-(5-(3,4-Diethoxyphenyl)-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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 84% yield, as a creamy solid. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 2.05 Hz); 8.04 (dd, 1 H, J = 8.46, 1 .98 Hz); 7.76 (dd, 1 H, J = 8.43, 2.0 Hz); 7.65 (d, 1 H, J = 1 .98 Hz) ; 7.07 (d, 1 H, J = 8.5 Hz); 6.96 (d, 1 H, J = 8.46 Hz); 5.63 (bs, 1 H); 4.24 - 4.09 (m, 4H); 1 .56 - 1 .42 (m, 6H).

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: When the product of Step B 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 66% yield, as creamy paste. ¹ H-NMR (CDCI₃) 8.35 (d, 1 H, J = 1 .57 Hz); 8.08 (dd, 1 H, J = 8.62, 1 .68 Hz) ; 7.79 (dd, 1 H, J = 8.44, 1 .94 Hz) ; 7.69 (d, 1 H, J = 1 .93 Hz) ; 7.52 (d, 1 H, J = 8.54 Hz) ; 6.96 (d, 1 H, J = 8.5 Hz); 6.75 (s, 1 H); 5.32 (b, 1 H); 4.36 - 4.15 (m, 8H); 3.95 (s, 2H); 1 .54 - 1 .47 (m, 21 H).

Step D: 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2-yl) propane- 1,3-diol: When 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- yl carbamate in Example 3, Step E, the similar procedure afforded the title compound in 61 % yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.27 (s, 1 H) ; 7.92 (d, 1 H, J = 8.23 Hz) ; 7.75 - 7.61 (m, 3H) ; 7.17 (d, 1 H, J = 8.34 Hz); 6.88 (s, 1 H); 4.78 (b, 2H); 4.15 - 4.00 (b, 4H); 3.65 - 3.64 (b, 2H) ; 3.57 - 3.55 (b, 2H); 1 .35(b, 6H).

Example 8

2-Amino-2-(5-(5-(4-propoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.58 (d, 1 H, J = 2.01 Hz) ; 8.06 (dd, 1 H, J = 8.61 , 2.07 Hz); 7.77 (dd, 1 H, J = 8.43, 1 .98 Hz) ; 7.66 (d, 1 H, J = 1 .92 Hz);

6.97 (d, 1 H, J = 8.46 Hz); 6.88 (d, 1 H, J = 8.7 Hz); 4.69 - 4.61 (m, 1 H); 4.06 (t, 2H, J = 6.81 Hz) ; 3.98 (s, 3H) ; 1 .93 - 1.88 (m, 2H); 1 .06 (t, 3H, J = 7.38 Hz).

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-

4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 80% yield, as creamy solid. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 1 .98 Hz) ; 8.04 (dd, 1 H, J = 8.46, 1 .98 Hz); 7.7 (dd, 1 H, J = 8.43, 2.01 Hz) ; 7.65 (d, 1 H, J = 1 .95 Hz) ; 7.07 (d, 1 H, J = 8.49 Hz) ; 6.97 (d, 1 H), J = 8.46 Hz) ; 5.63 (s, 1 H); 4.06 (t, 2H, J = 6.8 Hz); 4.02 (s, 3H); 1.94 - 1 .87 (m, 2H) ; 1 .06 (t, 3H, J = 7.41 Hz).

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: When the product of Step B 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. ¹ H-NMR (CDCI₃) 8.35 (d, 1 H, J = 1 .23 Hz); 8.08 (dd, 1 H, J = 8.61 , 1 .68 Hz); 7.8 (dd, 1 H, J = 8.41 , 1 .98 Hz); 7.68 (d, 1 H, J = 1 .92 Hz); 7.52 (d, 1 H, J = 8.64 Hz); 6.98 (d, 1 H, J = 8.49 Hz) ; 6.75 (s, 1 H); 5.32 (bs, 1 H); 4.26 (b, 4H) ; 4.06 (t, 2H, J = 6.81 Hz);

3.98 (s, 3H); 1 .93 - 1 .88 (m, 2H); 1 .49 (s, 9H); 1 .44 (s, 6H); 1 .06 (t, 3H, J = 7.38 Hz).

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. ¹ H-NMR (DMSO-d₆) 8.28 (s, 1 H); 7.92 (d, 1 H, J = 2.82 Hz) ; 7.61 (m, 3H); 7.16 (d, 1 H, J = 8.53 Hz); 6.88 (s, 1 H); 4.78 (b, 2H); 4.01 (t, 2H, J = 6.03 Hz) ; 3.99 (s, 3H); 3.77 - 3.57 (m, 4H); 1 .78 - 1 .71 (m, 2H); 0.96 (t, 3H, J = 7.29 Hz).

Example 9

5- (3,4-diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1 ,2,4-oxadiazole

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 N₂ 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 ZnCI₂ (0.3 gm] under nitrogen]. Pd (PPh₃)₄ (0.15 g) was added followed by the addition of catalytic amount of Cul. The mixture was stirred at room temperature for 3 hrs (tic) and quenched with saturated NH₄CI solution. The crude was taken in EtOAc (20 ml) and washed with H₂0. The organic layer was separated and dried over MgS0₄. The solvent was distilled and the crude was dissolved in 1 ,4-dioxane (4 ml) and TBAF (0.3 ml, 1 M solution in THF) was added followed by the stirring at reflux for 4 hrs. The solvent was distilled and the crude was purified over FCC (Si0₂, Hexane/EtOAc) to give the title compound (0.145 g, 91 %) as white solid. ¹ H-NMR (CDCI₃) 7.78 (s, 1 H); 7.46 - 7.44 (m, 2H); 6.41 (bs, 1 H); 2.47 (s, 3H).

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. ¹ H-NMR (CDCI₃) 8.28 (bs, 1 H); 8.00 (dd, 1 H, J = 8.55, 1 .68 Hz) ; 7.8 (dd, 1 H, J = 8.4, 1 .98 Hz) ; 7.68 (d, 1 H, J = 1 .92 Hz); 7.47 (d, 1 H, J = 8.58 Hz); 6.97 (d, 1 H, J = 8.46 Hz); 6.45 (s, 1 H); 4.23 - 4.16 (m, 4H); 2.48 (3H); 1 .52 - 1 .47 (m, 6H).

Example 10

2- Ami no-2-(5-(5-(6-meth oxybenzof u ran-2-yl)-1 ,2,4-oxad iazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol

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: CH₃OH: H₂0; 5 ml: 2 ml: 1 ml) and to the stirred solution was added a solution of LiOH (0.145 g, 6 mmol) in H₂0 (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. The solvent was distilled to give the title compound (0.21 g, 91 %) as a white solid. ¹ H-NMR (DMSO- d₆) 7.61 (d, 1 H, J = 8.67 Hz) ; 7.54 (s, 1 H); 7.24 (d, 1 H, J = 1 .59 Hz) ; 6.93 (dd, 1 H, J = 8.67, 2.4 Hz); 3.8 (s, 3H).

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. ¹ H-NMR (CDCI₃) 8.6 (d, 1 H, J = 2.04 Hz) ; 8.08 (dd, 1 H, J = 8.58, 2.1 Hz); 7.63 (b, 1 H); 7.57 (d, 1 H, J = 8.7 Hz); 7.13 (d, 1 H, J = 1 .8 Hz); 6.97 (dd, 1 H, J = 8.7, 2.19 Hz) ; 6.87 (d, 1 H, J = 8.73 Hz); 4.69 - 4.59 (m, 1 H); 3.88 (s, 3H); 1 .4 (d, 6H, J = 6.33 Hz).

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. ¹ H-NMR (CDCI₃) 8.53 (d, 1 H, J = 2.01 Hz); 8.06 (dd, 1 H, J = 8.49, 2.01 Hz); 7.64 (b, 1 H) ; 7.6 (d, 1 H, J = 8.7 Hz); 7.13 (b, 1 H); 7.08 (d, 1 H, J = 8.46 Hz); 6.98 (dd, 1 H, J = 8.7, 2.22 Hz) ; 3.89 (s, 3H).

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: When 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. ¹H-NMR (CD₃OD) 8.39 (d, 1 H, J = 1 .74 Hz) ; 8.08 (dd, 1 H, J = 8.73, 1 .89 Hz); 7.68 (b, 1 H); 7.63 (d, 1 H, J = 8.73 Hz) ; 7.58 (d, 1 H, J = 8.7 Hz) ; 7.14 (d, 1 H, J = 1 .8 Hz) ; 7.03 (s, 1 H) ; 6.92 (dd, 1 H, J = 8.7, 2.22 Hz); 3.98 (d, 2H, J = 1 1 .00 Hz); 3.88 (d, 2H, J = 1 1 .01 Hz); 3.85 (s, 3H).

Example 11

2-Amino-2-(5-(5-(4-propylphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

Step A: 3-(3-lodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1 ,2,4-oxadiazole: When 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. ¹ H-NMR (CDCI₃) 8.58 (d, 1 H, J = 2.04 Hz); 8.1 1 - 8.05 (m, 3H) ; 7.34 (d, 2H, J = 8.25 Hz) ; 6.88 (d, 1 H, J = 8.73 Hz); 4.7 - 4.59 (m, 1 H); 2.67 (t, 2H, J = 7.83 Hz); 1 .72 - 1 .41 (m, 2H); 0.95 (t, 3H, J = 7.29 Hz).

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. ¹H-NMR (CDCI₃) 8.48 (d, 1 H, J = 1 .98 Hz) ; 8.08 (d, 2H, J = 8.25 Hz); 8.03 (dd, 1 H, J = 8.49, 2.01 Hz) ; 7.33 (d, 2H, J = 8.25 Hz); 7.07 (d, 1 H, J = 8.49 Hz) ; 2.66 (t, 2H, J = 7.5 Hz) ; 1 .71 - 1 .61 (m, 2H); 0.95 (t, 3H, J = 7.29 Hz).

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: When the product of Step B 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 35% yield, as pale paste. ¹ H-NMR (CDCIg) 8.35 (s, 1 H) ; 8.13 - 8.06 (m, 3H) ; 7.52 (d, 1 H, J = 8.64 Hz); 7.34 (d, 2H, J = 8.22 Hz); 6.75 (s, 1 H); 5.35 (s, 1 H); 4.26 (b, 4H); 2.67 (t, 2H, J = 7.41 Hz); 1 .74 - 1 .67 (m, 2H); 1.64 (s, 6H); 1 .5 (s, 9H); 0.96 (t, 2H, J = 7.29 Hz).

Step D: 2-Amino-2-(5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol: When 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 28% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.30 (s, 1 H); 8.08 (d, 2H, J = 6.6 Hz); 7.94 (d, 1 H, J = 7.5 Hz) ; 7.68 (d, 1 H, J = 7.5 Hz); 7.46 (d, 2H, J = 7.5 Hz) ; 6.92 (s, 1 H); 3.67 (b, 2H) ; 3.59 (b, 2H) ; 2.65 (b, 2H); 1 .63 - 1 .6 (m, 2H); 0.88 (t, 2H, J = 6.3 Hz).

Example 12

2-Amino-2-(5-(5-(4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H- NMR (CDCI₃) 8.57 (d, 1 H, J = 2.04 Hz) ; 8.1 1 (d, 2H, J = 8.88 Hz) ; 8.05 (dd, 1 H, J = 8.58, 2.04 Hz) ; 6.99 (d, 2H, J = 8.88 Hz) ; 6.87 (d, 1 H, J = 8.67 Hz) ; 4.69 - 4.61 (m, 1 H); 4.1 1 (q, 2H, J = 6.99, 13.98 Hz); 1 .45(t, 3H, J = 6.99 Hz).

Step B: 4-(5-(4-Ethoxyphenyl)- 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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 87% yield, as white solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .95 Hz); 8.1 1 (d, 2H, J = 8.94 Hz) ; 8.03 (dd, 1 H, J = 8.46, 2.01 Hz) ; 7.07 (d, 2H, J = 8.49 Hz) ; 4.1 1 (q, 2H, J = 6.96, 13.98 Hz); 1 .45 (t, 3H, J = 6.96 Hz).

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: When the product of Step B 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 60% yield, as pale paste. ¹ H-NMR (CDCIg) 8.34 (s, 1 H); 8.14 (d, 2H, J = 8.88 Hz); 8.07 (dd, 1 H, J = 8.61 , 1 .68 Hz); 7.51 (d, 1 H, J = 8.52 Hz) ; 7.00 (d, 2H, J = 8.94 Hz); 6.75 (s, 1 H); 5.34 (s, 1 H) ; 4.3 - 4.14 (b, 4H); 4.1 (t, 2H, J = 7.02 Hz); 1 .44 - 1 .39 (b, 18H).

Step D: 2-Amino-2-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yljpropane -1,3-diol: When 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 32% yield, as light yellow solid. ¹ H-NMR (DMSO-d₆) 8.09 (s, 1 H); 7.96 (d, 2H, J = 8.4 Hz); 7.7 (d, 1 H, J = 8.4 Hz) ; 7.15 (d, 2H, J = 9 Hz) ; 6.98 (s, 1 H) ; 5.1 (b, 2H); 4.13 (q, 2H, J = 6.9, 13.8 Hz); 3.73 (d, 2H, J = 8.1 Hz) ; 3.64 (d, 2H, J = 8.1 Hz); 1 .34 (t, 3H, J = 6.9 Hz). Example 13

2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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 CF₃C0₂Ag (1 .3 g, 5.1 mmol) in CH₂CI₂ (50 ml) l₂ (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 CH₂CI₂. The combined filtrates were evaporated to dryness and the residue was purified by FCC (Si0₂, hexane/EtOAc) to give 2-chloro-5-iodo-4-isopropoxybenzonitrile (0.335 g, 26%), as white solid. 1 H NMR (CDCI₃) 7.99 (s, 1 H) ; 6.82 (s, 1 H) ; 4.66 - 4.58 (m, 1 H); 1 .41 (d, 6H, J = 6.03 Hz. This (0.32 g, 1 mmol) was converted to the title compound (0.335 g; 95 %) according to the procedure of Example 36 Step A. ¹H NMR (CDCI₃) 7.89 (s, 1 H); 6.79 (s, 1 H); 4.86 - 4.49 (m, 1 H); 1 .4(d, 6H)

Step B: 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1,2,4- oxadiazole: When the product of Step A and 4-propylbenzoic acid were substituted for A/-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid in Example 3, Step B, the similar procedure afforded the title compound in 20% yield, as white solid. ¹ H NMR (CDCI₃) 8.46 (s, 1 H); 8.10 (d, 2H, J = 8.25 Hz) ; 7.34 (d, 2H, J = 8.28 Hz); 6.92 (s, 1 H); 7.67 - 7.59 (m, 1 H); 2.67 (t, 2H, J = 7.35 Hz); 1 .72 - 1 .65 (m, 2H) ; 1 .43 (d, 6H, J = 6.06 Hz); 0.96 (t, 3H, J = 7.32 Hz). 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. ¹ H NMR (CDCI₃) 8.37 (s, 1 H); 8.10 (d, 2H, J = 8.25 Hz); 7.33 (d, 2H, J = 8.25 Hz) ; 7.16 (s, 1 H); 5.78 (b, 1 H); 2.67 (t, 2H, J = 7.38 Hz) ; 1.74 - 1 .56 (m, 2H); 0.96 (t, 3H, J = 7.32 Hz).

Step D: 2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol: When 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 (0.006 g, 40%) as white solid. ¹ H NMR (CD₃OD) 8.12 (d, 2H, J = 8.28 Hz) ; 8.12 (s, 1 H); 7.75 (s, 1 H); 7.43 (d, 2H, J = 8.31 Hz) ; 6.9 (s, 1 H) ; 3.88 (d, 2H, J = 10.9 Hz); 3.78 (d, 1 H, J = 10.9 Hz) ; 2.7 (t, 2H, J = 7.41 Hz); 1.76 - 1 .64 (m, 2H); 0.97 (t, 3H, J = 7.32 Hz).

Example 14

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 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 ^SC. The mixture was quenched with saturated NH₄CI and extracted with EtOAc (50 ml). The organic layer was washed with H₂0, dried over MgS0₄ and filtered. The filtrate was distilled off and the residue was dried in vacuo to give 1 -butyl-4-iodo-1 H-pyrazole (0.39 g, 100%), as colourless oil. ¹ H NMR (CDCI₃) 7.47 (s, 1 H); 7.39 (s, 1 H); 4.09 (t, 2H, J = 7.14 Hz); 1 .85 - 1 .75 (m, 2H); 1 .35 - 1 .23 (m, 2H) ; 0.91 (t, 3H, J = 7.32 Hz). To a stirred solution of the above product (0.36 g, 1 .44 mmol) in anhydrous THF (0.5 ml) 2M iPrMgCI in THF (2 ml) was added at 0 ^SC and after warming up to room temperature anhydrous DMF (1 ml) was added to it. This was stirred for 1 h at room temperature, than quenched with saturated NH₄CI and extracted with EtOAc (30 ml). The organic layer was washed with H₂0, dried over MgS0₄ and filtered. The filtrate was evaporated to dryness to give 1 - butyl-1 H-pyrazole-4-carbaldehyde (0.27 g; 100%), as pale oil. ¹H NMR (CDCI₃) 9.82 (s, 1 H); 7.93 (s, 1 H) ; 7.89 (s, 1 H); 4.13 (t, 2H, J = 7.11 Hz); 1 .9 - 1 .8 (m, 2H); 1 .4 - 1 .22 (m, 2H); 0.92 (t, 3H, J = 7.29 Hz). To a stirred solution of above aldehyde (0.22 g, 1.44 mmol) in the mixture of dioxane and H₂0 (15ml : 3 ml) KMn0₄ (0.25 g; 1.58 mmol) was added over a period of 30 min. The mixture was evaporated to dryness and the residue was treated in the mixture of EtOAc and MeOH (20 ml: 5 ml) and filtered through Celite pad. The filtrate was evaporated to dryness to give the title compound (0.24 g; 100%), as creamy crystalline solid.¹H NMR (CDCI₃) 7.8 (s, 1H); 7.56 (b, 1H); 4.05 (b, 2H); 1.7 (b, 2H); 1.18 (b, 2H); 0.83 (b, 3H).

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.¹H NMR (CDCI₃) 8.53 (d, 1 H, J = 2.07 Hz); 8.1 (s, 1H); 8.08 (s, 1H); 8.00 (dd, 1H, J = 8.61, 2.16 Hz); 8.87 (d, 1H, J = 8.73 Hz); 4.68-4.6 (m, 2H); 4.2 (t, 2H, J = 7.11 Hz); 2.02 - 1.85 (m, 2H); 1.42 - 1.32 (m, 2H); 0.95 (t, 3H, J = 7.32 Hz).

Step C: 4-(5-(1-Butyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4- isopropoxy phenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 72% yield, as creamy solid.¹H NMR (CDCI₃) 8.45 (d, 1 H, J = 1.98 Hz); 8.12 (s, 1H); 8.09 (s, 1H); 7.99 (dd, 1H, J = 8.49, 2.01 Hz); 7.06 (d, 1 H, J = 8.49 Hz); 4.2 (t, 2H, J = 7.08 Hz); 2.02 - 1.85 (m, 2H); 1.42 - 1.26 (m, 2H); 0.95 (t, 3H, J =7.29 Hz).

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.¹H NMR (CDCI₃) 8.3 (s, 1 H); 8.13 (s, 1 H); 8.01 (s, 1 H); 7.51 (d, 1 H, J = 8.7 Hz); 6.74 (s, 1 H); 5.32 (s, 1H); 4.29-4.18 (m, 6H); 2.02-1.91 (m, 2H); 1.54- 1.34 (b, 17 H); 0.96 (t, 3H, J = 7.35 Hz).

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: When the 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 in Example 3, Step E, the similar procedure afforded the title compound in 46% yield, as light creamy solid.¹H NMR (CD₃OD) 8.46 (broad s, 1 H); 8.32 (broad s, 1H); 8.13(broad s, 1H); 8.02 (d, 1 H, J = 7.98 Hz); 7.62 (d, 1H, J = 8.31 Hz); 6.97 (s, 1H); 4.25 (t, 2H, J = 6.21 Hz); 3.93 (b, 4H); 1.91 - 1.86 (m, 2H); 1.36-1.31 (m, 2H); 0.95 (t, 3H, J = 7.02 Hz). Example 15

2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

Step A: 3-Nitro-4-propoxybenzoic acid: To a stirred solution of 3-nitro-4- propoxymethylbenzoate (0.35 g, 1 .46 mmol) in a mixture of THF and EtOH (3 ml : 1 ml) the solution of LiOH (0.345 g; 15 mmol) in H₂0 (1 ml) was added and the mixture was stirred for 4 h at room temperature. The solvent was distilled off and the residue was treated with 1 M HCI and extracted with EtOAc (50 ml). The organic layer was washed with H₂0, dried over MgS0₄ and filtered. The filtrate was evaporated to dryness to give the title compound (0.32g, 97%), as creamy solid. ¹ H NMR (CDCI₃) 8.53 (d, 1 H, J = 1 .65 Hz); 8.21 (dd, 1 H, J = 8.79, 1 .62 Hz); 7.12 (d, 1 H, J = 8.82 Hz); 4.14 (t, 2H, J = 6.39 Hz) ; 1 .94 - 1 .82 (m, 2H); 1 .07 (t, 3H, J = 7.35 Hz).

Step B: 3-(3-lodo-4-isopropoxyphenyl)-5-(3-nitro-4-propoxyphenyl)- 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 66% yield, as creamy solid. ¹ H NMR (CDCI₃) 8.64 (d, 1 H, J = 2.13 Hz) ; 8.55 (d, 1 H, J = 2.1 Hz); 8.3 (dd, 1 H, J = 8.82, 2.16 Hz); 8.2 (dd, 1 H, J = 8.58, 2.01 Hz); 7.2 (d, 1 H, J = 8.88 Hz); 6.96 (d, 1 H, J = 8.85 Hz); 4.7 - 4.62 (m, 1 H) ; 4.16 (t, 2H, J = 6.39 Hz); 1 .94 - 1 .84 (m, 2H); 1 .42 (d, 6H, J = 6.03 Hz) ; 1 .08 (t, 3H, J = 7.35 Hz).

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. ¹ H NMR (CDCI₃) 8.65 (d, 1 H, J = 2.16 Hz); 8.47 (d, 1 H, J = 1 .95 Hz) ; 8.3 (dd, 1 H, J = 8.82, 2.19 Hz); 8.03 (dd, 1 H, J = 8.49, 2.01 Hz); 7.21 (d, 1 H, J = 8.88 Hz); 7.08 (d, 1 H, J = 8.49 Hz); 4.17 (t, 2H, J = 6.39 Hz); 1 .96 - 1 .84 (m, 2H); 1 .09 (t, 3H, J = 7.38 Hz).

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: 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 54% yield, as pale solid. ¹ H NMR (CDCI₃) 8.68 (d, 1 H, J = 2.16 Hz); 8.35 - 8.31 (m, 2H); 8.06 (dd, 1 H, J = 8.64, 1 .71 Hz); 7.54 (d, 1 H, J = 8.64 Hz); 7.21 (d, 1 H, J = 8.97 Hz); 6.76 (s, 1 H); 5.33 (s, 1 H) ; 4.3 - 3.95 (m, 6H) ; 2.41 - 1 .87 (m, 2H); 1 .58 - 1 .21 (m, 15H) ; 1.09 (t, 3H, J = 7.44 Hz). Step E: 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane-1 ,3-diol: When the product of Step D was substituted for 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 in Example 3, Step E, the similar procedure afforded the title compound in 49% yield, as creamy solid. ¹ H NMR (DMSO-d₆) 8.6 (s, 1 H) ; 8.37 (d, 1 H, J = 8.37 Hz) ; 8.31 (s, 1 H) ; 7.94 (d, 1 H, J = 8.52 Hz); 7.68 (d, 1 H, J = 8.52 Hz) ; 7.59 (d, 1 H, J = 8.82 Hz); 6.91 (s, 1 H) ; 4.87 (b, 2H); 4.23 (t, 2H, J = 5.82 Hz); 3.67 (d, 2H, J = 10.05 Hz); 3.58 (d, 2H, J = 9.96 Hz); 1 .78 - 1 .71 (m, 2H) ; 0.97 (t, 3H, J = 7.26 Hz).

