WO2010043000A1 - S1p receptors modulators and their use thereof - Google Patents

S1p receptors modulators and their use thereof Download PDF

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Publication number
WO2010043000A1
WO2010043000A1 PCT/AU2009/001371 AU2009001371W WO2010043000A1 WO 2010043000 A1 WO2010043000 A1 WO 2010043000A1 AU 2009001371 W AU2009001371 W AU 2009001371W WO 2010043000 A1 WO2010043000 A1 WO 2010043000A1
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WO
WIPO (PCT)
Prior art keywords
amino
oxadiazol
methyl
carbon
nmr
Prior art date
Application number
PCT/AU2009/001371
Other languages
French (fr)
Inventor
Gurmit S Gill
Damian W Grobelny
Original Assignee
Akaal Pharma Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2008905369A external-priority patent/AU2008905369A0/en
Priority to EP09820119.7A priority Critical patent/EP2344484B1/en
Priority to ES09820119.7T priority patent/ES2590904T3/en
Priority to AU2009304598A priority patent/AU2009304598B2/en
Priority to JP2011531305A priority patent/JP2012505836A/en
Priority to CA2740484A priority patent/CA2740484C/en
Application filed by Akaal Pharma Pty Ltd filed Critical Akaal Pharma Pty Ltd
Priority to NZ592748A priority patent/NZ592748A/en
Priority to CN200980141188.9A priority patent/CN102186845B/en
Priority to US13/124,549 priority patent/US8592399B2/en
Publication of WO2010043000A1 publication Critical patent/WO2010043000A1/en
Priority to US14/066,276 priority patent/US9193716B2/en
Priority to US14/920,780 priority patent/US9707205B2/en

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Definitions

  • This invention relates to novel compounds having S1 P receptors modulating activity and the use of such compounds to treat diseases associated with inappropriate S1 P receptor/s activity.
  • Sphingosine 1 -phosphate is a natural sphingolipid that functions as an intramolecular messenger in many types of cells and as an extracellular signalling molecule (for a recent review see Cooke et al, Annual Reports in Medicinal Chemistry, 2007, 42, pp 245 - 263 and references therein).
  • the cellular effects induced by S1 P are associated with platelet aggregation, cell morphology and proliferation, tumour cell invasion, endothelial cell chemotaxis and in vitro angiogenesis.
  • the extracellular signalling occurs through interaction of S1 P with G-protein-coupled receptors S1 P1 , S1 P2, S1 P3, S1 P4 and S1 P5.
  • S1 P and modulators 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.
  • the lymphocytes move from the peripheral circulation into the lymph nodes and mucosa associated tissues in order to generate immune responses.
  • T and B lymphocytes are effectively sequestered within the thymus and secondary lymphoid tissue.
  • S1 P and its receptor subtype -1 are required for lymphocytes to move out of the thymus and secondary lymphoid organs.
  • S1 P type molecular modulators have been shown to be effective in multiple animal disease models.
  • the S1 P signalling mainly through its receptor subtype - 1 , is important in halting the T reg response and has been recommended for immunotherapy of cancer and infectious disease (Liu, G., et al, Nature Immunology, 2009, 10, 769 - 777; Wolf, A. M., et al, J. Immunology, 2009, 183, 3751 -60).
  • the S1 P mediated trans-activation of insulin receptor has been reported to help treating insulin resistance and type 2 diabetes (Rapizzi E. et al, Cell MoI 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. ScL, 2005, 1044, 84 - 89; Kimura, et al, Blood, 2004, 103, 4478-86) and a have great potential applications in regenerative medicines.
  • S1 P receptors play critical role in endothelial barrier enhancement and vasculature maturation (McVerry, B.
  • vasculature normalization helps the cytotoxic T cells to access the remote and inner part of the tumour (Hamzah J. et al, Nature, 2008, 453, pp 410 - 414).
  • the lymphocyte egress and endothelial barrier function is mediated through S1 P1 receptor (Brinkmann, et al, American J.
  • S1 P type modulation reduces ischemia reperfusion injuries (Lein, Y. H., et al, Kidney International, 2006, 69, 1601 - 8; Tsukada, Y. T. et al, J Cardiovascular Pharmocol, 2007, 50, 660-9).
  • S1 P1 signalling is critical in preventing inflammation induced vascular leakage (Niessen, F. et al; Blood, 2009, 1 13, 2859-66; Wang L et al, Microvascular Research, 2009, 77, 39 -45; Lee, J. F., et al, AmJ.
  • 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 ).
  • HDACs Histone Deacylases
  • the S1 P has been reported to help treatment of the latent mycobacterium tuberculosis infection by promoting the processing and presentation of antigens (Santucci, M. B. et al, Biochem Biophys Res Comm, 2007, 361 , 687 -93). Additionally, the S1 P and its modulators have cardio protective effects (Means, C.
  • Fingolimod (2-amino-2-(2-[4-octylphenyl] ethyl)-1 ,3-propanediol) (FTY-720) is metabolised to a structural analogue of S1 P and has been found to effect S1 P receptors.
  • FTY-720 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 emerging novel drug for Multiple Sclerosis (MS) (Kieseier, B. C, et al, Pharmacological Research, 2009, 60, 207-1 1 ; Brown, B. A., The Annals of Pharmacotherapy, 2007, 41 , 1660-8) and has a direct cyto-protective and process extension effect in oligodendrocyte progenitors (Coelho, R. P. et al, J.
  • FTY-720 inhibits vascular endothelial cell growth factor induced vascular permeability (Sanchez, T., et al, J.
  • FTY-720 helps favourable central nervous system (CNS) gene expression and improves the blood brain barrier function (Foster, C. A., et al, Brain Pathology, 2009, 19, 254- 66). Few days of treatment with FTY-720 leads to complete eradication of chronic viral infection of lymphocytic choriomeningitis (Lanier, et al, Nature, 2008, 894 - 899). 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; ToIIe, M. et al, European J Clinical Investigation, 2007, 37, 171 -79). FTY720 was effective in the treatment of cerebral ischemia in the mouse model (Czech, B., et al, Biochem Biophys Res Comm, 2009, online), indicating the great potential of S1 P receptors modulators in the wide range of cardiovascular medicine. The derivatives of FTY-720 were reported as pulmonary barrier enhancers and thus potential agents for the development of critical care medicines (Camp, S. M., et al, J Pharmacol Experimental Therapeutics, 2009, online).
  • the amino alcohols and their respective monophosphates, amino phosphonates, amino acids, alkoxyamino alcohols, alkyl carboxylates appear to be the most effective S1 P receptors modulators. 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.
  • FTY-720 FTY-720 and in particular alternative compounds with improved properties and/or activity.
  • this could include compounds with greater range of activity, altered or enhanced specificity, improved pharmacological properties or reduction in side effects.
  • G represents an organic substituent comprising in any combination one or more nitrogen, oxygen or sulphur atom(s).
  • G is a group selected from the following:
  • R is independently selected from H, deuterium, CN, amino, alkylamino, CH 2 OH, alkoxy, CF3, an alkyl chain optionally containing one or more of deuterium, O, NR'R" (wherein R' and R" are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle) S, SO, S02, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond or a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, sulphonamide, hydroxyl, -CH 2 COOH, -COOH, - OPO 3 H 2 , -PO 3 H 2 , cyclic phosphate, cyclic phosphonates and/or salts, tetrazole, and n is 0-4, with the proviso that
  • Z represents an organic moiety comprising at least one aromatic centre.
  • X and Y separately, or in combination, are alkyl, alkyl-amino, alkoxy, an alkyl chain containing one or more of O, N, S, SO, SO 2 , halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon- heteroatom double bond, carbocycle, heterocycle or a group selected from the following: wherein R 1 is selected from H or alkyl, the asterisks indicating the attachment within formula (I).
  • X, Y and Z separately, or in any combination, are selected from the following
  • Z and G are selected from the following groups:
  • the group D when present, is selected from H, deuterium, alkyl, aryl, heterocycle or cycloalkyl.
  • the group m when present, is selected from unsubstituted or substituted aryl, carbocycle or heterocycle.
  • the group J when present, is selected from H, alkyl or one of the following groups:
  • n is 0-10
  • A is as defined above
  • R 4 is halogen, CN, amino, alkylamino, alkoxy, CF 3 , an alkyl chain containing one or more of O, N, S, SO, SO 2 , a carbon-carbon double bond, a carbon-carbon triple bond, a carbon- heteroatom double bond or a carbon-hetero atom triple bond.
  • a yet further aspect of the invention provides a pharmaceutical preparation comprising at least one compound described herein in any of its stereoisomeric 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).
  • the invention provides the use of a compound of the invention in any one of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio, for the production of a pharmaceutical for modulation of S1 P receptor activity and/or expression against target cells.
  • the invention provides the use of a compound of the invention in any one of its stereoisomeric and/or isotopic forms and mixtures thereof in any ratio and/or physiologically tolerable and/or therapeutically effective salts for the production of a pharmaceutical for modulation of S1 P receptor (extracellular and/or intracellular binders) activity and/or expression.
  • S1 P receptors are cell surface receptors which include known receptor subtypes 1 , 2, 3, 4, 5 and are regarded herein as S1 P receptors. These extracellular S1 P receptors may be present inside the cell on Golgi bodies, etc. There are other intracellular receptor/s, target/s, protein/s, enzyme/s where S1 P interacts and are regarded as S1 P receptor/s.
  • the compounds of the invention could function as substrates of Sphingosine Kinases like SK1 and SK2 which are responsible for phosphorylation of S1 P and are regarded as S1 P receptor/s.
  • Histone Deacylase/s HDACs are known intra-nuclear receptors of S1 P and thus are regarded as S1 P receptors.
  • the invention includes any receptor binder, agonists or antagonists, or inverse agonists of the S1 P receptor family including S1 P1 , S1 P2, S1 P3, S1 P4 and S1 P5, which is responsible for direct and or indirect effect of S1 P and regards them as S1 P receptor/s.
  • the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio.
  • the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression, for example, autoimmune disease.
  • a further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression such as autoimmune disease.
  • the compounds of the invention can 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.
  • Viral infections including but not limited to human immunodeficiency virus, Hepatitis (HAV, HBV, HCV), H1 N1 influenza, chickenpox, cytomegalovirus infection, dengue fever, Ebola hemorrhagic fever, hand foot and mouth disease, herpes simplex, herpes zoster, HPV, influenza (Flu), Lassa fever, measles, Marburg Hemorrhagic fever, infectious mononucleosis, mumps, norovirus, poliomyelitis, progressive multifocal Leu-encephalopathy, rabies, rubella, SARS, smallpox (Variola), viral encephalitis, viral gastroenteritis, viral meningitis, viral pneumonia, west Nile disease and yellow fever.
  • HAV Hepatitis
  • H1 N1 influenza chickenpox
  • cytomegalovirus infection dengue fever
  • Ebola hemorrhagic fever hand foot and mouth disease
  • herpes simplex herpe
  • Bacterial Infections including but not limited to actinomycosis, anaplasmosis, anthrax, bacterial meningitis, botulism, brucellosis, burkholderia infections, campylobacteriosis, cellulitis, chlamydiaceae infections, cholera, Clostridium infections, coccidiomycosis, diphtheria, ehrlichiosis, empyema, gonorrhea, impetigomelioidosis legionellosis, leprosy (Hansen's Diseases), leptospirosis, listeriosis, lyme disease, bacterial endocarditis, endophthalmitis, pseudomembranous enterocolitis, erysipelas, Escherichia coli infections, necrotizing fasciitis, Fournier gangrene, furunculosis, fusobacterium infections, gram negative bacterial infections, gram positive bacterial infections, granulo
  • Fungal infections including but not limited to aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, tinea pedis and histoplasmosis.
  • Prion infections including but not limited to transmissible spongiform encephalopathy, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Kuru fatal Familial insomnia and Alpers Syndrome.
  • the compounds of the invention can be used for the prevention and/or prophylaxis and/or treatment and/or immunotherapy of cancer and immune mediated diseases which include immune related and inflammatory diseases; autoimmune diseases; allergic conditions; pain; central nervous system diseases; neurodegenerative diseases, cardiovascular diseases; haematological pathologies.
  • immune related and inflammatory diseases include immune related and inflammatory diseases; autoimmune diseases; allergic conditions; pain; central nervous system diseases; neurodegenerative diseases, cardiovascular diseases; haematological pathologies.
  • 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, pruritus, arthritis, rheumatoid arthritis, osteoporosis, Sjogren Syndrome, uveitis, asthma, hay fever, sleep disorders, , macular degeneration, glaucoma, typei 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.
  • the compounds of the invention can be used for the prevention and/or prophylaxis and/or treatment and/or immunotherapy of or in, Down's syndrome, schizophrenia, bipolar disorder, drug dependence, Wernicke-Korsakoff syndrome, eating disorders, depression resulting from infection, hepatic encephalopathyjung diseases such as grain handler's, Hermansky-Pudlak Syndrome, and adult respiratory distress syndrome (ARDS, obesity, digestive tract disease, anxiety, hyperalgesia, migraine, epilepsy and neuromuscular disorder.
  • Down's syndrome schizophrenia, bipolar disorder, drug dependence, Wernicke-Korsakoff syndrome, eating disorders, depression resulting from infection, hepatic encephalopathyjung diseases such as grain handler's, Hermansky-Pudlak Syndrome, and adult respiratory distress syndrome (ARDS, obesity, digestive tract disease, anxiety, hyperalgesia, migraine, epilepsy and neuromuscular disorder.
  • the compounds of the invention can be used for prevention and/or treatment of vascular and/or cardiovascular diseases including, but not limited to, hypoxia, atherosclerosis, diabetic blood vessel disease like inflammation, hyper vascularisation related disorders such as cancer and neoplasm, heart failure, myocardial infarction, myocarditis, ischemia, hypotension, hypertension, reperfusion injury, angina pectoris, coronary artery disease, stroke, thrombosis, artery/vein blockage or obstruction, diabetic retinopathy, sepsis and kidney failure, reperfusion or injury.
  • hypoxia hypoxia
  • atherosclerosis diabetic blood vessel disease like inflammation
  • hyper vascularisation related disorders such as cancer and neoplasm
  • heart failure myocardial infarction
  • myocarditis ischemia
  • hypotension hypertension
  • reperfusion injury angina pectoris
  • coronary artery disease stroke
  • thrombosis artery/vein blockage or obstruction
  • diabetic retinopathy sepsis
  • the compounds of the invention can be used for prevention and/or prophylaxis and/or treatment and/or immunotherapy of liver diseases including but not limited to liver cirrhosis, viral liver infections, autoimmune hepatitis, liver failure, portal hypertension, hemochromatosis, Wilson's diseases, Gaucher disease, hepatoma, primary biliary cirrhosis, primary sclerosing cholangitis, sarcoidosis and Zwellweger syndrome.
  • liver diseases including but not limited to liver cirrhosis, viral liver infections, autoimmune hepatitis, liver failure, portal hypertension, hemochromatosis, Wilson's diseases, Gaucher disease, hepatoma, primary biliary cirrhosis, primary sclerosing cholangitis, sarcoidosis and Zwellweger syndrome.
  • the compounds of the invention can be used for the prevention and/or treatment and/or immunotherapy of solid and/or haematological cancers and tumor metastasis, including but not limited to acute B-cell leukaemia, lymphoma, chronic lymphocytic leukaemia, chronic myeloid leukaemia, hairy cell leukaemia, multiple myeloma, acute lymphocytic leukaemia , acute granulocytic leukaemia, acute myelogenous leukaemia, lung cancer, adrenal gland cancer, astrocytoma, glioma, brain cancer, bile duct cancer, bladder cancer, bone cancer, bowel cancer, colorectal cancer, breast cancer, cervical cancer, endometrial cancer, oesophageal cancer, melanoma, gallbladder cancer, Kaposi sarcoma, renal cancer, laryngeal cancer, liver cancer, mesothelioma, prostate cancer, sarcoma, skin cancer, stomach cancer,
  • the compounds of the invention can 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 compounds of the invention can be used for organ transplant and/or allograft and/or autograft, for example, kidney, liver, lung, heart, skin, stem cell or bone marrow transplant and in the treatment of graft versus host disease.
  • the disclosed molecules can be used for prevention and/or treatment and/or immunotherapy for the pathologies caused by bioterrorism agents.
  • the compounds of the invention can be used as a vaccine adjuvant to boost and/or enhance the action of a vaccine and/or immune agent and/or for immunization; for example antigen, tumour cell lysate, B cell vaccine, T cell vaccine, dendritic cell vaccine boosting the immune response of cytotoxic cells, helper T cells and dendritic cells and for eradication and immunotherapy of immune related diseases and other preventable diseases such as chickenpox, cholera, diphtheria, whooping cough, meningococcal disease, hepatitis, Hemophilus influenzae type B (HIB), measles, mumps , rubella, poliomyelitis and tetanus.
  • a vaccine adjuvant to boost and/or enhance the action of a vaccine and/or immune agent and/or for immunization
  • a vaccine adjuvant for example antigen, tumour cell lysate, B cell vaccine, T cell vaccine, dendritic cell vaccine boosting the immune response of cyto
  • the compounds of the invention can be used to mobilize the progenitor/ stem cells preferably towards the site of injury, ischemia, stroke etc.
  • the compounds can be used as cyto-protective agents, cardioprotective agent, neuro-protective agents and regenerative agents that may help host/patient to repair any organ damage, grow organs like muscle, nerve, blood vessel etc and to increase immune cells number.
  • 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.
  • An appropriate concentration level in treatment is from 0.01 nM to 1 Molar.
  • compositions of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents carriers and/or encapsulation formulations known in the art.
  • the compounds of the present invention can 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 and alclometasone.
  • immunosuppressants such as cyclosporine, tecrolimus, rapamycin, azathioprine, cyclophosphamide, dexamethasone, flunisolide, prednisolone, prednisone, amcinomide desonide, methylprednisolone, triamcinolone and alclometasone.
  • the compounds of the present invention can 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 compound which could make a delayed type hypersensitivity response.
  • any suitable adjuvant non limiting examples of which include, other anticancer, antiviral, antibacterial, antifungal, and/or any anti-pathogen agent, a compound which could make a delayed type hypersensitivity response.
  • the molecule/s or compounds of the present invention may be used with T cell, B cell, dendritic cell, antigen, protein, protein conjugate and or like which could be used for such immunization purpose.
  • Figure 1 illustrates post-treatment lymophocyte counts
  • compound 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.
  • an agent/s/compounds and compounds of the invention 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 the species, age and general condition of the subject, mode of administration and the like.
  • a "pharmaceutically acceptable" carrier, excipient or diluent may include a pharmaceutical vehicle comprised of a material that may not be biologically active or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any and/or a substantial adverse reaction.
  • Carriers may include excipients and other additives such as diluents, detergents, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
  • compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers or encapsulation formulations.
  • Effective combinations are those which provide favourable synergistic effect which assist in treatment and/or prevention and/or immunotherapy better than the agents alone.
  • alkyl 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-
  • cycloalkyl 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, ⁇ thylcyclohexyl, 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
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group as defined above.
  • alkenyl includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined.
  • alkenyl groups are vinyl, allyl, 1 -methylvinyl, butenyl, iso- butenyl, 3-methyl-2-butenyl, 1 -pentenyl, cyclopentenyl, 1 -methyl-cyclopentenyl, 1 - hexenyl, 3-hexenyl, cyclohexenyl, 1 -heptenyl, 3-heptenyl, 1 -octenyl, cyclooctenyl, 1 -nonenyl, 2-nonenyl, 3-nonenyl, 1 -decenyl, 3-decenyl, 1 ,3-butadienyl, 1 ,4- pentadienyl, 1 ,3-cyclopenta
  • alkynyl includes within its meaning acetylenically unsaturated alkyl groups as previously defined. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1 -butynyl, n- hexynyl, methyl-pentynyl, (C7-C12)alkynyl and (C7-C12)cycloalkynyl.
  • alkylidene refers to optionally unsaturated divalent alkyl radicals.
  • the term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system. Examples of such radicals are groups of the structures
  • aryl refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems.
  • groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquino
  • aralkyl refers to alkyl groups substituted with one or more aryl groups as previously defined. Examples of such groups are benzyl, 2-phenylethyl and 1 -phenylethyl.
  • aralkenyl and “aralkynyl” refer to alkenyl and alkynyl groups respectively, substituted with one or more aryl groups as previously defined. Examples of such groups are styryl, phenylacetylenyl and 2- phenyl-2-butenyl.
  • heterocyclic refers to any 3- to 16-membered monocyclic, bicyclic or polycyclic ring containing, for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7- membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 1 1 -membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16- membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur.
  • heterocyclic includes any group in which a heterocyclic ring is fused to a benzene ring.
  • heterocyclics are pyrryl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, piperidinyl, pyridinyl, furyl, thiophenyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolyl, pyrenyl, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, furfuryl, thienyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl,
  • heterocyclic or "saturated or unsaturated cyclic, bicyclic or fused ring system”.
  • alkylheterocyclic refers to a heterocyclic group as defined above, which is substituted with an alkyl group as defined above.
  • heterocyclic-oxy-alkyl refers to a group of the formula heterocyclic-O-alkyl, wherein the heterocyclic and alkyl are as defined above.
  • alkoxy refers to a group of the formula alkyl-O-, wherein the alkyl group is as defined above.
  • aryloxy refers to a group of the formula aryl-O-, wherein the aryl group is as defined above.
  • alkanoyloxy refers to a group of the formula alkyl-C(O)O-, wherein the alkyl group is as defined above.
  • group (a) refers to five member saturated or unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:
  • group (b) refers to five member unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:
  • each Ar and R are independently as previously defined and S and Se can be in the oxidized form S(O), S(O) 2 and Se(O) and Se(O) 2 respectively.
  • group (c) refers to five-six bicyclic member ring systems. Examples of such ring systems are:
  • each R, R 1 and Q 1 are independently as previously defined and S and Se can be in the oxidized form such as S(O), S(O) 2 and Se(O) and Se(O) 2 respectively.
  • group (d) refers to six-six hetero-bicyclic member ring system. Examples of such ring systems are:
  • 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.
  • G1 and G2 represent alternative groups for G
  • s represents a ring subsituent.
  • X , Y and G are as defined for formula (I).
  • the other compounds of invention including intermediates were prepared by using various known synthesis methods like reductive amination etc.
  • 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.
  • Step A 4-Hydroxy-3-iodobenzonithle: To a solution of A- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH 4 OH (22 ml) a solution of I 2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H 2 O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H 2 O (3 ml).
  • Step B 2-(Hydroxymethyl)benzofuran-5-carbonitrile: Propargyl alcohol (0.24 ml; 5.2 mmol) was added drop wise during 30 min to a refluxed suspension of the product of Step A (0.48 g; 1.96 mmol) and Cu 2 O (0.28 g; 1 .96 mmol) in anhydrous pyridine ( 4 ml) with stirring under N 2 . After additional reflux for 15 min, the mixture was cooled to room temperature, diluted to 20 ml with ethyl acetate (EtOAc) and insoluble material was removed by filtration.
  • EtOAc ethyl acetate
  • Step C N-Hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide: A mixture of the product of Step B (0.22 g; 1 ,27 mmol) and HCI x NH 2 OH (0.18 g; 2.59 mmol) and N,N-diisopropylethylamine (DIPEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at ⁇ 71 0 C. The solvents were removed in vacuo and the residue was treated with H 2 O (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 MgSO4, 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.
  • DIPEA N,N-diisopropyle
  • Step D (5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)methanol: 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 ⁇ 4O 0 C under N 2 .
  • DMSO dimethylsulfoxide
  • Step E 5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- carbaldehyde: A suspension of the product of Step D (0.13 g; 0.34 mmol) and MnO 2 (0.15 g; 1.7 mmol) in dioxane (4 ml) was refluxed for 1 h with stirring. After cooling to room temperature, the insoluble material was removed by filtration, washed with EtOAc (20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.13 g; 100%), as greyish solid.
  • Step F 5-(5-(3,4-Diethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- carboxylic acid;
  • EtOH 0.2 ml
  • H 2 O 0.1 ml
  • KOH 10% KOH
  • Step A Methyl 1 -((5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzo furan-2-yl)methyl)azetidine-3-carboxylate: A mixture the product of Example 1 , Step E (0.07 g; 0.85 mmol), azetidine-3-methylcarboxylate hydrochloride (0.03 g; 0.199 mmol) and DIPEA (0.035 ml, 0.2 mmol) in 1 ,2-dichloroethane (1 ml) and methanol (MeOH) (3 ml) was sonicated for 30 min at room temperature, then evaporated to dryness.
  • Methyl 1 -((5-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzo furan-2-yl)methyl)azetidine-3-carboxylate A mixture the product of Example 1 ,
  • Step 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.
  • TFA trifluoroacetic acid
  • Step B 2-(4-Octylbenzylamino)acetonitrile ⁇ T a suspension of the product of Step A (0.17 g; 0.78 mmol) and aminoacetonitrile bisulphate (0.18 g; 1.17 mmol) and NaBH(OAc) 3 in 1 ,2 dichloroethane (3 ml), DIPEA (0.2 ml; 1.17 mmol) was added at room temperature followed by AcOH (0.045 ml; 0.78 mmol). The resulting mixture was stirred over a weekend at room temperature under N 2 and quenched by an addition of 1 M NaOH (0.5 ml).
  • Step C N-(1H-Tetrazol-5-yl)methyl-4-n-octylbenzylamine: A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me 3 SiN 3 (0.36 ml; 2.71 mmol) and 1 M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 75 + 5 0 C for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N 2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et 2 O and dried to give a title compound (0.069 g; 84%) as colourless solid.
  • Step A 2-(4-Octylphenylamino)acetonitrile: A mixture of 4-n-octylaniline (0.21 g; 1 mmol), BrCH 2 CN (0.156 mmol; 1.3 mmol) and K 2 CO 3 (0.28 g; 2 mmol) in anhydrous CH 3 CN (3 ml) was stirred overnight at -60 0 C under N 2 , then concentrated under reduced pressure. The residue was partitioned between CH 2 CI 2 (20 ml) and H 2 O (10 ml). The organic phase was dried over anhydrous MgSO 4 and filtered.
  • Step B N-((1H-Tetrazol-5-yl)methyl)-4-n-octylaniline: When the product of Step A was substituted for 2-(4-octylbenzylamino)acetonitrile in Example 3, Step C, the identical process afforded the title compound in 77% yield, as creamy solid.
  • Step A 2,2-Dimethyl-N-(4-octylphenyl)-1,3-dioxan-5-amine: To a mixture of 4-n-octylaniline (0.205 g; 1 mmol) and 2,2-dimethyl-1 ,3-dioxan-5-one (Helvetica Chimica Acta, 2003, 86, 2467; 0.13 g; 1 mmol) and NaBH(OAc) 3 in 1 ,2 dichloroethane (3.5 ml), AcOH (0.06 ml; 1 mmol) was added and the mixture was stirred for 2h at room temperature under N 2 , diluted to 20 ml with Et 2 O and washed with 1 N NaOH, H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step B 2-(4-octylphenylamino)propane-1,3-diol: To a solution of the product of Step A (0.1 g; 0.31 mmol) in MeOH (1 ml) Me 3 SiCI (0.5 ml) was added at room temperature. After stirring for 1 h, the mixture was evaporated to dryness under reduced pressure to give a hydrochloride salt of the title compound (0.1 g; 100 %) as a colourless solid.
  • Step A 4-n-Octylbenzyl alcohol: NaBH 4 (0.04 g; 1 .06 mmol) was added portion wise to a solution of the product of Example 3, Step A in MeOH (5 ml) at room temperature, with vigorous stirring. After 30 min of stirring, the mixture was evaporated to dryness, diluted to 10 ml with Et 2 O and washed with 1 N NaOH, H 2 O, brine, dried over anhydrous MgSO 4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.082 g; 100%), as colourless syrup, which was used in next step without further purification.