Example 16

5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1 ,2,4-oxadiazol-5-yl)-2- propoxybenzonitrile

Step A: 3-Cyano-4-propoxybenzoic acid: To a stirred solution of 3-bromo-4- propoxybenzaldehyde (0.6 g, 2.47 mmol) in anhydrous DMF (5 ml) CuCN (0.67 g; 7.4 mmol) was added and the mixture was stirred for 4 h at reflux. After cooling to room temperature, the mixture was treated with EtOAc (50 ml) and 1 M HCI (10 ml) and stirred for 15 min. The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was evaporated to dryness to give 5-formyl-2-propoxybenzonitrile (0.41 g; 88%), as yellow oil ¹ H NMR (CDCI₃) 9.87 (s, 1 H) ; 8.07 (d, 1 H, J = 1 .95 Hz) ; 8.03 (dd, 1 H, J = 8.67, 2.1 Hz) ; 7.06 (d, 1 H, J = 8.7 Hz); 4.13 (t, 2H, J = 6.45 Hz); 1 .97 - 1 .85 (m, 2H); 1.1 (t, 3H, J = 7.35 Hz). The above benzaldehyde was oxidised via a similar procedure as described in Example 47 Step A, to give the title compound (0.29 g; 68%), as white solid. ¹ H NMR (CDCIg) 8.3 (d, 1 H, J = 1 .71 Hz) ; 8.23 (dd, 1 H, J = 8.88, 2.1 Hz); 7.00 (d, 1 H, J = 7.62 Hz); 4.12 (t, 2H, J = 6.48 Hz); 1 .97 - 1 .85 (m, 2H); 1 .09 (t, 3H, J = 7.38 Hz).

Step B: 5-(3-(3-lodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile: 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 57% yield, as creamy solid. ¹ H NMR (CDCI₃) 8.55 (d, 1 H, J = 2.1 Hz) ; 8.4 (d, 1 H, J = 2.1 Hz) ; 8.31 (dd, 1 H, J = 8.85, 2.16 Hz) ; 8.04 (dd, 1 H, J = 8.61 , 2.1 Hz) ; 7.09 (d, 1 H, J = 8.94 Hz); 6.88 (d, 1 H, J = 8.7 Hz); 4.7 - 4.6 (m, 1 H); 4.14 (t, 2H, J = 6.48 Hz); 1 .98 - 1 .87 (m, 2H); 1.42 (d, 6H, J = 6.06 Hz) ; 1 .18(t, 3H, J = 7.38 Hz).

Step C: 5-(3-(4-Hydroxy-3-iodophenyl)- 1 ,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile: 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 74% yield, as creamy solid. ¹ H NMR (CDCIg) 8.46 (d, 1 H, J = 1 .95 Hz) ; 8.4 (d, 1 H, J = 2.13 Hz) ; 8.31 (dd, 1 H, J = 8.88, 2.19 Hz); 8.02 (dd, 1 H, J = 8.49, 1 .68 Hz); 7.1 (d, 1 H, J = 8.94 Hz); 7.09 (d, 1 H, J = 8.49 Hz); 5.64 (bs, 1 H); 4.12 (t, 2H, J = 6.48 Hz); 2.02 - 1 .86 (m, 2H); 1.1 (t, 3H, J = 7.38 Hz).

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. ¹ H NMR (CDCI₃) 8.42 (d, 1 H, J = 2.16 Hz); 8.34 (dd, 1 H, J = 6.63, 2.19 Hz); 8.06 (dd, 1 H, J = 8.61 , 1.71 Hz); 7.99 (b, 1 H); 7.52 (d, 1 H, J = 8.58 Hz) ; 7.1 (d, 1 H, J = 8.94 Hz) ; 6.76 (s, 1 H); 5.33 (s, 1 H) ; 4.26 (t, 4H, J = 1 1 .4 Hz); 4.15 (t, 2H, J = 1 1 .4 Hz) ; 4.15 (t, 2H, J = 6.48 Hz); 2.02 - 1 .87 (m, 2H) ; 1 .56 - 1 .38 (m, 15H); 1 .1 (t, 3H, J = 7.38 Hz).

Step E: 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)benzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-propoxy benzonitrile: When 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. ¹H NMR (DMSO-d₆) 8.49 (d, 1 H, J = 2.22 Hz); 8.39 (dd, 1 H, J = 8.91 , 2.22 Hz); 8.28 (d, 1 H, J = 1 .41 Hz) ; 7.93 (dd, 1 H, J = 8.55, 1 .71 Hz); 7.68 (d, 1 H, J = 8.58 Hz) ; 7.48 (d, 1 H, J = 9.06 Hz); 6.89 (s, 1 H); 4.78 (b, 2H) ; 4.22 (t, 2H, J = 6.42 Hz); 3.68 - 3.52 (m, 4H) ; 1 .84 - 1 .73 (m, 2H) ; 1.0(t, 3H, J = 7.41 Hz).

Example 17

2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

Step A: 3-Bromo-4-propoxybenzoic acid: 3-Bromo-4-propoxybenzaldehyde was oxidized by KMn0₄, according to the procedure as described in Example 14, Step A, to give the title compound in 96%, as white solid. ¹ H-NMR (DMSO-d₆) 0.98 (t, 3H, J = 7.32 Hz); 1 .68 - 1 .79 (m, 2H); 4.06 (t, 2H, J = 6.39 Hz); 7.14 (d, 1 H, J = 8.7 Hz) ; 7.87 (dd, 1 H, J = 2.07, 8.61 Hz); 8.01 (d, 1 H, J = 2.04 Hz); 1 1 .2 (broad s, 1 H).

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. ¹ H NMR (CDCI₃) 8.47 (s, 1 H) ; 8.38 (s, 1 H); 8.08 (d, 1 H, J = 9.09 Hz); 8.03 (d, 1 H, J = 8.79 Hz); 7.7 (d, 1 H, J = 8.55 Hz) ; 6.98 (d, 1 H, J = 8.67 Hz); 4.08 (t, 2H, J = 6.39 Hz); 1 .96 - 1 .84 (m, 2H); 1 .1 (t, 3H, J = 7.35 Hz).

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: When the product of Step C is 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 10% yield, as light yellow solid. ¹ H NMR (CD₃OD) 8.32 (b, 2H) ; 8.1 (d, 1 H, J = 8.46 Hz); 8.00 (d, 1 H, J = 8.52 Hz) ; 7.59 (d, 1 H, J = 8.61 Hz) ; 7.18 (d, 1 H, J = 8.58 Hz); 6.91 (s, 1 H); 4.1 (t, 2H, J = 6.06 Hz) ; 3.91 (d, 2H, J = 10.98 Hz) ; 3.03 (d, 2H, J = 10.95 Hz) ; 3.32 (b, 2H); 1 .9 - 1 .8 (m, 2H); 1 .1 (t, 3H, J = 7.35 Hz).

Example 18

2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1 ,3-diol

Step A: 2-lodo-4-octylaniline: To a stirred mixture of 4-octyl aniline (0.33 g, 1 .6 mmol) and H₂0₂ (30 %, 0.5 ml) in CH₃OH (1.5 ml) was added l₂ (0.2 g, 0.8 mmol) and the mixture was stirred for overnight at room temperature ( ref; Journal of medicinal chemistry, 2005, 48 (18), 5832) when a solid separated out. The solvent was distilled and the crude was taken in CH₂CI₂ (10 ml), washed with water and dried over MgS0₄. The solvent was distilled to gave the title compound (0.46 g, 86%) as yellow paste. ¹ H NMR (CDCI₃) 7.44 (d, 1 H, J = 1 .83 Hz) ; 6.93 (dd, 1 H, J = 8.07, 1 .86 Hz); 6.65 (d, 1 H, J = 8.1 Hz); 4.1 (b, 2H) ; 2.43 (t, 2H, J = 7.5 Hz) ; 1 .54 - 1 .49 (m, 2H); 1.26 (b, 10H) ; 0.87 (t, 3H, J = 6.39 Hz).

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^SC was added ice cold solution of NaN0₂ (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 CS₂ (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. (JOC, 1999, 64 (26), pp-9650)] and the content was brought to 55 ^SC for 5 hrs. The mixture was extracted with EtOAc and washed with H₂0. The organic layer was separated and dried over MgS0₄. The solvent was distilled and the crude was taken in EtOH (20 ml) and KOH (500 mg, 3.62 mmol) was added and mixture was stirred at reflux for 5 hrs. The solvent was distilled and the crude was treated with 1 M HCI and extreacted with EtOAc. The organic layer was separated and dried over MgS0₄. The solvent was distilled and the crude was purifies over Si0₂ column to gave the title compound (0.1 g, 24%) as a yellow paste which was containing impurity and was used as such for next step. ¹ H NMR (CDCI₃) 7.75 (b, 1 H) ; 7.28 (d, 1 H, J = 7.95 Hz) ; 7.00 (dd, 1 H, J = 7.95, 2.0 Hz); 7.02 (s, 1 H); 2.51 - 2.45 (m, 2H); 1 .53 (b, 2H); 1 .25 (b, 10H) ; 0.86 (t, 3H, J = 6.42 Hz).

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. ¹ H NMR (CDCI₃) 7.65 (d, 1 H, J = 8.16 Hz) ; 7.47 (s, 1 H); 7.1 (d, 1 H, J = 6.18 Hz); 7.1 (s, 1 H); 5.44 (b, 1 H) ; 4.16 (b, 4H); 2.66 (t, 2H, J = 7.5 Hz); 1 .6 - 1 .1 (m, 27 H); 0.86 (t, 3H, J = 6.18 Hz).

Step D: 2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1,3-diol: When 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. ¹ H NMR (CD₃OD) 7.74 (d, 1 H, J = 8.28 Hz); 7.6 (s, 1 H); 7.4 (s, 1 H); 7.2 (dd, 2H, J = 8.34, 1 .59 Hz) ; 4.0 (d, 2H, J = 1 1 .46 Hz); 3.94 (d, 2H, J = 1 1 .46 Hz); 2.7 (t, 2H, J = 7.53 Hz); 1 .64 (b, 2H); 1 .34 - 1 .26 (b, 10H); 0.85 (t, 3H, J = 4.8 Hz). Example 19

2-Amino-2-(5-octylbenzofuran-2-yl)propane-1 ,3-diol

Step A: 2-lodo-4-octylphenol: A mixture of 4-octyl phenol (0.15 g, 0.73 mmol), silver trifluro acetate (0.25 g, 1 mmol) and l₂ (0.185 g, 0.73 mmol) was stirred at 0 ^SC for 0.5 hr and then at room temperature for 0.5 hr. The solution was filtered through celite bead and washed with CH₂CI₂ (30 ml). The solvent was distilled to give the title compound (0.21 g, 87%) as fawn oil. ¹ H NMR (CDCI₃) 7.32 (d, 1 H, J = 8.34 Hz) ; 7.28 (d, 1 H, J = 1 .26 Hz); 6.98 (dd, 1 H, 8.37, 1 .71 Hz) ; 6.62 (s, 1 H) ; 4.69 (t, 2H, J = 5.88 Hz); 3.62 - 3.38(m, 4H); 2.59 (t, 2H, J = 7.29 Hz); 1 .56 - 1 .51 (m, 2H); 1 .34 - 1 .2 (m, 10H); 0.81 (t, 3H, J = 6.48 Hz). 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. ¹ H NMR (CDCI₃) 7.33 (d, 1 H, J = 6.27 Hz); 7.32 (s, 1 H); 7.01 (dd, 1 H, J = 8.4, 1 .71 Hz) ; 6.59 (s, 1 H); 5.3 (s, 1 H); 4.17 (s, 4H) ; 2.64 (t, 2H, J = 7.77 Hz); 1 .62 - 1 .24 (m, 27H); 0.86 (t, 3H, J = 6.42 Hz).

Step C: 2-Amino-2-(5-octylbenzofuran-2-yl)propane-1,3-diol: When 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. ¹ H NMR (DMSO-d₆) 7.44 (d, 1 H, J = 1 .98 Hz); 7.0 (dd, 1 H, J = 8.28, 1 .98 Hz) ; 6.87 (d, 1 H, J = 8.22 Hz); 5.1 1 (s, 1 H); 2.47 (t, 2H, J = 7.5 Hz); 1 .56 - 1 .51 (m, 2H) ; 1 .27 - 1 .26 (m, 10H); 0.87 (t, 3H, J = 6.45 Hz).

Example 20

2-Amino-2-(5-(5-(2-cyclopropylbenzofuran-5-yl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H NMR (CDCI₃) 8.59 (d, 1 H, J = 2.04 Hz), 8.29(d, 1 H, J = 1 .44 Hz), 8.09 - 8.02(m, 2H), 7.46 (d, 1 H, J = 8.61 Hz), 6.9 (d, 1 H, J = 8.7 Hz), 6.45(s, 1 H), 4.7 - 4.6 (m, 1 H), 2.1 - 2.0(m, 1 H), 1 .42(d, 6H, J = 5.97 Hz), 1 .0 (b, 4H).

Step B: 4-(5-(2-Cyclopropylbenzofuran-5-yl)- 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- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 69% yield, as white solid. ¹ H-NMR (CDCI₃) 8.5 (d, 1 H, J = 1 .98 Hz), 8.29(d, 1 H, J = 1 .59 Hz), 8.07 - 8.02(m, 2H), 7.47(d, 1 H, J = 8.58 Hz), 7.08(d, 1 H, J = 8.49 Hz), 6.45(s, 1 H), 5.63(s, 1 H), 2.1 - 2.0(m, 1 H), 1 .0(b, 4H).

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

(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. ¹ H-NMR (DMSO-d₆) 8.33 (bs, 1 H), 7.99(bs, 2H), 7.7(bs, 2H), 6.97(s, 1 H), 6.75(bs, 1 H), 5.04(bs, 2H), 3.71 (bs, 2H), 3.66(bs, 2H), 2.15(bs, 1 H), 0.95(d, 4H).

Example 21

2-Amino-2-(5-(5-(4-isobutoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

Step A: 3-(3-lodo-4-isopropoxyphenyl)-5-(4-isobutoxyphenyl)- 1 ,2,4-oxadiazole: When 3-chloro-4-propoxybenzoic acid was substituted for 4-/^'so-butoxybenzoic acid [¹ H- NMR (DMSO-d₆) 7.77(b, 2H), 6.98(b, 2H), 3.78(b, 2H), 1 .99(b, 1 H), 0.94(d, 6H, J = 6.06 Hz] in Example 3, Step B, the similar process afforded the title compound in 54% yield, as creamy paste. ¹ H-NMR (CDCI₃) 8.57 (d, 1 H, J = 2.07 Hz), 8.1 (d, 2H, J = 6.93 Hz), 8.04 (dd, 1 H, J = 8.55, 2.01 Hz), 6.99(d, 2H, J = 8.91 Hz), 6.87 (d, 1 H, J = 8.73 Hz), 4.69 - 4.6(m, 1 H), 3.79(d, 2H, J = 6.54 Hz), 2.18 - 2.06(m, 1 H), 1 .41 (d, 6H, J = 6.03 Hz), 1 .04(d, 6H, J = 6.72 Hz).

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. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .98 Hz), 8.1 (d, 2H, J = 8.91 Hz), 8.03 (dd, 1 H, J = 8.46, 1 .98 Hz), 7.07 (d, 1 H, J = 8.5 Hz), 7.0(d, 2H, J = 8.94 Hz), 3.79 (d, 2H, J = 6.54 Hz), 2.14 - 2.07 (m, 1 H), 1.04 (d, 6H, J = 6.69 Hz).

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: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxy phenyl)- 1 ,2,4- oxadiazol-3-yl)- 2-iodophenol in Example 3, Step D, the similar process afforded the title compound in 61 % yield, as pale paste. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .38 Hz), 8.13(d, 2H, J = 8.91 Hz), 8.07 (dd, 1 H, J = 8.67, 1 .71 Hz), 7.52(d, 1 H, J = 8.61 Hz), 7.02(d, 2H, J = 8.91 Hz), 6.75(s, 1 H), 5.33(s, 1 H), 4.29 - 4.24(m, 4H), 3.8(d, 2H, J = 6.54 Hz), 2.2 - 2.5 (m, 1 H), 1 .56(s, 6H), 1 .52(s, 9H), 1 .04(d, 6H, J = 6.72 Hz).

Step D: 2-Amino-2-(5-(5-(4-isobutoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol: When the product of Step D 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 46% yield, as colourless solid. ¹ H-NMR (DMSO-d₆) 8.27 (s, 1 H), 8.08 (d, 2H, J = 7.23 Hz), 7.92 (d, 1 H, J = 7.59 Hz), 7.66 (d, 1 H, J = 7.62 Hz), 7.15 (d, 1 H, J = 7.62 Hz), 6.88 (s, 1 H), 4.78 (bs, 2H), 3.84 (d, 2H, J = 5.4 Hz), 3.64 (bs, 2H), 3.56 (bs, 1 H), 2.02(b, 1 H), 0.96(d, 6H, J = 5.49 Hz).

Example 22

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: 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. ¹H-NMR (CDCI₃) 8.45 (s, 1 H), 7.77 (dd, 1 H, J = 8.43, 2.01 Hz), 7.66 (d, 1 H, J = 1 .98 Hz), 6.97 (d, 1 H, J = 8.5 Hz), 6.92 (s, 1 H), 4.67 - 4.56 (m, 1 H), 4.23 - 4.14 (m, 6H), 1 .52 - 1 .46 (m, 6H), 1 .42 (d, 6H, J = 6.06 Hz).

Step B: 5-Chloro-4-(5-(3,4-diethoxyphenyl)- 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- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 64% yield, as white solid. ¹H-NMR (CDCI₃) 8.35 (s, 1 H), 7.77 (dd, 1 H, J = 8.43, 2.01 Hz), 7.65 (d, 1 H, J = 2.01 Hz), 7.16 (s, 1 H), 6.97(d, 1 H, J = 8.49 Hz), 4.23 - 4.14 (m, 4H), 1 .52 - 1 .46 (m, 6H).

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: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxy phenyl)- 1 ,2,4- oxadiazol-3-yl)- 2-iodophenol in Example 3, Step D, the similar process afforded the title compound in 57% yield, as creamy solid. ¹ H-NMR (CDCI₃) 8.1 1 (s, 1 H), 7.79 (dd, 1 H, J = 8.43, 1.92 Hz), 7.67 (d, 1 H, J = 1 .95 Hz), 7.63 (s, 1 H), 6.97 (d, 1 H, J = 8.55 Hz), 6.73(s, 1 H), 5.3(s, 1 H), 4.28 - 4.16(m, 8H), 1 .54 - 1 .39 (m, 21 H).

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: When 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 42% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.12 (bs 1 H), 7.9(bs, 1 H), 7.74(bs, 1 H), 7.59(bs, 1 H), 7.18(bs, 1 H), 6.88(bs, 1 H), 4.82(bs, 2H), 4.12(bs, 4H), 3.64(b, 4H), 1 .34(b, 6H). Example 23

2-Amino-2-(5-(5-(3-chloro-4-methoxyphenyl)-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. ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.04 Hz), 8.21 (d, 1 H, J = 2.1 Hz), 8.07 (dd, 1 H), 7.55 (dd, 1 H, J = 8.61 , 2.04 Hz), 7.04(d, 1 H, J = 8.67 Hz), 6.88 (d, 1 H, J = 8.7 Hz), 4.69 - 4.59 (m, 1 H), 3.99(s, 3H), 1 .42(d, 6H, J = 6.03 Hz).

Step B: 4-(5-(3-Chloro-4-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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 62% yield, as white solid. ¹ H-NMR (CDCI₃) 8.46 (d, 1 H, J = 1 .89 Hz), 8.21 (d, 1 H, J = 2.01 Hz), 8.01 (dd, 1 H, J = 8.76, 1.98 Hz), 7.52 (dd, 1 H, J = 8.58, 1 .95 Hz), 7.06(d, 1 H, J = 8.28 Hz), 7.01 (d, 1 H, J = 8.61 Hz), 3.99(s, 3H).

Step C: 2-Amino-2-(5-(5-(3-chloro-4-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: When 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- 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 32% yield, as white solid. ¹ H-NMR (DMSO-d₆) 8.31 (s, 1 H), 8.16 - 8.1 (m, 2H), 7.95 (d, 1 H, J = 8.22 Hz), 7.69 (d, 1 H, J = 8.37 Hz), 7.39 (d, 1 H, J = 8.7 Hz), 6.94 (s, 1 H), 4.96(bs, 2H), 3.96(s, 3H), 3.68(bs, 2H), 3.64(bs, 2H).

Example 24

2-Amino-2-(5-(5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.58 (d, 1 H, J = 2.07 Hz), 8.06 (dd, 1 H, J = 8.58, 2.07 Hz), 7.8 (dd, 1 H, J = 8.4, 1 .95 Hz), 7.66 (d, 1 H, J = 1 .89 Hz), 6.98(d, 1 H, J = 8.46 Hz), 6.88 (d, 1 H, J = 8.73 Hz), 4.69 - 4.57 (m, 1 H), 4.0(s, 3H), 3.96(s, 3H), 1 .41 (d, 6H, J = 6.09 Hz).

Step B: 4-(5-(3,4-Dimethoxyphenyl)-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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 55% yield, as white solid. ¹ H-NMR (CDCI₃) 8.49 (d, 1 H, J = 1 .83 Hz), 8.04 (dd, 1 H, J = 8.58, 2.04 Hz), 7.81 (dd, 1 H, J = 8.22, 1 .59 Hz), 7.66 (d, 1 H, J = 1 .71 Hz), 7.07(d, 1 H), 6.98(d, 1 H), 4.0(s, 3H), 3.97(s, 3H).

Step C: 2-Amino-2-(5-(5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol: When 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)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 15% yield, as white solid. ¹ H-NMR (DMSO-d₆) 8.32 (bs, 1 H), 7.95 (b, 1 H), 7.76(b, 1 H), 7.7(b, 1 H), 7.2(b, 1 H), 6.95(b, 1 H), 5.03(b, 2H), 3.86(b, 6H), 3.65(b, 4H).

Example 25

2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.01 Hz), 8.21 (d, 1 H, J = 2.04 Hz), 8.07 - 8.24 (m, 2H), 7.02(d, 1 H, J = 8.67 Hz), 6.87 (d, 1 H, J = 8.67 Hz), 4.72 - 4.6 (m, 1 H), 4.19 (q, 2H, J = 6.96, 13.95 Hz), 1 .52 (t, 3H, J = 6.93 Hz), 1 .42 (d, 6H, J = 6.03 Hz).

Step B: 4-(5-(3-Chloro-4-ethoxyphenyl)-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-4- isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound in 68% yield, as white solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .95 Hz), 8.21 (d, 1 H, J = 2.1 Hz), 8.05 - 8.01 (m, 2H), 7.08(d, 1 H, J = 8.49 Hz), 7.02 (d, 1 H, J = 8.67 Hz), 4.2 (q, 2H, J = 6.96, 13.98 Hz), 1 .52 (t, 3H, J = 6.99 Hz).

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: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxy phenyl)- 1 ,2,4- oxadiazol-3-yl)- 2-iodophenol in Example 3, Step D, the similar process afforded the title compound in 55% yield, as pale paste. ¹ H-NMR (CDCI₃) 8.33 (d, 1 H, J = 1 .38 Hz), 8.24 (d, 1 H, J = 2.13 Hz), 8.08 - 8.05 (m, 2H), 7.52(d, 1 H, J = 8.76 Hz), 7.0 (d, 1 H, J = 8.7 Hz), 6.75 (s, 1 H), 5.32 (bs, 2H), 4.22 (q, 2H, J = 5.94, 12.78 Hz), 1 .54 - 1 .36 (m, 18H).

Step D: 2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1,3-diol: When 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 35% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.3 (d, 1 H, J = 1 .35 Hz), 8.16 (d, 1 H, J = 2.04 Hz), 8.1 (dd, 1 H, J = 8.64, 2.1 Hz), 7.94 (dd, 1 H, J = 8.64, 1 .71 Hz), 7.68 (d, 1 H, J = 8.46 Hz), 7.38(d, 1 H, J = 8.7 Hz), 6.91 (s, 1 H), 4.86 (bs, 2H), 4.24 (q, 2H, J = 6.93, 13.89 Hz), 3.7 - 3.65 (m, 2H), 3.6 - 3.29 (m, 2H), 1 .38 (t, 3H, J = 6.96 Hz). Example 26

5-(3-(2-(2-amino-1 ,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1 ,2,4-oxadiazol-5-yl)-2- ethoxybenzonitrile

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-d₆) 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. ¹H-NMR (CDCI₃) 8.6 (b, 1 H), 8.51 (b, 1 H), 8.33 (dd, 1 H, J = 8.85, 2.16 Hz), 8.04 (dd, 1 H, J = 8.58, 2.13 Hz), 7.1 (d, 1 H, J = 8.94 Hz), 6.88 (d, 1 H, J = 8.73 Hz), 4.69 - 4.57 (m, 1 H), 4.25 (q, 2H, J = 6.99, 14.01 Hz), 1 .55 - 1 .5 (m, 9H).

Step B: 2-ethoxy-5-(3-(4-hydroxy-3-iodophenyl)-1 ,2,4-oxadiazol-5-yl)benzonitrile:

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. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .98 Hz), 8.4 (d, 1 H, J = 2.16 Hz), 8.32 (dd, 1 H, J = 8.9, 2.19 Hz), 8.02 (dd, 1 H, J = 8.49, 2.01 Hz), 7.12 - 7.07 (m, 2H), 4.26 (q, 2H, J = 7.02, 14.01 Hz), 1 .53 (t, 3H, J = 7.02 Hz). Step C: 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)benzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-ethoxybenzonitrile: When 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)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 32% yield, as pale solid. ¹ H-NMR (DMSO-de) 8.48 (s, 1 H), 8.39 (d, 1 H, J = 8.61 Hz), 8.31 (s, 1 H), 7.95 (d, 1 H, J = 7.77 Hz), 7.69 (d, 1 H, J = 8.61 Hz), 7.48 (d, 1 H, J = 9.06 Hz), 6.94 (s, 1 H), 4.99 (bs, 2H), 4.31 (bd, 2H, J = 6.84 Hz), 3.69 (bs, 2H), 3.63 (bs, 2H), 1 .39 (bs, 3H).

Example 27

2-amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-7-methyl- benzof uran-2-yl)propane-1 ,3-diol

Step A: N-Hydroxy-3-iodo-4-isopropoxy-5-methylbenzimidamide: (a) 4-Bromo-2- methylphenol: To a stirred solution of 2-methylphenol (1 gm, 9.3 mmol) in DCM (20 mL) at 0 ^SC was added bromine (500 μί, 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. ¹ H-NMR (CDCIg) 7.16 (dd, 1 H, J = 8.43, 2.4 Hz), 6.63 (d, 1 H, J = 8.46 Hz), 5.03 (s, 1 H), 2.2 (s, 3H). (b) 4-Hydroxy-3-methylbenzonitrile: The above product (1.2 gm, 6.42 mmol) was dissolved in dry DMF (5 mL) and CuCN (820 mg, 9 mmol) was added to it. The content was stirred at reflux for 7 hrs, brought to room temperature, poured in 1 M HCI (100 mL), stirred for 0.5 hr and diluted with ethyl acetate (100 mL). The organic layer was separated and dried over magnesium sulphate, passed through silica gel bead and the solvent was distilled to gave the product (920 mg) as pale oil. ¹ H-NMR (CDCI₃) 8.0(s, 1 H), 7.37 - 7.31 (m, 2H), 6.85 (d, 1 H, J = 8.28 Hz), 2.22 (s, 1 H). (c) 3-lodo-4-isopropoxy- 5-methylbenzonitrile: To a stirred solution of above product (850 mg, 6.4 mmol) in ammonium hydroxide solution (30 mL) was added a solution of iodine (1 .62 gm, 6.4 mmol) and Kl (3.2 gm, 19.2 mmol) in water (5 mL) and the mixture was stirred for overnight. The solvent was distilled and the crude was taken in 1 M HCI (5 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over magnesium sulphate and the solvent was distilled to gave the product (1 .1 gm, 66%) as pale paste which was dissolved in dry DMF (8 imL), potassium carbonate (700 mg, 5 mmol) was added follwed by the addition of 2 bromo propane (1 .5 ml_, excess) and the mixture was stirred at reflux for 3 hrs. Thew contenet was diluted with water (30 ml.) and extracted with ethyl acetate (50 ml. x 2). The organic layer was washed with water and dried over magnesium sulphate. The solvent was distilled to gave the product (990 mg, 78%) as pale oil. ¹ H-NMR (CDCI₃) 7.9 (d, 1 H, J = 1 .95 Hz), 7.42 (d, 1 H, J = 1 .29 Hz), 4.62 - 4.53 (m, 1 H), 2.3 (s, 3H), 1 .34(d, 6H, J = 6.15 Hz), (d) N-Hydroxy-3-iodo-4- isopropoxy-5-methylbenzimidamide: The above product (890 mg, 3.3 mmol), hydroxylamine hydrochloride (350 mg, 5 mmol) and sodium carbonate (530 mg, 5 mmol) were stirred in ethanol (40 ml.) for 36 hrs at room temperature. The solution was filtered and the solvent was distilled to gave the pale paste (1 .13 gm) which solidified on standing. ¹ H-NMR (CDCI₃) 7.86 (d, 1 H, J = 2.04 Hz), 7.4 (d, 1 H, J = 1 .62 Hz), 4.79 (b, 2H), 4.54 - 4.46 (m, 1 H), 2.29 (s, 3H), 1 .33(d, 6H, J = 6.15 Hz).

Step B: 5-(3-Chloro-4-ethoxyphenyl)-3-(3-iodo-4-isopropoxy-5-methylphenyl)- 1,2,4- oxadiazole: When 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, ¹ H-NMR (CDCI₃) 8.41 (d, 1 H, J = 1 .8 Hz), 8.21 (d, 1 H, J = 1 .8 Hz), 8.04(d, 1 H, J = 2.1 Hz), 8.03(s, 1 H), 7.02(d, 1 H, J = 8.67 Hz), 4.61 - 4.47 (m, 1 H), 4.23 - 4.14 (m, 2H), 2.36 (s, 3H), 1 .36 (t, 3H, J = 5.22 Hz).

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

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. ¹ H-NMR (CDCI₃) 8.29 (d, 1 H, J = 1 .74 Hz), 8.21 (d, 1 H, J = 1 .8 Hz), 8.03(dd, 1 H, J = 8.64, 2.13 Hz), 7.89(s, 1 H), 7.0(d, 1 H, J = 8.64 Hz), 5.58 (s, 1 H), 4.2(q, 2H, J = 13.92, 6.9 Hz), 2.37(s, 3H), 1 .51 (t, 3H, J = 7.02 Hz).

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: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxy phenyl)-1 ,2,4-oxadiazol-3-yl)-2- iodophenol in Example 3, Step D, the similar process afforded the title compound in 57% yield, as pale paste. ¹ H-NMR (CDCI₃) 8.25 (d, 1 H, J = 2.13 Hz), 8.16 (d, 1 H, J = 1 .1 1 Hz), 8.06 (dd, 1 H), 7.88(s, 1 H), 7.03(d, 2H, J = 8.7 Hz), 6.73(s, 1 H), 5.32(s, 1 H), 4.3 - 3.91 (m, 6H), 2.55(s, 3H), 1 .53 - 1 .39(m, 18H). 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: When the 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-yl carbamate in Example 3, Step E, the similar procedure afforded the title compound in 45% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.17 - 8.12 (m, 3H), 7.79 (s, 1 H), 7.37 (d, 1 H, J = 8.76 Hz), 6.9(s, 1 H), 4.9(s, H), 4.24(t, 2H), 3.68(b, 2H), 3.63 (b, 2H), 2.52 (s, 3H), 1 .38(t, 3H, J = 6.93 Hz).

Example 28

2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-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. ¹ H-NMR (CDCI₃) 8.43 (d, 1 H, J = 1 .98 Hz), 7.93 (d, 1 H, J = 1 .56 Hz), 7.76 (dd, 1 H, J = 8.43, 1 .98 Hz), 7.66 (d, 1 H, J = 1 .95 Hz), 6.96 (d, 1 H, J = 8.49 Hz), 4.61 - 4.53 (m, 1 H), 4.24 - 4.06 (m, 4H), 2.37 (s, 3H), 1 .52 - 1 .49 (m, 6H), 1 .37 (d, 6H, J = 6.21 Hz).

Step B: 4-(5-(3,4-Diet oxy phenyl)- 1,2,4-oxadiazol-3-yl)-2-iodo-6-methylphenol: 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 54% yield, as white solid. ¹ H-NMR (CDCI₃) 8.3 (d, 1 H, J = 2.9 Hz), 7.89 (d, 1 H, J = 1 .1 1 Hz), 7.76 (dd, 1 H, J = 8.43, 1 .98 Hz), 7.65 (d, 1 H, J = 1 .98 Hz), 6.96 (d, 1 H, J = 8.46 Hz), 5.58 (s, 1 H), 4.24 - 4.09 (m, 4H), 2.37 (s, 3H), 1 .53 - 1 .39 (m, 6H).

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: When the product of Step B was substituted for 4-(5-(3-chloro-4-propoxy phenyl)- 1 ,2,4- oxadiazol-3-yl)- 2- iodophenol in Example 3, Step D, the similar process afforded the title compound in 47% yield, as creamy paste. ¹H-NMR (CDCI₃) 8.18 (d, 1 H, J = 1 .41 Hz), 7.89 (s, 1 H), 7.79(dd, 1 H, J = 8.49, 2.01 Hz), 7.69 (d, 1 H, J = 1 .95 Hz), 6.98 - 6.96 (m, 2H), 6.73 (s, 1 H), 5.32(s, 1 H), 4.3 - 4.14(m, 8H), 2.55(s, 3H), 1 .51 - 1 .39 (m, 21 H).

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. ¹ H-NMR (CDCI₃) 8.15 (s, 1 H), 7.8(s, 1 H), 7.74(d, 1 H, J = 8.55 Hz), 7.61 (s, 1 H), 7.17 (d, 1 H, J = 8.52 Hz), 6.94(s, 1 H), 5.09(b, 2H), 4.13(q, 2H, J = 6.75, 13.1 Hz), 3.73 (b, 2H), 3.68(b, 2H), 2.53(s, 3H), 1 .38 - 1 .32(m, 6H).

Example 29

5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)-7-methylbenzofuran-5-yl)-1 ,2,4- oxadiazol-5-yl)-2-propoxybenzonitrile

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. ¹H-NMR (CDCI₃) 8.4 - 8.39 (m, 2H), 8.31 (dd, 1 H, J = 8.88, 2.16 Hz), 7.91 (d, 1 H, J = 1 .41 Hz), 7.09 (d, 1 H, J = 8.94 Hz), 4.61 - 4.53(m, 1 H), 4.14(t, 2H, J = 7.32 Hz), 2.36 (s, 3H), 1 .95 - 1.86 (m, 2H), 1 .36 (d, 6H, J = 6.18 Hz), 1 .1 (t, 3H, J = 7.41 Hz).

Step B: 5-(3-(4-Hydroxy-3-iodo-5-methylphenyl)- 1 ,2,4-oxadiazol-5-yl)-2- propoxybenzonitrile: 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 54.4% yield, as creamy white solid. ¹ H-NMR (CDCI₃) 8.4 (d, 1 H, J = 2.16 Hz), 8.33 - 8.28(m, 2H), 7.87(d, 1 H, J = 1 .02 Hz), 7.1 (d, 1 H, J = 8.94 Hz), 5.61 (s, 1 H), 4.14(t, 2H, J = 6.45 Hz), 2.37 (s, 3H), 1 .96 - 1 .89 (m, 2H), 1 .1 (t, 3H, J = 7.38 Hz).

Step C: 5-(3-(2-(2-Amino- 1,3-dihydroxypropan-2-yl)-7-methylbenzofuran-5-yl)- 1,2,4- oxadiazol-5-yl)-2-propoxybenzonitrile: When 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-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 43% yield, as creamy solid. ¹ H-NMR (DMSO-d₆) 8.46 (d, 1 H, J = 2.04 Hz), 8.37(dd, 1 H, J = 8.85, 1 .92 Hz), 8.12 (s, 1 H), 7.77(s, 1 H), 7.46(d, 1 H, J = 9.06 Hz), 6.89(s, 1 H), 4.93(bs, 2H), 4.2(t, 2H), 3.69(d, 2H, J = 10.53 Hz), 3.61 (d, 2H, J = 10.53 Hz), 2.51 (s, 3H), 1 .84 - 1 .72(m, 2H), 0.99(t, 3H, J = 7.38 Hz). Example 30

N-(5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1 ,2,4- oxadiazol-5-yl)-2-ethoxyphenyl)methanesulfonamide

Step A: 4-Ethoxy-3-nitrobenzoic acid: A mixture of 4-hydroxy-3-nitrobenzoic acid (0.22 g, 1 .2 mmol), K₂C0₃ (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 N₂. The mixture was concentrated in vacuo to about 2 ml, diluted to 30 ml with Et₂0, washed with H₂0 (3 x 10 ml), brine and dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness to give ethyl 4-ethoxy-3-nitro benzoate ( 0.27 g, 94%), as a creamy solid, which was used in the next step without further purification. ¹ H NMR (CDCI₃) 8.44 (d, 1 H, J = 2 Hz), 8.16 (dd, 1 H, (m, 1 H, J = 2, 8.8 Hz); 7.08 (d, 1 H, J = 8.85 Hz); 4.32 - 4.41 (m, 2H) ; 4.19 -4.27 (m, 2H); 1 .41 - 1 .48 (m, 3H) ; 1 .33 - 1 .37 (m, 3H). The mixture of ethyl 4-ethoxy-3-nitro benzoate (0.27 g, 1 .13 mmol), KOH (0.19 g, 3.39 mmol) and H₂0 (5 ml) in dioxane (10 ml) was refluxed for 1.2 h and evaporated to dryness under reduced pressure. The residue diluted to 10 ml with H₂0, filtered and the filtrate acidified to pH ~ 3 with concentrated HCI. The product was taken up with EtOAc (20 ml). The organic phase was dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness to give the title compound (0.22 g, 92 %), as colourless solid, which was used in the next step without further purification. ¹H NMR (CDCI₃) 8.53 (d, 1 H, J = 3 Hz), 8.24 (dd, 1 H, J = 3, 9 Hz), 7.13 (d, 1 H, J = 9 Hz), 4.26 (q, 2H, J = 6Hz), 1 .5 (tr, 3H, J = 6 Hz).

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 CH₂CI₂, 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. To a solution of above product (0.19 g, 1 .05 g) and Na₂C0₃ (0.13 g, 1 .22 mmol) in H₂0 (3 ml) CH₃S0₂CI (0.095 ml, 1 .22 mmol) was added at 0°C, with vigorous stirring. The mixture was additionally stirred for 2 h at room temperature, acidified to pH ~ 3 with concentrated HCI and the solid formed was filtered off, washed with fresh H₂0 (2 x 1 ml) and dried in vacuo to give the title compound (0.12 g, 44%), as colourless solid, which was used in the next step without further purification. ¹ H NMR (CDCIg) 8.21 (d, 1 H, J = 2.1 Hz), 7.89 (dd, 1 H, J = 2.1 , 8.6 Hz), 6.94 (d, 1 H, J = 8.6 Hz), 6.86 (s, 1 H), 4.2 (q, 2H, J = 7 Hz), 3.5 (s, 3H0, 3.02 (s, 3H), 1.45 (tr, 3H, J = 6.6 Hz). ¹ H NMR (CD₃OD) 8.03 (d, 1 H, 2.1 Hz), 7.85 (dd, 1 H, J = 2.1 , 8.6 Hz), 4.2 (q, 2H, J = 7 Hz), 1 .46 (tr, 3H, J = 7 Hz).

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 N₂. To this 1 M TBAF in THF (0.5 ml) was added and the mixture was stirred for 1 h at ~ 120°C, cooled to room temperature and diluted to 80 ml with EtOAc. This was washed with H₂0 (5 x 10 ml), brine, dried over anhydrous MgS0₄ and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 7/3) to give the title compound (0.08 g, 32%), as colourless foam. ¹ H NMR (CDCI₃) 8.56 (s, 1 H), 8.06 (d, 1 H, J = 8.6 Hz); 7.96 (d, 1 H, J = 8.6 Hz); 7.02 (d, 1 H, J = 8.6 Hz), 6.9 (broad s, 1 H); 6.87 (d, 1 H, J =

8.6 Hz) ; 4.61 - 4.7 (m, 1 H); 4.17 - 4.25 (m, 2H) ; 3.06 (s, 3H) ; 1.4 - 1 .6 (m, 9H + H₂0).

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 CH₂CI₂ (0.5 ml) 1 M BCI₃ in CH₂CI₂ (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. To this H₂0 (1 ml) was added and the mixture was diluted to 20 ml with EtOAc, washed with H₂0 (2 x 5 ml), brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness to give the title compound (0.07 g, 97%), as colourless foam, which was used in the next step without further purification. ¹ H NMR (CD₃OD) 8.41 (m, 2H), 8.2 (d, 1 H, J = 2.1 Hz), 7.98 (dd, 1 H, J = 2.1 , 8.6 Hz), 7.15 (d, 1 H, J = 8.7 Hz), 6.93 (s, 1 H), 4.7 (H₂0), 4.25 (q, 2H, J = 7 Hz), 3.0 (s, 3H), 1 .48 (tr, 3H, J = 7 Hz).

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 Cu₂0 (0.02 g, 0.14 mmol) in anhydrous pyridine (1 ml) was degassed under reduced pressure and saturated with N₂. This was stirred for 5 h at ~1 10°C, under N₂, cooled to room temperature, diluted to 20 ml with EtOAc and filtered. The filtrate was washed with 5% solution of NH₄CI (pH 8, adjusted with NH₄OH), H₂0, brine and dried over anhydrous MgS0₄ and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 7/3) to give the title compound (0.03 g, 34%), as colourless foam. ¹ H NMR (CDCI₃) 8.35 (m, 2H),

8.07 (dd, 1 H, J = 1 .7, 8.6 Hz), 7.97 (dd, 1 H, J = 2.1 Hz), 7.52 (d, 1 H, J = *.6 Hz)), 7.03 (d, 1 H, J = 8.6 Hz), 6.94 (broad s, 1 H), 6.75 (s, 1 H), 5.35 (broad s, 1 H), 3.06 (s, 1 H), 1 .36 - 1 .63 (m, 18H +H₂0).

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 CH₃CN (1 ml) Me₃SiCI (0.1 ml) was added and the mixture was stirred for 1 h at room temperature under N₂. After evaporation of solvents under reduced pressure, the residue was diluted to 2 ml with EtOH, and re evaporated to dryness. The residue was purified by FCC (Si0₂, CH₂CI₂ saturated with NH₄OH/MeOH 9/1 ) to give the title compound (0.008 g, 35%), as colourless solid. ¹ H NMR (CD₃OD) 8.29 (s, 1 H), 8.2 (s, 1 H), 7.99 (d, 1 H, J = 8.4 Hz), 7.56 (d, 1 H, J = 8.4 Hz), 7.19 (d, 1 H, J = 8.7 Hz), 6.87 (broad s, 1 H, J = 8.4 Hz), 4.23 (q, 2H, J = 6.8 Hz), 3.86 (broad s, 1 H), 3.0 (s, 3H), 1 .48 (tr, 3H, J = 6.8 Hz).

Example 31

2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-1 H-indol-2- yl)propane-1 ,3-diol

Step A: 4-Amino-3-iodobenzonitrile: To a solution of 4-aminobenzonitrile (2.4 g 20 mmol) and -30% H₂0_{2 (}not titrated before use) in MeOH (30 ml) a solution of l₂ (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 H₂0₂ (2 ml) was added every day. The mixture was concentrated under reduced pressure and treated with saturated solution of Na₂S₂0₃ until most of the colour disappeared. The solid formed was filtered off, diluted to 300 ml with EtOAc, washed with saturated, H₂0, brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness. The residue was purified by crystallization from EtOH to give the title compound (3 g). The residue was recrystallised from the mixture of CH₂CI₂/hexane to give more of the title compound (1 .4 g). Total yield 4.4 g (88%). ¹ H NMR (CDCIg) 7.87 (d, 1 H, J = 1 .8 Hz) ; 7.37 (dd, 1 H, J = 1 .8, 8.4), 6.68 (d, 1 H, J = 8.4 Hz), 4.62 (broad s, 2H).

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(SiMe₃)₂ in THF (2.62 ml) in anhydrous THF (2 ml) was stirred at ~-5°C for 30 min under N₂. 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. The residue was diluted to 50 ml with EtOAc, washed with H₂0, brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness. The residue was purified by crystallization from MeOH to give the title compound (0.26 g, 70%), as colourless solid. ¹ H NMR (CDCI₃) 8.46 (d, 1 H, J = 9 Hz), 8.03 (s, 1 H), 7.58 - 7.63 (m, 2H), 2.27 (s, 3H).

Step C: N-(4-(N-(Hydroxymethyl)carbamirnidoyl)-2-iodophenyl) acetamide: A mixture of the product of Step B (0.26 g, 0.91 mmol), HCIxH₂NOH (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 N₂. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 ml) and H₂0 (5 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness to give the title compound (0.24 g, 82%), as colourless solid, which was used in the next step without further purification.

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 CH₂CI₂ (5 ml) DIPEA (0.14 ml, 0.81 mmol) was added at room temperature. This was refluxed for 2 h, diluted to 80 ml with EtOAc and washed with H₂0, brine, dried over anhydrous MgS04, filtered and filtrate evaporated to dryness to give the coupling product (0.26 g, 68%) as creamy solid. This was diluted to 2 ml with anhydrous DMSO and 1 M TBAF in THF was added. The mixture was stirred at for 1 h at ~1 10°C under N₂, cooled to room temperature and H₂0 (4 ml) was added. The solid formed, was filtered off, washed with fresh H₂0 (2 x 2 ml) and dried to give the title compound (0.24 g; 94%), as colourless solid. ¹ H NMR (CDCI₃) 8.57 (d, 1 H, J = 1 .9 Hz), 8.41 (d, 1 H, J = 8.4 Hz), 8.12 (dd, 1 H, 1 .9, 8.6 Hz), 7.77 (dd, 1 H, J = 2, 8.4 Hz), 7.66 (d, 1 H, J = 2 Hz), 7.58 (s, 1 H); 6.96 (d, 1 H, J = 8.5 Hz), 4.14 - 4.24 (m, 4H), 2.27 (s, 3H), 1 .47 - 1 .55 (m, 6H + H₂0).

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), PdCI₂(PPh₃)₂ (0.02 g) and Cul (0.01 g) in anhydrous DMF (2ml) was degassed in vacuo, and saturated with N₂. To it DIPEA (0.8 ml) was added and the mixture was stirred for 7 h at room temperature. The solvents were removed in vacuo and the residue was diluted to 30 ml with EtOAc, washed with H₂0, NH₄CI solution, brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. Under reduced pressure. The residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 9/1 ) to give the title compound (0.15 g, 49%), as colourless solid. ¹ H NMR (CDCI₃) 9.05 (s, 1 H), 8.65 (d, 1 H, J = 8.6 Hz), 8.08 - 8.13 (m, 2H), 7.77 (dd, 1 H, J = 1 .9, 8.4 Hz), 7.66 (d, 1 H, J = 1 .9 Hz), 6.96 (d, 1 H, J = 8.5 Hz), 5.51 (s, 1 H), 4.01 - 4.24 (m, 8H), 2.38 (s, 3H), 1 .46 - 1 .56 (m, 21 H + H₂0).

Step F: N-(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. This was washed with H20 (2 x 5 ml), brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 9/1 ) to give the title compound (0.02 g, 27%), as colourless solid. ¹ H NMR (CDCI₃) 8.39 (s, 1 H), 7.98 (dd, 1 H, J = 2, 8.6 Hz), 7.79 (dd, 1 H, J = 2, 8.4 Hz); 7.69 (d, 1 H, J = 2 Hz), 7.44 (d, 1 H, J = 8.5 Hz), 6.97 (d, 1 H, J = 8.5 Hz), 6.32 (d, 1 H, J = 1 .2 Hz), 6.18 (s, 1 H), 4.47 (d, 2H, J = 1 1 .9 Hz), 4.07 - 4.23 (m, 6H), 2.13 (s, 3H), 1 .46 - 1 .69 (m, 12H + H₂0). MS 521 (M + 1 ).