  • Step B 4-n-octylbenzyl bromide: PBr 3 (0.23 ml) was added drop wise to a stirred solution of the product of Step A (0.082 g; 0.37 mmol) in Et 2 O (2 ml) at - 15 0 C. The mixture was allowed to warm up to room temperature and the stirring was continued for 4 h. This was poured onto ice (5 g) and the product was extracted with fresh Et 2 O (2 x 10 ml). The combined extracts were washed with 5%NaHCO 3 , H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step C 4-n-Octylbenzylamine: To a solution of the product of Step B (0.13 g; 0.459 mmol) in anhydrous hexamethylenedisilazane (HMDSA) 1 M NaHMDSA in THF was added at room temperature under N 2 with stirring. After stirring overnight at room temperature solvents were removed under reduced pressure and the residue was diluted to 5 ml with MeOH and 1 drop of concentrated HCI was added. This was evaporated under reduced pressure, diluted to 15 ml with Et 2 O and washed with 1 N NaOH, brine, dried over anhydrous MgSO 4 and filtered.
  • HMDSA hexamethylenedisilazane
  • Step D (2,2-Dimethyl- 1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine:
  • Step C (2,2-Dimethyl- 1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine:
  • Step E 2-((4-n-Octylbenzylamino)methyl)propane-1,3-dio ⁇ .
  • a solution of the product of Step D (0.6 g; 0.13 mmol) in 60% trifluoroacetic acid (TFA) in CH 2 CI 2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with MeOH and evaporated to dryness under reduced pressure. The residue was dissolved in iso-propanol (iPrOH) (2 ml) and one drop of concentrated HCI was added. This was evaporated under reduced pressure and treated with anhydrous Et 2 O.
  • TFA trifluoroacetic acid
  • Step A (2,2-dimethyl-1,3-dioxan-5-yl)-N-methyl-N-(4-octylbenzyl)methyl amine:
  • Step D is substituted for 4-n-octylaniline and 30% aqueous HCHO is substituted for 2,2-dimethyl-1 ,3-dioxan-5-one in Example 3, Step A, the identical process afforded the title compound in 100% yield, as a colourless syrup.
  • Step B 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-dio ⁇ .
  • Step E 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-dio ⁇ .
  • Step A tert-Butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan- 5-ylcarbamate: To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5- formyl-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (Ooii et al, J.Org.Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc) 3 (0.3g; 1 .4 mmol) in 1 ,2-dichloroethane (3.5 ml) AcOH (.06 ml; 1 mmol) was added at room temperature with stirring under N 2 .
  • Step B 4,4-(2,2-Dimethyl- 1,3-dioxanyl)-1-(4-octylphenyl)imidazolidin-2- one: A solution of the product of Step A (0.17 g; 0.38 mmol) and 60% NaH in mineral oil (0.043 g; 1 .14 mmol) in anhydrous DMF (4 ml) was stirred overnight at -55 0 C under N 2 . After removal of solvent in vacuo, the residue was diluted to 15 ml with Et 2 O, washed with 10% citric acid, H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step C 4,4-Bis(hydroxymethyl)-1-(4-octylphenyl)imidazolidin-2-one:
  • Step E the identical process afforded the title compound in 74% yield, as a colourless solid, after purification by FCC (SiO 2 , CH 2 CI 2 saturated with concentrated NH 4 OH/MeOH; 98:2).
  • Step A 4-n-Octyliodobenzene: To a suspension of n-octylbenzene (1 g; 5.2 mmol) and CF 3 SO 3 Ag (1 .35 g; 5.2 mmol) in anhydrous CH 2 CI 2 (15 ml) I 2 was added at 0 5 C. The resulting mixture was allowed to warm up to room temperature and stirred for additional 1 h, then filtered through a pad of Celite, washed with fresh CH 2 CI 2 (2 x 15 ml) and combined filtrates washed with 5% Na 2 SO 3 , H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step B tert-Butyl 4-(benzoyloxy)piperazine-1-carboxylate: To a suspension of benzoyl peroxide + 15% H 2 O (1.47 g; 4.55 mmol) and K 2 HPO 4 (1.19 g; 6.8 mmol) in DMF (1 1 .36 ml) N-BOC piperazine (Sengmany et al, Tetrahedron, 2007, 63, 3672; 1 g; 5.4 mmol) was added and the mixture was stirred for 1 h at room temperature. To it, H 2 O (20 ml) was added and the resulting mixture was vigorously stirred until homogenous. This was extracted with EtOAc (15 ml).
  • Step C tert-Butyl 4-(4-octylphenyl)piperazine-1-carboxylate: To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCI in THF (0.56 ml; 1.1 1 mmol) was added at -15 0 C under N 2 , followed 1.27 M solution of anhydrous ZnCI 2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at O 0 C.
  • Step D 1-(4-n-Octylphenyl)piperazine ⁇
  • a solution of the product of Step C (0.06 g; 0.16 mmol) in 60% TFA in CH 2 CI 2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with EtOH and evaporated to dryness under reduced pressure and kept in vacuo for 1 h, to give a TFA salt of the title compound (0.07 g; 100%).
  • Step E tert-Butyl 2-(4-(4-octylphenyl)piperazin-1-yl)acetate: To a solution of the product of Step D (0.04 g, 0.146 mmol) and tert-butyl bromoacetate (0.026 ml; 0.16 mmol) in CH 2 CI 2 (1 ml) DIPEA (0.052 ml; 0.32 mmol) was added at room temperature under N 2 . The mixture was stirred overnight at room temperature, diluted to 5 ml with Et 2 O and washed with 0.1 N HCI, H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step F 2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid: A solution of the product of Step E (0.05 g; 0.129 mmol) in 60% TFA in CH 2 CI 2 (5 ml) was refluxed for 2 h, cooled to room temperature then diluted to 7 ml with EtOH. The resulting mixture was evaporated to dryness under reduced pressure kept in vacuo for 1 h. The residue was treated dissolved in EtOH (2 ml) and 3 drops of concentrated NH 4 OH was added. The resulting mixture was partially concentrated under reduced pressure and the precipitate, formed was filtered off, washed with Et 2 O and dried to give the titled compound (0.02 g; 47%) as colourless solid.
  • Step A 1-Ethynyl-4-octylbenzene ⁇ A mixture of Example 3, Step A (0.1 g; 0.46 mmol), dimethyl(1 -diazo-2-oxoprpyl)phosphonate ( 0.1 1 g, 0.57 mmol) and anhydrous K 2 CO 3 (0.14 g, 1 .01 mmol) in dry MeOH (5 ml) was stirred for 8 h under N 2 . After removing solvent under reduced pressure, the residue was diluted to 15 ml with Et 2 O and washed with H 2 O (2 x 10 ml) and dried over anhydrous MgSO 4 and filtered.
  • Step B 2,2-Dimethyl-5-((4-octylphenyl)ethynyl)-1,3-dioxan-5-ol: To a solution of the product of Step A (0.05 g; 0.233 mmol) in anhydrous THF (2 ml) 2 M n-butyllithium in cylohexane (0.13 ml; 0.26 mmol) was added drop wise at - 15 0 C under N 2 .
  • Step C 2-(4-Octylphenethyl)propane-1,2,3-triol: A mixture of the product of Step B (0.03 g; 0.087 mmol) and 10% Pd/C (0.05 g) in 5% TFA in EtOH (10 ml) was stirred for 1 h under H 2 (balloon) at room temperature, then filtered through a pad of Celite , washed with CH 2 CI 2 (2 x 10 ml). To combined filtrates were evaporated to dryness under reduced pressure and dried in vacuo for 1 h to give title compound (0.027 g; 99%) as a colourless solid.
  • Step A Ethyl 3-(3-(4-octylphenyl)ureido)propanoate ⁇
  • 4-n-octylaniline 0.1 g; 0.49 mmol
  • ethyl 3-isocyanatopropionate 0.08 g; 0.54 mmol
  • the resulting mixture was diluted to 1 ml with CH 2 CI 2 , refluxed for 30 min and evaporated to dryness.
  • the residue was treated with Et 2 O (5 ml) and the solid formed was filtered off and dried to give the title compound (0.15 g; 87%), as colourless crystals.
  • Step B 3-(3-(4-n-Octylphenyl)ureido)propanoic acid: To a solution of the product of Step A (0.05 g; 0.143 mmol) in dioxane (1 ml) 2N KOH (0.36 ml; 0.72 mmol) was added and the mixture was refluxed for 15 min, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was diluted to 2 ml with H 2 O and filtered. The filtrate was acidified to pH ⁇ 4 with citric acid. The solid formed was filtered off, washed with H 2 O (3 x 2 ml), dried in vacuo to give the title compound (0.03 g; 65%), as a colourless solid.
  • Step A tert-Butyl 4-n-octylphenyl(methyl)carbamate ⁇
  • a mixture of A- noctylaniline (0.09 g; 0.44 mmol) and di-tert-butyl dicarbonate (0.1 g; 0.46 mmol) and a few drops of triethylamine was stirred at -5O 0 C for 1 h under N 2 , cooled to room temperature and kept in vacuo for 30 min.
  • the residue was dissolved in anhydrous DMF (2 ml) and %60 NaH in mineral oil (0.02 g: 0.47 mmol) was added to it, followed by MeI (0.03 ml; 0.47 mmol), after stirring for 30 min under N 2 .
  • Step B N-Methyl-4-n-octylaniline: A solution of the product of Step A (0.14 g; 0.44 mmol) in 60% TFA in CH 2 CI 2 (5 ml) was stirred for 30 min at room temperature and the mixture was diluted to 5 ml with EtOH and a few drops of concentrated HCI was added. This was evaporated to dryness under reduced pressure, kept in vacuo for 1 h and the residue was partitioned between saturated NaHCO 3 (5 ml) and Et 2 O (15 ml). The organic phase was dried over anhydrous MgSO 4 and filtered.
  • Step C Ethyl 3-(3-methyl-3-(4-octylphenyl)ureido)propanoate:
  • Step B When the product of Step B is substituted for 4-n-octylaniline in Example 1 1 , Step A, the identical process afforded the title compound in 99% yield, as a colourless solid .
  • Step D 3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid: When the product of Step C is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 84% yield, as a colourless solid.
  • Step A Ethyl 3-(3-(4-octylphenyl)-2-oxoimidazolidin-1-yl)propanoate: To a solution of the product of Example 1 1 , Step A (0.05 g; 0.143 mmol) in anhydrous DMF (2 ml) 60% NaH in mineral oil (0.014 g; 0.344 mmol) was added at room temperature. After stirring for 1 h, to it 1 ,2-dibromoethane (0.172 ml; 0.2 mmol) was added. This was stirred at -5O 0 C for 1 h under N 2 , cooled to room and solvents were removed in vacuo.
  • Step B 3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1-yl)propanoic acid:
  • the product of Step A is substituted for ethyl 3-(3-(4- octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 33% yield, as a colourless solid.
  • Step A Ethyl 2-(3-(4-octylbenzyl)ureido)acetate: When the product of Example 6, Step C was substituted for 4-n-octylaniline and ethyl 2- isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 1 1 , Step A, the identical process afforded the title compound in 75 % yield, as a colourless solid.
  • Step B 2-(3-(4-Octylbenzyl)ureido)acetic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 87% yield, as a colourless solid.
  • Step B tert-Butyl 2-(3-(4-octylbenzyl)-2-oxoimidazolidin-1-yl)acetate ⁇
  • anhydrous DMF 5 ml
  • 60% NaH in mineral oil 0.006 g; 0.15 mmol
  • Step B 0.042 g; 0.15 mmol
  • Step C 2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1-yl)acetic acid:
  • Step F 2-(4-(4-octylphenyl)piperazin-1 - yl)acetate in Example 9, Step F, the identical process afforded the title compound in 46% yield, as a colourless solid.
  • Step A tert-Butyl 2-(4-octylbenzylidene)hydrazinecarboxylate: To a mixture of Example 3, Step A (0.1 g; 0.46 mmol) and tert-butyl carbazate (0.06 g; 0.46 mmol) in anhydrous CH 2 CI 2 (5 ml) anhydrous MgSO 4 was added and the resulting suspension was vigorously stirred for 2 h at room temperature and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.13 g; 87%) as yellowish solid, which was used in next step without further purification.
  • Step B tert-Butyl 2-(4-octylbenzyl)hydrazinecarboxylate: To a solution of the product of Step A (0.13 g; 0.391 mmol) in anhydrous THF (1 ml) and glacial AcOH (0.6 ml) NaBH 3 CN (0.06 g; 0.95 mmol) was added at -O 0 C (ice bath). The resulting mixture was stirred overnight at room temperature then diluted to 15 ml with Et 2 O. This was washed with 5% NaHCO 3 . H 2 O, brine, dried over anhydrous MgSO 4 and filtered.
  • Step C tert-Butyl 2-(2-ethoxy-2-oxoethylcarbamoyl)-2-(4-octylbenzyl)- hydrazine-carboxylate:
  • Step B tert-Butyl 2-(2-ethoxy-2-oxoethylcarbamoyl)-2-(4-octylbenzyl)- hydrazine-carboxylate
  • Step D Ethyl 2-(1-(4-octylbenzyl)hydrazinecarboxamido)acetate:
  • Step C Ethyl 2-(1-(4-octylbenzyl)hydrazinecarboxamido)acetate:
  • Step E 2-(1-(4-Octylbenzyl)hydrazinecarboxamido)acetic acid: : When the product of Step D is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 78% yield, as a colourless solid.
  • Step B Ethyl 3-(5-iodoindoline-1-carboxamido)propanoate: When the product of Step A was substituted for 4-n-octylaniline in Example 1 1 , Step A, the identical process afforded the title compound in 99% yield, as a colourless solid .
  • Step C Ethyl 3-(5-(oct-1-ynyl)indoline-1-carboxamido)propanoate: A mixture of the product of Step B (0.16 g; 0.41 mmol), 1 -octyne (0.073 ml; 0.49 mmol), CI 2 Pd(PPh 3 ) 2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) was degassed under reduced pressure and saturated with dry N 2 . After addition of DIPEA (0.5 ml), the resulting mixture was stirred for 2 h at room temperature under N 2 .
  • DIPEA 0.5 ml
  • Step D Ethyl 3-(5-octylindoline-1-carboxamido)propanoate ⁇
  • a mixture of the product of Step C (0.1 g; 0.27 mmol) and 10% Pd/C (0.1 g) in EtOH (15 ml) was stirred at room temperature for 1 h under H 2 (balloon).
  • the catalyst was removed by filtration through the Celite pad, washed with CH 2 CI 2 (2 x 10 ml) and combined filtrates were evaporated to dryness under reduced pressure to give a title compound (0.09 g; 90%), as colourless solid.
  • Step E 3-(5-Octylindoline-1-carboxamido)propanoic acid: When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 84% yield, as a colourless solid.
  • Step A 4-Bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulfonamide: To a stirred solution of 4-bromo-benzenesulphonyl chloride (0.6 g, 2.34 mmol) in anhydrous CH 2 CI 2 (5 ml) and Et 3 N (0.65 ml, excess) at 0 5 C was added (-) cis-myrtanylamine (0.36 g, 2.34 mmol) and the stirring was continued overnight at room temperature. The reaction mixture was diluted with CH 2 CI 2 (15 ml) and washed with H 2 O (2 x 100 ml).
  • Step B N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl) benzene sulfonamide: A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1 -ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N 2 and CI 2 Pd(PPh 3 ) 2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature .
  • Step C N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybutyl) benzene sulfonamide: A mixture of the product of Step B (0.1 1 g, 0.3 mmol) and 10% Pd/C (0.06 g) in EtOH (10 ml) was stirred for 16 h under H 2 . The catalyst was filtered through Celite pad and the filtrate evaporated to dryness to give the title compound (0.11 g, 100%,) as creamy gum.
  • Step D 4-(4-(N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)sulfamoyl)phenyl) butyl-dihydrogen phosphate: To a stirred solution of POCI 3 (0.006 ml, 0.66 mmol) in anhydrous CH 2 CI 2 (3 ml) a solution of tert-butanol (0.062 ml, 0.65 mmol) and Et 3 N (0.09 ml, 0.65 mmol) was added drop wise at 0 5 C under N 2 .
  • Step B 2,2,2-Trifluoro-1-(1-(prop-2-ynyl)-1H-indol-3-yl)ethanone: A mixture of product of Step A (0.55 g, 2.58 mmol), K 2 CO 3 (0.43 g, 3.1 1 mmol) and propyrgyl bromide (2 ml) in anhydrous DMF (8 ml), was stirred for 4 h. The mixture was quenched with NH 4 CI solution and diluted to 50 ml with EtOAc. The organic layer separated and washed with H 2 O, dried over MgSO 4 and filtered. The filtrate was evaporated to give the title compound (0.57 g, 88%), as yellow crystalline material.
  • Step C 2,2,2-Trifluoro-1-(1-(3-(4-iodophenyl)prop-2-ynyl)-1H-indol-3-yl) ethanone: A mixture of product of Step B (0.25 g, 1 mmol), 1 ,4 di-idobenzene (0.4 g, 1 .2 mmol) CI 2 Pd(PPh 3 ) 2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N 2 .
  • Step D 2,2,2-Trifluoro-1-(1-(3-(4-(4-hydroxybut-1-ynyl)phenyl)prop-2-ynyl)- 1 H-indol-3-yl) ethanone:
  • Step C 2,2,2-Trifluoro-1-(1-(3-(4-(4-hydroxybut-1-ynyl)phenyl)prop-2-ynyl)- 1 H-indol-3-yl) ethanone:
  • Step E 2,2,2- Trifluoro- 1 -(1-(3-(4-(4-hydroxybutyl)phenyl)propyl) - 1 H-indol- 3-yl)ethanone:
  • the product of Step D was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybut-1 -ynyl) benzene sulphonamide in Example 18, Step C, the identical process afforded the title compound in 92% yield, as pale paste.
  • Step F 4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)propyl)phenyl)butyl- dihydrogen phosphate: When the product of Step E was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxy butyl)benzene sulphonamide in Example 18, Step D, the similar process afforded the title compound in 73% yield, as pale paste.
  • Step A 2-(2-(4-lodophenoxy)ethyl)-6,6-dimethylbicyclo[3.1. 1]heptane: To a stirred suspension of 4-iodophenol (0.5 g; 2.27 mmol) and 60% NaH (0.16 g, 2.3 mmol) in anhydrous DMF (5 ml) 2-(2-bromoethyl)-6,6- dimethylbicyclo[3.1 .1 ]heptane (0.5 g, 2.2 mmol) was added the and mixture was stirred for 3 h at room temperature.
  • Step B 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)but-3- yn-1-ol:
  • Step B 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)but-3- yn-1-ol:
  • Step C 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl) butan-1-ol:
  • Step C 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl) butan-1-ol:
  • Step C 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl) butan-1-ol:
  • Step D 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1 ]heptan-2-yl)ethoxy)phenyl) butyl-di-hydrogen phosphate: When the product of Step C was substituted for N- (6,6-dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybutyl) benzene sulfonamide in Example 18, Step D, the similar process afforded the title compound in 60% yield, as pale paste.
  • Step A 4-((6-Methoxybenzofuran-2-yl)ethynyl)phenyl acetate: When A- iodophenyl acetate and 2-ethynyl-6-methoxybenzofuran were substituted for A- bromo-N-(6,6-dimethylbicyclo [3.1 .1 ] heptan-2-yl)benzene sulphonamide and but- 3-yn-1 -ol respectively in Example 18, Step B, the similar process afforded the title compound in 56% yield, as creamy paste.
  • Step B 4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenol:
  • Step C 4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenol:
  • Step C Ethyl 2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl) phenoxy) acetate: To a stirred solution of the product of Step A (0.05 g, 0.19 mmol) and K 2 CO 3 (0.05 g, 0.36 mmol) in anhydrous DMF (5 ml) ethyl-bromo acetate (0.025 ml, 0.22 mmol) was added at room temperature. The mixture was stirred for 2 h and quenched with saturated NH 4 CI solution, extracted in EtOAc (100 ml) and washed with H 2 O. The organic layer was separated and dried over MgSO 4 and filtered.
  • Step D 2-(4-(2-(6-Methoxy-2, 3-dihydrobenzofuran-2-yl)ethyl)phenoxy) ethanol: To the stirred slurry of LiAIH 4 (0.01 g, 0.026 mmol) in anhydrous Et 2 O (5 ml) the solution of the product of Step C (0.04 g, 0.1 1 mmol) in anhydrous Et 2 O (2 ml) was added drop wise and stirring was continued for 0.5 h at room temperature. The reaction mixture was quenched with EtOAc: H 2 O: MeOH mixture (7 ml: 3 ml: 1 ml), diluted to 20 ml with EtOAc and filtered through Celite.
  • Step A 4-(5-(Hydroxymethyl)thiophen-2-yl)benzaldehyde: The thiphene-5- al-2-boronic acid (0.47 g, 2.97 mmol) was reduced with NaBH 4 (0.15 g, 3.95 mmol) in MeOH (3 ml) and solvent was evaporated to dryness. The residue was taken in 1 ,4-dioxane (12 ml) and 4-bromobenzaldehyde (0.65 g, 3.5 mmol) was added. To this Pd(PPh 3 J 4 (0.05 g) was added with stirring at 80 9 C, followed by the addition of a solution of NaHCO 3 (0.6 g) in H 2 O (2 ml).
  • Step B 4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl) benzaldehyde: To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH 2 CI 2 (10 ml) and Et 3 N (0.3 ml) mesyl chloride (0.4 ml) was added at 0 5 C and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H 2 O. The organic layer was separated and dried over MgSO 4 and filtered.
  • Step C Methyl-2-((4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl) thiophen-2-yl)benzyl) (methyl)amino) acetate: To a stirred solution of the product of Step B (0.09 g, 0.26 mmol) and sarcosine hydrochloride (0.07 g, 0.5 mmol) in 1 ,2-dichloroethane (5 ml) was added DIPEA (0.1 ml) and 10 drops of AcOH, followed by NaBH(OAc) 3 (0.1 1 g, 0.51 mmol).
  • Step D 2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzyl) (methyl) amino)ethanol:
  • Step D 2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzyl) (methyl) amino)ethanol:
  • Step A N-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzyl) -2,2-dimethyl-1,3-dioxan-5-amine: When 2,2-dimethyl-1 ,3-dioxan-5- amine was substituted for sarcosine hydrochloride in Example 22, Step C, the similar process afforded the the title compound in 90% yield, as creamy paste.
  • Step B 2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzylamino) propane-1 ,3-diol: A solution of the product of Step A (0.025 g, 0.05 mmol) in a mixture of solvents (CH 3 OH, CH 2 CI 2 , 30% HCI: 1 ml, 3 ml, 15 drops) was stirred for 3 h at room temperature. The solvents were evaporated and co-evaporated with iPrOH to give the title compound (0.012 g, 48%) as creamy paste.
  • solvents CH 3 OH, CH 2 CI 2 , 30% HCI: 1 ml, 3 ml, 15 drops
  • Step A N-(3-(4-(Diethoxymethyl)phenyl)prop-2-ynyl)-4-fluorobenzenamine: When 4-bromo-benzene-diethylacetal and 4-fluro-N-propyrgylaniline was substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1 ] heptan-2-yl)benzene sulphonamide and but-3-yn-1 -ol, respectively, in Example 18, Step B, the similar process afforded the title compound in 36% yield, as pale paste.
  • Step B N-(3-(4-(Diethoxymethyl)phenyl)propyl)-4-fluorobenzenamine:
  • Step C N-(3-(4-(Diethoxymethyl)phenyl)propyl)-4-fluorobenzenamine:
  • Step C 4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzaldehyde: A mixture of 4-(3-(4-flurophenylamino)propyl)benzaldehyde (0.09 g, 0.35 mmol) [prepared form the product of Step B by stirring in acidifies CHCI 3 ] and 2- bromopropane (0.2 ml) and K 2 CO 3 (0.1 g; 0.73 mmol) was stirred at reflux in anhydrous DMF (5 ml) for 6 h. The solvent was evaporated under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H 2 O.
  • Step D N-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzyl)-2,2- dimethyl-1,3-dioxan-5-amine: ⁇ Nhen the product of Step C and 2,2-dimethyl-1 ,3- dioxan-5-amine were substituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)- thiophen-2-yl) benzaldehyde and sarcosine hydrochloride in Example 22, Step C, the similar process afforded the title compound in 48% yield, as creamy paste.
  • Step E 2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino) propane- 1,3-diol hydrochloride salt: When the product of Step D was substituted for N-(4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl) -2,2- dimethyl -1 ,3-dioxan-5-amine in Example 23, Step B, the identical process afforded the title compound in 67% yield, as a creamy paste.
  • Step A 4-Bromo-N-(3-methoxyphenyl)benzenesulfonamide: To a stirred solution of 3-methoxyaniline (0.48 g, 3.92 mmol) in anhydrous pyridine (5 ml) 4- bromobenzene-sulphonyl chloride (0.5 g, 1 .96 mmol) was added and the mixture was stirred for 0.5 h. The solvent was removed in vacuo and the residue was purified by FCC (SiO 2 , hexane/EtOAc) to give the title compound (0.51 g, 37%) as creamy paste.
  • FCC SiO 2 , hexane/EtOAc
  • Step B 4-Bromo-N-(3-methoxyphenyl)-N-methylbenzenesulfonamide: To a stirred mixture of the product of Step A (0.5 g 1.46 mmol) and K 2 CO 3 (0.5 g) in anhydrous DMF (7 ml) was added CH 3 I (1 ml) and the stirring continued for 0.5 h at 50 5 C. The mixture was diluted to 50 ml with H 2 O and extracted with EtOAc (50 ml). The organic layer was washed with H 2 O and dried over MgSO 4 , passed through silica gel bead and the filtrate was evaporated to dryness to give the title compound (0.5 g, 96%) as pale solid.
  • Step C 4'-Formyl-N-(3-methoxyphenyl)-N-methylbiphenyl-4-sulfonamide:
  • Step D Methyl-1-((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were sunstituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process the title compound in 69% yield, as pale paste.
  • Step E 1-((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4-yl) methyl)azetidine-3-carboxylic acid: To a stirred solution of the product of Step D (0.06 g, 0.13 mmol) in THF (3 ml) a solution of LiOH (0.006 g, 0.25 mmol) in H 2 O (1 ml) was added at 80 5 C. The mixture was stirred for 0.5 h and solvents were evaporated to dryness. The residue was purified by FCC (SiO 2 ) to give the title compound (0.0026 g, 43%) as creamy solid.
  • Step A 4-Fluoro-N-isopropylaniline: A mixture of 4-fluoro-aniline (1 .12 g; 10 mmol), 2-bromopropane (1 .13 ml) and K 2 CO 3 (1 .38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H 2 O and extracted with EtOAc (50 ml). The organic layer was washed with H 2 O (2 x 20 ml) and dried over MgSO 4 and filtered.
  • Step B N-(4-Bromobenzyl)-4-fluoro-N-isopropylbenzenamine: When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2- yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste.
  • Step C 4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- carbaldehyde:
  • Step B 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl) thiophen-2- ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 65% yield, as creamy gum.
  • Step D Methyl-2-(((4'-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl- 4-yl)methyl)(methyl)amino) acetate: When the product of Step C was substituted for 4-(5-(((4-flurophenyl))isopropyl) amino)methyl) thiophen-2-yl)benzaldehyde in Example 22, Step C, the similar process afforded the title compound in 96% yield, as a creamy paste.
  • Step E 2-(((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) (methyl)amino)acetic acid:
  • Step E 2-(((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) (methyl)amino)acetic acid:
  • Step E 2-((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) (methyl)amino)acetic acid:
  • Step A Methyl-1-((4'-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate: When 4'-(((4-Fluorophenyl)(isopropyl) amino)methyl)biphenyl-4-carbaldehyde and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)- methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process afforded the title compound in 65% yield, as creamy paste.