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. The residue was purified by FCC (Si0₂, CH₂CI₂ saturated with NH₄OH/MeOH 9/1 ) to give the title compound (0.006 g, 37%), as colourless solid. ¹ H NMR (CD₃OD) 8.28 (d, 1 H, J = 1 Hz); 7.7 - 7.83 (m, 3H), 7.45 (d, 1 H, J = 8.5 Hz), 7.1 (d, 1 H, J = 8.5 Hz), 6.52 (s, 1 H), 4.15 - 4. 2 (m, 4H), 3.81 (s, 4H), 1.42 - 1 .49 (m, 6H). MS 439 (M + 1 ). Example 32

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

Step A: 2-Amino-4-iodopyridine: A mixture of 2-aminopyridine (2.4 g, 25 mmol), Nal0₄ (0.8 g, 3.75 mmol), and l₂ (2.7 g, 10.7 mmol) in a pre mixed solution of AcOH (60 ml), H₂0 (3 ml) and concentrated H₂S0₄ (0.5 ml) was stirred for 4 h at 80°C. This was poured onto 10% Na₂S₂0₃ (100 ml) and and resulting solution was extracted with EtOAc (3 x 50 ml). The organic phase was washed with 10% NaOH solution (3 x 30 ml), brine, dired over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from EtOH to give the title compound (3.5 g, 63%), as yellowish solid. ¹ H NMR (CDCI₃) 10.5 (broad s, 2 H), 8.05 (d, 1 H, J = 2 Hz), 7.62 (dd, 1 H, J = 2, 8.8 Hz) ; 6.34 (d, 1 H, J = 8.8 Hz).

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. ¹ H NMR (CDCI₃) 8.34 (d, 1 H, J = 2 Hz), 7.59 (dd, 1 H, J = 2, 8.7 Hz), 6.48 (dd, 1 H, J = 0.6, 8.6 Hz), 4.98 (broad s, 2H).

Step C: 2-Hydroxy-4-cyanopyridine: NaN0₂ (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 H₂S0₄ (1 .2 ml) and H₂0 (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 N₂. 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. The solid formed was filtered off, washed with H₂0 and dried in vacuo to give the title product (0.9 g, 92%) as colourless solid. ¹ H NMR (DMSO-d₆) 8.21 (d, 1 H, J = 2.4 Hz), 7.61 (dd, 1 H, 2.4, 9.6 Hz), 6.38 (d, 1 H, J = 9.6 Hz), 3.3 (broad s, 1 H + 2H₂0).

Step D: 2-Hydroxy-3-iodo-4-iodopyridine: A solution of the product of Step C

(0.2 g, 1 .67 mmol) and N-iodosuccinimide (0.41 g, 1 .83 mmol) in anhydrous DMF (30 ml) was stirred for 4 h at ~ 90°C, concentrated in vacuo to ~ 5 ml and this was poured onto ice. The solid formed was filtered off, washed with H20 (2 x 15 ml) and dried in vacuo to give the title compound (0.3 g, 73%), as brownish solid, which was used in the next step without further purification. ¹ H NMR (DMSO-d₆) 8.33 (d, 1 H, J = 2.3 Hz), 8.28 (d, 1 H, J = 2.3 Hz), 3.28 (broad s, 1 H + 1 1 H₂0).

Step E: N,6-dihydroxy-5-iodonicotinimidamide: A mixture of the product of Step D (0.3 g, 1 .22 mmol), HCI x H₂NOH (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 H₂0 (2 ml). The precipitate formed was filtered off, washed with fresh cold H₂0 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. To it 1 M TBAF in THF (0.5 ml) and the mixture was degassed in vacuo and saturated with N2, than stirred for 1 h at ~ 1 10oC. A fresh portion of 1 M TBAF (0.5 ml) was added and stirring was continued for 2 more h and the mixture was cooled to room temperature. This was partitioned between EtOAc (150 ml and H20 (20 ml). The organic phase was washed with brine, dried over anhydrous MgS04, filtered and the filtrate evaporated under reduced pressure and the residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 1 /1 ) to give the title compound (0.161 g, 25%), as colourless solid. ¹ H NMR (DMSO-d₆) 8.49 (s, 1 H), 8.09 (s, 1 H), 7.69 (d, 1 H, J = 6 Hz), 7,55 (s, 1 H), 7.13 (d, 1 H, J = 6 Hz), 4.1 1 (broad s, 4H), 1 .33 (broad s, 6H).

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 Cu₂0 (0.04 g, 0.28 mmol) in anhydrous pyridine (1 ml) was degassed under reduced pressure and saturated with N₂ and stirred for 1 .5 h at ~1 10°C. This was cooled to room temperature, diluted to 50 ml with EtOAc and filtered. The filtrate was washed with 10% NH₄CI solution (pH = 9, adjusted with NH₄OH), brine , dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (Si0₂, CH₂CI₂/EtOAc 9/1 ) to give the title compound (0.06 g, 43%), as a creamy solid. ¹ H NMR (CDCI₃) 9.08 (d, 1 H, J = 2 Hz), 8.61 (d, 1 H, J = 2 Hz), 7.80 (dd, 1 H, J = 2, 8.4 Hz), 7.68 (d, 1 H, J = 2 Hz), 6.98 (d, 1 H, J = 8.5 Hz) ; 6.81 (s, 1 H), 5.33 (broad s, 1 H), 4.34 (d, 2H, J = 12.5 Hz), 4.13 - 4.28 (m, 6H), 1 .29 - 1 .54 (m, 21 H + H₂0).

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 CH₃CN (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. The residue was suspended in H₂0 (2 ml) and the pH was adjusted to ~ 9 with diluted NH₄OH. The precipitate formed was filtered off, washed with Et₂0 (5 x 1 ml) and dried to give the title compound (0.056 g, 91 %), as colourless solid. ¹ H NMR (CDCI₃) 8.98 (d, 1 H, J = 1 .8 Hz), 8.53 (d, 1 H, J = 1 .2 Hz), 7.74 (dd, 1 H, J = 2, 8.4 Hz), 7.62 (d, 1 H, J = 2 Hz), 6.94 (d, 1 H, J = 8.5 Hz), 6.8 (s, 1 H), 4.13 - 4.23 (m, 4H), 3.95 (broad s, 4H), 2.1 1 ( broad s, 4H + 1/2H₂0), 1 .47 - 1 .53 (m, 6H). Example 33 2-Amino-2-(5-(5-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.HCI

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. ¹ H-NMR (CDCI₃) 8.58 (d, 1 H, J = 2.04 Hz); 8.06 (dd, 1 H, J = 8.55, 2.04 Hz); 7.77 (dd, 1 H, J = 8.43, 1 .98 Hz) ; 7.66 (d, 1 H, J = 1 .89 Hz); 6.96 (d, 1 H, J = 8.46 Hz) ; 6.87 (d, 1 H, J = 8.7 Hz) ; 4.69 - 4.61 (m, 1 H) ; 4.18 (q, 2H, J = 13.98, 6.99 Hz); 3.99 (s, 3H) ; 1 .5 (t, 3H, J = 6.96 Hz); 1 .4 (d, 6H, J = 6.06 Hz).

Step B: 4-(5-(4-Ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of above Step A was substituted for the product of Step B, Example 36, the similar procedure as described in Example 3, Step C, afforded the title compound (135 mg, 90%) as off white solid. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 1 .95 Hz); 8.3 (dd, 1 H, J = 8.46, 1 .95 Hz) ; 7.77 (dd, 1 H, J = 8.4, 1 .98 Hz) ; 7.65 (d, 1 H, J = 1 .92 Hz); 7.07 (d, 1 H, J = 8.46 Hz) ; 6.97 (d, 1 H, J = 8.49 Hz); 5.72 (s, 1 H); 4.18 (q, 2H, J = 14.01 , 6.99 Hz) ; 3.99 (s, 3H); 1.5 (t, 3H, J = 6.99 Hz).

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: When the product of above Step B was substituted for the product of Example 3, Step C, the similar procedure as described in Example 36, Step D afforded the title compound (90 mg, 53%) as a creamy paste. ¹ H-NMR (CDCI₃) 8.35 (d, 1 H, J = 1 .23 Hz); 8.08 (dd, 1 H, J = 8.64, 1 .59 Hz); 7.8 (dd, 1 H, J = 8.4, 1 .92 Hz) ; 7.69 (d, 1 H, J = 1 .83 Hz); 7.52 (d, 1 H, J = 8.64 Hz); 6.98 (d, 1 H, J = 8.49 Hz) ; 6.75 (s, 1 H) ; 5.32 (bs, 1 H); 4.30 - 4.15 (m, 6H); 3.99 (s, 3H); 1 .53 - 1 .5 (m, 18H).

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. ¹ H-NMR (DMDO-d₆) 8.67 (bs, 3H); 8.42 (, 1 H); 8.03 (d, 1 H, J = 10.02 Hz); 7.75 (d, 2H, J = 8.55 Hz); 7.62 (s, 1 H); 7.18 (d, 1 H, J = 8.7 Hz); 7.16 (s, 1 H); 5.66 (b, 2H); 4.14 (d, 2H, J = 6.78 Hz) ; 4.1 (d, 2H, J = 7.05 Hz); 3.87 (bs, 6H) ; 1 .35 (t, 3H, J = 6.9 Hz).

Example 34 2-Amino-2-(5-(5-(1-admantyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane-1 ,3- diol.HCI

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%). ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 2.07 Hz); 7.97 (dd, 1 H, J = 8.96, 2.65 Hz); 6.83 (d, 1 H, J = 8.67 Hz); 4.67 - 4.57 (m, 1 H); 2.1 1 - 1 .69 (m, 15H); 1 .4 (d, 6H, J = 6.06 Hz).

Step B: 4-(5-1 -Admantyl -1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of above Step A was substituted for the product of Example 36, Step B, the similar procedure as described in Example 3, Step C afforded the title compound (1 10 mg, 42%) as off white solid. ¹ H-NMR (CDCI₃) 8.38 (d, 1 H, J = 1 .62 Hz); 7.95 (dd, 1 H, J = 8.49, 1 .68 Hz); 7.03 (d, 1 H, J = 8.46 Hz); 5.58 (bs, 1 H); 2.11 (s, 9H); 1 .8 (s, 6H).

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: When the product of above Step B was substituted for the product of Example 3, Step C, the similar procedure as described in Example 36, Step D afforded the title compound (60 mg, 55%) as a yellow paste. ¹ H-NMR (CDCI₃) 8.26 (d, 1 H, J = 1 .47 Hz); 7.99 (dd, 1 H, J = 8.58, 1 .65 Hz); 7.48 (d, 1 H, J = 8.58 Hz); 6.71 (s, 1 H); 5.31 (bs, 1 H); 4.23 (broad, 4H) ; 2.14 (s, 9H) ; 1 .8 (s, 6H); 1 .53 (s, 6H) ; 1 .5 (s, 9H).

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. ¹ H-NMR (DMDO-d₆) 8.17 (d, 1 H, J = 1 .41 Hz); 8.82 (d, 1 H, J = 8.7 Hz); 7.76 (dd, 1 H, J = 8.7, 1 .8 Hz); 7.21 (s, 1 H) ; 4.06 (d, 2H, J = 1 1 .49 Hz); 4.02 (d, 2H, J = 1 1 .52 Hz); 2.07 (s, 9H) ; 1 .8 (s, 6H).

Example 35

2-((5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl amino)propane-1 ,3-diol. HCI

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: When 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. ¹ H- NMR (CDCIg) 8.33 (d, 1 H, J = 1 .32 Hz); 8.05 (dd, 1 H, J = 8.61 , 1 .65 Hz); 7.78 (dd, 1 H, J = 8.4, 1 .89 Hz); 7.68 (d, 1 H, J = 1 .89 Hz) ; 7.52 (d, 1 H, J = 8.58 Hz) ; 6.96 (d, 1 H, J = 8.46 Hz); 6.67 (s, 1 H); 4.24 - 4.13 (m, 4H); 4.02 - 3.97 (m, 4H); 3.78 - 3.72 (m, 2H); 2.76 - 2.70 (m, 1 H); 1 .52 - 1 .41 (m, 12H)

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 μΙ_, 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 ^SC for 2 hours to afford the title compound (34 mg, quantitative) as white solid. ¹ H-NMR (DMDO-d₆) 9.22 (bs, 3H); 8.43 (s, 1 H); 8.05 (d, 1 H, J = 8.76 Hz) ; 7.79 - 7.3 (m, 2H) ; 7.6 (s, 1 H); 7.26 (s, 1 H); 7.17 (d, 1 H, J = 8.52 Hz); 5.34 (s, 1 H); 4.49 (b, 2H); 4.15 - 4.08 (m, 4H); 3.68 (b, 4H); 3.17 (b, 2H); 1.35 - 1 .32 (m, 6H).

Example 36

2-amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-oxadiazol-2-yl)benzof uran-2- yl)propane-1 ,3-diol

Step A: 4-(5-(3-Chloro-4-propoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-iodophenol: (a) 3; Chloro-N'-(3-iodo-4-isopropoxybenzoyl)-4-propoxybenzo-hydrazide: To a stirred suspension of 3-iodo-4-isopropoxybenzoic acid [¹ H-NMR (DMSO-d₆) 8.24 (b, 1 H); 7.85 (b, 1 H), 6.94 (d, 1 H, J = 7.5 Hz), 4.68 - 4.62 (m, 1 H), 1.26 (d, 6H, J = 6 Hz)] (500 mg, 1 .63 mmol as off white solid) in dry DCM (50 mL) was added oxalyl chloride (200 μΙ_, 2.3 mmol) drop wise followed by the addition of dry DMF (150 μΙ_). The solution was stirred for half an hour at room temperature and solvent was distilled. The crude was dried under high vacuum to gave a pale oil which was dissolved in dry THF (1 mL) and was added drop wise to a stirred solution of 3-chloro-4-propoxybenzohydrazide (375 mg, 1 .63 mmol) in a mixture of solvent (THF:TEA; 3 mL: 480 μί). The mixture was stirred for half an hour at room temperature and the solvent was distilled. The crude product was taken in ethyl acetate (50 mL) and washed with 1 M HCI and then with water. The organic layer was dried over magnesium sulphate and the solvent was distilled to gave a pale paste which was purified over silica gel column to gave a product (330 mg, 64%) as pale foam and was used for the next step. The product (320 mg, 0.62 mmol) was taken in dry RBF (5 mL capacity) and POCI₃ (0.14 mL) was added to it. The mixture was stirred at 120 ^SC for two hours, cooled to room temperature, treated with sodium bicarbonate solution (20 ml, nearly saturated) and extracted with ethyl acetate (30 mL x 2). The organic layer was separated and dried over magnesium sulphate. The solvent as distilled to afford the title (220 mg, 69%) as a off white solid. The product was deprotected as described in Example 3, Step C to afford the title product (80 mg, 44%) as a white solid. ¹ H-NMR (CDCIg) 8.38 (d, 1 H, J = 2.04 Hz) ; 8.12 (s, 1 H), 8.01 (d, 1 H, J = 8.7 Hz), 7.96 (d, 1 H, J = 8.49 Hz), 7.32 (d, 1 H, J = 8.76 Hz), 7.02 (d, 1 H, J = 8.49 Hz), 4.1 (t, 2H, J = 6.39 Hz), 1 .8 - 1 .73 (m, 2H), 0.99 (t, 3H, J = 7.41 Hz).

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: When the product of above Step A was substituted for the product of Example 32, Step F the similar procedure as described in Example 32, Step G afforded the title compound (30 mg, 34%) as a white solid. ¹ H-NMR (CDCI₃) 8.29 (d, 1 H, J = 1 .35 Hz); 8.12 (d, 1 H, J = 2.1 Hz), 8.07 - 7.98 (m, 2H), 7.55 (d, 1 H, J = 8.64 Hz), 7.03 (d, 1 H, J = 8.7 Hz), 6.78 (s, 1 H), 5.33 (s, 1 H), 4.3 - 4.2 (b, 4H), 4.07 (t, 2H, J = 6.48 Hz), 1 .96 - 1 .84 (m, 2H), 1 .54 (s, 9H), 1 .5 (s, 6H), 1 .09 (t, 3H, J = 7.35 Hz).

Step C: 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1,3,4-oxadiazol-2- yl)benzofuran-2-yl)propane- 1,3-diol: When the product of above Step C was substituted for the product of Example 32, Step G the similar procedure as described in Example 32, Step H to afford the title compound (15 mg, quantitative) as a white solid. ¹ H-NMR (DMSO-d₆) 8.39 (d, 1 H, J = 1 .47 Hz) ; 8.15 (d, 1 H, J = 2.1 Hz), 8.06 - 8.0 (m, 2H), 7.72 (d, 1 H, J = 8.67 Hz), 7.35 (d, 1 H, J = 8.79 Hz), 6.96 (s, 1 H), 5.01 (bs, 2H), 4.12 (t, 2H, J = 6.39 Hz), 3.72 (d, 2H, J = 9.12 Hz), 3.62 (d, 2H, J = 9.42 Hz), 1 .83 - 1.71 (m, 2H), 1 .0 (t, 3H, J = 7.41 Hz).

Example 37

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-thiadiazol-2- yl)benzofuran-2-yl)propane-1 ,3-diol

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. The organic layer was separated and dried over magnesium sulphate to gave the crude product which was crystallized from methanol to afford the title compound (1 10 mg, 36%) as off white solid. ¹ H-NMR (CDCI₃) 8.37 (d, 1 H, J = 2.19 Hz); 7.98 (d, 1 H, J = 2.19 Hz), 7.92 (dd, 1 H, J = 8.58, 2.22 Hz), 7.82 (dd, 1 H, J = 8.58, 2.22 Hz), 7.04 (d, 1 H, J = 8.88 Hz), 6.86 (d, 1 H, J = 8.79 Hz), 4.71 - 4.6 (m, 1 H), 4.05 (t, 2H, J = 6.45 Hz), 1 .94 - 1 .83 (m, 2H), 1 .42 (d, 6H, J = 6.03 Hz), 1 .08 (t, 3H, J = 7.38 Hz).

Step B: 4-(5-(3-Chloro-4-propoxyphenyl)- 1,3,4-thiadiazol-2-yl)-2-iodophenol: When the product of above Step A was substituted for the product of Example 36, Step B the similar procedure as described in Example 3, Step C afforded the title compound (40 mg, 44%) as white solid. ¹H-NMR (CDCI₃) 8.43 (d, 1 H, J = 1 .98 Hz) ; 8.1 (d, 1 H, J = 2.1 Hz), 8.02 - 7.96 (m, 2H), 7.1 1 (d, 1 H, J = 8.55 Hz), 7.02 (d, 1 H, J = 8.79 Hz), 5.76 (bs, 1 H), 4.07 (t, 2H, J = 6.45 Hz), 1 .96 - 1 .86 (m, 2H), 1 .09 (t, 3H, J = 7.35 Hz).

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: When the product of above Step B was substituted for the product of Example 32, Step F the similar procedure as described in Example 32, Step G afforded the title compound (35 mg, 89%) as white solid. ¹ H-NMR (CDCI₃) 8.29 (d, 1 H, J = 1 .38 Hz) ; 8.12 (d, 1 H, J = 2.13 Hz), 8.06 - 7.98 (m, 2H), 7.56 (d, 1 H, J = 8.64 Hz), 7.02 (d, 1 H, J = 8.7 Hz), 6.78 (s, 1 H), 5.33 (bs, 2H), 4.27 (d, 2H, J = 1 1 .46 Hz), 4.22 (d, 2H), 4.08 (t, 2H, J = 6.48 Hz), 1 .96 - 1 .84 (m, 2H), 1 .56 (s, 6H), 1 .51 (s, 9H), 1 .09 (t, 3H, J = 7.35 Hz).

Step D: 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)- 1 ,3,4-thiadiazol-2- yl)benzofuran-2-yl)propane- 1,3-diol: When the product of above Step C was substituted for the product of Example 32, Step G the similar procedure as described in Example 32, Step H afforded the title compound (23 mg, quantitative) as a white solid. ¹ H-NMR (DMSO-d₆) 8.43 (s, 1 H), 8.15 (d, 1 H, J = 2.1 Hz) ; 8.04 (d, 1 H, J = 8.55 Hz), 7.75 (d, 1 H, J = 8.64 Hz), 7.35 (d, 1 H, J = 8.79 Hz), 7.0 (s, 1 H), 5.2 b, 2H), 4.13 (t, 2H, J = 6.33 Hz), 3.75 (b, 2H), 3.7 (b, 2H), 1 .81 - 1 .74 (m, 2H), 1 .09 (t, 3H, J = 7.41 Hz). Example 38

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 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%). The 4 (2,2,2-trifluroethoxy)methyl benzoate (0.3 gm, 1.28 mmol) was taken in tri-fluoroacetic acid (2 mL) and NCS (170 mg, 1.28 mmol) was added and stirred for overnight when more NCS (200 mg) was added and the mixture was stirred at reflux for 18 hrs. The solvent was distilled and crude was taken in sodium bicarbonate solution. The crude was extracted with ethyl acetate (20 mL x 3) and dried over magnesium sulphate. The solvent was distilled to gave a crude product as pale solid (350 mg). ¹ H-NMR (CDCI₃) 8.08 (d, 1 H, J = 2.07 Hz), 7.92 (dd, 1 H, J = 8.58, 2.1 Hz), 6.94 (d, 1 H, J = 8.61 Hz), 4.45 (q, 2H, 15.78, 7.89 Hz), 3.89 (s, 3H).The above product (0.35 gm, 1 .3 mmol) was taken in THF:MeOH 1 : 1 mixture (4 mL) when 1 ml aqueous solution of LiOH (0.3 gm) was added to it. The mixture was stirred at room temperate for 1 hr when the solvent was distilled. The crude was treated with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL x 2) The organic layer was dried over magnesium sulphate and the solvent was distilled and residue was sonicated in a mixture of solvents (ethyl acetate: hexane 1 mL: 20 mL) to afford the title compound (330 mg, quantitative) as a white solid. ¹H-NMR (DMSO-d₆) 7.93 (s, 1 H); 7.83 (d, 1 H, J = 8.52 Hz), 7.2 (d, 1 H, J = 8.52 Hz), 4.86 (q, 2H, 15.78, 7.89 Hz).

Step B: 5-(3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-(3-iodo-4- isopropoxyphenyl)-1,2,4-oxadiazole: When 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. ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.04 Hz); 8.26 (d, 1 H, 2.04 Hz), 8.1 - 8.03 (m, 2H), 7.06 (d, 1 H, J = 8.64 Hz), 6.88 (d, 1 H, J = 8.73 Hz), 4.7 - 4.59 (m, 1 H), 4.5 (q, 2H, J = 15.69, 7.83 Hz), 1 .42 (d, 6H, J = 6.03 Hz).

Step C: 4-(5-(3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol: When the product of above Step B was substituted for the product of Step B, Example 3 the similar procedure as described in Example 36, Step C afforded the title compound (75 mg, 54%) as white solid. ¹ H-NMR (CDCI₃) 8.46 (d, 1 H, J = 1 .98 Hz) ; 8.26 (d, 1 H, 2.07 Hz), 8.09 - 8.0 (m, 2H), 7.08 (d, 1 H, J = 8.49 Hz), 7.07 (d, 1 H, J = 8.64 Hz), 5.69 (s, 1 H), 4.5 (q, 2H, J = 7.83, 15.69 Hz).

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: When the product of above Step C was substituted for the product of Step F, Example 32 the similar procedure as described in Example 32, Step G afforded the title compound (30 mg, 34%) as a pale solid. ¹ H-NMR (CDCI₃) 8.33 (d, 1 H, J = 1 .35 Hz) ; 8.29 (d, 1 H, J = 2.04 Hz), 8.12 - 8.4 (m, 2H), 7.53 (d, 1 H, J = 8.7 Hz), 7.07 (d, 1 H, J = 8.67 Hz), 6.76 (s, 1 H), 5.33 (s, 2H), 4.5(q, 2H, J = 15.69, 7.83 Hz) 4.28 (d, 2H, J = 1 1 .43 Hz), 4.21 (d, 2H, J = 1 1 .01 Hz), 1 .55 (s, 9H), 1 .51 (s, 6H). 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: When the product of above Step D was substituted for the product of Example 32, Step G the similar procedure as described in Example 32, Step H afforded the title compound (10 mg, 96%) as a pale solid. ¹ H-NMR (DMSO-d₆) 8.41 (d, 1 H, J = 1 .68 Hz) ; 8.25 (d, 1 H, J = 1 .98 Hz), 8.18 (dd, 1 H, J = 8.61 - 1 .98 Hz), 8.1 (dd, 1 H, J = 8.67, 1 .83 Hz), 7.65 (d, 1 H, J = 8.73 Hz), 7.33 (d, 1 H, J = 8.73 Hz), 6.93 (s, 1 H), 4.99 - 4.9 (m, 6H), 3.71 - 3.59 (broad, 4H).