  • Step B 1-((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) azetidine-3-carboxylic acid: When the product of Step A was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy) benzyl) azetidine- 3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 60% yield, as creamy solid.
  • Step A 3-Bromo-1-(3,4,5-trimethoxyphenyl)but-2-en-1-one: 1 -(3,4,5- trimethoxyphenyl) but-2-yn-1 -one (0.5 g, 2.58 mmol) was dissolved in AcOH (5 ml) and 48% HBr (5 drops) was added to it. The mixture was stirred for 2 h at 50 5 C. This was evaporated to dryness and the residue was diluted to 50 ml with EtOAc, washed with NaHCO 3 solution and H 2 O. The organic layer was dried over MgSO 4 and filtered. The filtrate was evaporated to dryness and dried in vacuo to give the title compound (0.53 g, 65%), as a pale solid.
  • 1 H-NMR (CDCI 3 ) 7.30 (s, 1 H); 7.03 (s, 2H); 3.91 (s, 9H); 2.79 (s, 3H).
  • Step B 4-(4-Oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzaldehyde:
  • the product of Step A and 4-carbaldehyde-boronic acid were substituted for 5-(hydroxymethyl) thiophen-2-ylboronic acid and 4-bromobenzaldehyde, respectively, in Example 22, Step A, the similar process afforded the title compound in 81% yield, as creamy gum.
  • Step C Methyl- 1 -(4-(4-oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step-C, the similar process afforded the title compound in 66% yield, as pale paste.
  • Step D 1 -(4-(4-oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylic acid:
  • Step E the similar process afforded the title compound in 53% yield, as light yellow solid.
  • Step B 4'-But-2-ynoylbiphenyl-4-carbaldehyde: When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 58% yield, as a creamy gum.
  • Step C 4'-(3-Bromobut-2-enoyl)biphenyl-4-carbaldehyde:
  • the product of Step B was substituted for 1 -(3,4,5-trimethoxyphenyl) but-2-yn-1 -one in Example 28, Step A, the similar process afforded the title compound in 56% yield, as pale solid.
  • 1 H-NMR (CDCI 3 ) 10.07 (s, 1 H); 8.03 - 7.96 (m, 4H); 7.79 - 7.71 (m, 4H); 7.41 (s, 1 H); 2.84 (s, 3H).
  • Step D 4'-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- carbaldehyde: ⁇ Nhen the product of Step C and 3-trifluromethyl-boronic acid were substituted for 4-bromo benzaldehyde and 5-(hydroxymethyl) thiophen-2- ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 73% yield, as creamy gum.
  • Step E Methyl-1-((4'-(3-(3-(thfluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate:
  • Step D When the product of Step D and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 58% yield, as a pale paste.
  • Step F 1 -((4 '-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylic acid:
  • Step E the similar process afforded the title compound in 62% yield, as a light yellow solid.
  • Step A 5-Bromo-2-isopropoxybenzaldehyde: To a stirred solution of 2- isopropoxybenzaldehyde (0.51 g, 3.1 mmol), in DMF (10 ml) NBS (0.55 g, 3.1 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with NaHCO 3 solution and extracted in EtOAc (50 ml). The organic layer was washed with H 2 O, dried over MgSO 4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.62 g, 82%) as light yellow oil.
  • Step B 1-(5-Bromo-2-isopropoxyphenyl)-3-phenylprop-2-yn-1-one: To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgCI in THF (1.25 ml) was added drop wise at 0 5 C under N 2 . After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH 4 CI and extracted with EtOAc (50 ml).
  • Step C 4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzaldehyde: A solution of the product of Step B (0.3 g, 0.88 mmol), was treated with HBr/ AcOH, as described in Example 28, Step A, to give a light creamy solid (0.18 g, 68%).
  • Step D Methyl 1-(4-(4-oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3- carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for -(5-(((4-flurophenyl))isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, as in Example 22, Step C, the similar procedure afforded the title compound in 31 % yield, as light green paste.
  • Step E 1-(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3- carboxylic acid:
  • Step D When the product of Step D was substituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 36% yield, as creamy solid.
  • Step B 2-(1-Admantanyl)-4-bromomethoxybenzene: To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K 2 CO 3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH 3 I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H 2 O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO 4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94%), as light yellow green solid.
  • Step C 3'-(1-Admantanyl)4'methoxy-4-carbaldehyde: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for A- bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 42% yield, as pale solid.
  • Step D Methyl-1-3'-(1-admantanyl)4'methoxybiphenyl-4- yl)methyl)azetidine-3-carboxylate:
  • Step C When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively in Example 22, Step C, the similar procedure afforded the title compound in 82% yield, as pale paste.
  • Step E 3'-(1-Admantanyl)-4'methoxybiphenyl-4-yl)methyl)azetidine-3- carboxylic acid:
  • Step D 3'-(1-Admantanyl)-4'methoxybiphenyl-4-yl)methyl)azetidine-3- carboxylic acid:
  • Step A 3-(1-Admantanyl)-4-methoxybenzaldehyde: When A- hydroxybenzaldehyde was substituted for 4-bromophenol in Example 31 , Step A, the similar procedure afforded 3-(1 -admantanyl)-4-hydroxybenzaldehyde in 56% yield, as a pale white solid.
  • Step B 4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzaldehyde: To a stirred suspension of product of Step A (0.09 g, 0.32 mmol) in MeOH (5 ml) NaBH 4 (0.018 g, 0.47 mmol) was added and the mixture was stirred for 0.5 h. The solvent was evaporated to dryness and the residue was taken in NaHCO 3 solution and extracted with EtOAc (25 ml). The organic layer was separated, dried over MgSO 4 , and filtered. The filtrate was evaporated and the residue was dried in vacuo to give a relevant benzyl alcohol (0.095 g; 100%), as a creamy gum.
  • Step C Methyl 1 -(4-(3-(1 -admantanyl)-4-methoxybenzyloxy) benzyl)azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))- isopropyl)amino)methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 69% yield, as a pale paste.
  • Step D 1 -(4-(3-(1 -Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3- carboxylic acid:
  • Step E the similar procedure afforded the title compound in 61 % yield, as creamy solid.
  • Step A 4-(2-(6,6-Dimethylbicyclo[3.1. 1]heptan-2-yl)ethoxy)benzaldehyde: (6,6-Dimethylbicyclo[3.1 .1 ]hept-2-en-2-yl)ethanol was brominated as described in Example 32, Step B and the bromination product was used in next step without further purification, where it was treated with 4-hydroxybenzaldehyde as described in Example 32, Step B to afford the title compound in 91% yield, as creamy paste.
  • Step B Methyl- 1-(4-(2-(6, 6-dimethylbicyclo[3.1.1]heptan-2- yl)ethoxy)benzyl) azetidine-3-carboxylate: When the product of Step A and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4- flurophenyl))- isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 76% yield, as light yellow paste.
  • Step C 1-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl) azetidine-3-carboxylic acid: When the product of Step B was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 87% yield, as creamy paste.
  • Step A 6-Bromo-4-oxo-2-(phenylamino)-4H-chromene-3-carbaldehyde: To a stirred solution of 6-bromo-4-oxo-4H-chromene-3-carbaldehyde (2 g, 7.93 mmol) in anhydrous benzene (15 ml) phenyl-hydroxylamine (0.95 g, 8.71 mmol) was added. The solution was kept for 1 h at room temperature when the crystalline solid appeared. To this glacial AcOH (0.5 ml) was added and the mixture was stirred for 5 h at reflux.
  • Step B 2-Bromo-12H-chromeno[2,3-b]quinolin-12-one: To the product of Step A (1 g; 2.92 mmol) concentrated H 2 SO 4 (1 ml) was gently added with stirring. The mixture was kept in sealed vial for 24 h, at room temperature, than poured onto ice water and extracted with CH 2 CI 2 (50 ml). The organic layer was washed with NaHCO 3 solution, H 2 O, dried over MgSO 4 and filtered. The filtrate was distilled off and the residue was crystallized from CH 3 CN to give the title compound (0.73 g, 77%), as green yellow solid.
  • Step C 4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzaldehyde: When the product of Step B and 4-carbaldehyde-boronic were substituted for 4- bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 52% yield, as off white solid.
  • Step D Methyl- 1-(4-(12-oxo- 12H-chromeno[2,3-b]quinolin-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylat ⁇ hydrochloride were substituted for 4-(5-(((4- flurophenyl))isopropyl)amino) methyl) thiophen-2-yl) benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure affored the title compound in 48% yield, as pale paste.
  • Step E 1-(4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3- carboxylic acid: When the product of Step D was sunstituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 50% yield, as yellow solid.
  • Step A (5-Chlorobenzofuran-3-yl)methanol: To a mixture of 4-chloro-2- iodophenol (1 g, 3.92 mmol), tert-butyl(3-(tert-butyldimethylsilyl)prop-2-ynyloxy)- dimethylsilane (1 .93 g, 6.8 mmol), LiCI (0.15 g; 3.5 mmol) and Na 2 CO 3 (0.636 g; 6 mmol) in anhydrous DMF (10 ml) Pd(OAc) 2 (0.3 g) was added at 100 5 C under N 2 and heating was continued for 1 .5 h.
  • Step B 4-((5-Chlorobenzofuran-3-yl)methoxy)benzaldehyde: When the product of Step A was substituted for 3-(1 -admantanyl)-4-methoxy benzaldehyde in Example 32, Step B, the similar procedure afforded the title compound in 9% yield, as pale paste.
  • Step C Methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine- 3-carboxylate: When the product of Step B and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)- thiophen-2-yl) benzaldehyde and sarcosine hydrochloride, respectfully, in Example 22, Step C, the similar procedure afforded the title compound in 45% yield, as off white solid.
  • Step D 1 -(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3- carboxylic acid:
  • Step E the similar procedure afforded the title compound in 57% yield, as creamy solid.
  • Step A N-Hydroxy-3-iodo-4-isopropoxybenzimidamide: A suspension of 3- iodo-4-isopropoxybenzonitrile (0.576 g; 2 mmol), HCI x NH 2 OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50 5 C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H 2 O. The organic layer was separated, dried over MgSO 4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid.
  • Step B 5-(3-Chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1,2,4- oxadiazole: A mixture of S-chloro ⁇ -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 5 C . 1 M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 1 10 5 C. The reaction mixture was diluted to 20 ml with H 2 O and extracted with EtOAc (2 x 15 ml).
  • Step C 4-(5-(3-Chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2- iodophenol: To a solution of the product of Step B (0.2 g, 0.4 mmol) in anhydrous CH 2 CI 2 (2 ml) 1 M BCI 3 in CH 2 CI 2 (3 ml) was added drop wise at rt. After 1 h, more of 1 M BCI 3 in CH 2 CI 2 (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH 4 CI solution and extracted with CH 2 CI 2 (20 ml). The organic layer was separated, dried over MgSO 4 and filtered.
  • Step D tert-Butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: A solution of the product of Step C (0.1 g; 0.22 mmol) and ferf-butyl 5-ethynyl-2,2-dimethyl-1 ,3- dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml: 0.3 ml) was degassed with N 2 and CI 2 Pd(PPh 3 ) 4 (0.025 g) was added, followed by catalytic amount of CuI.
  • Step E 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol: To a stirred solution of product of Step D (0.1 g, 0.17 mmol) in CH 2 CI 2 (0.5 ml) TFA (1 ml) was added. After stirring for 1 h at room temperature, EtOH (2 ml) was added and stirring was continued for additional 1 h.
  • Step A (E)-3-(3-lodo-4-isopropoxyphenyl)-5-(4-methylstyryl)-1,2,4- oxadiazole: When (E)-3-p-tolylacrylic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar process afforded the title compound in 52% yield, as colourless solid.
  • Step B (E)-2-lodo-4-(5-(4-methylstyryl)-1,2,4-oxadiazol-3-yl)phenol:
  • Step C the similar procedure afforded the title compound in 53% yield, as colourless solid.
  • Step C (E)-tert-Butyl 2,2-dimethyl-5-(5-(5-(4-methylstyryl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step D the similar process afforded the title compound in 68% yield, as pale paste.
  • Step D (E)-2-Amino-2-(5-(5-(4-methylstyryl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl) propane- 1, 3-diol:
  • Step C 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 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid.
  • Step A 5-(4-Bromo-3-chlorophenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4- oxadiazole: When 4-bromo-3-chlorobenzoic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 72% yield, as creamy solid.
  • Step B 4-(5-(4-Bromo-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 86% yield, as creamy solid.
  • Step C tert-Butyl 5-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 58% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-bromo-3-chlorophenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step A tert-Butyl 5-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)-1,2,4- oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl- 1 ,3-dioxan-5-ylcarbamate: To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3- thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H 2 O (5 ml:1 ml), Pd(PPh 3 ) 4 (0.03 g) was added at 80 5 C, followed by the NaHCO 3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h.
  • Step B 2-Amino-2-(5-(5-(3-chloro-4-(thiophen-3-yl)phenyl)- 1 ,2,4-oxadiazol- 3-yl)benzofuran-2-yl)propane-1,3-diol:
  • Step E the similar procedure afforded the title compound in 48% yield, as colourless solid.
  • Step A 5-(3,4-Diethoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4- oxadiazole: When 3,4-diethoxy benzoic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 60% yield, as colourless solid.
  • Step B 4-(5-(3,4-Diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 84% yield, as a creamy solid.
  • Step C tert-Butyl 5-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 66% yield, as creamy paste.
  • Step D 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl) propane- 1,3-diol:
  • Step C 2-Amino-2-(5-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl) propane- 1,3-diol:
  • Step E the similar procedure afforded the title compound in 61 % yield, as creamy solid.
  • Step A 5-(4-Propoxy-3-methoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)- 1 ,2,4-oxadiazole: When 4-propoxy-3-methoxybenzoic acid was substituted for 3- chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 58% yield, as creamy solid.
  • Step B 4-(5-(4-Propoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2- iodophenol:
  • Step C the similar procedure afforded the title compound in 80% yield, as creamy solid.
  • Step C tert-Butyl 5-(5-(5-(4-propoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 68% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-Propoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-Propoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step A 2-Methylbenzofuran-5-carbonitrile: 2-lodo-4-cynophenol (0.25 g, 1 mmol) and saccharin (0.1 g) in HMDSA (2 ml) was refluxed for 2 h under N 2 , until the solution became clear. The solvent was distilled off under reduced pressure and the residue was dissolved in anhydrous THF (2 ml).
  • Step B 5-(3,4-Diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1,2,4- oxadiazole:
  • the product Step A was converted to ⁇ /-hydroxy-2-methylbenzofuran- 5-carboximidamide by method described for Example 36, Step A.
  • N- hydroxy-2-methylbenzofuran-5-carboximidamide and 3,4-diethoxybenzoic acid were substituted for ⁇ /-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro- 4-propoxybenzoic acid, respectively, in Example 36, Step B, the similar procedure afforded the title compound in 6% yield, as colourless solid.
  • Step A Ethyl 2-(2-formyl-5-methoxyphenoxy)acetate: A mixture of 2- hydroxy-4-methoxybenzaldehyd ⁇ (1 g; 6.58 mmol), BrCH 2 CO 2 Et (0.806 ml; 7.24 mmol) and K 2 CO 3 (1 g, 7.24 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and H 2 O (100 ml). The organic layer was separated and dried over MgSO 4 , and filtrate evaporated, to give the product (1 .29 g; 97%), as colourless solid.
  • Step B Ethyl 6-methoxybenzofuran-2-carboxylate: A mixture of the product of Step A (1 .28 g, 5.37 mmol) and DBU (0.3 ml) was heated for 3 h at 160 5 C with stirring, cooled to room temperature and dissolved in EtOAc: MeOH mixture (99:1 ). The mixture was filtered through the silica bead and the filtrate was evaporated to give the title compound (1 .1 1 g; 77%), as colourless solid.
  • Step C 6-Methoxybenzofuran-2-carboxylic acid: To a stirred solution of Product of Step B (0.25 g, 1.21 mmol) in a mixture of THF, MeOH and H 2 O (5 ml : 2 ml : 1 ml), LiOH (0.145 g, 6 mmol) in H 2 O (0.5 ml) was added and the mixture was stirred for 3 h at room temp. The solvents were distilled off and the residue was portioned between EtOAc (20 ml) and 1 M HCI (2 ml). The organic layer was washed with H 2 O, dried over MgSO 4 and filtered.
  • Step D 3-(3-lodo-4-isopropoxyphenyl)-5-(6-methoxybenzofuran-2-yl)- 1,2,4- oxadiazole:
  • Step E 2-lodo-4-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3- yl)phenol: When the product of Step D was substituted for 5-(3-chloro-4- propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 65% yield, as colourless solid.
  • Step F 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:
  • Step D the similar procedure afforded the title compound in 64 % yield, as pale paste.
  • Step G 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol:
  • Step F 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)- 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:
  • 4-propylbenzoic acid was substituted for 3-chloro-4-propoxy benzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 82% yield, as colourless solid.
  • Step B 2-lodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)phenol:
  • Step C 2-lodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)phenol:
  • Step C tert-Butyl 2,2-dimethyl-5-(5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl) benzo-furan-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 35% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-propylphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane -1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-propylphenyl)- 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-chlorc-4-propoxy benzoic acid in Example 36, Step B, the similar procedure affored the title compound in 53% yield, as white solid.
  • Step B 4-(5-(4-Ethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 87% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 60% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(4-ethoxyphenyl)- 1,2,4-oxadiazol-3-yl)benzofuran- 2-yl)propane -1,3-diol:
  • Step C 2-Amino-2-(5-(5-(4-ethoxyphenyl)- 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 CF 3 CO 2 Ag (1 .3 g, 5.1 mmol) in CH 2 CI 2 (50 ml) I 2 (1 g, 4 mmol) was added and the mixture was stirred for 6 h at reflux. This was filtered through the Celite bead and the washed with CH 2 CI 2 .
  • Step B 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1,2,4- oxadiazole:
  • Step B 3-(2-Chloro-5-iodo-4-isopropoxyphenyl)-5-(4-propylphenyl)- 1,2,4- oxadiazole:
  • Step C 5-Chloro-2-iodo-4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)phenol: When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3- (3-iodo-4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 55% yield, as creamy solid.
  • Step D 2-Amino-2-(6-chloro-5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • tert-butyl 5-(5-(5-(3-chloro-4- propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5- ylcarbamate was replaced with the tert-butyl 5-(6-chloro-5-(5-(4-propylphenyl)- 1 ,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) the similar procedure as in Example 36, Step E gave
  • 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 5 C. The mixture was quenched with saturated NH 4 CI and extracted with EtOAc (50 ml). The organic layer was washed with H 2 O, dried over MgSO 4 and filtered.
  • Step B 5-(1 -Butyl-1 H-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 36, Step B the similar procedure afforded the title compound in 17% yield, as creamy gum.
  • Step C 4-(5-(1 -Butyl-1 H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-2-iodophenol:
  • Step C the similar procedure afforded the title compound in 72% yield, as creamy solid.
  • Step D tert-Butyl 5-(5-(5-(1 -butyl-1 H-pyrazol-4-yl)-1, 2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 68% yield, as pale paste.
  • Step E 2-Amino-2-(5-(5-(1 -butyl- 1 H-pyrazol-4-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol:
  • Step D 2-Amino-2-(5-(5-(1 -butyl- 1 H-pyrazol-4-yl)- 1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol:
  • Step B 3-(3-lodo-4-isopropoxyphenyl)-5-(3-nitro-4-propoxyphenyl)-1,2,4- oxadiazole:
  • the product of Step A was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 66% yield, as creamy solid.
  • 1 H NMR (CDCI 3 ) 8.64 (d, 1 H, J
  • 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 36, Step C, the similar procedure afforded the title compound in 77% yield, as creamy solid.
  • Step D tert-Butyl 2,2-dimethyl-5-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4- oxadiazol-3-yl)benzofuran-2-yl)-1,3-dioxan-5-ylcarbamate:
  • Step D the similar procedure afforded the title compound in 54% yield, as pale solid.
  • Step E 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step D 2-Amino-2-(5-(5-(3-nitro-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol:
  • Step B 5-(3-(3-lodo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile:
  • Step B the similar procedure afforded the title compound in 57% yield, as creamy solid.
  • Step C 5-(3-(4-Hydroxy-3-iodophenyl)-1,2,4-oxadiazol-5-yl)-2-propoxy benzonitrile:
  • Step C the similar procedure afforded the title compound in 74% yield, as creamy solid.
  • Step D tert-Butyl 5-(5-(5-(3-cyano-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate: When the product of Step C was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)- 2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 44% yield, as pale paste.
  • Step E 5-(3-(2-(2-Amino-1,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1,2,4- oxadiazol-5-yl)-2-propoxy benzonitrile:
  • product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran- 2-yl)-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) in Example 36, Step E, the similar procedure afforded the title compound in 29% yield, as off white solid.
  • Step B 4-(5-(3-Bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol: When the product of Step A was substituted for 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 70% yield, as white solid.
  • Step C tert-Butyl 5-(5-(5-(3-bromo-4-propoxy-phenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl-carbamate: When 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 36, Step D, the similar procedure afforded the title compound in 98% yield, as pale paste.
  • Step D 2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol:
  • Step C 2-Amino-2-(5-(5-(3-bromo-4-propoxyphenyl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol:
  • Step B 2-lodo-4-octylbenzenethiol: : To a stirred mixture of the product of Step A (0.4 g; 1.21 mmol) in 35% HCI (0.2 ml) an ice cold solution of NaNO 2 (0.1 g, 1 .3 mmol) in H 2 O (1 ml) was added at O 5 C, followed by a solution of K- ethylxhanthate, freshly prepared by rapid stirring of a mixture of KOH (0.085 g, 1.5 mmol) and CS 2 (0.173 g, 1 .5 mmol) in a mixture of EtOH and H 2 O (1 ml : 1 .5 ml) for 2.5 h at room temperature.
  • Step C tert-Butyl 2,2-dimethyl-5-(5-octylbenzo[b]thiophen-2-yl)-1,3-dioxan- 5-ylcarbamate
  • Step D the similar procedure afforded the title compound in 24% yield, as white solid.
  • Step D 2-Amino-2-(5-octylbenzo[b]thiophen-2-yl)propane-1,3-diol:
  • tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)-2,2-dimethyl-1 ,3-dioxan -5-ylcarbamate was replaced with the product of Step C the similar procedure as described in Example 36, Step E gave the title compound (0.008 g, 38%) as light yellow solid.
  • Step B tert-Butyl 2,2-dimethyl-5-(5-octylbenzofuran-2-yl)-1,3-dioxan-5- ylcarbamate: When with the product of Step A was substituted for 4-(5-(3-chloro- 4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 53% yield, as a light yellow paste.
  • Step C 2-Amino-2-(5-octylbenzofuran-2-yl)propane-1,3-diol:
  • Step B When the product of Step B 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-yl- carbamate in Example 36, Step E, the similar procedure afforded the title compound in 51 % yield, as off white solid.
  • Step A N-Hydroxy-IH-indole-4-carboximidamide: A mixture of A- cyanoindol ⁇ (0.64 g; 4.5 mmol), HCI x H 2 NOH (1.1 g; 15.8 mmol), and Na 2 CO 3 (0.79 g; 7.43 mmol) in H 2 O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6h under N 2 . After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3 x 10 ml). The organic phase was separated, dried over anhydrous MgSO 4 and filtered.
  • Step B 5-(3,4-Diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole
  • 3,4-diethoxybenzoic acid 0.1 1 g; 0.52 mmol
  • PyBroP 0.25 g; 0.54 mmol
  • DIPEA 0.21 ml; 1.22 mmol
  • Step C 5-(3,4-Diethoxyphenyl)-3-(indolin-4-yl)-1,2,4-oxadiazole: To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1 M BH 3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at O 0 C with stirring. After the addition was completed ( ⁇ 5 min), the reaction was quenched with H 2 O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2 x 2 ml), brine and dried over anhydrous MgSO 4 and filtered.
  • Step D Ethyl 2-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)acetate:
  • Step E Ethyl 2-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)acetate:
  • Step E 2-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamidojacetic acid: When the product of Step D was substituted for ethyl 3- (3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B the identical process afforded the title compound in 75 % yield.
  • Step A Ethyl 3-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoate: When the product of Example 16 Step C was substituted for n-octylaniline in Example 11 , Step A the identical process afforded the title compound in 52 % yield.
  • Step B 3-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B the identical process afforded the title compound in 61 % yield.
  • the S1 P1 assay system was GTPgama-S35 binding in membranes from CHO K1 cells, expressing S1 P1 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 ⁇ M. 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 (EC 50 ) of the compounds relative to S1 P, shown in Table 10.
  • NA no activity
  • ND not determined.

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Abstract

The invention relates to novel compounds that have S1P receptor modulating activity. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, autoimmune response. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as autoimmune response.

Description

S1 P RECEPTORS MODULATORS AND THEIR USE THEREOF
FIELD OF INVENTION
This invention relates to novel compounds having S1 P receptors modulating activity and the use of such compounds to treat diseases associated with inappropriate S1 P receptor/s activity.
BACKGROUND
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 , S1 P2, S1 P3, S1 P4 and S1 P5. The intracellular activity of S1 P and modulators has not been fully explored. 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. The lymphocytes move from the peripheral circulation into the lymph nodes and mucosa associated tissues in order to generate immune responses. T and B lymphocytes are effectively sequestered within the thymus and secondary lymphoid tissue. Essentially, S1 P and its receptor subtype -1 are required for lymphocytes to move out of the thymus and secondary lymphoid organs.
S1 P type molecular modulators have been shown to be effective in multiple animal disease models. The S1 P signalling, mainly through its receptor subtype - 1 , is important in halting the Treg response and has been recommended for immunotherapy of cancer and infectious disease (Liu, G., et al, Nature Immunology, 2009, 10, 769 - 777; Wolf, A. M., et al, J. Immunology, 2009, 183, 3751 -60). The S1 P mediated trans-activation of insulin receptor has been reported to help treating insulin resistance and type 2 diabetes (Rapizzi E. et al, Cell MoI 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. ScL, 2005, 1044, 84 - 89; Kimura, et al, Blood, 2004, 103, 4478-86) and a have great potential applications in regenerative medicines. S1 P receptors play 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; Garcia, J. G. N., et al, J. Clinical Investigation, 2001 , 689-701 ). The vasculature normalization helps the cytotoxic T cells to access the remote and inner part of the tumour (Hamzah J. et al, Nature, 2008, 453, pp 410 - 414). The lymphocyte egress and endothelial barrier function is mediated through S1 P1 receptor (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, AmJ. 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; ToIIe, 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 ). Recently reported target of S1 P includes the family of Histone Deacylases (HDACs) (Hait, N. C, et al, Science, 2009, 325, 125-7), which are known for their role in epigenetic. The S1 P has been reported to help treatment of the latent mycobacterium tuberculosis infection by promoting the processing and presentation of antigens (Santucci, M. B. et al, Biochem Biophys Res Comm, 2007, 361 , 687 -93). 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. Role of S1 P receptor subtype - 1 in modulating nociception have recently been described (Selley S M J et al, Journal of Neurochemistry, 2009, 1 10, pp 1 191 - 1202).
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 of FTY-720 and its efficiency in animal models and clinical studies, related to many autoimmune diseases and cancer treatment, has resulted in research efforts into S1 P receptors.