Example 39

2-Amino-2-(5-(5-(4-butoxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-

2-yl)propane-1 ,3-diol

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. ¹ H-NMR (CDCI₃) 8.53 (d, 1 H, J = 2.07 Hz); 8.17 (d, 1 H, 2.1 Hz), 8.04 - 7.99 (m, 2H), 7.0 (d, 1 H, J = 8.7 Hz), 6.86 (d, 1 H, J = 8.76 Hz), 4.67 - 4.55 (m, 1 H), 4.1 (t, 2H, J = 6.45 Hz), 1 .86 - 1.79 (m, 2H), 1 .58 - 1 .48 (m, 2H), 1 .39 (d, 6H, J = 6.06 Hz), 0.97 (t, 3H, J = 7.38 Hz).

Step B: 4-(5-(4-Butoxy-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of above Step A was substituted for the product of Example 36, Step B the similar procedure as described in Example 3, Step C afforded the title compound (120 mg, 66%) as creamy solid. ¹ H-NMR (CDCI₃) 8.46 (d, 1 H, J = 1 .92 Hz); 8.2 (d, 1 H, 2.07 Hz), 8.04 - 8.0 (overlapping d, 2H), 7.07 (d, 1 H, J = 8.49 Hz), 7.0 (d, 1 H, J = 8.67 Hz), 5.72 (s, 1 H), 4.1 1 (t, 2H, J = 6.42 Hz), 1 .9 - 1 .81 (m, 2H), 1 .6 - 1 .48 (m, 2H), 1 .0 (t, 3H, J = 7.41 Hz).

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: When the product of above Step B was substituted for the product of Example 32, 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. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .32 Hz); 8.23 (d, 1 H, J = 2.1 Hz), 8.08 - 8.04 (m, 2H), 7.52 (d, 1 H, J = 8.64 Hz), 7.02 (d, 1 H, J = 8.7 Hz), 6.75 (s, 1 H), 5.34 (s, 2H), 4.12(t, 2H, J = 6.42 Hz) 1 .9 - 1 .8 (m, 2H), 1 .58 - 1 .36 (m, 17H), 1 .0 (t, 3H, J = 7.35 Hz).

Step D: 2-Amino-2-(5-(5-(4-butoxy-3-chlorophenyl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane- 1 ,3-diol: When the product of above Step C was substituted for the product of Example 32, Step G the similar procedure as described in Example 32, Step H afforded the title compound (55 mg, 79%) as a creamy solid. ¹ H-NMR (DMSO-d₆) 8.39 (s, 1 H), 8.2 - 8.4 (m, 2H), 8.07 (d, 1 H, J = 8.28 Hz); 7.63 (d, 1 H, J = 8.91 Hz), 7.2 (d, 1 H, J = 8.64 Hz), 6.89 (s, 1 H), 4.82 (s, 2H), 4.12 (t, 2H, J = 6.45 Hz), 3.69 - 3.27 (b, 4H), 1.77 - 1 .7 (m, 2H), 1 .49 - 1 .41 (m, 2H), 0.92 (t, 3H, J = 7.29 Hz).

Example 40

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran- 2-yl)ethanol

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: When the product of Step B, Example 3 was treated with tert-butyl 4-ethynyl-2,2-dimethyloxazolidine-3-carboxylate [¹ H-NMR (CDCI₃) 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. ¹ H-NMR (CDCI₃) 8.33 (s, 1 H), 8.23 (d, 1 H, J = 2.07 Hz); 8.07 - 8.04 (m, 2H), 7.52 (d, 1 H, J = 8.61 Hz), 7.0 (d, 1 H, J = 8.7 Hz), 6.63 (s, 1 H), 5.1 (bd, 1 H), 4.26 - 4.05(m, 4H),1 .6 (s, 9H), 1 .47 (s, 6H), 12.4 (t, 3H, J = 7.14 Hz).

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 ^SC for 5 minutes. The solvent was distilled and co-distilled with ethanol and dried under high vacuum. The isopropyl alcohol (1 ml.) was added and sonicated, the solid was filtered, washed with diethyl ether and dried under high vacuum and in oven at 60 ^SC for 0.5 hr to afford the title compound (1 10 mg, 82%) as a off white solid. ¹ H-NMR (DMSO-d₆) 8.76 (s, 3H); 8.42 (d, 1 H, J = 1 .41 Hz), 8.16 (d, 1 H, J = 2.13 Hz), 8.1 - 8.02 (m, 2H), 7.77 (d, 1 H, J = 5.76 Hz), 7.37 (d, 1 H, J = 8.79 Hz), 7.18(s, 1 H), 5.65 (t, 1 H, J = 4.98 Hz), 4.14 (t, 2H, J = 5.46 Hz), 3.9 (bs, 2H), 0.99 (t, 3H, J = 7.38 Hz).

Example 41

2-Amino-2-(5-((3-chloro-4-propoxyphenyl)ethynyl)benzofuran-2-yl)propane-1 ,3-diol

Step A: 2,4-diiodophenol: To a solution of 4-iodophenol (0.2 g; 1 mmol) in 25% NH₄OH (4 ml) a solution of Kl (0.8 g; 4.8 mmol) and l₂ (0.26 g; 1 mmol) in H20 was added at once. After stirring for 15 min at room temperature, the solvents were removed under reduced pressure and the residue was partitioned between Et₂0 (50 ml) and H₂0 (5 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness to give crude title compound, (0.32 g; 80%, -90% purity), as yellowish oil, which was used in the next step without further purification. ¹ H NMR (CDCIg) 7.91 (d, 1 H, J = 1 Hz) ; 7.48 (dd, 1 H, J = 1 , 8.6 Hz) ; 6.74 (d, 1 H, J = 8.6 Hz); 5.32 (s, 1 H).

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 (Si0₂, CH₂CI₂). ¹H-NMR (CDCI₃) 7.87 (d, 1 H, J = 1 .7 Hz); 7.5 (dd, 1 H, J = 1 .7, 8.6 Hz); 7.19 (d, 1 H, J = 8.6 Hz); 6.59 (s, 1 H); 5.29 (broad s, 1 H); 4.15 - 4.25 (m, 4H); 1.49 (s, 3H); 1 .48 (s, 3H); 1 .35 (broad s, 9H).

Step C: 3-Chloro-4-propoxybenzaldehyde: A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmol), 1 -bromopropane (0.3 ml) and K₂C0₃ (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 H₂0. The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was evaporated to dryness to give 4-propropoxybenzaldehyde (0.55 g, 82.3%), as yellow oil ¹ H-NMR (CDCI₃) 1 .0 (tr, 3H, J = 7.41 Hz); 1 .7 - 2.0 (m, 2H); 3.95 (tr, 2H, J = 6.57 Hz) ; 6.95 (d, 2H, J = 8.73 Hz) ; 8.00 (d, 2H, J = 8.76 Hz). To a stirred solution of this (0.5 g, 3.07 mmol) in anhydrous DMF (3 ml) NCS (0.5 g, 3.73 mmol) was added and the mixture was stirred overnight at room temperature. This was diluted to 100 ml with EtOAc and washed with NaHC0₃ solution (100 ml). The organic layer was separated, dried over MgS0₄ and filtered. The filtrate was evaporated to dryness to give the crude product (0.59 g; 97%), as light yellow oil. ¹H-NMR (CDCI₃) 9.81 (s, 1 H); 7.87(d, 1 H, J = 2.01 Hz); 7.71 (dd, 1 H, J = 2.02 - 8.47 Hz) ; 6.98 (d, 1 H, J = 8.47 Hz); 1 .82 - 1 .91 (m, 2H); 4.1 (tr, 2H, J = 6.3 Hz); 1.1 (tr, 3H, J = 7.4 Hz).

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 K₂C0₃ (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 Et₂0 (25 ml), washed with H₂0 (2 x 10 ml) and dried over MgS0₄ and filtered. The filtrate was evaporated to dryness, diluted to 1 ml CH₂CI_2, passed through short Si0₂ column, washed with CH₂CI₂ to give the title compound (0.07 g; 69%)_, as yellowish syrup. ¹ H-NMR (CDCI₃) 7.32 (dd, 1 H, J = 2, 8.5 Hz); 6.81 (d, 1 H, J = 8.5 Hz); 3.98 (tr, 2H, J = 6.5 Hz) : 2.99 (s, 1 H); 1 .78 - 1 .91 (m, 2H): 1.05 (tr, 3H, J = 7.4 Hz). Step E: tert-Butyl 5-(5-((3-chloro-4-propoxyphenyl)ethynyl) benzofuran-2-yl)-

2.2- dimethyl-1,3-dioxan-5-ylcarbamate: 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 (Si0₂, hexane/EtOAc 8 ; 2). ¹ H-NMR (CDCI₃) 7.67 (s, 1 H); 7.53 (d, 1 H, J = 2 Hz): 7.34 - 7.38 (M< 3H); 6.86 (d, 1 H, J = 8.6 Hz) ; 6.65 (s, 1 H): 5.3 (broad s, 1 H) ; 4.22 - 4.27 (m, 4H) ; 4.0 (tr, 2H, J = 6.5 Hz); 1 .8 - 1 .93 (m, 2H); 1 .2 - 1 .53 *m , 15H) ; 1.06 (tr, 3H, J = 7.4 Hz).

Step F: 2-Amino-2-(5-((3-chloro-4-propoxyphenyl)ethynyl) benzofuran-2- yl)propane-1 ,3-diol: When the product of Step E was substituted for 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 in Example 32, Step H, the identical process afforded the title compound in 36 % yield., as colourless solid, after purification by FCC (Si0₂, CH₂CI₂ saturated with NH₄OH, MeOH 95 : 5). ¹ H-NMR (CDCI₃) 7.67 (m, 1 H); 7.54 (d, 1 H, J = 2 Hz); 7.34 - 7.37 (m, 3H); 6.86 (d, 1 H, J = 8.55 Hz) ; 6.66 (s, 1 H); 4.0 (tr, 2H, J = 6.5 Hz): 3.87 (broad m, 1 .5 - 2.4 (m, 6H); 1 .06 (tr, 3H, J = 7.4 Hz).

Example 42

2-Amino-2-(5-(3-chloro-4-propoxyphenethyl)benzofuran-2-yl)propane-1 ,3- diol, HCI salt

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. The residue was purified by repeated purification by FCC (3x) (Si0₂, hexane : EtOAc, 9 ; 1 ) to give the title compound (0.09 g; 29%), as colourless solid. ¹ H-NMR (CDCI₃) 7.27 - 7.32 (m, 2H); 7.17 (d, 1 H, J = 2.04 Hz) ; 6.93 (dd, 1 H, J = 2.1 Hz, 8.3 Hz) ; 6.79 (d, 1 H, J = 8.4 Hz); 6.59 (s, 1 H); 5.3 (broad s, 1 H) ; 4.22 (m, 4H); 3.94 (tr, 2H, J = 6.5 Hz) ; 2.79 - 2.95 (m, 4H); 1.77 - 1 .89 (m, 15H); 1 .04 (tr, 3H, J = 7.4 Hz).

Step B: 2-Amino-2-(5-(3-chloro-4-propoxyphenethyl)benzofuran-2-yl)propane-

1.3- diol: A mixture of the product of Step A (0.009 g; 0.016 mmol) and 32% HCI (0.5 ml) in EtOH (0.5 ml) was evaporated to dryness under reduced pressure. The residue was diluted to 2 ml with fresh EtOH and re-evaporated to dryness under reduced pressure. The residue was kept in vacuo for 2 h. The residue was treated with anhydrous Et₂0, (1 ml). The solid was filtered off washed with fresh Et₂0 and dried in vacuo to give the title compound (5.4 mg; 75%), as greyish, hygroscopic solid. ¹ H-NMR (D₂0) 7.0 (broad s, 1 H); 6.82 (broad s, 2H); 6.59 (broad s, 1 H); 6.43 (broad s, 3H) ; 4.66 (H₂0); 3.5 - 3.63 (m, 6H); 2.28 (broad s, 4H): 1 .47 (broad s, 2H); 0.76 (broad s, 3H).

Example 43

2-Amino-2-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl)benzofuran-2- yl)propane-1 ,3-diol, HCI salt.

Step A:2-lodo-4-propylphenol: A solution of 4-propylphenol (0.08 g; 0.587 mmol), Nal (0.09 g; 0.6 mmol) and NaOH (0.024 g; 0.6 mmol) in MeOH (2 ml) was cooled to 0 °C. To it 7% NaOCI (o.62 ml; 0.59 mmol) was added dropwise with stirring, at rate that internal temperature was kept < 3 °C. After stirring for 1 h at 0°C 10% Na₂S0₃ was added and pH of the solution was adjusted to~5. This was extracted with Et20 (3 x 10 ml). The combined organic phase was dried over anhydrous MgS04, filtered and filtrate evaporated to dryness, to give crude title compound ().12 g), which was used in the next step without further purification.

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 CH₂CI₂ (3 ml), TiCI₄ (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 CH₂CI₂, the organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and evaporated to dryness. The residue was purified by FCC (Si0₂, CH₂CI₂ : hexane 1 : 1 ), to give the title compound (0.064 g; 47%) as creamy syrup. ¹H-NMR (CDCI₃) 7.4 (d, 1 H, J = 1 .9 Hz); 7.1 (d, 1 H, J = 1 .9 Hz) ; 5.75 (s, 1 H); 2.42 - 2.47 (m, 2H); 1 .51 - 1 .63 (m, 2H); 0.88 - 0.97 (m, 3H).

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 (Si0₂, CH₂CI₂). ¹ H-NMR (CDCI₃) 7.2 (d, 1 H, J = 1 .4 Hz) ; 7.09 (d, 1 H, J = 1 .4 Hz) ; 6.62 (s, 1 H); 4.76 (d, 2H, J = 6.3 Hz); 2.62 (tr, 2H, J = 7.3 Hz); 2.1 1 (tr, 2H, J = 6.4 Hz) ; 1 .57 - 1 .7 (m, 2H); 0.92 (tr, 3H, J = 7.3 Hz).

Step D: 7-Chloro-5-propylbenzofuran-2-carbaldehyde: A suspension of the product of Step C (0.03 g; 0.13 mmol) and Mn0₂ (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. ¹ H-NMR (CDCI₃) 9.88 (s, 1 H); 7.08 - 7.7 (m, 3H); 2.65 (tr, 2H, J = 7.2 Hz); 1 .6 - 1 .7 (m, 2H); 0.93 (m, 3H).

Step E: 7-Chloro-2-ethynyl-5-propylbenzofuran; When the product of Step D was substituted for 3-chloro-4-propoxybenzaldehyde in Example 41 , Step D, the identical process afforded the title compound in 65% yield as yellowish syrup, after purification by FCC (Si0₂, CH₂CI₂). ¹ H-NMR (CDCI₃) 7.21 (d, 1 H, J = 1 .4 Hz); 7.16 (d, 1 H, J = 1 .4 Hz); 6.94 (s, 1 H); 3.5 (s, 1 H); 2.6 (tr, 2H, J = 7.3 Hz); 1.58 - 1 .71 (m, 2H); 0.92 (tr, 3H, J = 7.3 Hz).

Step F: tert-Butyl 5-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl) benzofuran- 2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step E was substituted for 2-chloro-4-ethynyl-1 -propoxybenzene in Example 41 , Step E, the identical process afforded the title compound in 1 1 % yield., as deep reddish solid , after purification by FCC (Si0₂, hexane/EtOAc 9 : 1 ). ¹ H-NMR (CDCI₃) 7.84 (m, 1 H); 7.4 - 7.52 (m, 2H); 7.23 (d, 1 H, J = 1 .5 Hz) ; 7.15 (d, 1 H, J = 1 .5 Hz) ; 6.93 (s, 1 H) ; 6.68 (s, 1 H); 5.31 (broad s, 1 H); 4.18 - 4.28 (m, 4H); 2.63 (tr, 2H, J = 7.3 Hz); 1 .59 - 1 .73(m, 2H); 1 .48 - 1 .54 (m, 6H); 1 .36 (broad s, 9H); 0.96 (tr, 3H, J = 13 Hz).

Step G: 2-Amino-2-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl)benzofuran-

2-yl)propane-1 ,3-diol; A mixture of the product of Step F (5.1 mg; 0.009 mmol), 32% HCI (0.1 ml) and EtOH (1 ml) was brought to reflux and evaporated to dryness under reduced pressure. The residue was diluted to 1 ml with EtOH and re evaporated (x 3), and kept in vacuo for 2 h. This was treated with anhydrous Et₂0 and solid formed was separated by filtration washed with fresh Et₂0 and dried to give the title compound (3.1 mg; 76%) as reddish solid ¹ H-NMR (DMSO- d₃) 8.69 (broad m, 3H); 8.04 (m, 1 H); 7.57 - 7.7(m, 2H); 7.33 - 7.38 (m, 2H) ; 7.05 (s, 1 H); 5.67 (tr, 2H, J = 5.1 Hz) ; 3.85 (d, 4H, J = 5.1 Hz); 2.64 (tr, 2H, J = 14.5 Hz) ; 1 .53 - 1 .66 (m, 2H); 0.86 (tr, 3H, J = 7.2 Hz). Example 44

5-Amino-5-[5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran -2-yl]-1 ,3,2-dioxaphosphinan-2-ol 2-oxide

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 (Si0₂, CH₂CI₂ saturated with NH₄OH, MeOH 95 : 5). to give the title compound (0.07 g; 41 %), as colourless solid. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .3 Hz); 8.23 (d, 1 H, J = 2.1 Hz); 8.03 - 8.24 (m, 2H); 7.53 (d, 1 H, J = 8.6 Hz); 7.03 (d, 1 H, J = 8.7 Hz); 6.77 (s, 1 H0; 5.71 (broad s, 1 H); 4.13 - 4.2 (m 2H); 4.08 (tr, 2H, J = 6.5 Hz) ; 3.9 - 4.0 (m, 2H); 3.28 (broad s, 2H) ; 1 .44 (s, 9H); 1 .09 (tr, 3H, J = 7.4 Hz).

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; To a solution of POCI₃ (0.018 ml; 0.19 mmol) in anhydrous CH₂CI₂ (0.5 ml) 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 CH₂CI₂ (1 ml) was added dropwise at 0°C under N₂ with stirring. The mixture was stirred for 10 min at 0°C and additional 1 h at room temperature. After removal of solvents under reduced pressure the residue was kept in vacuo for 1 h, then suspended in anhydrous acetonitrile (2 ml). This was combined with 0.5 N NaOH (1 .15 ml). The resulting mixture was evaporated to dryness under reduced pressure. The residue was treated with H₂0 (2 ml) and the pH of this was adjusted to ~9 with 0.5 N NaOH and resulting mixture was filtered through Whatman glass microfibre to remove any trace of solid material. The filtrate was acidified to ph ~ 2 with HCI and was extracted with EtOAc (3 x 10 ml). The organic phase was dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. The residue was treated with CH₂CI_2, saturated with NH₃ (2 ml) and evaporated to dryness to give the title compound (ammonium salt) (0.04 g; 51 %), as creamy solid. ¹ H-NMR (DMSO-d₃) 8.31 (s, 1 H); 8.1 1 (s, 1 H); 8.05 (d, 1 H, J = 8.6 Hz); 7.93 (d, 1 H, J = 8.3 Hz); 7.63 (d, 1 H, J = 8.6 Hz); 7.32 (d, 1 H, J = 8.7 Hz); 7.26 (broad s, 5H); 6.88 (s, 1 H) ; 4.2 - 4.61 (broad m, 4H); 4.1 1 (tr, 2H, J = 6.2 Hz); 1 .74 - 1 .82 (m, 2H); 1 .3 (broad s, 9H); 0.99 (tr, 3H, J = 7.4 Hz). MS (M-1 ) 604.

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; 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 + NH₄OH). ¹ H-NMR (DMSO-d₃ + D₂0; 330 K) 8.36 (s, 1 H); 7.95 - 8.15 (m, 3H); 7.75 (d, 1 H, J = 8.51 Hz) ; 7.31 (d, 1 H, J = 8.8 Hz); 7.23 (s, 1 H); 4.55 - 4.7 (broad m, 2H); 4.25 - 4.45 (broad m, 2H); 4.1 (tr, 2H, J = 6.2 Hz); 1 .65 - 1 .85 (m, 2H); 0.97 (tr, 3H, J = 7.3 Hz) ; MS (M -1 ) 504; MS (M + 1 ) 506.

Example 45

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: 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 CH₂CI₂ (15 ml) TiCL₄ (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. The residue was diluted to 80 ml with EtOAc, washed with H₂0, (3 x 10 ml), 5 % Na₂S₂0₃ (10 ml), brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si0₂, CH₂CI₂) to give the title compound (1 .82 g, 65%), as colorless solid. ¹ H-NMR (CDCI₃) 8.36 (d, 1 H, J = 2 Hz) ; 7.92 (dd, 1 H, J = 2, 8.5 Hz) ; 7.0 (d, 1 H, J = 8.5 Hz); 5.7 (s, 1 H); 3.27 (s, 3H).

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 K₂C0₃ (0.57 g; 4.1 mmol) in anhydrous DMF (2.5 ml) was stirred for 2 h at ~ 55°C under N₂. This was partitioned between hexane (30 ml) and water. The aqueous phase was extracted with fresh hexane and combined organic phase was washed with water (20 ml), brine, dried over anhydrous MgS0₄ , filtered and filtrate evaporated to dryness, to give the title compound (1 .24 g, 95%), as colourless oil). ¹ H-NMR (CDCI₃) 8.43 (d, 1 H, J = 2.1 Hz); 7.97 (dd, 1 H, J = 2.1 , 8.6 Hz); 6.77 (d, 1 H, J = 8.6 Hz); 4.02 (tr, 2H, J = 6.3 Hz) ; 3.88 (s, 3H); 1 .8 - 1 .93 (m, 2H); 1.09 )tr, 3H, J = 7.4 Hz).

Step C: Methyl 4-propoxy-3-(trifluoromethyl)benzoate: Methyl 2,2-difluoro-2-

(fluorosulfonyl)acetate (0.7 ml; 5.5 mmol) was added dropwise to a mixture of the product of Step B (0.35 g; 1 .09 mmol) and Cul (0.2 g; 1 .1 mmol) in anhydrous DMF (3.2 ml) under N₂, with stirring at ~ 70 °C. This was stirred for 6 h at 80 - 90 °C, cooled to room temperature and mixed with saturated NH₄CI (4 ml). This was extracted with Et₂0 (3 x 20 ml). The combined organic phase was washed with watewr (2 x 10 ml), brine, dried over anhydrous MgS0₄ , filtered and filtrate evaporated to dryness. The crude product was purified by FCC (Si0₂, hexane /EtOAc 9:1 ) to give the title compound (0.28 g; 98%), as colorless solid. ¹ H-NMR (CDCI₃) 8.24 (d, 1 H, J = 1 .9 Hz); 8.14 (dd, 1 H, J = 1 .9, 8.7 Hz) ; 6.98 (d, 1 H, J = 8.7 Hz) ; 4.05 (tr, 2H, J = 6.3 Hz) ; 3.89 (s, 3H); 1 .78 - 1 .9 (m, 2H); 1 .04 - 1 .08 (m, 3H). 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), H₂0 (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 MgS0₄ , 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. ¹ H- NMR (CDCIg) 8.32 (s, 1 H) ; 8.2 (d, 1 H, J = 8.6 Hz); 7.02 (d, 1 H, J = 8.8 Hz); 4.08 (tr, 2H, J = 6.21 Hz) ; 1 .8 - 1 .93 (m, 2H); 1.06 (tr, 3H, J = 7.4 Hz).

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 N₂. To this 1 M TBAF in THF (0.3 ml) was added and the mixture was stirred for 2 h at ~ 120°C, cooled to room temperature and diluted to 5 ml with MeOH. This was kept at -18 ^SC over a weekend. The solid formed was filtered off, washed with fresh MeOH, dried in vacuo to give the title compound (0.2 g; 36%), as colourless solid. ¹ H-NMR (CDCI₃) 8.57 (d, 1 H, J = 2 Hz) ; 8.4 (s, 1 H) ; 8.29 dd, 1 H, J = 8.6 Hz) ; 8.06 (dd, 1 H, J = 2, 8.6 Hz); 7.1 1 (d, 1 H, J = 8.8 Hz); 6.88 (d, 1 H, J = 8.6 Hz) ; 4.6 - 4.7 (m, 1 H) ; 4.1 1 (tr, 2H, J = 6.3 Hz); 1 .82 - 1 .94 (m, 2H); 1 .42 (d, 6H, J = 6 Hz); 1 .08 (tr, 3H, J = 7.5 Hz).