Figure imgf000004_0001
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 emerging 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 ). It is effective against autoimmune related pathologies such as type-1 diabetes (Yang, Z., et al, Clin Immunology, 2003, 107, 30-5), arthritis (Matsuura, et al, lnflamm Res, 2000, 49, 404-10) and oxazolone stimulated colitis (Daniel, et al, Molecular Immunology, 2007, 44, 3305-16). FTY- 720 interaction with cytosolic Phospholipase A2 and modulation the eicosanoids synthesis (Payne S. G. et al; Blood, 2007, 109, pp 1077 - 1085) indicates its potential as anti-inflammatory and antinociceptive agents and a safe pain killer (Costθ, O., et al, J. Cell MoI. Med., 2008, VoI 12, 995 - 1004). The anticancer activity of FTY-720 is well documented by in vitro apoptotic activity studies as well as numerous animal model studies. The apoptotic mechanism observed in hepatocellular carcinoma cell lines is linked to the activation of protein kinase C delta (PKC-δ) (Hung, J. H., et al, 2008, 68, 1204-12). The apoptotic activity of FTY-720 against chronic myelogenous leukaemia and Philadelphia chromosome positive acute lymphocytic leukaemia was reported to be due to its control of Protein Phosphates 2A (PP2A) (Neviani et al, J of Clinical Investigation, 2007, 1 17, 24-21 ). 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 , was described recently (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). Few days of treatment with FTY-720 leads to complete eradication of chronic viral infection of lymphocytic choriomeningitis (Lanier, et al, Nature, 2008, 894 - 899). 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; ToIIe, 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.
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.
SUMMARY OF INVENTION
In one aspect of the present invention there is provided a compound of formula (I)
Figure imgf000006_0001
(I)
wherein G represents an organic substituent comprising in any combination one or more nitrogen, oxygen or sulphur atom(s). In one embodiment of this aspect of the invention, G is a group selected from the following:
Figure imgf000007_0001
NH2
NH2 R "NR , H L R
.O * ^O.
OH •"•O NH2 O OH
Figure imgf000007_0002
wherein R is independently selected from H, deuterium, CN, amino, alkylamino, CH2OH, alkoxy, CF3, an alkyl chain optionally containing one or more of deuterium, O, NR'R" (wherein R' and R" are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle) S, SO, S02, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond or a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, sulphonamide, hydroxyl, -CH2COOH, -COOH, - OPO3H2, -PO3H2, cyclic phosphate, cyclic phosphonates and/or salts, tetrazole, and n is 0-4, with the proviso that if an amino group is present on the same carbon atom as R in group G, R is not hydroxyl, -'' '"> represents an optional bridging group; the asterisks indicating the attachment within formula (I).
In the compound of formula (I), Z represents an organic moiety comprising at least one aromatic centre. X and Y separately, or in combination, are alkyl, alkyl-amino, alkoxy, an alkyl chain containing one or more of O, N, S, SO, SO2, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon- heteroatom double bond, carbocycle, heterocycle or a group selected from the following:
Figure imgf000008_0001
wherein R1 is selected from H or alkyl, the asterisks indicating the attachment within formula (I).
In an alternative or further preferred embodiment of this aspect of the invention, X, Y and Z separately, or in any combination, are selected from the following
Figure imgf000008_0002
R3 R3 r-° , -s
R2 L/N *
R2 R2 R2 R2
Figure imgf000008_0003
wherein the asterisks indicate the attachment within formula (I), R2 is selected from halogen, H, deuterium, CN, amino, alkylamino, alkoxy, CF3, an alkyl chain (up to 20 carbon atom) optionally containing one or more of deuterium, OH, NR'R" (wherein R' and R" are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle) O, N, S, SO, SO2, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond or a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, sulphonamide and A represents one or more ring atoms or groups independently selected from the group consisting of C, N, O, S, CO, C=NR, SO or SO2, R3 may be a linking group or alkyl, aryl, heterocycle or an optionally substituted alkyl chain.
In a further alternative embodiment of this aspect of the invention Z and G, in combination, are selected from the following groups:
Figure imgf000009_0001
wherein R is as defined for group G, wherein A is defined as above and X is independently selected from the group consisting of heteroatom or heteroatom containing species such as O, N, S, SO, S02, CO or C=NR and R2 is as defined above, the asterisks indicating the attachment within formula (I).
Figure imgf000009_0002
wherein A is defined as above, X and Y are independently selected from the group consisting of heteroatom or heteroatom containing species such as O, N, S, SO, S02, CO or C=NR and R2 is as defined above, the asterisks indicating the attachment within formula (I).
In the compound of Formula (I), the groups J, m and D separately, or in any combination, are selected from hydrogen, deuterium, alkyl, alkoxy, alkylamino, halogen, amino, hydroxy, oxo (=0), imino (=NR), cyano, aryl, variously substituted aryl, variously substituted heterocycle, variously substituted carbocycle, alkyl chain of 1 -15 carbon atom optionally containing carbon-carbon multiple bond, carbon-hetero multiple bond wherein one or more carbon atoms can be independently replaced with oxygen, sulphur, SO, SO2, NR (wherein R is a substituent), aryl, carbocycle and heterocycle.
In one embodiment the group D, when present, is selected from H, deuterium, alkyl, aryl, heterocycle or cycloalkyl. In a further embodiment the group m, when present, is selected from unsubstituted or substituted aryl, carbocycle or heterocycle. In a yet further embodiment, the group J, when present, is selected from H, alkyl or one of the following groups:
Figure imgf000010_0001
wherein n is 0-10, A is as defined above, R4 is halogen, CN, amino, alkylamino, alkoxy, CF3, an alkyl chain containing one or more of O, N, S, SO, SO2, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon- heteroatom double bond or a carbon-hetero atom triple bond.
In a further aspect of the invention there is provided compounds having S1 P receptor modulating activity and/or expression against target cells.
A yet further aspect of the invention provides a pharmaceutical preparation comprising at least one compound described herein in any of its stereoisomeric 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 the invention provides the use of a compound of the invention in any one of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures 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 further aspect the invention provides the use of a compound of the invention in any one of its stereoisomeric and/or isotopic forms and mixtures thereof in any ratio and/or physiologically tolerable and/or therapeutically effective salts for the production of a pharmaceutical for modulation of S1 P receptor (extracellular and/or intracellular binders) activity and/or expression.
S1 P receptors are cell surface receptors which include known receptor subtypes 1 , 2, 3, 4, 5 and are regarded herein as S1 P receptors. These extracellular S1 P receptors may be present inside the cell on Golgi bodies, etc. There are other intracellular receptor/s, target/s, protein/s, enzyme/s where S1 P interacts and are regarded as S1 P receptor/s. The compounds of the invention could function as substrates of Sphingosine Kinases like SK1 and SK2 which are responsible for phosphorylation of S1 P and are regarded as S1 P receptor/s. Histone Deacylase/s (HDACs) are known intra-nuclear receptors of S1 P and thus are regarded as S1 P receptors. In broad terms, the invention includes any receptor binder, agonists or antagonists, or inverse agonists of the S1 P receptor family including S1 P1 , S1 P2, S1 P3, S1 P4 and S1 P5, which is responsible for direct and or indirect effect of S1 P and regards them as S1 P receptor/s.
Further, the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio.
Further, the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric and/or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression, for example, autoimmune disease.
A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention in any of its stereoisomeric or isotopic forms or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression such as autoimmune disease.
In yet a further aspect of the invention, the compounds of the invention can 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.
Viral infections including but not limited to human immunodeficiency virus, Hepatitis (HAV, HBV, HCV), H1 N1 influenza, chickenpox, cytomegalovirus infection, dengue fever, Ebola hemorrhagic fever, hand foot and mouth disease, herpes simplex, herpes zoster, HPV, influenza (Flu), Lassa fever, measles, Marburg Hemorrhagic fever, infectious mononucleosis, mumps, norovirus, poliomyelitis, progressive multifocal Leu-encephalopathy, rabies, rubella, SARS, smallpox (Variola), viral encephalitis, viral gastroenteritis, viral meningitis, viral pneumonia, west Nile disease and yellow fever.
Bacterial Infections including but not limited to actinomycosis, anaplasmosis, anthrax, bacterial meningitis, botulism, brucellosis, burkholderia infections, campylobacteriosis, cellulitis, chlamydiaceae infections, cholera, Clostridium infections, coccidiomycosis, diphtheria, ehrlichiosis, empyema, gonorrhea, impetigomelioidosis legionellosis, leprosy (Hansen's Diseases), leptospirosis, listeriosis, lyme disease, bacterial endocarditis, endophthalmitis, pseudomembranous enterocolitis, erysipelas, Escherichia coli infections, necrotizing fasciitis, Fournier gangrene, furunculosis, fusobacterium infections, gram negative bacterial infections, gram positive bacterial infections, granuloma inguinale, hidradenitis suppurativa, histoplasmosis, hordeolum, impetigo, Klebsiella infections, ludwig's angina, lymphogranuloma venereum, maduromycosis, mycobacterium infections, MRSA infection, Mycoplasma infections, nocardia infections, onychomycosis, osteomyelitis, paronychia, pelvic inflammatory disease, plague pneumococcal infections, pseudomonas infections, psittacosis, puerperal infection, respiratory tract infections, retropharyngeal abscess, rheumatic fever, rhinoscleroma, rickettsia infections, rocky mountain disease, salmonella infections, scarlet fever, scrub typhus, sinusitis, shigellosis, spotted fever, bacterial skin disease, staphylococcal infections, streptococcal infections, syphilis, tetanus, trachoma, tick borne disease, epidemic typhus, tuberculosis, tularaemia, typhoid fever, urinary tract infections, Whipple disease, whooping cough, vibrio infections, Yersinia infections, zoonoses, and zygomycosis,
Fungal infections including but not limited to aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, tinea pedis and histoplasmosis. Prion infections including but not limited to transmissible spongiform encephalopathy, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Kuru fatal Familial insomnia and Alpers Syndrome.
In a further aspect of the invention, the compounds of the invention can 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, pruritus, arthritis, rheumatoid arthritis, osteoporosis, Sjogren Syndrome, uveitis, asthma, hay fever, sleep disorders, , macular degeneration, glaucoma, typei 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.
The compounds of the invention can be used for the prevention and/or prophylaxis and/or treatment and/or immunotherapy of or in, Down's syndrome, schizophrenia, bipolar disorder, drug dependence, Wernicke-Korsakoff syndrome, eating disorders, depression resulting from infection, hepatic encephalopathyjung diseases such as grain handler's, Hermansky-Pudlak Syndrome, and adult respiratory distress syndrome (ARDS, obesity, digestive tract disease, anxiety, hyperalgesia, migraine, epilepsy and neuromuscular disorder.
In another embodiment the compounds of the invention can be used for prevention and/or treatment of vascular and/or cardiovascular diseases including, but not limited to, hypoxia, atherosclerosis, diabetic blood vessel disease like inflammation, hyper vascularisation related disorders such as cancer and neoplasm, heart failure, myocardial infarction, myocarditis, ischemia, hypotension, hypertension, reperfusion injury, angina pectoris, coronary artery disease, stroke, thrombosis, artery/vein blockage or obstruction, diabetic retinopathy, sepsis and kidney failure, reperfusion or injury. In another embodiment the compounds of the invention can be used for prevention and/or prophylaxis and/or treatment and/or immunotherapy of liver diseases including but not limited to liver cirrhosis, viral liver infections, autoimmune hepatitis, liver failure, portal hypertension, hemochromatosis, Wilson's diseases, Gaucher disease, hepatoma, primary biliary cirrhosis, primary sclerosing cholangitis, sarcoidosis and Zwellweger syndrome. In another embodiment the compounds of the invention can be used for the prevention and/or treatment and/or immunotherapy of solid and/or haematological cancers and tumor metastasis, including but not limited to acute B-cell leukaemia, lymphoma, chronic lymphocytic leukaemia, chronic myeloid leukaemia, hairy cell leukaemia, multiple myeloma, acute lymphocytic leukaemia , acute granulocytic leukaemia, acute myelogenous leukaemia, lung cancer, adrenal gland cancer, astrocytoma, glioma, brain cancer, bile duct cancer, bladder cancer, bone cancer, bowel cancer, colorectal cancer, breast cancer, cervical cancer, endometrial cancer, oesophageal cancer, melanoma, gallbladder cancer, Kaposi sarcoma, renal cancer, laryngeal cancer, liver cancer, mesothelioma, prostate cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, thyroid cancer, and pancreatic cancer.
In another embodiment the compounds of the invention can 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 related to nociceptive pain, peripheral neuropathy, central neuropathy, neuralgia, migraine, psychotic, inflammatory and or neurological disorders.
In another embodiment the compounds of the invention can 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 another embodiment the disclosed molecules can be used for prevention and/or treatment and/or immunotherapy for the pathologies caused by bioterrorism agents.
In another embodiment the compounds of the invention can be used as a vaccine adjuvant to boost and/or enhance the action of a vaccine and/or immune agent and/or for immunization; for example antigen, tumour cell lysate, B cell vaccine, T cell vaccine, dendritic cell vaccine boosting the immune response of cytotoxic cells, helper T cells and dendritic cells and for eradication and immunotherapy of immune related diseases and other preventable diseases such as chickenpox, cholera, diphtheria, whooping cough, meningococcal disease, hepatitis, Hemophilus influenzae type B (HIB), measles, mumps , rubella, poliomyelitis and tetanus.
In another embodiment the compounds of the invention can be used to mobilize the progenitor/ stem cells preferably towards the site of injury, ischemia, stroke etc. The compounds can be used as cyto-protective agents, cardioprotective agent, neuro-protective agents and regenerative agents that may help host/patient to repair any organ damage, grow organs like muscle, nerve, blood vessel etc and to increase immune cells number.
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.
An appropriate concentration level in treatment is from 0.01 nM to 1 Molar.
The compounds and compositions of the invention may be administered in combination with a variety of 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 of the present invention can 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 and alclometasone.
In case of treatment of infection and or cancer the compounds of the present invention can 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 compound which could make a delayed type hypersensitivity response.
During vaccination/s and or immunization/s the molecule/s or compounds of the present invention 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. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates post-treatment lymophocyte counts
DETAILED DESCRIPTION OF THE INVENTION
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 "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 an agent/s/compounds and compounds of the invention 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 the species, age and general condition of the subject, mode of administration and the like.
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 of the invention may be administered in combination with a variety of 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" means that one or more hydrogen atoms may be replaced by a group or groups selected from: -D, -F, -Cl, -Br, -I, -CF3, -OH, -0R7, -NH2, -NHR7, -NR7R8, -CN, -N02, -SH, -SR7, -SOR7, -SO2R7, =0, =S, =NOH, =NOR7, -NHOH, -NHOR7, -CHO, 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" 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-thmethylbutyl, 1 ,1 ,3-thmethylbutyl, octyl, 6-methylheptyl, 1 -methylheptyl, 1 ,1 ,3,3-tetramethylbutyl, nonyl, 1 -, 2-, 3-, A-, 5-, 6- or 7-methyl-octyl, 1 -, 2-, 3-, 4- or 5-ethylheptyl, 1 -, 2- or 3-propylhexyl, decyl, 1 -, 2-, 3-, A-, 5-, 6-, 7- or 8-methylnonyl, 1 -, 2-, 3-, A-, 5- or 6-ethyloctyl, 1 -, 2-, 3- or 4-propylheptyl, undecyl, 1 -, 2-, 3-, A-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1 -, 2- , 3-, A-, 5, 6- or 7-ethylnonyl, 1 -, 2-, 3-, 4- or 5-propyloctyl, 1 -, 2- or 3-butylheptyl, 1 -pentylhexyl, dodecyl, 1 -, 2-, 3-, A-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1 -, 2-, 3-, A-, 5-, 6-, 7- or 8-ethyldecyl, 1 -, 2-, 3-, A-, 5- or 6-propylnonyl, 1 -, 2-, 3- or 4-butyloctyl, 1 - or 2-pentylheptyl, and the like.
A used herein, the term "cycloalkyl" 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, θthylcyclohexyl, 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 "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group as defined above.
As used herein, the term "alkenyl" includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined. Examples of such alkenyl groups are vinyl, allyl, 1 -methylvinyl, butenyl, iso- butenyl, 3-methyl-2-butenyl, 1 -pentenyl, cyclopentenyl, 1 -methyl-cyclopentenyl, 1 - hexenyl, 3-hexenyl, cyclohexenyl, 1 -heptenyl, 3-heptenyl, 1 -octenyl, cyclooctenyl, 1 -nonenyl, 2-nonenyl, 3-nonenyl, 1 -decenyl, 3-decenyl, 1 ,3-butadienyl, 1 ,4- pentadienyl, 1 ,3-cyclopentadienyl, 1 ,3-headienyl, 1 ,4-hexadienyl, 1 ,3- cyclohexadienyl, 1 ,4-cyclohexadienyl, 1 ,3 cycloheptadienyl, 1 ,3,5- cycloheptatrienyl and 1 ,3,5,7-cyclooctatetraenyl.
As used herein, the term "alkynyl" includes within its meaning acetylenically unsaturated alkyl groups as previously defined. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1 -butynyl, n- hexynyl, methyl-pentynyl, (C7-C12)alkynyl and (C7-C12)cycloalkynyl.
As used herein, the term "alkylidene" refers to optionally unsaturated divalent alkyl radicals. Examples of such radicals are -CH2-, -CH2CH2-, - CH=CH-, -CH2CH2CH2-, -C(=CH2)CH2-, -CH2CH=CH-, -(CH2)4-, - CH2CH2CH=CH-, -CH2CH=CHCH2-, and -(CH2)r- where r is 5-8. The term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system. Examples of such radicals are groups of the structures
Figure imgf000018_0001
Figure imgf000019_0001
and similar groups wherein any N or O atom is replaced by S or Se.
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 "aralkyl" refers to alkyl groups substituted with one or more aryl groups as previously defined. Examples of such groups are benzyl, 2-phenylethyl and 1 -phenylethyl.
As used herein, the terms "aralkenyl" and "aralkynyl" refer to alkenyl and alkynyl groups respectively, substituted with one or more aryl groups as previously defined. Examples of such groups are styryl, phenylacetylenyl and 2- phenyl-2-butenyl.
As used herein the term "saturated or unsaturated cyclic, bicyclic or fused ring system" refers to a cyclic system of up to 16 carbon atoms, up to 3 of which may be replaced by O, S or N, which ring system may be substituted with one or more of R, -NH2, -NHR, -NR2, -CHO, -C(O)R, -CN, halo, -CF3, , -SR, -S(O)R, - S(O)2R, -CONH2, -CONHR, -CONR2, -NHOH, -NHOL, -N02, =0, =S or - NHNH2; wherein each R are independently as previously defined. Examples of such ring systems are those cyclic alkylidene groups exemplified above and
Figure imgf000020_0001
Figure imgf000020_0002
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.
Configurations which result in unstable heterocyclics are not included within the scope of the definition of "heterocyclic" or "saturated or unsaturated cyclic, bicyclic or fused ring system".
As used herein, the term "alkylheterocyclic" refers to a heterocyclic group as defined above, which is substituted with an alkyl group as defined above.
As used herein, the term "heterocyclic-oxy-alkyl" refers to a group of the formula heterocyclic-O-alkyl, wherein the heterocyclic and alkyl are as defined above.
As used herein, the term "alkoxy" refers to a group of the formula alkyl-O-, wherein the alkyl group is as defined above.
As used herein, the term "aryloxy" refers to a group of the formula aryl-O-, wherein the aryl group is as defined above.
As used herein, the term "alkanoyloxy" refers to a group of the formula alkyl-C(O)O-, wherein the alkyl group is as defined above.
As used herein, the term group (a) refers to five member saturated or unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:
Figure imgf000022_0001
Figure imgf000022_0002
As used herein, the term group (b) refers to five member unsaturated cyclic or heterocyclic ring systems. Examples of such ring systems are:
Figure imgf000022_0003
wherein each Ar and R are independently as previously defined and S and Se can be in the oxidized form S(O), S(O)2 and Se(O) and Se(O)2 respectively.
As used herein, the term group (c) refers to five-six bicyclic member ring systems. Examples of such ring systems are:
Figure imgf000022_0004
wherein each R, R1 and Q1 are independently as previously defined and S and Se can be in the oxidized form such as S(O), S(O)2 and Se(O) and Se(O)2 respectively. As used herein, the term group (d) refers to six-six hetero-bicyclic member ring system. Examples of such ring systems are:
Figure imgf000023_0001
wherein each R, R1 and Q are independently as previously defined.
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).
Representative compounds in accordance with the invention are described in the following Tables. Table 1 :
Compounds of formula
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0002
and variations thereof.
G1 and G2 represent alternative groups for G
Table 2: Compounds of Formula
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0003
and variations thereof.
Table 3:
Compounds of formula
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0003
and variations thereof.
Table 4:
Compounds of formula
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
and variations thereof.
Table 5:
Compounds of formula
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000036_0001
and variations thereof.
Table 6:
Figure imgf000036_0002
Compounds of formula
Figure imgf000036_0003
Figure imgf000037_0001
and variations thereof. Table 7:
Figure imgf000038_0001
Compound of formula
X = O, N, S
Figure imgf000038_0002
Figure imgf000039_0003
and variations thereof.
Table 8:
Compound of formula
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000040_0002
And variations thereof. s represents a ring subsituent.
Table 9: Compound of formula
Figure imgf000040_0001
X , Y and G are as defined for formula (I).
Figure imgf000040_0003
Figure imgf000041_0001
And variations thereof. s represents a ring substituent. Methods of Synthesis:
The examples (28) to (30) were prepared by the use of following procedure as in Scheme - 1
Figure imgf000042_0001
Scheme - 1 (i a) THF, stirring; (i b) MnO2 /Dioxane reflux; (ii) HBr / AcOH; (iii) Pd(PPh3)2, RB(OH)2, NaHCO3 /Dioxane, H2O, 80 eC - reflux; (iv) K2CO3.
The examples (36) to (52) were prepared by the use of following procedure as in Scheme - 2 (a - b).
Figure imgf000042_0002
R = substituent R' = substituent X = OPr, NHBoc
Scheme - 2a (i) Na2CO3, NH2OH. HCI / EtOH or DIEA, NH2OKHCI / EtOH; (ii a) EDC / DMF; (ii b) TBAF / DMF.
Figure imgf000043_0001
R = substituent
Figure imgf000043_0002
R = R' = substituent
Scheme - 2b (i) BCI3/ CH2CI2 or AICI3/ CH2CI2; (ii) CI2PdPPh3/Cul, DMF/DIEA; (iii) TFA / CH2CI2.
The other compounds of invention including intermediates were prepared by using various known synthesis methods like reductive amination etc. 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). Some important Lit ref are Kim S et al, Synthesis, 2006, 5, 753 - 755. EXAMPLES
The following Examples describe the preparation of compounds according to the invention and are intended to illustrate the invention. The Examples are not be construed as limiting in any way the scope of the present invention. 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.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Example 1 5-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2-carboxylic acid
Step A: Step A: 4-Hydroxy-3-iodobenzonithle: To a solution of A- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H2O (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 H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-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 Cu2O (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 H2O (5 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by flash column chromatography (FCC) (SiO2, CH2CI2 and EtOAc, 9 : 1 ) to give the title compound (0.23 g; 67%) as a colourless solid. 1H- 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 N,N-diisopropylethylamine (DIPEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at ~ 71 0C. The solvents were removed in vacuo and the residue was treated with H2O (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 MgSO4, 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- yl)methanol: 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 ~ 4O0C 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 0C, then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2CI2) to give the title compound (0.13 g; 34%), as greyish solid. 1H-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 MnO2 (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. 1H-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 + H2O).
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 AgNO3 (0.06 g; 0.14 mmol) in EtOH (0.2 ml) H2O (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 0C and cooled to room temperature and filtered. The insoluble material was washed with H2O (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 MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO2, CH2CI2/ acetic acid (AcOH) 98/2) to give the title compound (0.00012 g; 12.8 %), as a creamy solid. 1H-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 MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (SiO2, EtOAc) to give the title compound (0.06 g; 68%), as creamy syrup. 1H-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 (SiO2, 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 9m, 6H).
Example 3 N-(1H-Tetrazol-5-yl)methyl-4-octylbenzylamine
Step A: 4-n-Octylbenzaldehyde: A mixture of n-octylbenzene (1 .2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid (TFA) was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO3 and extracted with diethyl ether (Et2O) (3 x 5ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67 %). 1H-NMR (CDCI3) 9.96 (s, 1 H); 7.77 (d, 2H, J = 8.1 Hz); 7.31 (d, 2H, J = 8.1 Hz); 2.67 (t, 2H, J = 7.9 Hz); 1 .6 (m, 2H); 1 .26 (m, 1 OH); 0.86 (t, 3H, J = 6.9 Hz);
Step B: 2-(4-Octylbenzylamino)acetonitrile\ T a suspension of the product of Step A (0.17 g; 0.78 mmol) and aminoacetonitrile bisulphate (0.18 g; 1.17 mmol) and NaBH(OAc)3 in 1 ,2 dichloroethane (3 ml), DIPEA (0.2 ml; 1.17 mmol) was added at room temperature followed by AcOH (0.045 ml; 0.78 mmol). The resulting mixture was stirred over a weekend at room temperature under N2 and quenched by an addition of 1 M NaOH (0.5 ml). This was diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was diluted to 3 ml with anhydrous MeOH and to it NaBH4 (0.1 g; 2.6 mmol) was added portion wise at room temperature with stirring. After stirring overnight, the mixture was evaporated to dryness and the residue was diluted to 15 ml with Et2O, washed with 1 N NaOH, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 6:4) to give the title compound (0.07 g; 28%) as a colourless syrup. 1H-NMR (CDCI3) 7.23 (d, 2H, J = 8.01 Hz); 7.14 (d, 2H, J = 8.01 Hz); 3.88 (s, 2H); 3.55 (s, 2H); 2.58 (t, 2H, J = 7.94 Hz); 1 .6 (m, 3H); 1.27 (m, 1 OH); 0.86 (t, 3H, J = 6.93 Hz).
Step C: N-(1H-Tetrazol-5-yl)methyl-4-n-octylbenzylamine: A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me3SiN3 (0.36 ml; 2.71 mmol) and 1 M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 75 + 50C for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et2O and dried to give a title compound (0.069 g; 84%) as colourless solid. 1 H-NMR (CD3OD) 7.32 (d, 2H, J = 8.0 Hz); 7.21 (d, 2H, J = 8.0 Hz); 4.72 (s, CD3OH); 4.34 (s, 2H); 4.16 (s, 2H); 2.59 (t, 2H, J = 7.76 Hz); 1 .57 (t, 2H, J = 7.19 Hz); 1.25 (m, 10H); 0.84 (t, 3H, J = 6.93 Hz); Example 4 N-((1H-Tetrazol-5-yl)methyl)-4-n-octylaniline
Step A: 2-(4-Octylphenylamino)acetonitrile: A mixture of 4-n-octylaniline (0.21 g; 1 mmol), BrCH2CN (0.156 mmol; 1.3 mmol) and K2CO3 (0.28 g; 2 mmol) in anhydrous CH3CN (3 ml) was stirred overnight at -60 0C under N2 , then concentrated under reduced pressure. The residue was partitioned between CH2CI2 (20 ml) and H2O (10 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from hexane to give the title compound (0.18 g; 74%) as creamy solid. 1H-NMR (CDCI3) 7.06 (d, 2H, J = 8.48 Hz); 6.63 (d, 2H, J = 8.48 Hz); 4.06 (d, 2H, J = 5.75 Hz); 3.83 (broad m, 1 H); 2.51 (t, 2H, J = 7.92 Hz); 1.55 (m, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J = 6.87 Hz).
Step B: N-((1H-Tetrazol-5-yl)methyl)-4-n-octylaniline: When the product of Step A was substituted for 2-(4-octylbenzylamino)acetonitrile in Example 3, Step C, the identical process afforded the title compound in 77% yield, as creamy solid. 1 H-NMR (CDCI3) 6.94 (d, 2H1 J = 8.37 Hz); 6.61 (broad s, 2H); 6.49 (d, 2H, J = 8.37 Hz); 4.68 (m, 2H); 2.44 (t, 2H, J = 7.94 Hz); 1 .49 (t, 2H, J = 7.55 Hz); 1.24 (m, 10H); 0.85 (t, 3H, J = 6.95 Hz).
Example 5 2-(4-Octylphenylamino)propane-1,3-diol
Step A: 2,2-Dimethyl-N-(4-octylphenyl)-1,3-dioxan-5-amine: To a mixture of 4-n-octylaniline (0.205 g; 1 mmol) and 2,2-dimethyl-1 ,3-dioxan-5-one (Helvetica Chimica Acta, 2003, 86, 2467; 0.13 g; 1 mmol) and NaBH(OAc)3 in 1 ,2 dichloroethane (3.5 ml), AcOH (0.06 ml; 1 mmol) was added and the mixture was stirred for 2h at room temperature under N2, diluted to 20 ml with Et2O and washed with 1 N NaOH, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified crystallization from hexane to give the title compound (0.2 g; 63%) as a colourless solid. 1 H-NMR (CDCI3) 6.97 (d, 2H, J = 8.4 Hz); 6.54 (d, 2H, J = 8.4 Hz); 4.1 (dd, broad s, 3H, J = 4.2, 11 .9 Hz); 3.74 (dd, 2H, J = 4.2, 1 1.9 Hz); 3.4 (m, 1 H); 2.47 (t, 2H, J = 7.91 Hz); 1 .55 (m, 2H + H2O); 1 .46 (s, 3H); 1.43 (s,3H); 1 .25 (m, 10H); 0.86 (m, 3H). Step B: 2-(4-octylphenylamino)propane-1,3-diol: To a solution of the product of Step A (0.1 g; 0.31 mmol) in MeOH (1 ml) Me3SiCI (0.5 ml) was added at room temperature. After stirring for 1 h, the mixture was evaporated to dryness under reduced pressure to give a hydrochloride salt of the title compound (0.1 g; 100 %) as a colourless solid. 1H-NMR (CDCI3) 10.66 (bs, 2H); 7.53 (d, 2H, J = 7.98 Hz); 7.18 (d, 2H, J = 7.98 Hz); 4.82 (broad s, 2H); 3.98 (broad m, 4H); 3.51 (broad m, 1 H); 2.58 (t, 2H, J = 7.68 Hz); 1 .56 (m, 2H); 1 .43 (s, 3H); 1.27 (m, 10H); 0.86 (t, 3H, J = 6.96 Hz).
Example 6 2-((4-n-Octylbenzylamino)methyl)propane-1,3-diol
Step A: 4-n-Octylbenzyl alcohol: NaBH4 (0.04 g; 1 .06 mmol) was added portion wise to a solution of the product of Example 3, Step A in MeOH (5 ml) at room temperature, with vigorous stirring. After 30 min of stirring, the mixture was evaporated to dryness, diluted to 10 ml with Et2O and washed with 1 N NaOH, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.082 g; 100%), as colourless syrup, which was used in next step without further purification. 1 H-NMR (CDCI3) 7.26 (d, 2H, J = 8 Hz); 7.15 (d, 2H, J = 8 Hz); 4.64 (s, 2H); 2.58 (t, 2H, J = 7.9 Hz); 1 .56 (m, 3H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 6.9 Hz).
Step B: 4-n-octylbenzyl bromide: PBr3 (0.23 ml) was added drop wise to a stirred solution of the product of Step A (0.082 g; 0.37 mmol) in Et2O (2 ml) at - 150C. The mixture was allowed to warm up to room temperature and the stirring was continued for 4 h. This was poured onto ice (5 g) and the product was extracted with fresh Et2O (2 x 10 ml). The combined extracts were washed with 5%NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.04 g; 40%) as a colourless solid. 1H- NMR (CDCI3) 7.28 (d, 2H, J = 8 Hz); 7.13 (d, 2H, J = 8 Hz); 4.48 (s, 2H); 2.57 (t, 2H, J = 7.9 Hz); 1.57 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Step C: 4-n-Octylbenzylamine: To a solution of the product of Step B (0.13 g; 0.459 mmol) in anhydrous hexamethylenedisilazane (HMDSA) 1 M NaHMDSA in THF was added at room temperature under N2 with stirring. After stirring overnight at room temperature solvents were removed under reduced pressure and the residue was diluted to 5 ml with MeOH and 1 drop of concentrated HCI was added. This was evaporated under reduced pressure, diluted to 15 ml with Et2O and washed with 1 N NaOH, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.1 g; 100%), as colourless oil, which was used in the next step without further purification. 1 H-NMR (CDCI3) 7.2 (d, 2H, J = 8 Hz); 7.13 (d, 2H, J = 8 Hz); 3.82 (s, 2H); 2.57 (t, 2H, J = 7.9 Hz); 1.58 (m, 2H); 1 .41 (s, 2H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Step D: (2,2-Dimethyl- 1,3-dioxan-5-yl)-N-(4-octylbenzyl)methylamine: When the product of Step C was substituted for 4-n-octylaniline in Example 5, Step A, the identical process afforded the title compound in 86% yield, as a colourless syrup. 1H-NMR (CDCI3) 7.23 (d, 2H, J = 8 Hz); 7.1 1 (d, 2H, J = 8 Hz); 3.96 (dd, 2H, J = 5.57, 1 1.73 Hz); 1 1.73 Hz); 3.83 (s, 2H); 3.75 (dd, 2H, J = 5.57, 2.69 (m, 1 H); 2.56 (t, 2H, J = 7.88 Hz); 1 .81 (broad s, 1 H + H2O); 1 .4 (m, 5H); 1.25 (m, 13H); 0.86 (t, 3H, J = 6.96 Hz).
Step E: 2-((4-n-Octylbenzylamino)methyl)propane-1,3-dioϊ. A solution of the product of Step D (0.6 g; 0.13 mmol) in 60% trifluoroacetic acid (TFA) in CH2CI2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with MeOH and evaporated to dryness under reduced pressure. The residue was dissolved in iso-propanol (iPrOH) (2 ml) and one drop of concentrated HCI was added. This was evaporated under reduced pressure and treated with anhydrous Et2O. The precipitate formed was filtered off, dried in vacuo for 1 h to give a hydrochloride salt of the title compound (0.04 g; 85%), as a colourless solid. 1H-NMR (D2O) 7.32 (d, 2H, J = 7.56 Hz); 7.21 (d, 2H, J = 7.56 Hz); 4.2 (s, 2H); 4.66 (DHO); 3.69 (s, 4H); 3.36 (s, 2H); 2.52 (t, 2H, J = 7.47 Hz); 1.49 (s, 2H); 1.16 (m, 10H); 0.74 (m, 3H).
Example 7 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-diol
Step A: (2,2-dimethyl-1,3-dioxan-5-yl)-N-methyl-N-(4-octylbenzyl)methyl amine: When the product of Example 6, Step D is substituted for 4-n-octylaniline and 30% aqueous HCHO is substituted for 2,2-dimethyl-1 ,3-dioxan-5-one in Example 3, Step A, the identical process afforded the title compound in 100% yield, as a colourless syrup. 1 H-NMR (CDCI3) 7.2 (d, 2H, J = 7.75 Hz); 7.1 1 (d, 2H, J = 7.75 Hz); 3.83 (s, 2H); 3.94 (m, 4H); 3.64 (s, 2H); 2.83 (m, 1 H); 2.56 (d, 2H, J = 7.3 Hz); 2.29 (s, 3H); 1 .58 (m, 2H + H2O); 1 .25 - 1.42 (m, 18H); 0.86 (m, 3H).
Step B: 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1,3-dioϊ. When the product of Step A is substituted for (2,2-dimethyl-1 ,3-dioxan-5-yl)-N-(4- octylbenzyl) methylamine in Example 6, Step E, , the identical process afforded the title compound in 79% yield, as a glassy solid. 1H-NMR (D2O) 7.3 (d, 2H, J = 7.8 Hz); 6.96 (d, 2H, J = 7.8 Hz); 4.66 (DHO); 4.24 (s, 2H); 3.73 (m, 4H); 3.32 (m, 1 H); 2.7 (s, 3H); 2.3 (t, 2H, J = 7.63 Hz); 1.36 (m, 2H); 1 .15 (s, 2H); 1 .15 (m, 1 OH); 0.73 (t, 3H, J = 6.73 Hz).
Example 8 4,4-Bis(hydroxymethyl)-1-(4-octylphenyl)imidazolidin-2-one
Step A: tert-Butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan- 5-ylcarbamate: To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5- formyl-2,2-dimethyl-1 ,3-dioxan-5-ylcarbamate (Ooii et al, J.Org.Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc)3 (0.3g; 1 .4 mmol) in 1 ,2-dichloroethane (3.5 ml) AcOH (.06 ml; 1 mmol) was added at room temperature with stirring under N2. After stirring for 2 h, the mixture was diluted to 20 ml with Et2O, washed with 1 .M NaOH (2 x 5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexane (5 ml) and kept in the freezer (-180C) overnight. The crystals formed were filtered off, washed with small volume of hexane and dried to give the title compound (0.32g; 71 %), as colourless crystals. 1H-NMR (CDCI3) 6.96 (d, 2H, J = 8.4 Hz); 6.58(d, 2H, J = 8.4 Hz); 4.84 (broad S, 1 H); 4.01 (d, 2H, J = 11 .9); 3.85 (broad S, 1 H); 3.8 (d, 2H, J = 1 1.9 Hz); 3.44 (s, 2H); 2.46 (t, 2H, J = 7.9 Hz); 1.5(171, 2H); 1 .45(s, 3H); 1.43 (s, 9H); 1 .42 (s, 3H); 1.26 (m, 1 OH); 0.86 (t, 2H, J = 6.95 Hz).
Step B: 4,4-(2,2-Dimethyl- 1,3-dioxanyl)-1-(4-octylphenyl)imidazolidin-2- one: A solution of the product of Step A (0.17 g; 0.38 mmol) and 60% NaH in mineral oil (0.043 g; 1 .14 mmol) in anhydrous DMF (4 ml) was stirred overnight at -550C under N2. After removal of solvent in vacuo, the residue was diluted to 15 ml with Et2O, washed with 10% citric acid, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 8:2) to give the title compound (0.06 g; 42%) as a colourless solid and starting material (0.1 g; 58 %). 1H-NMR (CDCI3) 7.41 (d, 2H, J = 8.58 Hz); 7.12 (d, 2H, J = 8.58 Hz); 5.27 (broad S, 1 H); 3.84 (d, 2H, J = 11 .3 Hz); 3.78 (d, 2H, J = 1 1.3 Hz); 3.68 (s, 2H); 2.55 (t, 2H, J = 7.83 Hz); 1 .56 (m, 2H); 1.28 (m, 10H); 0.84 (t, 3H, J = 6.76 Hz).
Step C: 4,4-Bis(hydroxymethyl)-1-(4-octylphenyl)imidazolidin-2-one: When the product of Step B is substituted for (2,2-dimethyl-1 ,3-dioxan-5-yl)-N-(4- octylbenzyl)methylamine in Example 6, Step E, the identical process afforded the title compound in 74% yield, as a colourless solid, after purification by FCC (SiO2, CH2CI2 saturated with concentrated NH4OH/MeOH; 98:2). 1H-NMR (CDCI3) 7.30 (d, 2H, J = 8.49 Hz); 7.02 (d, 2H, J = 8.49 Hz); 6.53 (s, 1 H); 4.65 (broad S, 2H); 3.48 -3.62 (m, 6H); 2.47 (t, 2H, J = 7.94 Hz); 1 .51 (m, 2H); 1 .25 (m, 10H); 0.87 (t, 3H, J = 6.94 Hz).
Example 9 2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid
Step A: 4-n-Octyliodobenzene: To a suspension of n-octylbenzene (1 g; 5.2 mmol) and CF3SO3Ag (1 .35 g; 5.2 mmol) in anhydrous CH2CI2 (15 ml) I2 was added at 0 5C. The resulting mixture was allowed to warm up to room temperature and stirred for additional 1 h, then filtered through a pad of Celite, washed with fresh CH2CI2 (2 x 15 ml) and combined filtrates washed with 5% Na2SO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title product and 2-iodo isomer (1.64 g; 100%), as creamy oil, which was used in the next step without further purification. 1H-NMR (CDCI3) 7.7 - 7.8 (m, 0.3H); 7.56 (d, 1.7 H, J = 8.3 Hz); 7.29 -7.16 (m, 0.6H); 6.9 (d, 1 .4H, J = 8.3 Hz); 6.85 - 6.82 (m, 0.3H); 2.68 (t, 0.6, J = 8.01 Hz); 2.52 (t, 1.4H, J = 7.89 Hz); 1.56 (m, 2H); 1.25 (m, 10H); 0.86 (m, 3H).
Step B: tert-Butyl 4-(benzoyloxy)piperazine-1-carboxylate: To a suspension of benzoyl peroxide + 15% H2O (1.47 g; 4.55 mmol) and K2HPO4 (1.19 g; 6.8 mmol) in DMF (1 1 .36 ml) N-BOC piperazine (Sengmany et al, Tetrahedron, 2007, 63, 3672; 1 g; 5.4 mmol) was added and the mixture was stirred for 1 h at room temperature. To it, H2O (20 ml) was added and the resulting mixture was vigorously stirred until homogenous. This was extracted with EtOAc (15 ml). The organic phase was washed with H2O and combined aqueous phase was extracted with fresh EtOAc (3 x 10 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title product (0.9 g; 65%), as a colourless solid. 1H-NMR (CDCI3) 8 - 7.96 (m, 2H); 7.59 - 7.53 (m, 1 H); 7.45 - 7.38 (m, 2H); 4.01 (m, 2H); 3.41 - 3.2 (m, 4H); 2.9 (m, 2H); 1 .46 (s, 9H).
Step C: tert-Butyl 4-(4-octylphenyl)piperazine-1-carboxylate: To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCI in THF (0.56 ml; 1.1 1 mmol) was added at -15 0C under N2, followed 1.27 M solution of anhydrous ZnCI2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at O0C. The resulting mixture was stirred for 30 min on ice-bath under N2 and the solution of the product of Step B (0.16 g; 0.51 mmol) and CuCI2 (2.5 mol%) in anhydrous THF (10 ml) was added. The resulting mixture was allowed to warm up to room temperature and stirred for additional 10 min. This was diluted to 20 ml with Et2O and washed with 5% NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1 ) to give the title compound (0.06 g; 31%), as a creamy syrup. 1 H-NMR (CDCI3) 7.07 (d, 2H, J = 8.6 Hz); 6.84 (d, 2H, J = 8.6 Hz); 3.55 (t, 4H, J = 5 Hz); 3.06 (t, 4H, J = 5 Hz); 2.51 (t, 2H, J = 7.94 Hz); 1 .55 - 1.38 (m, 1 1 H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 6.93 Hz).
Step D: 1-(4-n-Octylphenyl)piperazine\ A solution of the product of Step C (0.06 g; 0.16 mmol) in 60% TFA in CH2CI2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with EtOH and evaporated to dryness under reduced pressure and kept in vacuo for 1 h, to give a TFA salt of the title compound (0.07 g; 100%). 1H-NMR (CDCI3) 9.5 (broad s, 2H); 7.29 (m, 4H); 3.8 - 3.16 (m, 8H); 2.6 (t, 2H, J = 8 Hz); 1 .58 (m, 2H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 6.9 Hz).
Step E: tert-Butyl 2-(4-(4-octylphenyl)piperazin-1-yl)acetate: To a solution of the product of Step D (0.04 g, 0.146 mmol) and tert-butyl bromoacetate (0.026 ml; 0.16 mmol) in CH2CI2 (1 ml) DIPEA (0.052 ml; 0.32 mmol) was added at room temperature under N2. The mixture was stirred overnight at room temperature, diluted to 5 ml with Et2O and washed with 0.1 N HCI, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 7:3) to give the title compound (0.05 g; 88%), as a colourless heavy syrup. 1H-NMR (CDCI3) 7.05 (d, 2 H, J = 8.6 Hz); 6.83 (d, 2H, J = 8.6 Hz); 3.32 - 3.15 (m, 6H); 2.73 (m, 4H); 2.5 (t, 2H, J = 7.9 Hz); 1.55 (m, 2H); 1.46 (s, 9H); 1.26 (m, 1 OH); 0.86 (m, 3H).
Step F: 2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid: A solution of the product of Step E (0.05 g; 0.129 mmol) in 60% TFA in CH2CI2 (5 ml) was refluxed for 2 h, cooled to room temperature then diluted to 7 ml with EtOH. The resulting mixture was evaporated to dryness under reduced pressure kept in vacuo for 1 h. The residue was treated dissolved in EtOH (2 ml) and 3 drops of concentrated NH4OH was added. The resulting mixture was partially concentrated under reduced pressure and the precipitate, formed was filtered off, washed with Et2O and dried to give the titled compound (0.02 g; 47%) as colourless solid. . 1H-NMR ( CD3OD + CDCI3) 7.07 (d, 2H, J = 8.6 Hz); 6.86 (d, 2H, J = 8.6 Hz); 4.63 (s, CD3OH); 3.58 (s, 2H); 3.38 (m, 8H); 2.49 (t, 2H, J = 7.8 Hz); 1.53 (m, 2H); 1.24 (m, 10H); 0.83 (m, 3H).
Example 10 2-(4-Octylphenethyl)propane-1,2,3-triol
Step A: 1-Ethynyl-4-octylbenzene\ A mixture of Example 3, Step A (0.1 g; 0.46 mmol), dimethyl(1 -diazo-2-oxoprpyl)phosphonate ( 0.1 1 g, 0.57 mmol) and anhydrous K2CO3 (0.14 g, 1 .01 mmol) in dry MeOH (5 ml) was stirred for 8 h under N2. After removing solvent under reduced pressure, the residue was diluted to 15 ml with Et2O and washed with H2O (2 x 10 ml) and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.05 g; 51 %) as colourless oil. 1 H-NMR (CDCI3) 7.38 (d, 2H, J = 8.1 Hz); 7.1 1 (d, 2H, J = 8.1 Hz); 3.0 (s, 1 H); 2.58 (t, 2H, J = 7.8Hz); 1 .58 (t, 3H, J = 6.96 Hz); 1 .27 (m, 10H); 0.86 (t, 3H, J = 6.96 Hz).
Step B: 2,2-Dimethyl-5-((4-octylphenyl)ethynyl)-1,3-dioxan-5-ol: To a solution of the product of Step A (0.05 g; 0.233 mmol) in anhydrous THF (2 ml) 2 M n-butyllithium in cylohexane (0.13 ml; 0.26 mmol) was added drop wise at - 150C under N2. After stirring for 15 min at -150C, 2,2-dimethyl-1 ,3-dioxan-5-one (0.034 g; 0.26 mmol) was added and the resulting mixture was allowed to warm up to room temperature, diluted to 15 ml with Et2O and washed with H2O (2 x 10 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, hexane/ EtOAc 95 ; 5) to give the title compound (0.03 g; 63%) as colourless oil. 1H-NMR (CDCI3) 7.33 (d, 2H, J = 8.09 Hz); 7.09 (d, 2H, J = 8.09 Hz); 4.1 1 (d, 2H, J = 1 1 .76 Hz); 3.83 (d, 2H, J = 1 1.76 Hz); 3.99 (s, 1 H); 2.57 (t, 2H, J = 7.88Hz); 1.56 (t, 3H, J = 6.94 Hz); 1 .49 (s, 3H); 1 .46 (s, 3H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 6.96 Hz).
Step C: 2-(4-Octylphenethyl)propane-1,2,3-triol: A mixture of the product of Step B (0.03 g; 0.087 mmol) and 10% Pd/C (0.05 g) in 5% TFA in EtOH (10 ml) was stirred for 1 h under H2 (balloon) at room temperature, then filtered through a pad of Celite , washed with CH2CI2 (2 x 10 ml). To combined filtrates were evaporated to dryness under reduced pressure and dried in vacuo for 1 h to give title compound (0.027 g; 99%) as a colourless solid. 1H-NMR (CDCI3) 7.05 (s, 4H); 3.66 (broad m, 7H); 2.61 (m, 2H); 2.51 (t, 2H, J = 7.92 Hz); 1 .73 (m 2H); 1.55 (t, 3H, J = 6.93 Hz); 1.26 (m, 10H); 0.87 (t, 3H, J = 6.93 Hz).
Example 11 3-(3-(4-n-Octylphenyl)ureido)propanoic acid
Step A: Ethyl 3-(3-(4-octylphenyl)ureido)propanoate\ To 4-n-octylaniline (0.1 g; 0.49 mmol) ethyl 3-isocyanatopropionate (0.08 g; 0.54 mmol) was added at room temperature. The resulting mixture was diluted to 1 ml with CH2CI2, refluxed for 30 min and evaporated to dryness. The residue was treated with Et2O (5 ml) and the solid formed was filtered off and dried to give the title compound (0.15 g; 87%), as colourless crystals. 1 H-NMR (CDCI3) 7.22 - 7.07 (m, 4H); 6.34 (broad s, 1 H); 5.34 (m, 1 H); 4.15 - 4.07 (m, 2H); 3.54 - 3.46 (m, 2H); 2.73 (m, 4H); 2.57 - 2.51 (m, 4H); 1 .58 (m, 2H); 1.27 -1 .19 (m, 13H); 0.86 (m, 3H).
Step B: 3-(3-(4-n-Octylphenyl)ureido)propanoic acid: To a solution of the product of Step A (0.05 g; 0.143 mmol) in dioxane (1 ml) 2N KOH (0.36 ml; 0.72 mmol) was added and the mixture was refluxed for 15 min, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was diluted to 2 ml with H2O and filtered. The filtrate was acidified to pH ~4 with citric acid. The solid formed was filtered off, washed with H2O (3 x 2 ml), dried in vacuo to give the title compound (0.03 g; 65%), as a colourless solid. 1H-NMR (CD3OD + CDCI3) 7.16 (d, 2H, J = 8.4Hz); 7.0 (d, 2H, J = 8.4Hz); 4.21 (s, CD3OH ); 3.4 (t, 2H, J = 6.7 Hz); 2.73 (m, 4H); 2.5 - 2.44 (m, 4H); 1 .5 (m, 2H); 1 .2 (m, 10H); 0.81 (m, 3H).
Example 12 3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid
Step A: tert-Butyl 4-n-octylphenyl(methyl)carbamate\ A mixture of A- noctylaniline (0.09 g; 0.44 mmol) and di-tert-butyl dicarbonate (0.1 g; 0.46 mmol) and a few drops of triethylamine was stirred at -5O0C for 1 h under N2, cooled to room temperature and kept in vacuo for 30 min. The residue was dissolved in anhydrous DMF (2 ml) and %60 NaH in mineral oil (0.02 g: 0.47 mmol) was added to it, followed by MeI (0.03 ml; 0.47 mmol), after stirring for 30 min under N2. The resulting mixture was stirred for 3 h at room temperature and solvent was removed in vacuo. The residue was diluted to 15 ml with Et2O and washed with 5% Na2SO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.14 g; 100%), as a creamy solid. 1H-NMR (CDCI3) 7.14 - 6.99 (m, 4H); 3.22 (s, 3H); 2.55 (m, 2H); 1 .56 (m, 2H); 1.43 (s, 9H); 1.26 (m, 10H); 0.86 (m, 3H).
Step B: N-Methyl-4-n-octylaniline: A solution of the product of Step A (0.14 g; 0.44 mmol) in 60% TFA in CH2CI2 (5 ml) was stirred for 30 min at room temperature and the mixture was diluted to 5 ml with EtOH and a few drops of concentrated HCI was added. This was evaporated to dryness under reduced pressure, kept in vacuo for 1 h and the residue was partitioned between saturated NaHCO3 (5 ml) and Et2O (15 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1 ) to give the title compound (0.055 g; 57%), as a creamy solid. 1H-NMR (CDCI3) 7.01 (d, 2H, J = 8.2 Hz); 6.55 (d, 2H, J = 8.2 Hz); 3.55 (broad S, 1 H); 2.81 (s, 3H); 2.49 (t, 2H, J = 7.9 Hz); 1.56 (m, 2H); 1 .28 (m, 10H); 0.88 (t, 3H, J = 6.8 Hz).
Step C: Ethyl 3-(3-methyl-3-(4-octylphenyl)ureido)propanoate: When the product of Step B is substituted for 4-n-octylaniline in Example 1 1 , Step A, , the identical process afforded the title compound in 99% yield, as a colourless solid . 1H-NMR (CDCI3) 7.15 (d, 2H, J = 8.2 Hz); 7.05 (d, 2H, J = 8.2 Hz); 4.77 (m, 1 H); 4.03 (q, 2H, J = 7.14 Hz); 3.54 (m, 2H); 3.37 (qr, 2H, J = 6.1 Hz); 3.18 (s, 3H); 2.55 (t, 2H, J = 7.5 Hz); 2.44 (t, 2H, J = 6.1 Hz); 1 .57 (m, 2H); 1 .25 (m, 10H); 1.13 (t, 3H, J = 7.14 Hz); 0.83 (t, 3H, J = 6.9 Hz).
Step D: 3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid: When the product of Step C is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. 1H-NMR (CDCI3) 7.19 (d, 2H, J = 8.3 Hz); 7.09 (d, 2H, J = 8.3 Hz); 4.83 (m, 1 H); 3.54 (m, 2H); 3.4 (m, 2H); 3.22 (s, 3H); 2.6 - 2.5 (m, 4H); 1 .59 (no, 2H); 1 .27 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Example 13 3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1-yl)propanoic acid
Step A: Ethyl 3-(3-(4-octylphenyl)-2-oxoimidazolidin-1-yl)propanoate: To a solution of the product of Example 1 1 , Step A (0.05 g; 0.143 mmol) in anhydrous DMF (2 ml) 60% NaH in mineral oil (0.014 g; 0.344 mmol) was added at room temperature. After stirring for 1 h, to it 1 ,2-dibromoethane (0.172 ml; 0.2 mmol) was added. This was stirred at -5O0C for 1 h under N2, cooled to room and solvents were removed in vacuo. The residue was diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9.5:0.5) to give the title compound (0.02 g; 37%) as a colourless solid. 1H-NMR (CDCI3) 7.4 (d, 2H, J = 8.5 Hz); 7.1 (d, 2H, J = 8.5 Hz); 4.13 (q, 2H, J = 7.1 Hz); 3.76 (m, 2H); 3.57 (t, 2H, J = 6.7 Hz); 3.5 (m, 2H); 2.6 (t, 2H, J = 6.7 Hz); 2.53 (t, 2H, J = 7.9 Hz); 1.55 (m, 2H); 1.24 (m, 13H); 0.85 (t, 3H, J = 6.9 Hz).
Step B: 3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1-yl)propanoic acid: When the product of Step A is substituted for ethyl 3-(3-(4- octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 33% yield, as a colourless solid. 1 H-NMR (CDCI3) 7.39 (d, 2H, J = 8.4 Hz); 7.1 1 (d, 2H, J = 8.4 Hz); 3.78 (t, 2H, J = 7.3 Hz); 3.6 - 3.4 (m, 4H); 3.22 (s, 3H); 2.66 (t, 2H, J = 6.5 Hz); 2.53 (t, 2H, J = 7.7 Hz); 1.55 (m, 2H); 1 .25 (m, 10H); 0.85 (t, 3H, J = 6.9 Hz). Example 14 2-(3-(4-Octylbenzyl)ureido)acetic acid
Step A: Ethyl 2-(3-(4-octylbenzyl)ureido)acetate: When the product of Example 6, Step C was substituted for 4-n-octylaniline and ethyl 2- isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 1 1 , Step A, the identical process afforded the title compound in 75 % yield, as a colourless solid. 1H-NMR (CDCI3) 7.18 (d, 2H, J = 8 Hz); 7.1 1 (d, 2H, J = 8 Hz); 4.86 (m, 1 H); 4.78 (m, 1 H); 4.32 (d, 2H, J = 5.6 Hz); 4.16 (q, 2H, J = 7.1 Hz); 3.97 (d, 2H, J = 5.3 Hz); 2.56 (t, 2H, J = 8 Hz); 1.56 (m, 2H); 1 .25 (m, 13H); 0.86 (t, 3H, J = 6.9 Hz).