Step F: 2-lodo-4-(5-(4-propoxy-3-(trifluoromethyl)phenyl)- 1,2,4-oxadiazol-3- yljphenol: When 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. ¹ H-NMR (CDCI₃) 8.48 (s,1 H); 8.4 (s, 1 H); 8.29 (d, 1 H, J = 8.9 Hz) ; 8.04 (d, 1 H, J = 8.4 Hz); 7.07 - 7.13 (m, 2H); 4.1 1 (tr, 2H, J = 6.2 Hz); 1 .82 - 1 .92 (m, 2H); 1 .07 (tr, 3H, J = 6.2 Hz).

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. , as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.44 (s, 1 H); 8.3 - 8.36 (m, 2H) ; 8.08 (d, 1 H, J = 8.6 Hz); 7.53 (d, 1 H, J = 8.6 Hz) ; 7.12 (d, 1 H, J = 8.8 Hz); 6.76 (s, 1 H) ; 5.33 (broad s, 1 H); 4.0 - 4.3 (m, 6H); 1 .82 - 1 .92 (m, 2H); 1 .2 - 1.54 (m, 15 H); 1 .08 (tr, 3H, J = 7.1 Hz).

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: 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 91 %, as colourless solid. ¹ H-NMR (DMSO- d₃) 8.67 (broad s, 3H); 8.44 (s, 1 H); 8.40 (d, 1 H, J = 19.1 Hz) ; 8.3 (s, 1 H); 8.05 (d, 1 H, J = 8.5 Hz); 7.77 (d, 1 H, J = 8.5 Hz) ; 7.51 (d, 1 H, J = 8.9 Hz) ; 7.16 (s, 1 H) ; 5.67 (broad s, 2H) ; 4.2 (tr, 2H, J = 5.5 Hz); 3.89 (broad s, 4H); 1 .73 - 1 .8 (m, 2H); 0.98 (tr, 3H, J = 7.3 Hz).

Example 46

2-Amino-2-(5-(5-(3-chloro-4-isopropoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol.

Step A: 3-Chloro 4-hydroxybenzoic acid: To a solution of 4-hydroxybenzoic acid

(0.66 g; 4.8 mmol) and N-chlorosuccinimide (0.64 g; 4.8 mmol) in EtOAc (15 ml) TiCI₄ (0.06 ml; 0.5 mmol) was added at room temperature. After stirring for 2 h at room temperature the mixture was poured onto ice (50 ml) with stirring. To it fresh EtOAc (65 ml) was added and organic phase was separated, washed with H₂0 (20 ml), brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from H₂0 to give the title compound (0.69 g; 84%), as colorless solid. ¹ H-NMR (DMSO-d₆) 1 1 .03 (s, 1 H); 7.8 (d, 1 H, J = 2 Hz); 7.7 (dd, 1 H, J = 2 Hz, 8.5 Hz); 7.0 (d, 1 H, 8.5 Hz).

Step B: 3-Chloro-4-hydroxybenzoyl chloride: To a suspension of the product of Step A (0.61 g; 3.53 mmol) in anhydrous CH₂CI₂ (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:

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 N₂, 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% NH₄CI (20 ml) and EtOAc (80 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄, 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. The solid was purified by crystallization from MeOH to give the title compound (1 .1 g; 71 %), as creamy solid. ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.1 Hz) ; 8.21 (d, 1 H, J = 2 Hz); 8.0 - 8.06 (m, 2H0; 7.17 (d, 1 H, J = 8.6 Hz); 6.87 (d, 1 H, J = 8.7 Hz) ; 6.04 (s, 1 H); 4.6 - 4.7 (m, 1 H); 1 .42 (d, 6H, J = 6 Hz).

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 CH₂CI₂ (5 ml) 1 M BCI₃ in CH₂CI₂ (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 MgS0₄, filtered and filtrate evaporated to dryness. The solids were combined to give the title compound (0.94 g; 100%), as creamy solid. ¹ H- NMR (CDCIg) 8.47 (d, 1 H, J = 2 Hz) ; 8.2 (d, 1 H, J = 2 Hz) ; 8.03 (dd, 1 H, J = 8.5 Hz); ; 7.17 (d, 1 H, J = 8.6 Hz) ; 7.08 (d, 1 H, J = 8.4 Hz); 6.02 (s, 1 H); 5.62 (s, 1 H).

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 Cu₂0 (0.3 g, 2.1 mmol) in anhydrous pyridine (4 ml) was degassed under reduced pressure and saturated with N₂. This was stirred for 1 h at ~1 10°C, under N₂, cooled to room temperature, diluted to 20 ml with CH₂CI₂ and filtered. The solids were filtered, washed with fresh CH₂CI₂ (20 ml) and combined filtrates were evaporated to dryness under reduced pressure. The residue was kept in vacuo for 1 h, than purified by FCC (Si02; EtOAc/hexane 1 :1 ), to give the title compound (0.7 g; 57%), as pinkish solid. ¹H-NMR (CDCI₃) 8.1 (broad s, 1 H) ; 8.06 (s, 1 H) ; 8.0 (dd, 1 H, J = 1 .4, 8.6 Hz); 7.75 (broad m, 2H); 7.49 (d, 1 H, J = 8.6 Hz); 6.75 - 7.1 (broad m, 2H); 6.68 (d, 1 H, J = 8.6 Hz) ; 5.48 (broad s, 1 H); 4.19 - 4.31 (m, 4H); 1 .51 (s, 6H) ; 1 .41 (broad s, 9H).

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 K₂C0₃ (0.07 g; 0.51 mmol) in anhydrous DMF (1 .5 ml) was stirred overnight at ~ 55 °C under N₂. After cooling to room temperature, the mixture was diluted to 50 ml with EtOAc, washed with water (3 x 15 ml) brine ( 15 ml), dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from EtOAc/hexane, to give the title compound (0.25 g; 89%), as creamy solid. ¹ H-NMR (CDCI₃) 8.12 (d, 1 H, J = 1 .4 Hz); ); 8.02 - 8.09 (m, 2H) ; 7.53 (d, 1 H, J = 8.6 Hz); 7.75 (broad m, 2H); 7.04 (d, 1 H, J = 8.8 Hz) ; 6.75 (s, 1 H); 5.33 (broad s, 1 H); 4.6 - 4.74 (m, 1 H) ; 4.19 - 4.3 (m, 4H);1.51 (s, 6H); 1 .43 (d, 6H, J = 6.1 Hz); 1 .36 (broad s, 9H).

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 MeS0₃H (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 H₂0 and to it 25% NH₄OH (0.3 ml) was added. The solid formed was filtered off, washed with H₂0 (2 x 1 ml) and dried in vacuo. The solid was purified by crystallization from EtOAc/hexane the title compound (0.1 145 g) as a colourless solid. The filtrate was evaporated to dryness and the residue was purified by FCC (Si0₂, CH₂CI₂ , saturated with concentrated NH₄OH : MeOH 95:5) to give the additional title compound (0.06 g), as colourless solid (total yield 0.175 g; 96%). ¹ H-NMR (CDCI₃) 8.24 (s, 1 H); 8.14 (d, 1 H, J = 1 .9 Hz); 7.94 - 8.0 (m, 2H); 7.46 (d, 1 H, J = 8.5 Hz) ; 6.97 (d, 1 H, J = 8.9 Hz); 6.77 (s, 1 H); 4.61 - 4.7 (m, 1 H) ; 3.93 (broad s, 4H); 2.39 (broad s, 7H + 1 .5 H₂0), 1 .41 (d, 6H, J = 6 Hz).

Example 47

2-Amino-2-(5-(5-(4-isopropoxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol Methanesulfonic acid Salt: To a suspension of the product of Example 46 (0.06 g; 0.135 mmol) in MeOH (1 ml) MeS0₃H (0.01 ml; 0.154 mmol) was added at room temperature. The resulting homogenous solution was evaporated to dryness under reduced pressure and the residue was purified by crystallization from Et₂0/MeOH to give the title compound (0.0557 g; 76 %), as creamy hygroscopic solid. ¹ H-NMR (DMSO-d₆) 8.63 (broad s, 3H); 8.44 (s, 1 H); 8.02 - 8.17 (m, 3H); 7.77 (d, 1 H, J = 8.7 Hz) ; 7.42 (d, 1 H, J = 8.9 Hz) ; 7.15 (s, 1 H); 5.5 (broad s, 2H); 4.81 - 4.9 (m, 1 H); 3.82 - 3.92 (m, 4H); 2.29 (s, 3H); 1 .33 (d, 6H, J = 6 Hz). Example 48

2-Amino-2-(5-(5-(4-benzyloxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol, HCI Salt.

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 K₂C0₃ (0.026 g; 0.19 mmol) in anhydrous DMF (1 ml) was stirred at room temperature for 3 h under N₂. The mixture was diluted to 60 ml with EtOAc, washed with water (3 x 10 ml), brine (15 ml), dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from EtOAc/hexane, to give the title compound (0.1 12 g; 93%), as creamy solid. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1.2 Hz); 8.27 (d, 1 H, J = 2 Hz); 8.03 - 8.09 (m, 2H); 7.3 - 7.55 (m, 6H); 7.1 (d, 1 H, J = 8.7 Hz); 6.75 (s, 1 HO; 5.33 (broad s, 1 H); 5.26 (s, 2H); 4.19 - 4.31 (m, 4H); 1 .51 (s, 6H) ; 1 .36 (broad s, (H).

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. ¹ H-NMR (DMSO-de) 8.59 (broad s, 3H) ; 8.43 (d, 1 H; J = 1 .5 Hz) ; 8.21 (d, 1 H, J = 2.1 Hz) ; 8.12 (dd, 1 H, J = 2.1 , 8.7 Hz) ; 7.77 (d, 1 H, J = 8.7 Hz); 7.34 - 7.53 (m, 6H) ; 7.15 (s, 1 H); 5.63 (broad s, 2H); 5.35 (s, 2H); 3.85 - 3.88 (m, 4H).

Example 49

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 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: When ally I bromide was substituted for benzyl bromide in Example 48, Step A, the identical process afforded the title compound in 96% yield., as colourless solid, after purification by crystallization from EtOAc/hexane. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, 1 .3 Hz); 8.25 (d, 1 H, J = 2.1 Hz); 8.04 - 8.09 (m, 2H) ; 7.53 (d, 1 H, J = 8.6 Hz); 7.35 (d, 1 H, J = 10.6 Hz) ; 7.05 (d, 1 H, J = 8.7 Hz); 6.75 (s, 1 H); 6.03 - 6.13 (m, 1 H); 5.5 (dd, 1 H, 1 .3, 17.2 Hz); 5.33 (broad s, 1 H); 4.7 - 4.73 (m, 2H); 4.19 - 4.31 (m, 4H); 1 .51 s, 6H); 1 .36 (broad s, 9H).

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: When the product of Step A 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 in 85% yield., as colourless solid, after purification by crystallization from acetonitrile/EtOH. ¹ H-NMR (DMSO-d₆) 8.62 (broad s, 3H); 8.43 (d, 1 H; J = 1 .3 Hz); 8.19 (d, 1 H, J = 2.1 Hz) ; 8.1 1 (dd, 1 H, J = 2.1 , 8.6 Hz) ; 7.78 (d, 1 H, J = 8.7 Hz); 7.41 (d, 1 H, J = 8.8 Hz) ; 7.15 (s, 1 H) ; 6.0 - 6.12 (m, 1 H) ; 5.64 (tr, 2H, J = 5.3 Hz) ; 5.46 (dd, 1 H, J = 1 .6, 15.6 Hz) ; 5.32 (dd, 1 H, J = 1 .6, 10.6 Hz); 4.8 (d, 2H, J = 5 Hz); 3.8 - 3.9 (m, 4H).

Example 50

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 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 N₂. 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 N₂. 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 Et₂0, washed with 1 M NaOH (2 x 10 ml), H₂0 (2 x 15 ml), brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness under reduced pressure. The residue was passed through short column (Si0₂, CH₂CI₂/EtOAc 9:1 ) to give the title compound (0.14 g; 88%), as creamy solid. ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .4 Hz) ; 8.23 (d, 1 H, J = 2.1 Hz); 8.06 - 8.09 (m, 2H); 7.53 (d, 1 H, J = 8.6 Hz) ; 7.04 (d, 1 H, J = 8.7 Hz) ; 6.75 (s, 1 H); 5.33 (broad s, 1 H); 4.19 - 4.3 (m, 4H); 4.15 (tr, 2H, J = 6.5 Hz); 1 .87 - 1 .95 (m, 2H); 1 .74 - 1 .86 (m, 2H); 1 .51 (s, 6H); 1 .36 (broad s, 9H); 0.99 (d, 6H, J = 6.5 Hz).

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: When the product of Step A 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 in 69% yield as colourless solid, after purification by crystallization from acetonitrile/EtOH.¹H-NMR (DMSO-d₆) 8.65 (broad s, 3H); 8.43 (d, 1H; J = 1.3 Hz); 8.17 (d, 1 H, J = 2.2 Hz); 8.11 (dd, 1H, J = 2.2, 8.6 Hz); 8.04 (dd, 1H, J = 1.8, 8.7 Hz); 7.77 (d, 1H, J = 8.7 Hz); 7.42 (d, 1H, J = 8.8 Hz); 7.15 (s, 1H); 5.65 (tr, 2H, J = 5.3 Hz); 4.22 (tr, 2H, J = 6.5 Hz); 3.8 - 3.95 (m, 4H); 1.77 - 1.86 (m.1 H; 1.64 - 1.71 (m, 1 H); 0.93 (d, 6H, J = 6.5 Hz).

Example 51

2-amino-2-(5-(5-(3-isobutoxy-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1,3-diol.

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.¹H-NMR (CDCI₃) 8.58 (d, 1 H, J = 2.01 Hz); 8.06 (dd, 1 H, J = 8.55, 2.01 Hz); 7.78 (dd, 1 H, J = 8.4, 1.86 Hz); 7.64 (d, 1 H, J = 1.86 Hz); 6.97 (d, 1 H, J = 8.46 Hz); 6.88 (d, 1 H, J = 8.67 Hz); 4.69 - 4.61 (m, 1 H); 3.94 (s, 3H); 3.88 (d, 2H, J = 6.75 Hz); 2.28 - 2.14 (m, 1 H); 1.42 (d, 6H, J = 6.03 Hz); 1.07 (d, 6H, J = 6.69 Hz).

Step B: 2-iodo-4-(5-(3-isobutoxy-4-methoxyphenyl)-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 (0.36 g; 77%), as off white solid.¹H-NMR (CDCI₃) 8.48 (d, 1H, J = 1.92 Hz); 8.04 (dd, 1H, J = 8.4, 1.92 Hz); 7.78 (dd, 1H, J = 8.4, 1.1 Hz); 7.64 (d, 1 H, J = 1.89 Hz); 7.1 (d, 1H, J = 8.46 Hz); 6.97 (d, 1H, J = 8.5 Hz); 5.6 (s, 1H); 3.94 (s, 3H); 3.88 (d, 2H, J = 6.75 Hz); 2.25 - 2.16 (m, 1H); 1.07 (d, 6H, J = 6.7 Hz).

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 Example 30, Step E the similar procedure afforded the title compound (0.34 g; 78%), as pale solid.¹H-NMR (CDCI₃) 8.36 (d, 1H, J = 1.62 Hz); 8.08 (dd, 1 H, J = 8.6, 1.6 Hz); 7.8 (dd, 1H, J = 8.4, 1.9 Hz); 7.67 (d, 1H, J = 1.89 Hz); 7.52 (d, 1H, J = 8.61 Hz); 6.97 (d, 1H, J = 8.5 Hz); 6.75 (s, 1H); 5.34 (broad s, 2H); 4.26 -4.23 (b, 4H); 3.94 (s, 3H); 3.88 (d, 2H, J = 6.75 Hz); 2.28-2.14 (m, 1H); 1.5-1.4 (b, 15H); 1.07(d, 6H, J = 6.7 Hz). 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. The solid was filtered and dried in vacuo to gave the title compound (95 mg; 78%), as creamy solid. ¹ H-NMR (DMSO-d₆) 8.29 (s, 1 H); 7.93 (dd, 1 H, J = 8.5, 1 .6 Hz); 7.77 (dd, 1 H, J = 8.5, 1 .7 Hz); 7.67 (d, 1 H, J = 8.64 Hz); 7.61 (d, 1 H, J = 1 .74 Hz); 7.19 (d, 1 H, J = 8.6 Hz); 6.9 (s, 1 H); 4.81 (broad s, 2H); 3.86 - 3.83 (b, 5H); 3.65 (b, 2H); 3.58 (b, 2H) ; 2.1 - 1 .9 (m, 1 H); 1.0 (d, 6H, J = 6.7 Hz).

Example 52

2-amino-2-(5-(5-(3-ethoxy-4-methoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol.

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. ¹ H-NMR (CDCI₃) 8.58 (d, 1 H, J = 1 .98 Hz); 8.06 (dd, 1 H, J = 8.58, 2.01 Hz); 7.79 (dd, 1 H, J = 8.4, 1 .86 Hz); 7.66 (d, 1 H, J = 1 .8 Hz); 6.97 (d, 1 H, J = 8.46 Hz) ; 6.87 (d, 1 H, J = 8.67 Hz) ; 4.69 - 4.61 (m, 1 H) ; 4.22 (q, 2H, J = 13.98, 6.99 Hz); 3.95 (s, 3H) ; 1 .52 (t, 3H, J = 6.96 Hz); 1 .41 (d, 6H, J = 6.03 Hz).

Step B: 4-(5-(3-ethoxy-4-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- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound (0.14 g; 80%), as off white solid. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 1 .98 Hz) ; 8.04 (dd, 1 H, J = 8.5, 2.01 Hz) ; 7.79 (dd, 1 H, J = 8.4, 1 .98 Hz); 7.65 (d, 1 H, J = 1 .95 Hz); 7.07 (d, 1 H, J = 8.46 Hz) ; 6.98 (d, 1 H, J = 8.4 Hz); 5.64 (s, 1 H); 4.21 (q, 2H, J = 13.98, 6.99 Hz); 3.95 (s, 3H); 1 .52 (t, 3H, J = 6.99 Hz).

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 Example 30, Step E the similar procedure afforded the title compound (85 mg; 52%), as pale solid. ¹H-NMR (CDCI₃) 8.35 (d, 1 H, J = 1 .29 Hz); 8.07 (dd, 1 H, J = 8.6, 1 .7 Hz); 7.8 (dd, 1 H, J = 8.4, 1 .9 Hz); 7.68 (d, 1 H, J = 1 .92 Hz) ; 7.51 (d, 1 H, J = 8.64 Hz); 6.98 (d, 1 H, J = 8.5 Hz); 6.75 (s, 1 H) ; 5.33 (s, 2H); 4.29 - 4.19 (b, 6H) ; 1 .5 - 1 .4 (b, 18H).

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. The solid was filtered and dried in vacuo to gave the title compound (60 g; quantitative), as off white solid. ¹ H-NMR (DMSO-d₆) 8.29 (d, 1 H, J = 1 .23 Hz) ; 7.94 (dd, 1 H, J = 8.55, 1 .56 Hz) ; 7.77 (dd, 1 H, J = 8.4, 1 .8 Hz); 7.67 (d, 1 H, J = 8.55 Hz); 7.61 (d, 1 H, J = 1 .77 Hz) ; 7.19 (d, 1 H, J = 8.58 Hz); 6.9 (s, 1 H) ; 4.85 (broad s, 2H); 4.13 (q, 2H, J = 13.8, 6.84 Hz); 3.86 (s, 3H) ; 3.66 (b, 2H) ; 3.59 (b, 2H); 1 .36 (t, 3H, J = 6.87 Hz).

Example 53

2-amino-2-(5-(5-(4-isobutoxy-3-methylphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol, HCI salt.

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. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 1 .95 Hz); 8.05 - 7.97 (m, 3 H); 7.07 (d, 1 H, J = 8.46 Hz) ; 6.89 (d, 1 H, J = 8.13 Hz); 5.6 (s, 1 H); 3.81 (d, 2H, J = 6.39 Hz); 2.33 (s, 3H); 2.3 - 2.1 (m, 1 H) ; 1 .06 (d, 6H, J = 6.72 Hz).

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 Example 30, Step E the similar procedure afforded the title compound (0.1 1 g; 87%), as pale solid. ¹H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .1 1 Hz) ; 8.1 - 7.99 (m, 3H); 7.52 (d, 1 H, J = 8.64 Hz); 6.9 (d, 1 H, J = 8.31 Hz); 6.75 (s, 1 H) ; 5.33 (s, 1 H); 4.33 - 4.2 (m, 4H) ; 3.81 (d, 6H, J = 6.39 Hz); 2.31 (s, 3H) ; 2.24 - 2.1 (m, 1 H); 1 .54 (s, 6H); 1 .51 (s, 9H); 1 .06 (d, 6 H, J = 6.72 Hz).

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. ¹ H-NMR (DMSO-d₆) 8.77 (bs, 3H) ; 8.4 (d, 1 H, J = 1 .41 Hz) ; 8.02 (dd, 1 H, J = 8.64, 1 .71 Hz) ; 7.98 (dd, 1 H, J = 10.74, 2.13 Hz); 7.96 (s, 1 H); 7.76 (d, 1 H, J = 8.67 Hz) ; 7.18 (s, 1 H); 7.13 (d, 1 H, J = 8.55 Hz); 5.6 (b, 2H); 3.84 (d, 1 H, J = 6.4 Hz); 2.24 (s, 3H); 2.1 - 2.01 (m, 1 H); 0.99 (d, 6H, J = 6.69 Hz).

Example 54

2-amino-2-(5-(5-(3-chloro-4-isobutoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol, HCI salt.

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. ¹H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.01 Hz) ; 8.2 (d, 1 H, J = 2.01 Hz) ; 8.06 - 8.01 (m, 2H); 7.0 (d, 1 H, J = 8.67 Hz); 6.87 (d, 1 H, J = 8.61 Hz); 4.69 - 4.61 (m, 1 H); 3.87 (d, 1 H, J = 6.48 Hz) ; 2.24 - 2.14 (m, 1 H); 1 .41 (d, 6H, J =

6.06 Hz) ; 1 .07 (d, 6H, J = 6.72 Hz).

Step B: 4-(5-(3-chloro-4-isobutoxyphenyl)- 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- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 3, Step C, the similar procedure afforded the title compound (0.25 g; 68%), as off white solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 1 .95 Hz); 8.21 (d, 1 H, J = 2.13 Hz) ; 8.05 - 8.01 (m, 3H); 7.08 (d, 1 H, J = 8.46 Hz); 7.0 (d, 1 H, J = 8.64 Hz); 5.61 (s, 1 H); 3.87 (d, 2H, J = 6.48 Hz) ; 2.23 - 2.15 (m, 1 H); 1 .08 (d, 6H, J = 6.72 Hz).

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 Example 30, Step E the similar procedure afforded the title compound (0.27 g; 85%), as pale solid. ¹H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .23 Hz) ; 8.23 (d, 1 H, J = 2.04 Hz) ; 8.09 - 8.03 (m, 2H); 7.52 (d, 1 H, J = 8.61 Hz) ; 7.1 (d, 1 H, J =

8.7 Hz); 6.75 (s, 1 H); 5.33 (s, 1 H); 3.87 (d, 2H, J = 6.45 Hz); 2.26 - 2.12 (m, 1 H); 1 .5 - 1 .36 (b, 15H); 1.08 (d, 6H, J = 6.72 Hz).

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. ¹ H-NMR (DMSO-d₆) 8.73 (s, 3H); 8.42 (s, 1 H); 8.16 - 8.01 (m, 3H); 7.76 (d, 1 H, J = 8.37 Hz) ; 7.38 (d, 1 H, J = 8.52 Hz); 7.17 (s, 1 H); 5.67 (bs, 2H); 3.95 (d, 2H, J = 5.67 Hz); 3.32 (b, 4H); 2.07 (bm, 1 H); 0.99 (d, 6H, J = 6.21 Hz).

Example 55

2-Amino-2-(5-(5-(3-chloro-4-propoxy-5-cynophenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol.