Step B: 2-(3-(4-Octylbenzyl)ureido)acetic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 87% yield, as a colourless solid. 1H-NMR (CDCI3 + CD3OD) 7.15 (d, 2H, J = 8 Hz); 7.07 (d, 2H, J = 8 Hz); 4.63 (CD3OH); 4.26 (s, 2H); 3.86 (s, 2H); 2.52 (t, 2H, J = 7.8 Hz); 1.54 (m, 2H); 1 .22 (m, 10H); 0.83 (t, 3H, J = 7 Hz).
Example 15 2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1-yl)acetic acid
Step A: tert-Butyl 2-(2-oxoimidazolidin-1-yl)acetate: To a solution of imidazolidin-2-one (0.2 g; 2.3 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.18 g; 4.6 mmol) was added at room temperature, under N2. After stirring for 1 h, tert-butyl 2-bromoacetate (0.35 ml; 2.3 mmol) was added. The resulting mixture was stirred for additional 2h and solvents were removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, EtOAc) to give the title compound (0.12 g; 26%) as a colourless solid. 1 H-NMR (CDCI3) 4.61 (broad s, 1 H); 3.83 (s, 2H); 3.58 - 3.41 (m, 4H); 1.44 (s, 9H).
Step B: tert-Butyl 2-(3-(4-octylbenzyl)-2-oxoimidazolidin-1-yl)acetate\ To a solution of the product of Step A (0.03 g; 0.15 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.006 g; 0.15 mmol) was added at room temperature, under N2. After stirring for 1 h, the product of Example 4, Step B (0.042 g; 0.15 mmol) was added. The resulting mixture was stirred for additional 4h and solvents were removed in vacuo. The residue was diluted to 10 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.01 g; 16%) as a colourless solid. 1H- NMR (CDCI3) 7.16 (d, 2H, J = 8.1 Hz); 7.1 1 (d, 3H, J = 8.1 Hz); 4.34 (s, 2H); 3.95 (s, 2H); 3.4 (m, 2H); 3.21 (m, 2H); 2.56 (t, 3H, J = 7.9 Hz); 1.65 (m, 2H); 1.43 (s, 9H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Step C: 2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1-yl)acetic acid: When the product of Step B was substituted for tert-butyl 2-(4-(4-octylphenyl)piperazin-1 - yl)acetate in Example 9, Step F, the identical process afforded the title compound in 46% yield, as a colourless solid. 1H-NMR (CDCI3 + CD3OD) 7.0 (m, 4H); 4.42 (s, 2H); 3.72 (s, 2H); 3.31 (m, 2H); 3.1 1 (m, 2H); 2.44 (t, 2H, J = 7.8 Hz); 1 .43 (m, 2H); 1 .13 (m, 10H); 0.73 (t, 3H, J = 7 Hz).
Example 16 2-(1-(4-Octylbenzyl)hydrazine-carboxamido)acetic acid
Step A: tert-Butyl 2-(4-octylbenzylidene)hydrazinecarboxylate: To a mixture of Example 3, Step A (0.1 g; 0.46 mmol) and tert-butyl carbazate (0.06 g; 0.46 mmol) in anhydrous CH2CI2 (5 ml) anhydrous MgSO4 was added and the resulting suspension was vigorously stirred for 2 h at room temperature and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.13 g; 87%) as yellowish solid, which was used in next step without further purification. 1 H-NMR (CDCI3) 7.8 (broad s, 1 H); 7.56 (d, 2H, J = 8.1 Hz); 7.15 (d, 2H, J = 8.1 Hz); 2.58 (t, 2H, J = 7.9 Hz); 1.59 (m, 2H); 1.52 (s, 9H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Step B: tert-Butyl 2-(4-octylbenzyl)hydrazinecarboxylate: To a solution of the product of Step A (0.13 g; 0.391 mmol) in anhydrous THF (1 ml) and glacial AcOH (0.6 ml) NaBH3CN (0.06 g; 0.95 mmol) was added at -O0C (ice bath). The resulting mixture was stirred overnight at room temperature then diluted to 15 ml with Et2O. This was washed with 5% NaHCO3. H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.01 g; 16%) as a colourless syrup, which was used in the next step without further purification. 1 H-NMR (CDCI3) 7.23 (d, 2H, J = 8 Hz); 7.12 (d, 3H, J = 8 Hz); 6.0 (s, 1 H); 4.1 (broad s, 2H); 3.94 (s, 2H); 2.57 (t, 3H, J = 7.9 Hz); 1 .56 (m, 2H); 1 .45 (s, 9H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Step C: tert-Butyl 2-(2-ethoxy-2-oxoethylcarbamoyl)-2-(4-octylbenzyl)- hydrazine-carboxylate: When the product of Step B was substituted for 4-n- octylbenzylamnie in Example 14, Step A, the identical process afforded the title compound in 84% yield, as a colourless solid. 1H-NMR (CDCI3) 7.14 (m, 4H); 5.95 (s, 1 H); 5.87 (t, 1 H, J = 5 Hz); 4.5 (broad s, 1 H); 4.19 (q, 2H, J = 7.1 Hz); 4.03 (d, 2H, J = 5 Hz); 2.57 (t, 2H, J = 7.9 Hz); 1 .56 (m, 2H); 1.44 (s, 9H); 1 .27 (m, 13H); 0.86 (t, 3H, J = 7 Hz).
Step D: Ethyl 2-(1-(4-octylbenzyl)hydrazinecarboxamido)acetate: When the product of Step C was substituted for tert-butyl 4-n-octylphenyl(methyl)carbamate in Example 12, Step B, the identical process afforded the title compound in 89% yield, as a creamy solid, which was used in the next step without further purification. 1 H-NMR (CDCI3) 7.15 (m, 4H); 6.84 (broad m, 1 H); 4.66 (s, 2H); 4.2 (q, 2H, J = 7.14 Hz); 4.02 (d, 2H, J = 5.8 Hz); 3.42 (bs, 2H); 2.57 (t, 2H, J = 7.9 Hz); 1 .57 (m, 2H); 1 .27 (m, 13H); 0.86 (t, 3H, J = 6.9 Hz).
Step E: 2-(1-(4-Octylbenzyl)hydrazinecarboxamido)acetic acid: : When the product of Step D is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 78% yield, as a colourless solid. 1H-NMR (CDCI3) 7.15 (m, 4H); 6.91 (t, 1 H, J = 5.7 Hz); 4.66 (s, 2H); 4.02 (d, 2H, J = 5.7 Hz); 3.56 (bs, 3H); 2.57 (t, 2H, J = 7.9 Hz); 1.58 (m, 2H); 1 .26 (m, 10H); 0.86 (t, 3H, J = 7 Hz).
Example 17 3-(5-Octylindoline-1-carboxamido)propanoic acid
Step A: 5-iodoindoline: To a solution of 5-iodoindole (0.2 g; 0.82 mmol) in AcOH (5 ml) NaBH3CN (0.2 g; 3.8 mmol) was added at -1 O0C under N2. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue was diluted to 30 ml with Et2O and washed with 1 N NaOH (5 ml), H2O (2 x 5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.2g; 99%), which was used in next step without further purification. 1H-NMR (CDCI3 ) 7.35 (s, 1 H); 7.25 (d, 1 H, J = 8.15 Hz); 6.43 (d, 1 H, J = 8.15 Hz); 5.21 (bs, 1 H); 3.54 (t, 2H, J = 8.36 Hz); 2.99 (t, 2H, J = 8.36 Hz). Step B: Ethyl 3-(5-iodoindoline-1-carboxamido)propanoate: When the product of Step A was substituted for 4-n-octylaniline in Example 1 1 , Step A, , the identical process afforded the title compound in 99% yield, as a colourless solid . 1H-NMR (CDCI3) 7.67 (d, 1 H, J = 8.3 Hz); 7.4 (no, 2H); 5.34 (m, 1 H); 4.14 (q, 2H, J = 7.1 Hz); 3.86 (t, 2H, J = 8.8 Hz); 3.56 (q, 2H, J = 5.9 Hz); 3.13 (t, 2H, J = 8.6 Hz); 2.58 (t, 2H, J = 5.7 Hz); 1.26 (t, 3H, J = 7.1 Hz).
Step C: Ethyl 3-(5-(oct-1-ynyl)indoline-1-carboxamido)propanoate: A mixture of the product of Step B (0.16 g; 0.41 mmol), 1 -octyne (0.073 ml; 0.49 mmol), CI2Pd(PPh3)2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) was degassed under reduced pressure and saturated with dry N2. After addition of DIPEA (0.5 ml), the resulting mixture was stirred for 2 h at room temperature under N2. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc and washed with 5% citric acid, 5% NaHCO3, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2CI2) to give the title compound (0.1 g; 65%) as a brownish solid. 1H-NMR (CDCI3) 7.75 (d, 1 H, J = 8.4 Hz); 7.16 (d, 1 H, J = 8.4 Hz); 7.1 (s, 1 H); 5,34 (t, 1 H, J = 5.8 Hz); 4.1 1 (q, 2H, J = 7.1 Hz); 3.82 (t, 2H, J = 8.8 Hz); 3.52 (m, 2H); 3.06 (t, 2H, J = 8.8 Hz); 2.56 (t, 2H, J = 5.8 Hz); 2.33 (t, 2H, J = 7.1 Hz); 1.53 (m, 2H); 1.52 (m, 2H); 1 .26 (m, 6H); 1.23 (t, 2H, J = 7.1 Hz); 0.86 (t, 3H, J = 6.9 Hz).
Step D: Ethyl 3-(5-octylindoline-1-carboxamido)propanoate\ A mixture of the product of Step C (0.1 g; 0.27 mmol) and 10% Pd/C (0.1 g) in EtOH (15 ml) was stirred at room temperature for 1 h under H2 (balloon). The catalyst was removed by filtration through the Celite pad, washed with CH2CI2 (2 x 10 ml) and combined filtrates were evaporated to dryness under reduced pressure to give a title compound (0.09 g; 90%), as colourless solid. 1H-NMR (CDCI3) 7.71 (d, 1 H, J = 8.8 Hz); 6.94 (d, 1 H, J = 8.8 Hz); 6.93 (s, 1 H); 5.29 (m, 1 H); 4.14 (q, 2H, J = 7 Hz); 3.82 (t, 2H, J = 8.8 Hz); 3.57 (q, 2H, J = 5.9 Hz); 3.1 1 (t, 2H, J = 8.6 Hz); 2.59 (t, 2H, J = 5.7 Hz); 2.51 (t, 2H, J = 7.7 Hz); 1 .57 (m, 2H); 1 .26 (m, 13H); 0.86 (t, 3H, J = 7 Hz).
Step E: 3-(5-Octylindoline-1-carboxamido)propanoic acid: When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. 1H-NMR (CDCI3) 7.68 (d, 1 H, J = 8.7 Hz); 6.94 (m, 2H); 5.24 (t, 1 H, J = 5.9 Hz); 3.86 (t, 2H, J = 8.7 Hz); 3.58 (q, 2H, J = 5.9 Hz); 3.1 1 (t, 2H, J = 8.5 Hz); 2.67 (t, 2H, J = 5.8 Hz); 2.5 (t, 2H1 J = 8Hz); 1.54 (m, 2H); 1.25 (m, 10H); 0.86 (t, 3H, J = 6.8 Hz).
Example 18
Φt^N-tejθ-DimethylbicycloIS.I.Ilheptan^-yOsulfamoyOphenyObutyl- dihydrogen phosphate:
Step A: 4-Bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulfonamide: To a stirred solution of 4-bromo-benzenesulphonyl chloride (0.6 g, 2.34 mmol) in anhydrous CH2CI2 (5 ml) and Et3N (0.65 ml, excess) at 0 5C was added (-) cis-myrtanylamine (0.36 g, 2.34 mmol) and the stirring was continued overnight at room temperature. The reaction mixture was diluted with CH2CI2 (15 ml) and washed with H2O (2 x 100 ml). The organic layer was separated and dried over MgSO4 and the solvent was distilled to afford the title compound (0.87 g, 100%), as pale paste, which was solidified on standing. 1H-NMR (CDCI3) 7.70 (d, 2H, J = 6.78 Hz); 6.64 (d, 2H, J = 6.90 Hz); 2.91 (t, 2H, J = 7.59 Hz); 2.32 - 2.29 (m, 1 H); 2.1 1 - 2.06 (m, 1 H); 1 .91 - 1 .81 (m, 6H); 1 .39 - 1 .31 (m, 1 H); 1.1 1 (s, 3H); 0.86 (s, 3H).
Step B: N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl) benzene sulfonamide: A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1 -ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N2 and CI2Pd(PPh3)2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature . The reaction was quenched with saturated NH4CI solution and diluted with H2O followed by the extraction with EtOAc (100 ml). The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the product (0.1 1 g, 60%), as creamy paste. 1H-NMR (CDCI3) 7.66 (d, 2H, J = 8.43 Hz); 7.51 (d, 2H, J = 8.43 Hz); 3.81 (b, 2H); 3.01 - 2.86 (m, 2H); 2.71 - 2.67 (m, 4H); 2.50 - 2.10 (m, 2H); 1 .94 - 1 .82 (m, 5H); 1 .52 - 1.48 (m, 1 H); 1.18 (s, 3H); 1 .02 (s, 3H).
Step C: N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybutyl) benzene sulfonamide: A mixture of the product of Step B (0.1 1 g, 0.3 mmol) and 10% Pd/C (0.06 g) in EtOH (10 ml) was stirred for 16 h under H2. The catalyst was filtered through Celite pad and the filtrate evaporated to dryness to give the title compound (0.11 g, 100%,) as creamy gum. 1H-NMR (CDCI3) 7.74 (d, 2H, J = 7.89 Hz); 7.29 (d, 2H, J = 8.01 Hz); 4.9 (bs, 1 H, NH); 3.71 - 3.65 (m, 2H); 2.92 - 2.87 (m, 2H); 2.70 (t, 2H, J = 7.74 Hz); 2.45 - 2.30 (m, 1 H); 2.25 - 2.10 (m, 1 H); 1.86 - 1 .58 (m, 9H); 1.3 - 1 .1 (m, 2H); 1 .08 (s, 3H); 0.83 (s, 3H).
Step D: 4-(4-(N-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)sulfamoyl)phenyl) butyl-dihydrogen phosphate: To a stirred solution of POCI3 (0.006 ml, 0.66 mmol) in anhydrous CH2CI2 (3 ml) a solution of tert-butanol (0.062 ml, 0.65 mmol) and Et3N (0.09 ml, 0.65 mmol) was added drop wise at 0 5C under N2. The mixture was stirred for 0.5 h and to it a solution of the product of Step C (0.08 g, 0.22 mmol) in a mixture of anhydrous CH2CI2 (1 ml) and Et3N (0.03 ml) was added drop wise. The mixture was stirred for 1 h at room temperature. The solvent was evaporated under reduced pressure and the residue was treated dropwise with a solution of 10% NaOH until the mixture become homogenous. This was washed with CH2CI2 (2 x10 ml), and the aqueous phase was acidified with 2M HCI. The product was extracted with CH2CI2 (20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.065 g, 65%) as pale paste. 1H-NMR (CDCI3) 7.67 (d, 2H, J = 7.13 Hz); 7.23 (d, 2H); 3.94 (bs, 1 H, NH); 3.86 (d, 2H, J = 7.67 Hz); 2.58 (b, 2H); 2.28 (b, 1 H); 2.13 (b, 1 H); 1 .84 - 1.82 (b, 5H); 1.35 (b, 4H); 1 .22 - 1 .24 (b, 2H); 0.96 (s, 3H); 0.86 (s, 3H).
Example 19
4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1 H-indol-1-yl)propyl)phenyl)butyl- dihydrogen phosphate
Step A: 2,2,2-Trifluoro-1-(1H-indol-3-yl)ethenone: To a stirred solution of indole (0.5 g, 4.3 mmol) in anhydrous Et2O (10 ml) anhydrous pyridine (0.5 ml) was added at 0 5C, followed by drop wise addition of (CF3CO)2O (0.87 ml, 5.16 mmol). The mixture was stirred for 15 min and the solvent was evaporated to dryness. The residue was diluted to 20 ml with EtOAc , washed with H2O, dried over MgSO4, filtered and the filtrate was evaporated to dryness. The residue was crystallized from CH3OH to give the title compound (0.56 g; 61 %), as colourless solid. 1 H-NMR (CDCI3) 9.04 (broad s, 1 H); 8.40 (t, 1 H1 J = 4.1 1 Hz); 8.06 (s, 1 H); 7.48 -7.45 (m, 1 H); 7.40 -7.35 (m, 2H).
Step B: 2,2,2-Trifluoro-1-(1-(prop-2-ynyl)-1H-indol-3-yl)ethanone: A mixture of product of Step A (0.55 g, 2.58 mmol), K2CO3 (0.43 g, 3.1 1 mmol) and propyrgyl bromide (2 ml) in anhydrous DMF (8 ml), was stirred for 4 h. The mixture was quenched with NH4CI solution and diluted to 50 ml with EtOAc. The organic layer separated and washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to give the title compound (0.57 g, 88%), as yellow crystalline material. 1H-NMR (CDCI3) 8.41 - 8.38 (b, 1 H); 7.99 (s, 1 H); 7.48 - 7.31 (m, 3H); 4.96 (d, 2H, J = 2.55 Hz); 2.58 (t, 1 H, J = 2.55 Hz).
Step C: 2,2,2-Trifluoro-1-(1-(3-(4-iodophenyl)prop-2-ynyl)-1H-indol-3-yl) ethanone: A mixture of product of Step B (0.25 g, 1 mmol), 1 ,4 di-idobenzene (0.4 g, 1 .2 mmol) CI2Pd(PPh3)2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N2. This was stirred overnight at room temperature, quenched with NaHCO3 solution and diluted to 50 ml with EtOAc. The organic layer was separated and washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.28 g, 51%), as light yellow solid. 1H- NMR (CDCI3) 8.43 - 8.40 (b, 1 H); 8.12 (b, 1 H); 7.66 (t, 2H, J = 8.36 Hz); 7.55 - 7.51 (m, 1 H); 7.44 - 7.38 (m, 2H); 7.14 (d, 2H, J = 8.30 Hz); 5.16 (s, 2H).
Step D: 2,2,2-Trifluoro-1-(1-(3-(4-(4-hydroxybut-1-ynyl)phenyl)prop-2-ynyl)- 1 H-indol-3-yl) ethanone: When the product of Step C was substituted for A- bromo-N-(6,6-dimethylbicyclo[3.1.1] heptan-2-yl) benzene sulphonamide in Example 18, Step B, the identical process afforded the title compound in 84% yield, as creamy paste. 1H-NMR (CDCI3) 8.43 - 8.40 (m, 1 H); 8.14 (s, 1 H); 7.56 - 7.53 (m, 1 H); 7.44-7.37 (m, 2H); 7.37 (s, 4H); 5.19 (s, 2H); 3.8 (t, 2H, J = 6.24 Hz); 2.69 (t, 2H, J = 6.24 Hz); 1 .76 (bs, 1 H).
Step E: 2,2,2- Trifluoro- 1 -(1-(3-(4-(4-hydroxybutyl)phenyl)propyl) - 1 H-indol- 3-yl)ethanone: When the product of Step D was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybut-1 -ynyl) benzene sulphonamide in Example 18, Step C, the identical process afforded the title compound in 92% yield, as pale paste. 1 H-NMR (CDCI3) 8.40 (broad s, 1 H); 7.86 (s, 1 H); 7.37 - 7.32 (m, 3H); 7.1 1 (d, 2H, J = 8.07 Hz); 7.05 (d, 2H, J = 8.07 Hz); 4.19 (t, 2H, J = 7.17 Hz); 3.72 - 3.63 (m, 4H); 2.66 - 2.59 (m, 4H); 1.68 - 1.60 (m, 4H).
Step F: 4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)propyl)phenyl)butyl- dihydrogen phosphate: When the product of Step E was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxy butyl)benzene sulphonamide in Example 18, Step D, the similar process afforded the title compound in 73% yield, as pale paste. 1H-NMR (CDCI3) 8.35 (broad s, 1 H); 7.83 (s, 1 H); 7.36 - 7.30 (m, 3H); 7.10 - 6.93 (m, 4H); 3.98 (m, 2H); 2.55 - 2.50 (m, 6H); 2.23 - 2.15 (m, 2H); 1.59 (b, 4H).
Example 20
4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)butyl- dihydrogen phosphate
Step A: 2-(2-(4-lodophenoxy)ethyl)-6,6-dimethylbicyclo[3.1. 1]heptane: To a stirred suspension of 4-iodophenol (0.5 g; 2.27 mmol) and 60% NaH (0.16 g, 2.3 mmol) in anhydrous DMF (5 ml) 2-(2-bromoethyl)-6,6- dimethylbicyclo[3.1 .1 ]heptane (0.5 g, 2.2 mmol) was added the and mixture was stirred for 3 h at room temperature. After addition of more of 2-(2-bromoethyl)- 6,6-dimethylbicyclo[3.1 .1]heptane (0.2 g) the mixture was stirred for additional 2 h, quenched with NH4CI solution and diluted to 20 ml with EtOAc. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 73%), as a colourless paste. 1 H-NMR (CDCI3) 7.51 (d, 2H, J = 8.91 Hz); 6.64 (d, 2H, J = 8.88 Hz); 3.88 (t, 2H, J = 3.21 Hz); 2.34 - 1 .84 (m, 10H); 1.17 (s, 3H); 1.01 (s, 3H).
Step B: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl)but-3- yn-1-ol: When the product of Step A was substituted for 4-bromo-N-(6,6- dimethylbicyclo[3.1 .1 ] heptan-2-yl)benzene sulphonamide in Example 18, Step B, the similar process afforded the title compound in 78% yield, as pale paste. 1 H- NMR (CDCI3) 7.29 (d, 2H, J = 8.76 Hz); 6.78 (d, 2H, J = 8.82 Hz); 3.80 - 3.76 (m, 2H); 3.92 (t, 2H, J = 1.89 Hz); 2.65 (t, 2H, J = 6.21 Hz); 1 .92 - 1 .81 (m, 10H); 1.18 (s, 3H); 1.01 (s, 3H).
Step C: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)phenyl) butan-1-ol: When the product of Step B was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybut-1 -ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title compound in 99% yield, as a colourless paste. 1H-NMR (CDCI3) 7.05 (d, 2H, J = 8.54 Hz); 6.78 (d, 2H, J = 8.58 Hz); 3.91 (t, 2H, J = 6.81 Hz); 3.64 (t, 2H, J = 6.02 Hz); 2.57 - 2.53 (m, 2H); 1 .90 - 1 .57 (m, 14 H); 1 .18 (s, 3H); 1.01 (s, 3H). Step D: 4-(4-(2-(6,6-Dimethylbicyclo[3.1.1 ]heptan-2-yl)ethoxy)phenyl) butyl-di-hydrogen phosphate: When the product of Step C was substituted for N- (6,6-dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybutyl) benzene sulfonamide in Example 18, Step D, the similar process afforded the title compound in 60% yield, as pale paste. 1H-NMR (CDCI3) 7.05 (d, 2H, J = 8.31 Hz); 6.74 (d, 2H, J = 8.16 Hz); 3.93 - 3.84 (m, 4H); 2.53 - 2.15 (m, 16H); 1 .15 (s, 3H); 0.99 (s, 3H).
Example 21 2-(4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)ethanol
Step A: 4-((6-Methoxybenzofuran-2-yl)ethynyl)phenyl acetate: When A- iodophenyl acetate and 2-ethynyl-6-methoxybenzofuran were substituted for A- bromo-N-(6,6-dimethylbicyclo [3.1 .1 ] heptan-2-yl)benzene sulphonamide and but- 3-yn-1 -ol respectively in Example 18, Step B, the similar process afforded the title compound in 56% yield, as creamy paste. 1 H-NMR (CDCI3) 7.56 (d, 2H, J = 8.67 Hz); 7.41 (d, 1 H, J = 8.58 Hz); 7.10 (d, 2H, J = 8.7 Hz); 6.97 (d, 1 H, J = 1.92 Hz); 6.9 (s, 1 H); 6.88 (bd, 1 H, J = 8.61 Hz); 3.85 (s, 3H); 2.3 (s, 3H).
Step B: 4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenol: When the product of Step A was substituted for N-(6,6-dimethyl bicyclo[3.1 .1 ]heptan-2- yl)-4-(4-hydroxybut-1 -ynyl)benzenesulphonamide in Example 18, Step C, the similar process (higher pressure of H2) afforded the title compound in 96% yield, as creamy paste. 1H-NMR (CDCI3) 7.25 - 7.19 (m, 2H); 7.02 - 6.97 (m, 3H); 6.38 - 6.35 (m, 2H); 4.81 - 4.72 (m, 1 H); 3.75 (s, 3H); 3.24 - 3.16 (m, 1 H); 2.83 - 2.73 (m, 3H); 2.27 (s, 3H); 2.13 - 2.07 (m, 1 H); 2.06 - 1.92 (m, 1 H). Step C: Ethyl 2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl) phenoxy) acetate: To a stirred solution of the product of Step A (0.05 g, 0.19 mmol) and K2CO3 (0.05 g, 0.36 mmol) in anhydrous DMF (5 ml) ethyl-bromo acetate (0.025 ml, 0.22 mmol) was added at room temperature. The mixture was stirred for 2 h and quenched with saturated NH4CI solution, extracted in EtOAc (100 ml) and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.07 g; 100%), as pale oil. 1H-NMR (CDCI3) 7.10 (d, 2H, J = 8.39 Hz); 6.97 (d, 1 H, J = 8.46 Hz); 6.80 (t, 2H, J = 8.36 Hz); 6.35 - 6.33 (m, 2H); 4.75 - 4.71 (m, 1 H); 4.56 (s, 2H); 4.22 (q, 2H, J = 14.36, 7.17 Hz); 3.72 (s, 3H, OMe); 3.2 - 3.13 (m, 1 H); 2.79 - 2.69 (m, 3H); 2.0 - 1 .87 (m, 2H); 1 .26 (t, 3H, J = 7.12 Hz). Step D: 2-(4-(2-(6-Methoxy-2, 3-dihydrobenzofuran-2-yl)ethyl)phenoxy) ethanol: To the stirred slurry of LiAIH4 (0.01 g, 0.026 mmol) in anhydrous Et2O (5 ml) the solution of the product of Step C (0.04 g, 0.1 1 mmol) in anhydrous Et2O (2 ml) was added drop wise and stirring was continued for 0.5 h at room temperature. The reaction mixture was quenched with EtOAc: H2O: MeOH mixture (7 ml: 3 ml: 1 ml), diluted to 20 ml with EtOAc and filtered through Celite. The filtrate was evaporated under reduced pressure and dried in vacuo to give the title compound (0.032 g, 94%), as colourless solid. 1H-NMR (CDCI3) 7.13 (d, 2H, J = 8.54 Hz); 6.99 (d, 1 H, J = 8.56 Hz); 6.84 (d, 2H, J = 8.58 Hz); 6.38 - 6.34 (m, 2H); 4.79 - 4.74 (m, 1 H); 4.65 (t, 2H, J = 4.14 Hz); 3.96 - 3.90 (m, 2H); 3.75 (s, 3H); 3.22 - 3.14 (m, 1 H); 2.82 - 2.68 (m, 2H); 2.1 1 - 1 .91 (m, 3H).
Example 22
2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl) (methyl) amino)ethanol
Step A: 4-(5-(Hydroxymethyl)thiophen-2-yl)benzaldehyde: The thiphene-5- al-2-boronic acid (0.47 g, 2.97 mmol) was reduced with NaBH4 (0.15 g, 3.95 mmol) in MeOH (3 ml) and solvent was evaporated to dryness. The residue was taken in 1 ,4-dioxane (12 ml) and 4-bromobenzaldehyde (0.65 g, 3.5 mmol) was added. To this Pd(PPh3J4 (0.05 g) was added with stirring at 80 9C, followed by the addition of a solution of NaHCO3 (0.6 g) in H2O (2 ml). The mixture was stirred at reflux for 1 h and the solvents were evaporated to dryness under reduced pressure. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. Tthe filtrate was evaporatedto dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 80%), as creamy paste. 1H- NMR (CDCI3) 9.98 (s, 1 H, CHO); 7.87 (d, 2H, J = 8.3 Hz); 7.72 (d, 2H, J = 8.31 Hz); 7.31 (d, 1 H, J = 3.74 Hz); 7.0 (d, 2H, J = 3.7 Hz); 4.84 (s, 2H).
Step B: 4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl) benzaldehyde: To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH2CI2 (10 ml) and Et3N (0.3 ml) mesyl chloride (0.4 ml) was added at 0 5C and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which was taken up in anhydrous toluene and 4-fluro-Λ/-isopropylaniline (0.5 ml) was added to it. The mixture was stirred overnight at reflux and the solvent was evaporated. The residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.14 g, 20%), as light creamy paste. 1 H-NMR (CDCI3) 9.98 (s, 1 H,); 7.82 (d, 2H, J = 8.31 Hz); 7.66 (d, 2H, J = 8.31 Hz); 7.28 (d, 1 H, J = 3.69 Hz); 6.93 - 6.86 (m, 3H); 6.81 - 6.76 (m, 2H); 4.79 (s, 2H); 4.08 - 3.99 (m, 1 H); 1 .22 (d, 6H, J = 6.6 Hz).
Step C: Methyl-2-((4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl) thiophen-2-yl)benzyl) (methyl)amino) acetate: To a stirred solution of the product of Step B (0.09 g, 0.26 mmol) and sarcosine hydrochloride (0.07 g, 0.5 mmol) in 1 ,2-dichloroethane (5 ml) was added DIPEA (0.1 ml) and 10 drops of AcOH, followed by NaBH(OAc)3 (0.1 1 g, 0.51 mmol). The mixture was stirred overnight at room temperature and diluted to 20 ml with CH2CI2. The organic layer was washed with NaHCO3 solution, H2O and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.1 13 g, 100%) as creamy paste. 1H- NMR (CDCI3) 7.47 (d, 2H, J = 8.19 Hz); 7.28 (d, 2H, J = 8.18 Hz); 7.10 (d, 1 H, J = 3.62 Hz); 6.88 - 6.85 (m, 3H); 6.85 - 6.77 (m, 2H); 4.44 (s, 2H); 4.07 - 3.98 (m, 1 H); 3.69 (s, 3H); 3.24 (s, 2H); 2.37 (s, 3H); 1 .21 (d, 6H, J = 6.6 Hz).
Step D: 2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzyl) (methyl) amino)ethanol: When the product of Step C was substituted for ethyl-2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)acetate in Example 21 , Step D, the similar process afforded the title compound in 28% yield, as light yellow paste. 1H NMR (CDCI3) 7.47 (d, 2H, J = 8.05 Hz); 7.24 (d, 2H, J = 8.04 Hz); 7.10 (d, 1 H, J = 3.60 Hz); 6.91 - 6.85 (m, 3H); 6.81 - 6.76 (m, 2H); 4.44 (s, 2H); 4.07 - 3.98 (m, 1 H); 3.61 (t, 2H, J = 5.31 Hz); 3.53 (s, 3H); 2.58 (t, 2H, J = 5.31 Hz); 2.21 (s, 3H); 1.21 (d, 6H, J = 6.56 Hz).
Example 23
2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzylamino) propane-1,3-diol
Step A: N-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzyl) -2,2-dimethyl-1,3-dioxan-5-amine: When 2,2-dimethyl-1 ,3-dioxan-5- amine was substituted for sarcosine hydrochloride in Example 22, Step C, the similar process afforded the the title compound in 90% yield, as creamy paste. 1 H NMR (CDCI3) 7.47 (d, 2H, J = 8.2 Hz); 7.29 (d, 2H, J = 8.2 Hz); 7.0 (d, 1 H, J = 3.61 Hz); 6.9 - 6.85 (m, 3H); 6.82 - 6.76 (m, 2H); 4.38 (s, 2H); 4.07 - 4.0 (m, 1 H); 3.96 (dd, 2H, J = 1 1.7, 3.5 Hz); 3.81 (s, 2H); 3.72 (dd, 2H, J = 1 1 .8, 5.34 Hz); 2.68 - 2.63 (m, 1 H); 1.41 (s, 3H); 1.4 (s, 3H); 1 .21 (d, 6H, J = 6.6 Hz).
Step B: 2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzylamino) propane-1 ,3-diol: A solution of the product of Step A (0.025 g, 0.05 mmol) in a mixture of solvents (CH3OH, CH2CI2, 30% HCI: 1 ml, 3 ml, 15 drops) was stirred for 3 h at room temperature. The solvents were evaporated and co-evaporated with iPrOH to give the title compound (0.012 g, 48%) as creamy paste. 1H-NMR (CDCI3) 7.45 (d, 2H, J = 8.12 Hz); 7.23 - 7.33 (m, 4H); 7.16 - 7.09 (m, 3H); 6.88 (d, 2H, J = 3.68 Hz); 4.95 (bs, 1 H); 4.21 (s, 2H); 4.07 - 4.02 (m, 1 H); 3.92 - 3.68 (m, 6H); 3.29 - 3.26 (m, 1 H); 1.03 (d, 6H, J = 6.6 Hz).
Example 24
2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino)propane-1 ,3- diol hydrochloride
Step A: N-(3-(4-(Diethoxymethyl)phenyl)prop-2-ynyl)-4-fluorobenzenamine: When 4-bromo-benzene-diethylacetal and 4-fluro-N-propyrgylaniline was substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1 ] heptan-2-yl)benzene sulphonamide and but-3-yn-1 -ol, respectively, in Example 18, Step B, the similar process afforded the title compound in 36% yield, as pale paste. 1 H-NMR (CDCI3) 7.38 (d, 2H, J = 8.7 Hz); 6.84 (d, 2H, J = 8.6 Hz); 6.92 (t, 2H, J = 7.8 Hz); 6.68 - 6.64 (m, 2H); 5.46 (s, 1 H); 4.10 (s, 3H); 3.62 - 3.44 (m, 4H); 1 .21 (t, 6H, J = 7.04 Hz).
Step B: N-(3-(4-(Diethoxymethyl)phenyl)propyl)-4-fluorobenzenamine: When the product of Step A was substituted for N-(6,6- dimethylbicyclo[3.1 .1 ]heptan-2-yl)-4-(4-hydroxybut-1 -ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title crude product (0.195 g; 96%) as creamy paste. 1H-NMR (CDCI3) 7.35 (d, 2H, J = 8.01 Hz); 7.14 (d, 2H, J = 8.1 Hz); 6.85 (t, 2H, J = 7.54Hz); 6.51 - 6.45 (m, 2H); 5.46 (s, 1 H); 3.73 - 3.48 (m, 4H); 3.07 (t, 2H, J = 6.97 Hz); 2.71 (t, 2H, 7.45 Hz); 1 .96 - 1 .85 (m, 2H); 1.22 (t, 6H, J = 7.07 Hz). Step C: 4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzaldehyde: A mixture of 4-(3-(4-flurophenylamino)propyl)benzaldehyde (0.09 g, 0.35 mmol) [prepared form the product of Step B by stirring in acidifies CHCI3] and 2- bromopropane (0.2 ml) and K2CO3 (0.1 g; 0.73 mmol) was stirred at reflux in anhydrous DMF (5 ml) for 6 h. The solvent was evaporated under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc), to give the title compound (0.078 g, 83%) as creamy paste. 1H- NMR (CDCI3) 10 (s, 1 H); 7.78 (d, 2H, J = 8.13 Hz); 7.32 (d, 2H, J = 8.07 Hz); 6.93 - 6.86 (m, 2H); 6.82 - 6.66 (m, 2H); 3.07 (t, 2H, J = 7.5 Hz); 2.71 (t, 2H, J = 7.5 Hz); 2.71 (t, 2H, 7.62 Hz); 2.27 -2.21 (m, 1 H); 1 .86 - 1 .83 (m, 1 H); 1 .08 (d, 6H, J = 6.6 Hz).
Step D: N-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzyl)-2,2- dimethyl-1,3-dioxan-5-amine: \Nhen the product of Step C and 2,2-dimethyl-1 ,3- dioxan-5-amine were substituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)- thiophen-2-yl) benzaldehyde and sarcosine hydrochloride in Example 22, Step C, the similar process afforded the title compound in 48% yield, as creamy paste. 1 H-NMR (CDCI3) 7.24 (d, 2H, J = 7.92 Hz), 7.1 1 (cl, 2H, J = 7.92 Hz), 6.87(t, 2H, J = 8.9 Hz), 6.69 - 6.62(m, 2H), 3.95(dd, 2H, J = 1 1.7, 3.6 Hz), 3.83 - 3.69(m, 4H), 3.06(t, 2H, J = 7.54 Hz), 2.66 - 2.58(m, 3H), 1 .83 - 1 .76(m, 3H), 1.41 (s, 3H), 1.4(s, 3H), 1 .08(d, 2H, J = 6.59 Hz).
Step E: 2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino) propane- 1,3-diol hydrochloride salt: When the product of Step D was substituted for N-(4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl) -2,2- dimethyl -1 ,3-dioxan-5-amine in Example 23, Step B, the identical process afforded the title compound in 67% yield, as a creamy paste. 1H-NMR (CDCI3) 7.39 - 7.19 (m, 6H); 7.1 1 (d, 2H, J = 7.99 Hz); 4.21 (s, 2H); 3.94 - 3.67 (m, 5H); 3.4 - 3.7 (m, 2H); 3.3 - 3.26 (m, 1 H); 2.56 (b, 2H); 1.68 (b, 1 H); 1 .22 (b, 1 H); 1.04 (d, 6H, J = 6.2 Hz). Example 25
1-((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid
Step A: 4-Bromo-N-(3-methoxyphenyl)benzenesulfonamide: To a stirred solution of 3-methoxyaniline (0.48 g, 3.92 mmol) in anhydrous pyridine (5 ml) 4- bromobenzene-sulphonyl chloride (0.5 g, 1 .96 mmol) was added and the mixture was stirred for 0.5 h. The solvent was removed in vacuo and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.51 g, 37%) as creamy paste. 1H-NMR (CDCI3) 7.65 (d, 2H, J = 8.57 Hz); 7.52 (d, 2H, J = 8.57 Hz); 7.10 (t, 1 H, J = 8.09 Hz); 6.69 - 6.61 (m, 2H); 4.37 (s, 2H); 3.71 (s, 3H, OMe).
Step B: 4-Bromo-N-(3-methoxyphenyl)-N-methylbenzenesulfonamide: To a stirred mixture of the product of Step A (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) was added CH3I (1 ml) and the stirring continued for 0.5 h at 50 5C. The mixture was diluted to 50 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O and dried over MgSO4, passed through silica gel bead and the filtrate was evaporated to dryness to give the title compound (0.5 g, 96%) as pale solid. 1H-NMR (CDCI3) 7.58 (d, 2H, J = 8.64 Hz); 7.40 (d, 2H, J = 8.67 Hz); 7.18 (t, 1 H, J = 8.15 Hz); 6.80 (dd, 1 H, J = 8.34, 2.5 Hz); 6.69 (t, 1 H, J = 2.20 Hz); 6.58 (bd, 1 H); 3.75 (s, 3H, OMe); 3.14 (s, 3H, N- Me).
Step C: 4'-Formyl-N-(3-methoxyphenyl)-N-methylbiphenyl-4-sulfonamide: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 73% yield, as pale solid. 1H-NMR (CDCI3) 10.07 (s, 1 H); 7.98 (d, 2H, J = 6.56 Hz); 7.75 (d, 2H, J = 8.24 Hz); 7.7 (d, 2H, J = 8.82 Hz); 7.66 (d, 2H, J = 8.75 Hz); 7.19 (t, 1 H, J = 8.13 Hz); 6.81 (dd, 1 H, J = 8.30, 2.45 Hz); 6.74 (t, 1 H, J = 2.17 Hz); 6.65 (dd, 1 H, J = 7.96, 1 .24 Hz); 3.76 (s, 3H); 3.20 (s, 3H).
Step D: Methyl-1-((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were sunstituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process the title compound in 69% yield, as pale paste. 1 H-NMR (CDCI3) 7.64 (d, 2H, J = 8.8 Hz); 7.58 (d, 2H, J = 8 Hz); 7.54 (d, 2H, J = 8.15 Hz); 7.36 (d, 2H, J = 8.12 Hz); 7.17 (t, 1 H, J = 8.14 Hz); 6.80 (dd, 1 H, J = 8.07, 2.21 Hz); 6.72 (t, 1 H, J = 2.10 Hz); 6.64 (dd, 1 H, J = 7.80, 1.67 Hz); 3.74 (s, 3H); 3.71 (s, 2H); 3.69 (s, 3H); 3.64 - 3.58 (m, 2H); 3.42 - 3.36 (m, 4H); 3.18 (s, 3H).
Step E: 1-((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4-yl) methyl)azetidine-3-carboxylic acid: To a stirred solution of the product of Step D (0.06 g, 0.13 mmol) in THF (3 ml) a solution of LiOH (0.006 g, 0.25 mmol) in H2O (1 ml) was added at 80 5C. The mixture was stirred for 0.5 h and solvents were evaporated to dryness. The residue was purified by FCC (SiO2) to give the title compound (0.0026 g, 43%) as creamy solid. 1H-NMR (CDCI3ICD3OD) 7.58 (s, 4H); 7.58 (d, 2H, J = 8 Hz); 7.56 (d, 2H, J = 7.23 Hz); 7.49 (d, 2H, J = 8.25 Hz); 7.13 (t, 1 H, J = 8.14 Hz); 6.76 (dd, 1 H, J = 8.33, 2.05 Hz); 6.68 (t, 1 H, J = 2.15 Hz); 6.58 (dd, 1 H, J = 7.94, 1.32 Hz); 4.25 (s, 2H); 4.21 - 4.02 (m, 4H); 3.70 (s, 3H); 3.38 - 3.32 (m, 3H); 3.13 (s, 3H).
Example 26
2-(((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl)(methyl) amino)acetic acid
Step A: 4-Fluoro-N-isopropylaniline: A mixture of 4-fluoro-aniline (1 .12 g; 10 mmol), 2-bromopropane (1 .13 ml) and K2CO3 (1 .38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O (2 x 20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. 1H-NMR (CDCI3) 6.89 - 6.82 (m, 2H); 6.53 - 6.47 (m, 2H); 3.58 - 3.49 (m, 1 H); 1 .18 (d, 6H, J = 6.25 Hz).
Step B: N-(4-Bromobenzyl)-4-fluoro-N-isopropylbenzenamine: When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2- yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. 1 H-NMR (CDCI3) 7.39 (d, 2H, J = 8.18 Hz); 7.14 (d, 2H, J = 8.08 Hz); 6.91 - 6.81 (m, 2H); 6.62 - 6.57 (m, 2H); 4.26 (s, 2H); 4.1 1 - 4.04 (m, 1 H); 1.18 (d, 2H, J = 5.34 Hz).
Step C: 4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- carbaldehyde: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl) thiophen-2- ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 65% yield, as creamy gum. 1 H-NMR (CDCI3) 10.03 (s, 1 H); 7.92 (d, 2H, J = 7.97 Hz); 7.56 (d, 2H, J = 7.95 Hz); 7.38 (d, 2H, J = 8.29 Hz); 6.86 (t, 2H, J = 8.46 Hz); 6.67 - 6.62 (m, 2H); 4.38 (s, 2H); 4.17 - 4.12 (m, 1 H); 1.2 (d, 6H, J =6.96 Hz).
Step D: Methyl-2-(((4'-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl- 4-yl)methyl)(methyl)amino) acetate: When the product of Step C was substituted for 4-(5-(((4-flurophenyl))isopropyl) amino)methyl) thiophen-2-yl)benzaldehyde in Example 22, Step C, the similar process afforded the title compound in 96% yield, as a creamy paste. 1H-NMR (CDCI3) 7.54 - 7.49 (m, 4H); 7.38 - 7.31 (m, 4H); 6.86 (t, 2H, J = 8.45 Hz); 6.83 - 6.64 (m, 2H); 4.37 (s, 2H); 4.19 - 4.09 (m, 1 H); 3.70 (s, 3H); 3.69 (s, 2H); 3.28 (s, 2H); 2.4 (s, 3H); 1 .17 (d, 6H, J = 7.71 Hz).
Step E: 2-(((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) (methyl)amino)acetic acid: When the product of Step D was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3- carboxylate in Example 25, Step E, the similar process afforded the title compound in 87% yield, as creamy solid. 1H-NMR (CDCI3 + CD3OD) 7.40 - 7.18 (m, 8H); 6.76 (t, 2H, J = 8.82 Hz); 6.61 - 6.56 (m, 2H); 4.25 (s, 2H); 4.16 (s, 2H); 4.07 - 4.01 (m, 1 H); 2.59 (s, 3H); 1 .1 1 (d, 6H, J= 6.48 Hz).
Example 27
1-((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid:
Step A: Methyl-1-((4'-(((4-fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate: When 4'-(((4-Fluorophenyl)(isopropyl) amino)methyl)biphenyl-4-carbaldehyde and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))isopropyl)amino)- methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar process afforded the title compound in 65% yield, as creamy paste. 1H-NMR (CDCI3) 7.53 (d, 2H, J = 8.12 Hz); 7.48 (d, 2H, J = 8.2 Hz); 6.85 (t, 2H, J = 9.09 Hz); 6.67 - 6.62 (m, 2H); 4.37 (s, 2H); 4.16 - 4.1 1 (m, 1 H); 3.86 (bs, 4H); 3.69 (s, 3H); 3.58 - 3.51 (m, 1 H); 1 .19 (d, 6H, J = 6.63 Hz).
Step B: 1-((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl) azetidine-3-carboxylic acid: When the product of Step A was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy) benzyl) azetidine- 3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 60% yield, as creamy solid. 1H-NMR (CDCI3 + CD3OD) 7.66 (d, 2H, J = 8.13 Hz); 7.62 - 7.57 (m, 4H); 7.41 (d, 2H, J = 8.07 Hz); 6.95 - 6.85 (m, 2H); 6.85 - 6.75 (m, 2H); 4.44 (s, 2H); 4,39 (s, 2H); 4.39 - 4.2 (m, 2H); 3.5 - 3.45 (m, 1 H); 1 .26 (d, 6H, J = 6.54 Hz).
Example 28
1-(4-(4-Oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzyl)azetidine-3- carboxylic acid
Step A: 3-Bromo-1-(3,4,5-trimethoxyphenyl)but-2-en-1-one: 1 -(3,4,5- trimethoxyphenyl) but-2-yn-1 -one (0.5 g, 2.58 mmol) was dissolved in AcOH (5 ml) and 48% HBr (5 drops) was added to it. The mixture was stirred for 2 h at 50 5C. This was evaporated to dryness and the residue was diluted to 50 ml with EtOAc, washed with NaHCO3 solution and H2O. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to dryness and dried in vacuo to give the title compound (0.53 g, 65%), as a pale solid. 1H-NMR (CDCI3) 7.30 (s, 1 H); 7.03 (s, 2H); 3.91 (s, 9H); 2.79 (s, 3H).
Step B: 4-(4-Oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzaldehyde: When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 5-(hydroxymethyl) thiophen-2-ylboronic acid and 4-bromobenzaldehyde, respectively, in Example 22, Step A, the similar process afforded the title compound in 81% yield, as creamy gum. 1H-NMR (CDCI3) 10.05 (s, 1 H); 7.92 (d, 2H, J = 8.25 Hz); 7.68 (d, 2H, J = 8.28 Hz); 7.23 (s, 2H); 7.10 (s, 1 H); 3.91 (s, 9H); 2.55 (s, 3H).
Step C: Methyl- 1 -(4-(4-oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step-C, the similar process afforded the title compound in 66% yield, as pale paste. 1H-NMR (CDCI3) 7.49 (d, 2H, J = 8.28 Hz); 7.30 (d, 2H, J = 8.29 Hz); 7.22 (s, 2H), 7.06 (s, 1 H); 3.90 (s, 9H); 3.68 (s, 3H); 3.64 (s, 2H); 3.56 - 3.52 (m, 2H); 3.37 - 3.32 (m, 3H).
Step D: 1 -(4-(4-oxo-4-(3, 4, 5-trimethoxyphenyl)but-2-en-2-yl)benzyl) azetidine-3-carboxylic acid: When the product of Step C was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 53% yield, as light yellow solid. 1 H-NMR (CDCI3 + CD3OD) 7.31 (d, 2H, J = 8.18 Hz); 7.28 (d, 2H, J = 8.28 Hz); 6.71 (s, 2H); 6.62 (s, 1 H); 4.24 (s, 2H); 4.17 - 4.04 (m, 4H); 3.55 - 3.38 (s, 1 H); 2.15 (s, 3H).
Example 29
1-((4'-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid:
Step A: 1-(4-Bromophenyl)but-2-yn-1-one: To an ice cold solution of 4- bromobenzaldehyde (1 .3 g, 7 mmol) 0.5 M solution of propynyl magnesium bromide in THF(15 ml, 7.5 mmol) was added under N2. The mixture was stirred for 10 min, quenched with saturated NH4CI solution and diluted to 50 ml with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was dissolved in 1 ,4- dioxane (25 ml). To it MnO2 (2 g) was added and the resulting suspension was stirred for 4 h at reflux. The mixture was filtered through Celite pad and the filtrate was evaporated to dryness and dried in vacuo to give the title compound (1 .29 g, 83%) as a pale solid. 1H-NMR (CDCI3) 7.97 (d, 2H, J = 9 Hz); 7.61 (d, 2H, J = 9 Hz); 2.14 (s, 3H).
Step B: 4'-But-2-ynoylbiphenyl-4-carbaldehyde: When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 58% yield, as a creamy gum. 1 H-NMR (CDCI3) 10.07 (s, 1 H); 8.23 (d, 2H, J = 8.4 Hz); 7.98 (d, 2H, J = 8.4 Hz); 7.78 (d, 2H, J = 8.24 Hz); 7.72 (d, 2H, J = 8.54 Hz); 2.18 (s, 3H).
Step C: 4'-(3-Bromobut-2-enoyl)biphenyl-4-carbaldehyde: When the product of Step B was substituted for 1 -(3,4,5-trimethoxyphenyl) but-2-yn-1 -one in Example 28, Step A, the similar process afforded the title compound in 56% yield, as pale solid. 1H-NMR (CDCI3) 10.07 (s, 1 H); 8.03 - 7.96 (m, 4H); 7.79 - 7.71 (m, 4H); 7.41 (s, 1 H); 2.84 (s, 3H).
Step D: 4'-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- carbaldehyde: \Nhen the product of Step C and 3-trifluromethyl-boronic acid were substituted for 4-bromo benzaldehyde and 5-(hydroxymethyl) thiophen-2- ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 73% yield, as creamy gum. 1H-NMR (CDCI3) 10.07 (s, 1 H); 8.1 (d, 2H, J = 8.5 Hz); 7.99 - 7.93 (m, 3H); 7.8 - 7.57 (m, 5H); 7.18 (s, 1 H); 2.61 (s, 3H).
Step E: Methyl-1-((4'-(3-(3-(thfluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylate: When the product of Step D and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 58% yield, as a pale paste. 1 H-NMR (CDCI3) 8.04 (d, 2H, J = 8.4 Hz); 7.78 - 7.51 (m, 8H); 7.4 (d, 2H, J = 8.2 Hz); 7.16 (d, 1 H, J = 1.21 Hz); 3.76 (s, 2H); 3.7 (s, 3H); 3.73 - 3.62 (m, 4H); 3.47 - 3.41 (m, 3H); 2.58 (bs, 3H).
Step F: 1 -((4 '-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl) azetidine-3-carboxylic acid: When the product of Step E was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy) benzyl) azetidine- 3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 62% yield, as a light yellow solid. 1H-NMR (CDCI3 + CD3OD) 7.84 (d, 2H, J = 8.34 Hz); 7.59 - 7.33 (m, 6H); 4.7 (d, 2H); 3.96 - 3.92 (m, 4H); 3.19 - 3.14 (m, 1 H); 2.36 (s, 3H).
Example 30 1-(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3-carboxylic acid:
Step A: 5-Bromo-2-isopropoxybenzaldehyde: To a stirred solution of 2- isopropoxybenzaldehyde (0.51 g, 3.1 mmol), in DMF (10 ml) NBS (0.55 g, 3.1 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with NaHCO3 solution and extracted in EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.62 g, 82%) as light yellow oil. 1 H-NMR (CDCI3) 10.37 (s, 1 H); 7.89 (d, 1 H, J = 2.52 Hz); 7.55 (dd, 1 H, J = 8.85, 2.58 Hz); 6.87 (d, 1 H, J = 8.88 Hz); 4.67 - 4.58 (m, 1 H); 1.35 (d, 6H, J = 6.03 Hz).
Step B: 1-(5-Bromo-2-isopropoxyphenyl)-3-phenylprop-2-yn-1-one: To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgCI in THF (1.25 ml) was added drop wise at 0 5C under N2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH4CI and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [1H-NMR (CDCI3) 7.68 (d, 1 H, J = 2.49 Hz); 7.46 - 7.43 (m, 2H); 7.36 (dd, 1 H, J = 8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1 H, J = 6.77 Hz); 5.79 (d, 1 H, J = 5.23 Hz); 4.64 - 4.58 (m, 1 H); 3.13 (d, 1 H, J = 5.91 Hz); 1 .37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. 1H-NMR (CDCI3) 8.00 (d, 1 H, J = 2.61 Hz); 7.61 - 7.52 (m, 3H); 7.44 - 7.35 (m, 3H); 6.88 (d, 1 H, J = 8.91 Hz); 4.68 - 4.60 (m, 1 H); 1 .36 (d, 6H).
Step C: 4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzaldehyde: A solution of the product of Step B (0.3 g, 0.88 mmol), was treated with HBr/ AcOH, as described in Example 28, Step A, to give a light creamy solid (0.18 g, 68%). 1 H- NMR (CDCI3) 8.36 (d, 1 H, J = 2.43 Hz); 7.92 - 7.88 (m, 2H); 7.77 (dd, 1 H, J = 8.88, 2.46 Hz); 7.58 - 7.50 (m, 3H); 7.47 (d, 1 H, J = 8.86 Hz); 6.83 (s, 1 H)], which was reacted with 4-carbaldehyde-boronic acid in Example 22, Step A, to give the title compound (0.078 g, 48%), as creamy solid. 1H-NMR (CDCI3) 10.07 (s, 1 H); 8.5 (d, 1 H, J = 2.31 Hz); 8.00 - 7.93 (m, 2H); 7.84 (d, 2H, J = 8.22 Hz); 7.71 - 7.63 (m, 3H); 7.56 - 7.48 (m, 3H); 6.87 (s, 1 H).