Step A: 3-chloro-4-isopropoxy-5-cynobenzoic acid: (i) 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 TiCI₄ (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 ^SC 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%). ¹ H-NMR (CDCI₃) 8.3 (d, 1 H, J = 2.01 Hz) ; 8.0 (d, 1 H, J = 1 .98 Hz); 3.99 (t, 2H, J = 6.6 Hz); 3.89 (s, 3H); 1 .97 - 1 .83 (m, 2H); 1 .1 (t, 3H, J = 7.41 Hz), (ii) 3-chloro-4-isopropoxy-5-cyno-methylbenzoate: To a stirred solution of above product (2 gms, 5.6 mmol) in dry DMF (3 mL) under nitrogen was added Cu(l)CN (1 .1 gms, 12 mmol) and the content was stirred at 110 ^aC for 8hrs and then at room temperature for overnight. The mixture was then poured into 1 M HCI solution (300 mL) and extracted with the EtOAc (100 mL x 3). The organic layer was dried over magnesium sulphate and the solvent was passed through silica gel bead (2 x 3 cm). The solvent was distilled and crude was purified over silica gel column to gave a pale oil (0.35 gms, 25%). ¹H-NMR (CDCI₃) 8.2 (d, 1 H, J = 2.07 Hz) ; 8.15 (d, 1 H, J = 2.13 Hz); 4.3 (t, 2H, J = 6.51 Hz); 3.92 (s, 3H); 1 .96 - 1 .83 (m, 2H) ; 1 .1 (t, 3H, J = 7.38 Hz), (iii) 3-chloro-4-isopropoxy-5-cynobenzoic acid: The above product (0.35 gms, 1 .38 mmol) was dissolved in dioxane:water mixture (30 mL: 5 mL) and a solution of KOH (0.2 gms in 3mL water) was added to it. The solution was stirred at 100 ^SC for 3 hrs (tic). The solvent was distilled and the crude was dissolved in water (10 mL) and concentrated HCI (1 mL) was added to it. The white solid was filtered and washed with water and dried in oven at 55 ^SC to gave a white solid (0.2 gms, 61 %). ¹ H-NMR (CDCI₃) 8.3 (d, 1 H, J = 2.07 Hz); 8.2 (d, 1 H, J = 2.1 Hz) ; 4.34 (t, 2H, J = 6.51 Hz) ; 1 .97 - 1 .85 (m, 2H); 1 .1 (t, 3H, J = 7.38 Hz).

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. ¹H-NMR (CDCI₃) 8.55 (d, 1 H, J = 2.07 Hz) ; 8.4 (d, 1 H, J = 2.1 Hz); 8.3 (d, 1 H, J = 2.07 Hz); 8.04 (dd, 1 H, J = 8.61 , 2.07 Hz); 6.88 (d, 1 H, J = 8.73 Hz) ; 4.7 - 4.63 (m, 1 H) ; 4.35 (t, 2H, J = 6.48 Hz); 1 .99 - 1 .87 (m, 2H); 1 .42 (d, 6H, J = 6.93 Hz); 1 .1 (t, 3H, J = 7.41 Hz).

Step C: 4-(5-(3-chloro-4-isopropoxy-5-cynophenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol: 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 (0.08 g; 67%), as off white solid. ¹ H- NMR (CDCIg) 8.46 (d, 1 H, J = 1 .95 Hz); 8.4 (d, 1 H, J = 2.1 Hz) ; 8.3 (d, 1 H, J = 2.07 Hz); 8.04 (d, 1 H, J = 1 .95 Hz) ; 7.1 (d, 1 H, J = 8.52 Hz) ; 5.68 (bs, 1 H); 4.36 (t, 2H, J = 6.48 Hz); 2.03 - 1 .87 (m, 2H); 1 .12 (t, 3H, J = 7.41 Hz).

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. ¹ H-NMR (CDCI₃) 8.43 (d, 1 H, J = 2.1 Hz); 8.34 (d, 1 H, J = 2.07 Hz); 8.1 (d, 1 H, J = 1 .65 Hz); 8.0 (d, 1 H, J = 1 .65 Hz); 6.77 (s, 1 H); 5.33 (s, 1 H) ; 4.4 (t, 2H, J = 6.51 Hz); 4.3 - 4.2 (m, 4H); 2.03 - 1.87 (m, 2H); 1 .53 (s, 9H); 1.51 (s, 6H); 1 .12 (t, 3H, J = 7.35 Hz).

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. ¹ H-NMR (DMSO-d₆) 8.55 (s, 1 H) ; 8.53 (s, 1 H); 8.32 (s, 1 H) ; 7.95 (d, 1 H, J = 8.16 Hz); 7.7 (d, 1 H, J = 8.07 Hz); 6.94 (bs, 1 H); 4.3 (t, 2H, J = 6.36 Hz); 3.3 (b, 4H); 1 .87 - 1 .76 (m, 2H); 1 .03 (t, 3H, J = 7.32 Hz).

Example 56 2-Amino-2-(5-(5-(4-butyl-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol. Hydrochloride salt.

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% NaHC0₃ (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. ¹H-NMR (CDCI₃) 8.09 (d, 1 H, J = 1 .4 Hz); 7.75 (dd, 1 H, J = 1 .4; 8.3 Hz); 6.68 (d, 1 H), J = 8.3 Hz); 3.91 (s, 3H).

Step B: Methyl 4-n-butyl-3-chlorobenzoate: ZnBr₂ (0.56 g; 2.49 mmol) was kept in vacuo at 1 10°C for 1 h. After cooling to room temperature under N₂, 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 N₂ with stirring, followed by CIPd(PPh₃)₂ (0.12 g) and Cul (0.05 g). The mixture was allowed to warm up to room temperature and stirred for 2 h. To it MeOH (4 ml) was added and solvents were removed under reduced pressure. The residue was partitioned between EtOAc (50 ml) and 5% NH₄CI (10 ml). The organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si0₂; CH₂CI₂/hexane 1 :1 ) to give the title compound (0.39 g; 57%), as creamy solid). ¹H-NMR (CDCI₃) 7.99 (d, 1 H, J = 1 .7 Hz); 7.81 (dd, 1 H, J = 1 .7; 8 Hz); 7.26 (d, 1 H, J = 8 Hz); 3.89 (s, 3H); 2.75 (tr, 2H, J = 7.6 Hz) ; 1 .54 - 1 .64 (m, 2H); 1 .31 - 1 .45 (m, 2H); 0.93 (tr, 3H, J = 7.3 Hz). In addition n- butyl 4-nbutyl-3-chlorobenzoate (0.17 g; 21 %) was isolated, as colourless oil). ¹ H-NMR (CDCIg) 7.98 (d, 1 H, J = 1 .7 Hz); 7.82 (dd, 1 H, J = 1 .7; 8 Hz) ; 7.25 (d, 1 H, J = 8 Hz); 4.3 (tr, 2H, J = 6.6 Hz) ; 2.76 (tr, 2H, J = 7.6 Hz); 1 .36 - 1 .78 (m, 8H, + H₂0); 0.93 - 0.98 (m, 6H).

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 H₂0 (2 ml) in dioxane (5 ml) was refluxed until become homogenous (~ 10 min).

After evaporation of solvents under reduced pressure, the residue was diluted to 5 ml with H₂0, acidified to pH ~ 1 with concentrated HCI and extracted with EtOAc (2 x 30 ml).

The organic phase was washed with brine, dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness to give the title compound (0.43 g ; 88%) as colorless solid. ¹ H-NMR (CDCI₃) 8.06 (d, 1 H, J = 1 .6 Hz); 7.89 (dd, 1 H, J = 1 .6; 8 Hz); 7.31 (d, 1 H, J = 8 Hz); 2.78 (tr, 2H, J = 7.6 Hz); 1 .56 - 1 .66 (m, 2H) ; 1 .33 - 1 .46 (m, 2H); 0.94 (tr, 3H, J = 7.3 Hz).

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 CH₂CI₂ (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%). To a suspension of above product (0.2 g; 0.75 mmol) and the product of Example 36, 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 N₂. This was stirred for 2 h at room temperature, diluted to 50 ml with EtOAc, washed with H₂0 (2 x 15 ml), brine (10 ml), dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness, to give the creamy solid. This was diluted to 2 ml with anhydrous DMSO and 1 M TBAF in THF (0.5 ml) was added and the resulting mixture was stirred at ~120°C for 1 h, cooled to room temperature and H₂0 (10 ml) was added. The product was taken up by extraction with EtOAc (3 x 20 ml). The organic phase was washed with H₂0 (20 ml), brine (10 ml), dried over anhydrous MgS0₄, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si0₂, CH₂CI₂) to give the title compound (0.19 g; 49%), as colourless solid. ¹ H-NMR (CDCI₃) 8.57 (d, 1 H, J = 2 Hz); 8.17 (d, 1 H, J = 2.1 Hz) ; 8.06 (dd, 1 H, J = 2.1 ; 8.6 Hz); 7.98 (dd, 1 H, J = 1 .7; 8 Hz) ; 7.38 (d, 1 H, J = 8 Hz) ;

6.88 (d, 1 H, J = 8.6 Hz) ; 4.6 - 4.7 (m, 1 H) ; 2.8 (tr, 2H, J = 7.6 Hz); 1 .58 - 1 .68 (m, 2H); 1.35 - 1 .45 (m, 2H); 0.946 (tr, 3H, J = 7.3 Hz).

Step E: 2-lodo-4-(5-(4-n-butyl-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenol: 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 colourless solid. ¹ H-NMR (CDCI₃) 8.48 (d, 1 H, J = 2 Hz) ; 8.17 (d, 1 H, J = 1 .7 Hz) ; 8.04 (dd, 1 H, J = 2; 8.5 Hz) ; 7.98 (dd, 1 H, J = 1 .7; 8 Hz) ; 7.38 (d, 1 H, J = 8 Hz) ; 7.09 (d, 1 H, J = 8.5 Hz); 5.6 (2, 1 H) ; 2.8 (tr, 2H, J = 7.7 Hz) ; 1 .35 -1 .69 (m, 4H + H₂0) ; 0.96 (tr, 3H, J = 7.3 Hz).

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: 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 86% yield., as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/BOAc 95:5). ¹ H-NMR (CDCI₃) 8.35 (d, 1 H, J = 21 .7 Hz); 8.2 (d, 1 H, J = 1.7 Hz); 8.08 (dd, 1 H, J = 1 .7; 8.6 Hz); 8.0 (dd, 1 H, J = 1 .7; 8 Hz) ; 7.53 (d, 1 H, J = 8.6 Hz); 7.39 (d, 1 H, J = 8 Hz); 6.76 (s, 1 H) ; 5.33 (broad s, 1 H); 4.2 - 4.31 (m, 4H); 2.81 (tr, 2H, J = 7.6 Hz); 1 .59 -1 .67 (m, 2H ); 1 .53 (s, 3H); 1.51 (s, 3H) ; 1 .36 - 1 .48 (m, 1 1 H); 0.96 (tr, 3H, J = 7.3 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.71 (broad s, 3H); 8.44 (d, 1 H, J = 1 .4 Hz); 8.15 (d, 1 H, J = 1 .7 Hz); 8.06 - 8.08 (m, 1 H) ; 8.03

- 8.05 (m, 1 H); 7.78 (d, 1 H, J = 8.6 Hz) ; 7.62 (d, 1 H, J = 8.1 Hz) ; 7.17 (s, 1 H); 5.68 (broad s, 2H); 4.2 (tr, 2H, J = 5.5 Hz) ; 3.8 - 3.95 (bm, 4H) ; 2.79 (tr, 2H, J = 7.5 Hz); 1.52

- 1 .63 (m, 2H); 1 .28 - 1 .41 (m, 2H); 0.9 (tr, 3H, J = 7.3 Hz).

Example 57

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.

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 CH₂CI₂ (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. The organic phase was washed with H₂0 (2 x 10 ml), brine (10 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (Si0₂, CH₂CI₂) to give the title compound (0.19 g; 65%), as colourless solid. ¹ H-NMR (CDCI₃) 7.96 s, 2H) ; 6.18 (s, 1 H): 3.89 (s, 3H).

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 (CDCI₃) 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. ¹ H-NMR (CDCI₃) 8.02 s, 2H); 4.06 (tr, 2H; J = 6 Hz); 1 .83 - 1 .91 (m, 2H) ; 1.05 - 1 .1 m, 3H).

Step D: 3-(3-lodo-4-isopropoxyphenyl)-5-(3,5-dichloro-4-propoxyphenyl)- 1,2,4- oxadiazole: When 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. ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2 Hz) ; 8.13 (s, 2H) ; 8.05 (dd, 1 H, J = 2; 8.6 Hz): 6.88 (d, 1 H, J = 8.6 Hz); 4.62 - 4.71 (m, 1 H); 4.08 (tr, 2H, J = 6.6 Hz); 1.84 - 1 .97 (m, 2H); 1.42 (d, 6H, J = 6.1 Hz) ; 1 .1 (tr, 3H, J = 7.4 Hz).

Step E: 2-lodo-4-(5-(3,5-dichloro-4-n-propoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)phenol: 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 creamy solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 2 Hz); 8.13 (s, 2H); 8.03 (dd, 1 H, J = 2; 8.5 Hz) ; 7.09 (d, 1 H, J = 8.5 Hz); 5.61 (s, 1 H); 4.08 (tr, 2H, J = 6.6 Hz); 1 .84 -1 .97 (m, 2H); 1 .1 (tr, 3H, J = 7.4 Hz).

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. , as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .5 Hz) ; 8.16 (s, 2H) ; 8.06 (dd, 1 H, J = 1 .7; 8.7 Hz); 7.54 (d, 1 H, J = 8.6 Hz); 6.76 (s, 1 H); 5.33 (broad s, 1 H) ; 4.19 - 4.31 (m, 4H); 4.09 (tr, 2H, J = 6.6 Hz) ; 1 .87 -1 .95 (m, 2H ); 1 .53 (s, 3H) ; 1.51 (s, 3H) ; 1.37 (broad s, 9H); 1 .1 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.71 (broad s, 3H); 8.45 (d, 1 H, J = 1 .4 Hz); 8.23 (s, 2H); 8.05 (dd, 1 H, J = 1 .8; 8.7 Hz); 7.79 (d, 1 H, J = 8.7 Hz); 7.17 (s, 1 H); 4.06 (tr, 2H, J = 6.4 Hz); 3.82 - 3.95 (m, 4H); 3.62 (broad s, 2H + H₂0); 1.74 - 1 .85 (m, 2H); 1 .02 (tr, 3H, J = 7 Hz).

Example 58 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.

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. The mixture was diluted to 50 ml with EtOAc, organic phase separated and washed with H₂0 (10 ml), brine (10 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, The residue was purified by crystallization from H₂0 to give the title compound (0.26 g; 70%) as shiny creamy crystals. ¹ H-NMR (DMSO- d₆) 1 1 .32 (s, 1 H); 8.02 (d, 1 H, J = 9 Hz) ; 7.27 (d, 1 H, J = 9 Hz); 2.21 (s, 3H).

Step B: Methyl 3-chloro-4-hydroxy-5-methylbenzoate: When 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 (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 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: When 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 (CDCI₃) 7.88 (m, 1 H); 7.75 (m, 1 H);

3.8 - 3.93 (m, 2H); 3.86 (s, 3H); 2.32 (s, 3H); 1 .79 - 1 .91 (m, 2H) ; 1 .04 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (CDCI₃) 7.96 (d, 1 H, J = 1 .9 Hz); 7.82 d, 1 H, J = 1 .9 Hz) ; 3.94 (tr, 2H, J = 6.6 Hz) ; 2.34 (s, 3H) ; 1 .8 - 1 .92 (m, 2H); 1 .08 (tr, 3H, 7.4 Hz).

Step E: 3-(3-lodo-4-isopropoxyphenyl)-5-(3-chloro-5-methyl-4-propoxyphenyl)- 1 ,2,4-oxadiazole: When 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. ¹ H-NMR (CDCI₃) 8.57 (d, 1 H, J = 2.1 Hz): 8.03 - 8.08 (m, 2H);

7.9 - 7.93 (m, 1 H); 6.88 (d, 1 H, J = 8.7 Hz) ; 4.61 - 4.7 (m, 1 H) ; 3.96 (tr, 2H, J = 6.6 Hz): 2.39 (s, 3H); 1 .8 - 1 .94 (m, 2H) ; 1 .42 (d, 6H, J = 6.1 Hz) ; 1 .09 (tr, 3H, J = 7.4 Hz). Step F: 2-lodo-4-(5-(3-chloro-5-methyl-4-n-propoxyphenyl)- 1,2,4-oxadiazol-3- yljphenol: When 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 a creamy solid. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 2 Hz): 8.01 - 8.2 (m, 2H); 7.91 (d, 1 H; J = 1 .4 Hz); ); 7.08 (d, 1 H, J = 8.5 Hz); 5.67 (s, 1 H); 3.96 (tr, 2H, J = 6.6 Hz): 2.39 (s, 3H); 1 .81 - 1 .94 (m, 2H); 1 .09 (tr, 3H, J = 7.4 Hz).

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: 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 86% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .3 Hz) ; 8.05 - 8.09 (m, 2H) ; 7.94 (d, 1 H, J = 1 .4 Hz); 7.53 (d, 1 H, J = 8.6 Hz): 6.75 (s, 1 H); 5.32 (broad s, 1 H); 4.2 - 4.31 (m, 4H); 3.97 (tr, 2H, J = 6.6 Hz) ; 2.4 (s, 3H); 1 .82 - 1 .95 (m, 2H); 1 .52 (d, 6H, J = 5.4 Hz); 1 .36 (broad s, 9H); 1 .1 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.7 (broad s, 3H) ; 8.43 (d, 1 H, J = 1 .4 Hz); 8.02 - 8.07 (m, 3H); 7.78 (d, 1 H, J = 8.6 Hz); 7.16 (s, 1 H); 5.67 (tr, 2H, J = 4.7 Hz) ; 3.94 (tr, 2H, J = 6.4 Hz) ; 3.88 (d, 4H; J = 4.7 Hz); 2.38 (s, 3H); 1 .76 - 1 .85 (m, 2H); 1 .02 (tr, 3H, J = 7.4 Hz).

Example 59

2-Amino-2-(5-(5-(2-chloro-6-propoxypyridin-4-yl)-1 ,2,4-oxadiazol-3- y\)benzofuran-2-yl)propane-1,3-diol. HCI salt.

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 H₂0 and pH was adjusted to ~ 5 with citric acid. The product was extracted with EtOAc (3 x 50 ml) and combined organic phase washed with brine (120 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, to give the title compound (0.56 g; 100%), as brownish solid. ¹ H-NMR (CDCI₃) 9.8 (broad s, 1 H) ; 7.44 (d, 1 H, J = 1 Hz); 7.26 (d, 1 H, J = 1 Hz) ; 4.28 (tr, 2H, J = 6.6 Hz); 1 .74 - 1 .85 (m, 2H); 0.96 (tr, 3H, J = 7.4 Hz).

Step B: 5-(2-Chloro-6-propoxypyridin-4-yl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4- oxadiazole: When the product of Step A was substituted for 4-ethoxy-3- (methylsulfonamido)benzoic acid in Example 30, Step C, the identical process afforded the title compound in 34% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂). ¹ H-NMR (CDCIg) 8.56 (d, 1 H, J = 2.1 Hz): 8.05 (dd, 1 H, J = 2.1 , 8.6 Hz); 7.61 (d, 1 H, J = 1 Hz); 7.39 (d, 1 H, J = 1 Hz) ; 6.88 (d, 1 H, J = 8.8 Hz) ; 4.62 - 4.71 (m, 1 H); 4.32 (tr, 2H, J = 6.7 Hz) : 1 .75 - 1 .88 (m, 2H); 1 .43 (d, 6H, J = 6.1 Hz) ; 1 .04 (tr, 3H, J = 7.4 Hz).

Step C: 4-(5-(2-Chloro-6-propoxYpyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol: 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. ¹ H-NMR (CDCI₃) 8.47 (d, 1 H, J = 2 Hz) : 8.03 (dd, 1 H, J = 2, 8.5 Hz) ; 7.61 (d, 1 H, J = 1 .1 Hz) ; 7.39 (d, 1 H, J = 1 1 .04 (tr, 3H, J = 7.4 Hz).

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: 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 65% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .3 Hz); 8.05 (dd, 1 H, J = 1 .7, 8.6 Hz):); 7.64 (d, 1 H, J = 1 .1 Hz) ; 7.54 (d, 1 H, J = 8.6 Hz): 7.41 (d, 1 H, J = 1 .1 Hz); 6.76 (s, 1 H); 5.33 (broad s, 1 H); 4.33 (tr, 2H, J = 6.7 Hz); 4.1 - 4.28 (m, 4H) ; 1.76 - 1 .89 (m, 2H); 1.52 (d, 6H, J = 57.7 Hz) ; 1 .37 (broad s, 9H); 1 .04 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.72 (broad s, 3H); 8.44 (d, 1 H, J = 1 .4 Hz); 8.05 (dd, 1 H, 1 .7, 8.6 Hz); ); 7.8 (d, 1 H, J = 8.7 Hz); 7.7 (d, 1 H, J = 1 .1 Hz) : 7.46 (d, 1 H, J = 1 .1 Hz) 7.18 (s, 1 H); 5.68 (tr, 2H, J = 5.3 Hz); 4.27 (tr, 2H, J = 6.6 Hz); 3.8 - 3.9 (m, 4H); 1 .71 - 1 .76 (m, 2H); 0.97 (tr, 3H, J = 7.4 Hz).

Example 60

2-Amino-2-(5-(5-(3-fluoro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol. HCI salt

Step A: 2-Fluoro-4-lodophenol: To a stirred solution of 2-fluorophenol (0.47 g; 4.18 mmol) in concentrated NH₄OH (22 ml) a solution of l₂ (1.06 g; 4.18 mmol) was added at once at room temperature. After stirring overnight at room temperature the mixture was evaporated to dryness under reduced pressure and the residue was partitioned between EtOAc (100 ml) and H₂0 (40 ml). The organic phase was washed with 5% NaHS0₃, brine (10 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (Si0₂, CH₂CI₂ /EtOAc 9:1 ) to give the title compound (0.42 g; 42%), as colourless solid. ¹ H-NMR (CDCI₃) 7.3 - 7.4 (m, 2H); 6.75 (tr, 8.8 Hz) ; 5.17 (m, 1 H).

Step B: 3-Fluoro-4-n-propoxy-iodobenzene: 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 creamy solid. ¹ H-NMR (CDCI₃) 7.3 - 7.39 (m, 2H); 6.65 - 6.72 (m, 1 H); 3.94 (tr, 2H, J = 6.6 Hz); 1 .75 - 1 .88 (m, 2H); 1.02 (tr, 3H, J = 7.4 Hz).

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 N₂, with stirring. After stirring for 30 min at -50 °C, the mixture was cooled to -78°C, degassed under reduced pressure and saturated with C0₂ ( balloon). This was stirred at room temperature for 30 min and evaporated to dryness under reduced pressure. The residue was diluted to 50 ml with EtOAc, washed with diluted HCI (10 ml), brine (10 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, The residue was purified by crystallization from EtOAc/hexane to give title compound (0.25 g; 80%), as colourless solid. ¹ H-NMR (CDCI₃) 7.76 - 7.88 (m, 2H); 6.98 (tr, 1 H, J = 8.3 Hz); 4.06 (tr, 2H, J = 6.6 Hz); 1 .84 - 1 .94 (m, 2H); 1 .06 (tr, 3H, J = 7.4 Hz).

Step D: 5-(3-Fluoro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When 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 (Si0₂, CH₂CI₂). ¹ H-NMR (CDCI₃) 8.56 (d, 1 H, J = 2.1 Hz) ; 8.05 (dd, 1 H, J = 2.1 , 8.6 Hz) ; 7.87 - 7.94 (m, 2H); 7.06 (tr, 1 H, J = 8.7 Hz); 6.88 (d, 1 H, J = 8.7 Hz); 4.6 - 4.7 (m, 1 H); 4.08 (tr, 2H, J = 6.6 Hz); 1.82 - 1 .95 (m, 2H); 1.42 (d, 6H, J = 6.1 Hz) ; 1 .07 (tr, 3H, J = 7.4 Hz).

Step E: 4-(5-(3-Fluoro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:

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. ¹ H-NMR (CDCI₃) 8.41 (d, 1 H, J = 2 Hz) ; 7.93 (dd, 1 H, J = 2, 8.5 Hz); 7.78 - 7.86 (m, 2H); 6.96 - 7.03 (m, 2H) ; 6.65 (broad s, 1 H); 4.02 (tr, 2H, J = 6.6 Hz); 1 .78 - 1 .88 (m, 2H); 1 .04 (tr, 3H, J = 7.4 Hz).

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: 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 95% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.34 (d, 1 H, J = 1 .4 Hz); 8.07 (dd, 1 H, J = 1 .7, 8.6 Hz); 7.9 - 7.97 (m, 2H); 7.53 (d, 1 H, J = 8.6 Hz) ; 7.08 (tr, 1 H, J = 8.6 Hz) ; 6.76 (s, 1 H); 4.18 - 4.31 (m, 4H); 4.08 (tr, 2H, J = 6.5 Hz) ; 1 .85 - 1 .93 (m, 2H) ; 1.54 (s, 3H + H₂0); 1 .51 (s, 3H); 1 .36 (broad s, 9H); 1 .08 (7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.73 (broad s, 3H); 8.4 (d, 1 H, J = 1 .4 Hz) ; 8.03 (dd, 1 H, 1 .7, 8.6 Hz); 7.93 - 7.99 (m, 2H); 7.77 (d, 1 H, J = 8.7 Hz) ; 7.42 (tr, 1 H, J = 9 Hz): 7.18 (s, 1 H) ; 5.68 (tr, 2H, J = 5 Hz); 4.13 (tr, 2H, J = 6.5 Hz); 3.89 (d, 4H; J = 5Hz); 1.71 - 1 .84 (m, 2H) ; 0.98 (tr, 3H, J = 7.4 Hz). Example 61

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.

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. ¹ H-NMR (CDCI₃) 8.74 (d, 1 H, J = 2.1 Hz); 8.23 (d, 1 H, J = 2.1 Hz) 4.42 (tr, 2H, J = 6.7 Hz) ; 1 .79 - 1 .92 (m, 2H0;

1 .04 (tr, 3H, J = 7.4 Hz).

Step B: 5-(5-Chloro-6-propoxypyridin-3-yl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: When the product of Step A 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 (Si0₂, CH₂CI₂). ¹H-NMR (CDCIg) 8.81 (d, 1 H, J = 2.1 Hz); 8.56 (d, 1 H, J = 2.1 Hz); 8.37 (d, 1 H, J = 2.1 Hz) ; 8.05 (d, 1 H, J = 2.1 , 8.6 Hz) ; 6.88 (d, 1 H, J = 8.7 Hz); 4.6 - 4.7 (m, 1 H); 4.44 (tr, 2H, J = 6.7 Hz) ; 1 .81 - 1 .94 (m, 2H); 1 .42 (d, 6H, J = 6.1 Hz) ; 1 .06 (tr, 3H, J = 7.4 Hz).

Step C: 4-(5-(5-chloro-6-propoxypyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-2-iodophenol: 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. ¹ H-NMR (CDCI₃) 8.84 (d, 1 H, J = 2.1 Hz); 8.47 (d, 1 H, J = 2 Hz); 8.37 (d, 1 H, J = 2.1 Hz) ; 8.03 (dd, 1 H, J = 2, 8.5 Hz) ; 7.09 (d, 1 H, J = 8.75 Hz) ; 5.64 (s, 1 H); 4.44 (tr, 2H, J = 6.7 Hz); 1.81 - 1 .94 (m, 2H) ; 1 .06 (tr, 3H, J = 7.5 Hz).

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: 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 in Example 30, Step E, the identical process afforded the title compound in 74% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.87 (d, 1 H, J = 2.1 Hz); 8.4 (d, 1 H, J = 2.1 Hz); 8.34 (d, 1 H, J = 1 .4 Hz); 8.07 (dd, 1 H, J = 1 .6, 8.6 Hz) ; 7.54 (d, 1 H, J = 8.7 Hz); 6.76 (s, 1 H); 5.33 (broad, s, 1 H); 4.45 (tr, 2H, J = 6.7 Hz); 4.2 - 4.31 (m, 4H) ; 1.84 - 1 .92 (m, 2H); 1.53 (s, 3H + H₂0); 1 .51 (s, 3H); 1 .37 (broad s, 9H) ; 1 .06 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.91 (d, 1 H, J - 2.1 Hz) ; 8.68 (broad s, 3H) ; 8.55 (d, 1 H, J = 2.1 Hz) ; 8.43 (d, 1 H, J = 1 .4 Hz);

8.05 (dd, 1 H, 1 .7, 8.6 Hz); 7.79 (d, 1 H, J = 8.6 Hz) ; 7.17 (s, 1 H) ; 5.66 (tr, 2H, J = 5.2 Hz); 4.41 (tr, 2H, J = 6.56 Hz); 3.88 (d, 4H; J = 5.2 Hz); 1 .74 - 1 .82 (m, 2H) ; 0.98 (tr, 3H, J = 7.4 Hz). Example 62

2-Amino-2-(6-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol. HCI salt

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. ¹ H- NMR (CDCI₃) 7.87 (d, 1 H, J = 8 Hz); 6.91 - 6.98 (m, 2H) ; 4.52 - 4.61 (m, 1 H); 1 .4 (d, 6H, J = 6.1 Hz).

Step B: N-Hydroxy-4-iodo-3-isopropoxybenzimidamide: A mixture of the product of Step A (0.48 g; 1 .67 mmol) HCI x NH₂OH (0.23 g; 3.34 mmol) ans DIPEA (0876 ml;

5.0 mmol) in anhydrous EtOH (2 ml) was stirred for 2 h at room temperature under N₂. After evaporation od solvents under reduced pressure, the residue was partitioned between EtOAc (100 ml) and H₂0 (25 ml). The organic phase was washed with brine (20 ml), dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness, to give the title compound (0.52 g; 97%), as colourless foam. ¹ H-NMR (CDCI₃) 7.77 (d, 1 H, J =

8.1 Hz) ; 7.09 (d, 1 H, J = 1 .8 Hz) ; 6.88 (dd, 1 H, J = 1 .9, 8.1 Hz); 4.83 (broad s, 2H) ; 4.56 - 4.65 (m, 1 H); 1.37 (d, 6H, J = 6.1 Hz).

Step C: 5-(3-Chloro-4-propoxyphenyl)-3-(4-iodo-3-isopropoxyphenyl)- 1,2,4- oxadiazole: When the 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 (Si0₂, CH₂CI₂). ¹ H-NMR (CDCI₃) 8.22 (d, 1 H, J = 2.1 Hz) ; 8.04 (dd, 1 H, J = 2.1 , 8.7 Hz); 7.89 (d, 1 H, J = 8 Hz); 7.56 (d, 1 H, J = 1 .7 Hz) ; 7.46 (dd, 1 H, J = 1 .7, 8 Hz); 7.03 (d, 1 H, J = 8.7 Hz) 4.7 - 4.76 (m, 1 H); 4.09 (tr, 2H, J = 6.4 Hz); 1 .87 - 1 .95 (m, 2H); 1 .43 (d, 6H, J = 6 Hz); 1 .1 (tr, 3H, J = 7.4 Hz).

Step D: 5-(5-(3-Chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:

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. ¹ H-NMR (CDCI₃) 8.21 (d, 1 H, J = 2.1 Hz); 8.04 (dd, 1 H, J = 2.1 , 8.7 Hz); 7.79 (d, 1 H, J = 8.2 Hz); 7.76 (d, 1 H, J = 1 .9 Hz) ; 7.45 (dd, 1 H, J = 1 .9, 8.2 Hz) ; 7.03 (d, 1 H, J = 8.7 Hz); 5.48 (s, 1 H); 4.08 (tr, 2H, J = 6.5 Hz); 1 .84 - 1 .95 (m, 2H) ; 1.09 (tr, 3H, J = 7.4 Hz).

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: When the product of Step D 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 53% yield, as colourless solid, after purification by FCC (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.2 - 8.26 (m, 2H) ; 8.0 - 8.09 (m, 2H); 7.62 (d, 1 H, J = 8.1 Hz); 7.03 (d, 1 H, J = 8.7 Hz) ; 6.74 (s, 1 H) ; 4.16 - 4.32 (m, 4H); 4.08 (tr, 2H, J = 6.4 Hz) ; 1 .84 - 1 .95 (m, 2H) ; 1 .54 (s, 3H + H₂0); 1 .51 (s, 3H); 1 .37 (broad s, 9H); 1 .1 (7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.73 (broad s, 3H); 8.17 - 8.19 (m, 2H) ; 8.1 1 (dd, 1 H, J = 2.1 8.7 Hz) ; 7.99 (dd, 1 H, J = 1 .3, 8.1 Hz) ; 7.87 (d, 1 H, J = 8.2 Hz); 7.39 (d, 1 H, J = 8.7 Hz); 7.13 (d, 1 H, J = 0.7 Hz) ; 5.67 (tr, 2H, J = 5.2 Hz); 4.15 (tr, 2H, J = 6.4 Hz) ; 3.89 (d, 4H, 5.2 Hz); 1 .71 - 1 .82 (m, 2H); 1 .0 (tr, 3H, J = 7.4 Hz).

Example 63

2-Amino-2-(4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol. HCI salt

Step A: 2-lodo-3-hydroxybenzonitrile: To a solution of 3-hydroxybenzonitrile (1 g; 8.39 mmol) in concentrated NH₄OH (44 ml) a solution of l₂ (2.07 g; 8.67 mmol) and Kl (6.82 g; 41 .08 mmol) in H₂0 (10 ml) was added at once with stirring at room temperature. After stirring overnight at room temperature the solvent was removed under reduced pressure, the residue was partitioned between EtOAc (150 ml) and H₂0 (50 ml) The organic phase was washed with H₂0 (20 ml), brine, dried over anhydrous MgS0₄, filtered and the filtrate evaporated to dryness. The residue was purified by crystallization from EtOAc/hexane, followed by crystallization from CH₂CI₂ to give pure title compound (0.77 g; 38%), as creamy solid. ¹ H-NMR (CDCI₃) 7.33 (tr, 1 H, J = 7.8 Hz); 7.15 - 7.23 (m, 2H); 5.64 (s, 1 H). 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 (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 7.64 (d, 1 H, J = 8.3 Hz); 7.53 (d, 1 H, J = 7.6 Hz); 7.3 (m, 1 H); 6.9 (s, 1 H) ; 4.1 - 4.29 (m, 4H) ; 1 .5 (s, 6H) ; 1 .37 (broad s, 9H).

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 NH₂OH (0.16 g; 2.3 mmol) and K₂C0₃ (0.16 g; 1 .15 mmol) in anhydrous EtOH (3 ml) was stirred at -70 °C for 6 h under N₂. After evaporation of solvent under reduced pressure the residue was treated with H₂0 ( 5 ml). The solid formed was filtered off, washed with cold H₂0 (2 ml) and dried in vacuo and purified by FCC (Si0₂, EtOAc) to give the title compound (0.1 g; 62%) as colourless foam. ¹ H-NMR (CDCI₃) 7.38 - 7.49 (m 2H); 7.23 - 7.28 (m, 1 H + CDCI₃) ; 7.07 (s, 1 H); 5.42 (s, 1 H); 4.92 (broad s, 2H); 4.22 (m, 4H); 1 .8 (s, 6H) ; 1 .35 (broad s, 9H).

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: When the 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 (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCI₃) 8.25 (d, 1 H, J = 2.1 Hz) ; 8.05 - 8.12 (m, 1 H) ; 7.58 (d, 1 H, J = 8.2 Hz); 7.35 - 7.42 (m, 2H); 7.05 (d, 1 H, J = 8.6 Hz); 5.4 (s, 1 H) ; 4.2 - 4.35 (m, 4H0; 4.1 (tr, 2H, J = 6.6 Hz) ; 1.8 - 1 .96 (m, 2H) ; 1 .53 (s, 3H + H₂0); 1 .51 (s, 3H); 1 .36 (broad s, 9H); 1 .1 (tr, 3H, J = 7.4 Hz).

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. ¹ H-NMR (DMSO- d₆) 8.7 (broad s, 3H); 8.24 (d, 1 H, J = 2.1 Hz) ; 8.17 (dd, 1 H, J = 2.1 8.76 Hz) ; 8.08 (d, 1 H, J = 7.1 Hz); 7.85 (d, 1 H, J = 8.3 Hz); 7.65 (s, 1 H); 7.54 (tr, 1 H, J = 8 Hz) ; 7.42 (d, 1 H, J = 8.8 Hz); 5.67 (tr, 2H, J = 5.2 Hz); 4.16 (tr, 2H, J = 6.4 Hz); 3.8 - 4.0 (m, 4H); 1 .74 - 1 .88 (m, 2H); 1 .01 (tr, 3H, J = 7.3 Hz). Example 64

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

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% D₂0 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 (Si0₂, CH₂CI₂/EtOAc 95:5). ¹ H-NMR (CDCIg) 8.35 (d, 1 H, J = 1 .7 Hz); 8.08 (dd, 1 H, J = 1 .7; 8.7 Hz) ; 7.79 (dd, 1 H, J = 2; 8.5 Hz); 7.69 (d, 1 H, J = 2 Hz); 7.53 (d, 1 H, J = 8.7 Hz) ; 6.98 (d, 1 H, J = 8.5 Hz); 5.32 (broad s, 1 H); 4.1 - 4.3 (m, 8H); 1 .4 - 1 .56 (m, 12H + H₂0); 1 .36 (broad s, 9H). 90% D isotopic purity.

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. ¹ H-NMR (DMSO- d₆) 8.69 (broad s, 3H); 8.42 (d, 1 H, J = 1 .74 Hz); 8.04 (dd, 1 H, J = 1 .74; 8.7 Hz); 7.76 (d, 1 H, J = 8.7 Hz); 7.75 (dd, 1 H, J = 2; 8.4 Hz); 7.62 (d, 1 H, J = 2 Hz) ; 7.19 (d, 1 H, J = 8.6 Hz); 5.67 (tr, 2H, J = 5.3 Hz) ; 4.14 (q, 4H, J = 6.9 Hz); 3.88 (d, 4H; J = 5.3 Hz); 1 .3 - 1 .4 (m, 6H); 90% D isotopic purity. Example 65

S1 P receptors activity evaluation

Independently, selected compounds were evaluated for S~\ Pi and S1 P₃ agonistic activity. The S1 assay system was GTPgama-S35 binding in membranes from CHO K1 cells, expressing S1 Ρτ human receptor. The S1 P₃ assay system was calcium mobilization in CHO K1 cells expressing S1 P₃ 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 μΜ. 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. These analyses provided efficacy (Emax) and potency (EC₅₀) of the compounds relative to S1 P, shown in Table 1 . The activity of endogenous ligand S1 P on S1 P1 receptor has been reported as 0.4 nM (Sanna M G et al, Chem Biol, 2005, 12(6), 703- 15) and was taken as comparator to calculate the activity.

Table 1 :

and S1 P₃ agonistic activity of selected compounds of Formula (I)

NA = Activity above 5000. Example 66

Lymphopenia Assay

The study was performed on B57.BL6 mice and the reduction in lymphocyte count was observed by administrating a single oral dose of vehicle and drug (examples 7 or 12). The blood was taken at 6 and 24 hour time point and the direct comparison in reduction of lymphocyte count in vehicle and drug treated mice was observed as shown in Table 2. Table 2: Immunosuppressive activity of selected compounds of Formula (I)

Example 67

Experimental Autoimmune Encephalomyelitis (EAE) Assay

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. There was marked efficacy with EAE inhibition comparable to the drug Gilenya™ (FTY720) during the course of treatment as shown in Figure 1 . AK refers to the compound of example 3. Example 68

Cytokine inhibition assay

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 and MOG refers to an antigen.

Example 69

Contact hypersensitivity assay

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. 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.

Example 70

Acute inflammation mediated by Phorbol ester

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. 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.

Example 71

Excitotoxic and inflammatory neurodegeneration induced by Kainic acid

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. On the third day the histopathology of brain section was performed and stained with cresyl violet to check the level of neurodegeneration. There was marked inhibition in neurodegeneration as shown in Figure 5. (Control refers to not challenged and treated with vehicle, vehicle refers to challenged and treated with vehicle and AK refers to challenged and treated with the compound of example 3).

Example 72

Seizure induced by Kainic acid

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.

Example 73

Stroke induced by Middle Cerebral Artery Occlusion

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

Example 74

Lipopolysaccharide (LPS) induced Sepsis

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.

Claims

THE CLAIMS DEFINI NG THE INVENTION ARE AS FOLLOWS: 1 . A compound of formula (I)

(I) wherein RT is selected from H, deuterium, halogen, CN, CF₃, -COOH, amide, sulphonamide, an alkyl chain (d-₅) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl, cycloalkyl (C₃.₇) and carbocycle; wherein R₂ is selected from H, deuterium, halogen, CN, CF₃, an alkyl chain (d-₄) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl or cycloalkyl (C₃-₇) and carbocycle; wherein R₃ is selected from H, deuterium, halogen, an alkyl chain (d-₇) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl or cycloalkyl (C₃.₇) and carbocycle; wherein R₄ is selected from H, deuterium, halogen, CN, CF₃, an alkyl chain (d-₄) said alkyl chain optionally containing one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, a multiple bond, heterocycle, aryl and cycloalkyl (C₃.₇); wherein A is optional and when present is selected to replace one or more ring carbon atoms by N; wherein L is selected from H, deuterium, F, CI, Br and alkyl (d-₃) ; wherein G is a group selected from one of the following:

wherein R is selected from H, COOH, alkyl (d-₄) and hydroxy-alkyl (Ci-₄);

wherein FT and R" are independently selected from H and alkyl (C1-4) ;

X = H, Me, -CH₂-, -CH₂CH₂- m = 0, 1 , 2

wherein - represents an optional bridging group;

2. A compound according to claim 1 wherein the compound has the structure (II):

wherein R^ R₂, R₃, R₄, A, L, R, R' and R" are as defined in claim 1 .

A compound according to claim 1 wherein the compound has the structure (II)

(II) wherein R is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

;

O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

^■

wherein R₃ is selected from H, deuterium, halogen, Pr, butyl, OMe, OEt, OPr, OiPr, O- isobutyl, O-isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl and

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein R" is selected from H and Me;

wherein L is selected from H, deuterium, Me and CI; and

wherein A is defined as in claim 1 .

4. A compound according to claim 1 wherein the compound has the structure (III)

(III) wherein R^ , R₂, R₃, R₄, A, L, X and m are as defined in claim 1 .

5. A compound according to claim 1 wherein the compound has the structure (III):

(III)

wherein R is selected from F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O- isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

^■

wherein R₂ is selected from H, deuterium, F, CI, Br, CN, CF₃, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein L is selected from H, deuterium, Me and CI;

wherein X is selected from H, Me, -CH₂ or -CH₂CH₂-; and

wherein A and m are as defined as in claim 1 .

6. A compound according to claim 1 wherein the compound has the structure (IV)

(IV) wherein R R₂, R₃, R₄, A, L, R and R' are as defined in claim 1 .

7. A compound according to claim 1 wherein the compound has the structure (IV)

O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

;

wherein R₄ is selected from H, deuterium, Me and Et;

wherein R is selected from H, Me or -CH₂OH;

wherein R' is selected from H and Me;

wherein L is selected from H, deuterium, Me and CI; and

wherein A is defined as in claim 1 .

8. A compound according to claim 1 selected from the group consisting of:

5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid

1 - ((5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl)azetidine-3- carboxylic acid

2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

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

2-Amino-2-(5-(5-(4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol 2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

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

2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1 ,3-diol

2-Amino-2-(5-octylbenzofuran-2-yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(4-isobutoxyphenyl)-1 , 2, 4-oxadiazol-3-yl)benzofuran-2-yl)propane-1 ,3- diol

2-Amino-2-(5-(5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

2-amino-2-(5-(5-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-7-methyl-benzofuran-2- yl)propane-1 ,3-diol

5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)-7-methylbenzofuran-5-yl)-1 ,2,4-oxadiazol-5- yl)-2-propoxybenzonitrile

2-Amino-2-((4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)phenyl) ethynyl) propane-1 ,3- diol

2-Amino-2-((2-amino-5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)phenyl)

ethynyl)propane-1 ,3-diol N-(5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1 ,2,4-oxadiazol-5-yl)-2- ethoxyphenyl)methanesulfonamide

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

2-Amino-2-(5-(5-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.

2-((5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)methyl

amino)propane-1 ,3-diol

2-Amino-2-((4-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-oxadiazol-2- yl)phenyl)ethynyl)propane-1 ,3-diol

2-Amino-2-((4-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-thiadiazol-2-yl)phenyl)

ethynyl)propane-1 ,3-diol

2-Amino-2-((4-(5-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)phenyl)

ethynyl)propane-1 ,3-diol

5-(3-(4-(3-Amino-4-hydroxy-3-(hydroxymethyl)but-1 -ynyl)phenyl)-1 ,2,4-oxadiazol-5-yl)-2- propoxybenzonitrile

2-Amino-2-((4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)phenyl)

ethynyl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-oxadiazol-2-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,3,4-thiadiazol-2-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(4-butoxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)ethanol 2-Amino-2-(5-((3-chloro-4-propoxyphenyl)ethynyl)benzofuran-2-yl)propane-1 ,3-diol 2-Amino-2-(5-(3-chloro-4-propoxyphenethyl)benzofuran-2-yl)propane-1 ,3-diol

2-Amino-2-(5-((7-chloro-5-propylbenzofuran-2-yl)ethynyl)benzofuran-2-yl)propane-1 ,3- diol

5-Amino-5-[5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran -2-yl]-1 ,3,2- dioxaphosphinan-2-ol 2-oxide

2-Amino-2-(5-(5-(4-propoxy-3-(trifluoromethyl)phenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol 2-Amino-2-(5-(5-(3-chloro-4-isopropoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.

2-Amino-2-(5-(5-(4-isopropoxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol Methanesulfonic acid Salt

2-Amino-2-(5-(5-(4-benzyloxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(4-allyloxy-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-isopentyloxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-isobutoxy-4-methoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.

2-Amino-2-(5-(5-(3-ethoxy-4-methoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-aAmino-2-(5-(5-(4-isobutoxy-3-methylphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-isobutoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-chloro-4-propoxy-5-cynophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol.

2-Amino-2-(5-(5-(4-butyl-3-chlorophenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)propane- 1 ,3-diol

2-Amino-2-(5-(5-(3,5-dichloro-4-n-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

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

2-Amino-2-(5-(5-(2-chloro-6-propoxypyridin-4-yl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(3-fluoro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(5-(5-(5-chloro-6-propoxypyridin-3-yl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(6-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol 2-Amino-2-(4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

2-Amino-2-(3-deutero-5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol

and their physiologically accepted prodrugs.

9. A compound as claimed in any one of claims 1 to 8 wherein the compound has S1 P receptor activity and/or immune modulator activity.

10. A pharmaceutical, comprising at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio together with a pharmaceutically acceptable carrier(s) or excipient(s) in a desired mode of administration including oral, intravenous, topical or subcutaneous modes.

1 1 . 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 according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

12. A method of cell mobilization including immune cell, progenitor and/or stem cells by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

13. 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 according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

14. A method of treating immunological and/or, vascular and/or nervous system disorders by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need. 15. A method of treating inflammation and/or inflammatory disorders by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

16. A method of treating autoimmune disorders by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

17. The method of claim 16 wherein the autoimmune disorder includes eczema, acne, skin cancer, dermatitis, vitiligo or psoriasis. 18. A method of treating nervous system diseases or neurodegenerative diseases including Multiple Sclerosis by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need. 19. A method of treating infection including sepsis by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

20. A method of treating epileptic conditions including seizures, convulsions and epilepsy neurodegeneration by the administration of an effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer and/or isotopic form or a pharmaceutically acceptable salt and/or derivative or excipient thereof, to a subject in need.

21 . The use of a pharmaceutical comprising at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric 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 directly or indirectly with inappropriate S1 P receptor modulating activity and/or expression and or immune activity.

22. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the treatment and/or immunotherapy of 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.

23. The use of a compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the cell mobilization including immune cell, progenitor and/or stem cells.

24. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio as adjuvant for vaccination/immunization.

25. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the treatment of nervous system diseases or neurodegenerative diseases including Multiple Sclerosis.

26. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for treatment of infection including sepsis.

27. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the treatment of skin disorders including eczema, acne, skin cancer, dermatitis, vitiligo or psoriasis.

28. The use of at least one compound as claimed in any one of claims 1 to 8 in any of its stereoisomeric and/or isotopic forms and/or physiologically tolerable and/or therapeutically effective salts or mixtures or excipients thereof in any ratio for the treatment of epileptic conditions including seizures, convulsions and epilepsy neurodegeneration.

29. The method as claimed in any one of claims 1 1 to 20 or the use as claimed in any one of claims 21 to 28 for the treatment of animals.