Step D: Methyl 1-(4-(4-oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3- carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for -(5-(((4-flurophenyl))isopropyl)amino) methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, as in Example 22, Step C, the similar procedure afforded the title compound in 31 % yield, as light green paste. 1H-NMR (CDCI3) 8.43 (d, 1 H, J = 2.29 Hz); 7.96 - 7.91 (m, 3H); 7.63 (d, 3H); 7.54 - 7.39 (m, 3H); 7.38 (d, 2H, J = 8.18 Hz); 6.85 (s, 1 H); 3.73 (s, 3H); 3.71 (s, 2H); 3.71 - 3.62 (broad, 2H); 3.42 - 3.35 (b, 3H).
Step E: 1-(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3- carboxylic acid: When the product of Step D was substituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 36% yield, as creamy solid. 1H-NMR (CDCI3 + CD3OD) 8.31 (broad s, 1 H); 7.86 (broad s, 3H); 7.77 - 7.52 (m, 7H); 6.69 (s, 1 H); 4.21 (broad s, 2H); 4.18 - 4.02 (m, 4H); 3.3 (s, 1 H).
Example 31
3'-(1-Admantanyl)-4'methoxybiphenyl-4-yl)methyl)azetidine-3-carboxylic acid:
Step A: 2-(1 -Admantanyl)-4-bromophenol: To a stirred solution of A- bromophenol (1 g; 5.8 mmol) and admant-1 -ol (0.88 g; 5.8 mmol) in AcOH (5 ml) concentrated H2SO4 (1 ml) was added drop wise and stirring was continued for 50 h. The solvent was distilled to half of the volume and the mixture was poured onto ice cold H2O (100 ml) and extracted with EtOAc (150 ml). The organic layer was washed with NaHCO3 solution, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.976 g, 55%), as a colourless solid. 1H-NMR (CDCI3) 7.27 (d, 1 H, J = 2.43Hz); 7.13 (dd, 1 H, J = 8.4 - 2.43 Hz); 6.51 (d, 1 H, J = 8.37 Hz); 4.76 (s, 1 H, OH); 2.07 (s, 10H); 1.75 (b, 5H).
Step B: 2-(1-Admantanyl)-4-bromomethoxybenzene: To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K2CO3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH3I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H2O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94%), as light yellow green solid. 1H-NMR (CDCI3) 7.27 - 7.22 (m, 2H); 6.31 (d, 1 H, J = 6.5 Hz); 3.78 (s, 3H); 2.04 (s, 10H); 1.74 (b, 5H).
Step C: 3'-(1-Admantanyl)4'methoxy-4-carbaldehyde: When the product of Step B and 4-carbaldehyde-boronic acid were substituted for A- bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 42% yield, as pale solid. 1H-NMR (CDCI3) 10.02 (s, 1 H); 7.90 (d, 2H, J = 8.22 Hz); 7.70 (d, 2H, J = 8.22 Hz); 7.51 (d, 1 H, J = 2.31 Hz); 7.46 (dd, 1 H, J = 8.4 - 2.3 Hz); 6.95 (d, 1 H, J = 8.4 Hz); 3.88 (s, 3H); 2.14 (b, 6H); 2.07 (b, 3H); 1 .8 (b, 6H).
Step D: Methyl-1-3'-(1-admantanyl)4'methoxybiphenyl-4- yl)methyl)azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively in Example 22, Step C, the similar procedure afforded the title compound in 82% yield, as pale paste. 1H-NMR (CDCI3) 7.48 (d, 2H, J = 8.16 Hz); 7.42 (d, 1 H, J = 2.3 Hz); 7.37 (dd, 1 H, J = 8.4 - 2.3 Hz); 7.28 (d, 2H, J = 8.15 Hz); 6.91 (d, 1 H, J = 8.4 Hz); 3.85 (s, 3H); 3.7 (s, 3H); 3.62 (s, 2H); 3.56 - 3.52 (m, 2H); 3.35 - 3.31 (m, 3H); 2.13 (b, 5H); 2.06 (b, 3H); 1 .77 (b, 5H); 1.65 (b, 2H).
Step E: 3'-(1-Admantanyl)-4'methoxybiphenyl-4-yl)methyl)azetidine-3- carboxylic acid: When the product of Step D was substituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded title compound in 37% yield, as creamy solid. 1 H-NMR (CDCI3 + CD3OD) 7.53 (broad s, 4H); 7.36 (d, 1 H, J = 2.1 Hz); 7.31 (broad d, 1 H, J = 8.35 Hz); 6.87 (d, 2H, J = 8.47 Hz); 4.3 (s, 2H); 4.19 - 4.15 (m, 4H); 3.81 (s, 3H); 3.54 - 3.51 (m, 1 H); 2.07 - 2.00 (m, 9H); 1 .73 - 1 .71 (m, 6H).
Example 32
1-(4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3-carboxylic acid:
Step A: 3-(1-Admantanyl)-4-methoxybenzaldehyde: When A- hydroxybenzaldehyde was substituted for 4-bromophenol in Example 31 , Step A, the similar procedure afforded 3-(1 -admantanyl)-4-hydroxybenzaldehyde in 56% yield, as a pale white solid. 1H-NMR (CDCI3) 9.84 (s, 1 H); 7.78 (d, 1 H, J = 2.07 Hz); 7.61 (dd, 1 H, J = 8.13, 2.01 Hz); 6.77 (d, 1 H, J = 8.16 Hz); 5.88 (bs, 1 H); 2.12 (s, 6H); 2.09 (s, 3H); 1 .78 (s, 6H). This was methylated by similar procedure as described in Example 31 , Step B, to give the title compound in 64% yield, as light yellow solid. 1 H-NMR (CDCI3) 9.86 (s, 1 H); 7.76 (d, 1 H, J = 2.07 Hz); 7.7 (dd, 1 H, J = 8.4, 2.1 Hz); 6.95 (d, 1 H, J = 8.4 Hz); 3.91 (s, 3H); 2.09 (s, 9H); 1.76 (s, 6H).
Step B: 4-(3-(1-Admantnyl)-4-methoxybenzyloxy)benzaldehyde: To a stirred suspension of product of Step A (0.09 g, 0.32 mmol) in MeOH (5 ml) NaBH4 (0.018 g, 0.47 mmol) was added and the mixture was stirred for 0.5 h. The solvent was evaporated to dryness and the residue was taken in NaHCO3 solution and extracted with EtOAc (25 ml). The organic layer was separated, dried over MgSO4, and filtered. The filtrate was evaporated and the residue was dried in vacuo to give a relevant benzyl alcohol (0.095 g; 100%), as a creamy gum. 1H-NMR (CDCI3) 7.21 (d, 1 H, J = 2.17 Hz); 7.16 (dd, 1 H, J = 8.21 , 2.17 Hz); 6.83 (d, 1 H, J = 8.21 Hz); 4.59 (bd, 2H, J = 4.24 Hz); 3.82 (s, 3H, OMe); 2.08 (s, 6H); 2.05 (s, 3H); 1.76 (s, 6H). To a stirred solution of above product in anhydrous CH2CI2 (5 ml) CBr4 (0.14 g, 0.42 mmol) was added, followed by PPh3 (0.1 1 g, 0.42 mmol). The mixture was stirred for 1 h at room temperature and the solvent was distilled off. The residue was taken in EtOAc (10 ml) and the insoluble material was filtered off. The filtrate was evaporated to give the relevant benzyl bromide (0.14 g), which was added as a solution in DMF (2 ml) to a stirred suspension of 4-hydroxybenzaldehyde (0.069 g, 0.57 mmol) and K2CO3 (0.080 g, 0.58 mmol) in anhydrous DMF (3 ml) and this was stirred for 2 h at 70 5C. The mixture was quenched with saturated NH4CI solution and extracted with EtOAc (50 ml). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.05 g, 31 .4%), as colourless solid. 1H-NMR (CDCI3) 9.88 (s, 1 H); 7.82 (d, 2H, J = 8.78 Hz); 7.26 - 7.21 (m, 3H); 7.01 (d, 2H, J = 8.7 Hz); 6.87 (d, 1 H, J = 8.2 Hz); 5.04 (s, 2H); 3.83 (s, 3H); 2.08 (s, 6H); 2.05 (s, 3H); 1.76 (s, 6H).
Step C: Methyl 1 -(4-(3-(1 -admantanyl)-4-methoxybenzyloxy) benzyl)azetidine-3-carboxylate: When the product of Step B and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4-flurophenyl))- isopropyl)amino)methyl) thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 69% yield, as a pale paste. 1 H-NMR (CDCI3) 7.24 - 7.20 (m, 2H); 7.16 (d, 2H, J = 8.55 Hz); 6.91 (d, 2H, J = 8.62 Hz); 6.85 (d, 1 H, J = 8.17 Hz); 4.92 (s, 2H); 3.82 (s, 3H); 3.69 (s, 3H); 3.52 (s, 2H); 3.49 (s, 1 H); 3.47 (s, 2H); 3.31 - 3.24 (m, 3H); 2.08 (s, 6H); 2.04 (s, 3H); 1.75 (s, 6H).
Step D: 1 -(4-(3-(1 -Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3- carboxylic acid: When the product of Step C was substituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 61 % yield, as creamy solid. 1H-NMR (CDCI3:CD3OD) 7.33 (d, 2H, J = 8.59 Hz); 7.17 - 7.12 (m, 2H); 6.92 (d, 2H, J = 8.64 Hz); 6.79 (d, 1 H, J = 8.21 Hz); 4.87 (s, 2H); 4.13 (s, 2H); 4.08 - 4.02 (m, 4H); 2.0 (s, 6H); 1.97 (s, 3H); 1 .68 (s, 6H).
Example 33
1-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl)azetidine-3- carboxylic acid:
Step A: 4-(2-(6,6-Dimethylbicyclo[3.1. 1]heptan-2-yl)ethoxy)benzaldehyde: (6,6-Dimethylbicyclo[3.1 .1 ]hept-2-en-2-yl)ethanol was brominated as described in Example 32, Step B and the bromination product was used in next step without further purification, where it was treated with 4-hydroxybenzaldehyde as described in Example 32, Step B to afford the title compound in 91% yield, as creamy paste.
Step B: Methyl- 1-(4-(2-(6, 6-dimethylbicyclo[3.1.1]heptan-2- yl)ethoxy)benzyl) azetidine-3-carboxylate: When the product of Step A and azatadine 3 methylcaboxylate hydrochloride were substituted for 4-(5-(((4- flurophenyl))- isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure afforded the title compound in 76% yield, as light yellow paste. 1 H-NMR (CDCI3) 7.17 (d, 2H, J = 8.56 Hz); 6.81 (d, 2H, J = 8.61 Hz); 3.91 (t, 2H, J = 1 .98 Hz); 3.71 - 3.65 (m, 7H); 3.44 - 3.41 (m, 3H); 2.03 - 1.17 (m, 10H); 1 .17 (s, 3H); 1.01 (s, 3H).
Step C: 1-(4-(2-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)ethoxy)benzyl) azetidine-3-carboxylic acid: When the product of Step B was substituted for methyl-1 -(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 87% yield, as creamy paste. 1H-NMR (CDCI3 + CD3OD) 7.21 (d, 2H, J = 7.98 Hz); 6.79 (d, 2H, J = 7.99 Hz); 3.94 - 3.71 (m, 8H); 3.27 - 3.25 (m, 1 H); 2.36 - 1 .20 (m, 10H); 1.14 (s, 3H); 0.97 (s, 3H).
Example 34
1-(4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3- carboxylic acid:
Step A: 6-Bromo-4-oxo-2-(phenylamino)-4H-chromene-3-carbaldehyde: To a stirred solution of 6-bromo-4-oxo-4H-chromene-3-carbaldehyde (2 g, 7.93 mmol) in anhydrous benzene (15 ml) phenyl-hydroxylamine (0.95 g, 8.71 mmol) was added. The solution was kept for 1 h at room temperature when the crystalline solid appeared. To this glacial AcOH (0.5 ml) was added and the mixture was stirred for 5 h at reflux. The solvent was distilled off and the residue was crystallized from MeOH to give the title compound (2.1 g, 78%), as yellow crystalline solid. 1H-NMR (CDCI3) 12.43 (broad s, 1 H); 10.28 (s, 1 H); 8.34 (d, 1 H, J = 2.46 Hz); 7.69 (dd, 1 H, J = 8.76, 2.49 Hz); 7.46 - 7.29 (m, 6H).
Step B: 2-Bromo-12H-chromeno[2,3-b]quinolin-12-one: To the product of Step A (1 g; 2.92 mmol) concentrated H2SO4 (1 ml) was gently added with stirring. The mixture was kept in sealed vial for 24 h, at room temperature, than poured onto ice water and extracted with CH2CI2 (50 ml). The organic layer was washed with NaHCO3 solution, H2O, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was crystallized from CH3CN to give the title compound (0.73 g, 77%), as green yellow solid. 1 H-NMR (CDCI3) 9.28 (s, 1 H); 8.44 (d, 1 H, J = 2.1 Hz); 8.1 - 8.06 (m, 2H); 7.94 - 7.84 (m, 2H); 7.63 (t, 1 H, J = 7.88 Hz); 7.51 (d, 1 H, J = 8.83 Hz).
Step C: 4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzaldehyde: When the product of Step B and 4-carbaldehyde-boronic were substituted for 4- bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 52% yield, as off white solid. 1H-NMR (CDCI3) 10.08 (s, 1 H); 9.33 (s, 1 H); 8.6 (d, 1 H, J = 2.34 Hz); 8.14 - 8.05 (m, 3H); 8.00 (d, 2H, J = 8.25 Hz); 7.96 - 7.89 (m, 1 H); 7.85 (d, 2H, J = 8.22 Hz); 7.74 (d, 1 H, J = 8.7 Hz); 7.64 (t, 1 H, J = 7.8 Hz).
Step D: Methyl- 1-(4-(12-oxo- 12H-chromeno[2,3-b]quinolin-2-yl)benzyl) azetidine-3-carboxylate: When the product of Step C and azatadine 3 methylcaboxylatθ hydrochloride were substituted for 4-(5-(((4- flurophenyl))isopropyl)amino) methyl) thiophen-2-yl) benzaldehyde and sarcosine hydrochloride, respectively, in Example 22, Step C, the similar procedure affored the title compound in 48% yield, as pale paste. 1H-NMR (CDCI3) 9.32 (s, 1 H); 8.53 (s, 1 H); 8.12 - 8.07 (m, 2H); 8.00 (dd, 1 H, J = 8.7, 2.4 Hz); 7.91 (t, 1 H, J = 5.55 Hz); 7.7 - 7.6 (m, 4H); 7.38 (d, 2H, J = 8.22 Hz); 3.71 (s, 3H); 3.67 (s, 2H); 3.57 - 3.53 (m, 2H); 3.39 - 3.35 (m, 3H).
Step E: 1-(4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3- carboxylic acid: When the product of Step D was sunstituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy)benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 50% yield, as yellow solid. 1H-NMR (CDCI + CD3OD) 9.25 (broad s, 1 H); 8.44 (m, 2H); 7.76 - 7.54 (m, 5H); 4.31 - 4.07 (m, 4H); 4.27 - 3.95 (m, 2H).
Example 35 1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylic acid
Step A: (5-Chlorobenzofuran-3-yl)methanol: To a mixture of 4-chloro-2- iodophenol (1 g, 3.92 mmol), tert-butyl(3-(tert-butyldimethylsilyl)prop-2-ynyloxy)- dimethylsilane (1 .93 g, 6.8 mmol), LiCI (0.15 g; 3.5 mmol) and Na2CO3 (0.636 g; 6 mmol) in anhydrous DMF (10 ml) Pd(OAc)2 (0.3 g) was added at 100 5C under N2 and heating was continued for 1 .5 h. The solvent was removed in vacuo and the residue was diluted to 100 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the coupling product (0.64 g; 26%). This was dissolved in THF (5 ml) and 1 M TBAF in THF (2 ml) was added to it and the mixture was stirred for 4 h at reflux. The solvent was distilled off and the residue was dilute to 50 ml with EtOAc, washed with 1 M HCI, H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.33 g; 99%), as creamy paste. 1 H-NMR (CDCI3) 7.63 (d, 1 H, J = 2.1 1 Hz); 6.60 (b, 1 H); 7.37 (d, 1 H, J = 8.72 Hz); 7.25 (dd, 1 H, J = 8.71 , 2.13 Hz); 4.79 (s, 2H).
Step B: 4-((5-Chlorobenzofuran-3-yl)methoxy)benzaldehyde: When the product of Step A was substituted for 3-(1 -admantanyl)-4-methoxy benzaldehyde in Example 32, Step B, the similar procedure afforded the title compound in 9% yield, as pale paste. 1 H-NMR (CDCI3) 9.89 (s, 1 H); 7.84 (d, 2H, J = 8.74 Hz); 7.72 (s, 1 H); 7.60 (d, 1 H, J = 2.07 Hz); 7.41 (d, 1 H, J = 8.76 Hz); 7.28 (dd, 1 H, J = 8.75, 2.09 Hz); 7.09 (d, 2H, J = 8.73 Hz); 5.23 (s, 2H).
Step C: Methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl) azetidine- 3-carboxylate: When the product of Step B and azatadine 3-methylcaboxylate hydrochloride were substituted for 4-(5-(((4- fluorophenyl)(isopropyl)amino)methyl)- thiophen-2-yl) benzaldehyde and sarcosine hydrochloride, respectfully, in Example 22, Step C, the similar procedure afforded the title compound in 45% yield, as off white solid. 1H-NMR (CDCI3) 7.68 (s, 1 H); 7.60 (bs, 1 H); 7.39 (d, 2H, J = 8.77 Hz); 7.28 - 7.18 (m, 3H); 6.93 (d, 2H, J = 6.62 Hz); 5.12 (s, 2H); 3.69 (s, 3H); 3.54 - 3.47 (m, 5H); 3.36 - 3.28 (m, 4H).
Step D: 1 -(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3- carboxylic acid: When the product of Step C was substituted for methyl-1 -(4-((5- chlorobenzofuran-3-yl)methoxy) benzyl) azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 57% yield, as creamy solid. 1H-NMR (CDCI3 + CD3OD) 7.78 (s, 1 H); 7.57 (d, 2H, J = 2.06 Hz); 7.53 (s, 1 H); 7.39 (d, 1 H, J = 8.8 Hz); 7.36 (d, 2H, J = 8.66 Hz); 7.24 (dd, 1 H, J = 8.75, 2.12 Hz); 7.04 (d, 2H, J = 8.67 Hz); 5.18 (s, 2H); 4.20 - 4.06 (m, 6H); 3.36 - 3.27 (m, 1 H).
Example 36
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 5C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. 1H-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- oxadiazole: A mixture of S-chloro^-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 5C . 1 M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 1 10 5C. The reaction mixture was diluted to 20 ml with H2O and extracted with EtOAc (2 x 15 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.22 g, 47.4%), as a colourless solid. 1 H-NMR (CDCI3) 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 MgSO4 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 ferf-butyl 5-ethynyl-2,2-dimethyl-1 ,3- dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml: 0.3 ml) was degassed with N2 and CI2Pd(PPh3)4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45 5C under N2, diluted to 20 ml with saturated NH4CI and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, 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, 2 H, 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 (SiO2, 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 37
(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 (E)-3-p-tolylacrylic acid was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar process afforded the title compound in 52% yield, as colourless 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 the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo- 4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 53% yield, as colourless solid. 1H-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 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 36, Step D, the similar process afforded the title compound in 68% yield, as pale paste. 1H-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 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 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. 1H-NMR (DMSOd6) 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 38
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 36, Step B, the similar procedure afforded the title compound in 72% yield, as creamy solid. 1H-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 36, Step C, the similar procedure afforded the title compound in 86% yield, as creamy solid. 1H-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 36, 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 36, Step E, the similar procedure afforded the title compound in 39% yield, as creamy solid. 1H-NMR (DMSO-de) 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 39
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 H2O (5 ml:1 ml), Pd(PPh3)4 (0.03 g) was added at 80 5C, followed by the NaHCO3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2, hexane/EtOAc), to give the title compound (0.065 g, 71 %), as pale paste. 1H-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: When 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 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. 1 H-NMR (DMSOd6) 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 40
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 36, Step B, the similar procedure afforded the title compound in 60% yield, as colourless solid. 1H-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 36, Step C, the similar procedure afforded the title compound in 84% yield, as a creamy solid. 1H-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 36, Step D, the similar procedure afforded the title compound in 66% yield, as creamy paste. 1H-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 36, Step E, the similar procedure afforded the title compound in 61 % yield, as creamy solid. 1H-NMR (DMSOd6) 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 41
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 36, 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 36, Step C, the similar procedure afforded the title compound in 80% yield, as creamy solid. 1H-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 36, Step D, the similar procedure afforded the title compound in 68% yield, as pale paste. 1H-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: 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 36, Step E, the similar procedure afforded the title compound in 57% yield, as colourless solid. 1H-NMR (DMSO-de) 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 42 5-(3,4-Diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1,2,4-oxadiazole
Step A: 2-Methylbenzofuran-5-carbonitrile: 2-lodo-4-cynophenol (0.25 g, 1 mmol) and saccharin (0.1 g) in HMDSA (2 ml) was refluxed for 2 h under N2, until the solution became clear. The solvent was distilled off under reduced pressure and the residue was dissolved in anhydrous THF (2 ml). This was added to a solution made by mixing anhydrous ZnCI2 (0.3 g; 2.2 mmol) with 0.5 M 1 -propynyl magnesium bromide in THF (7.8 ml) in anhydrous THF (5 ml) at room temperature under N2 To it, Pd (PPh3)4 (0.15 g) was added at room temperature under N2 followed by catalytic amount of CuI. The mixture was stirred at room temperature for 3 h and quenched with saturated NH4CI solution. The mixture was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was dissolved in 1 ,4-dioxane (4 ml) and 1 M TBAF in THF (0.3 ml) was added and this was stirred for 4 h at reflux. The solvent was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.145 g, 91 %), as colourless solid. 1H-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: The product Step A was converted to Λ/-hydroxy-2-methylbenzofuran- 5-carboximidamide by method described for Example 36, Step A. When N- hydroxy-2-methylbenzofuran-5-carboximidamide and 3,4-diethoxybenzoic acid were substituted for Λ/-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro- 4-propoxybenzoic acid, respectively, in Example 36, Step B, the similar procedure afforded the title compound in 6% yield, as colourless solid. 1H-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 43
2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1,3-diol
Step A: Ethyl 2-(2-formyl-5-methoxyphenoxy)acetate: A mixture of 2- hydroxy-4-methoxybenzaldehydθ (1 g; 6.58 mmol), BrCH2CO2Et (0.806 ml; 7.24 mmol) and K2CO3 (1 g, 7.24 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and H2O (100 ml). The organic layer was separated and dried over MgSO4, and filtrate evaporated, to give the product (1 .29 g; 97%), as colourless solid. 1H- NMR (CDCI3) 1.28 (tr, 3H, J = 7.1 1 Hz); 3.84 (s, 3H); 4.25 (q, 2H, J = 7.14, 14.28 Hz); 4.69 (s, 2H); 6.30 (d, 1 H, J = 2.16 Hz); 6.58 (dd, 1 H, J = 1 .77, 8.73 Hz); 7.83 (d, 1 H, J = 8.7 Hz); 10.36 (S1 1 H).
Step B: Ethyl 6-methoxybenzofuran-2-carboxylate: A mixture of the product of Step A (1 .28 g, 5.37 mmol) and DBU (0.3 ml) was heated for 3 h at 160 5C with stirring, cooled to room temperature and dissolved in EtOAc: MeOH mixture (99:1 ). The mixture was filtered through the silica bead and the filtrate was evaporated to give the title compound (1 .1 1 g; 77%), as colourless solid. 1H- NMR (CDCI3) 1.40 (tr, 3H, J = 7.13 Hz); 3.85 (s, 3H); 4.40 (q, 2H, J = 7.13, 14.25 Hz); 4.45 (s, 1 H); 6.91 (dd, 1 H, J = 2.25, 8.68 Hz); 7.04 (d, 1 H, J = 1.87 Hz); 7.51 (d, 1 H, J = 5.17 Hz),
Step C: 6-Methoxybenzofuran-2-carboxylic acid: To a stirred solution of Product of Step B (0.25 g, 1.21 mmol) in a mixture of THF, MeOH and H2O (5 ml : 2 ml : 1 ml), LiOH (0.145 g, 6 mmol) in H2O (0.5 ml) was added and the mixture was stirred for 3 h at room temp. The solvents were distilled off and the residue was portioned between EtOAc (20 ml) and 1 M HCI (2 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.21 g, 91 %), as a colourless solid. 1H-NMR (DMSO-de) 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 D: 3-(3-lodo-4-isopropoxyphenyl)-5-(6-methoxybenzofuran-2-yl)- 1,2,4- oxadiazole: When the product of Step C was substituted for 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 67% yield, as colourless solid. 1H-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 E: 2-lodo-4-(5-(6-methoxybenzofuran-2-yl)-1,2,4-oxadiazol-3- yl)phenol: When the product of Step D was substituted for 5-(3-chloro-4- propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1 ,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 65% yield, as colourless solid. 1H-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 F: 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 the product of Step E was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)- 2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 64 % yield, as pale paste..
Step G: 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)- 1,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol: When the product of Step F 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 36, Step E, the similar procedure afforded the title compound in 26% yield, 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 44
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 36, Step B, the similar procedure afforded the title compound in 82% yield, as colourless solid. 1H-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: 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 36, 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 36, Step D, the similar procedure afforded the title compound in 35% yield, as pale paste. 1 H-NMR (CDCI3) 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- 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 36, Step E, the similar procedure afforded the title compound in 28% yield, as creamy solid. 1 H-NMR (DMSOd6) 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 45
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-chlorc-4-propoxy benzoic acid in Example 36, Step B, the similar procedure affored 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 36, 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 36, Step D, the similar procedure afforded the title compound in 60% yield, as pale paste. 1 H-NMR (CDCI3) 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-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 36, Step E, the similar procedure afforded the title compound in 32% yield, as light yellow solid. 1H-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 46
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 CF3CO2Ag (1 .3 g, 5.1 mmol) in CH2CI2 (50 ml) I2 (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 (SiO2, 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 Λ/-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4- propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 20% yield, as white solid. 1H 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 36, 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 36, 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 47
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 5C. The mixture was quenched with saturated NH4CI and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 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. 1H 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 5C 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 H2O, dried over MgSO4 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 = 7.1 1 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 H2O (15ml : 3 ml) KMnO4 (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. 1 H NMR (CDCI3) 7.8 (s, 1 H); 7.56 (b, 1 H); 4.05 (b, 2H); 1.7 (b, 2H); 1 .18 (b, 2H); 0.83 (b, 3H). Step B: 5-(1 -Butyl-1 H-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 36, Step B the similar procedure afforded the title compound in 17% yield, as creamy gum. 1 H NMR (CDCI3) 8.53 (d, 1 H, J = 2.07 Hz); 8.1 (s, 1 H); 8.08 (s, 1 H); 8.00 (dd, 1 H, J = 8.61 , 2.16 Hz); 8.87 (d, 1 H, J = 8.73 Hz); 4.68 - 4.6 (m, 2H); 4.2 (t, 2H, J = 7.1 1 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-1 H-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 36, Step C, the similar procedure afforded the title compound in 72% yield, as creamy solid. 1 H NMR (CDCI3) 8.45 (d, 1 H, J = 1 .98 Hz); 8.12 (s, 1 H); 8.09 (s, 1 H); 7.99 (dd, 1 H, 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-1 H-pyrazol-4-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 4-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)- 2-iodophenol in Example 36, 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, 1 H); 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 36, Step E, the similar procedure afforded the title compound in 46% yield, as light creamy solid. 1 H NMR (CD3OD) 8.46 (broad s, 1 H); 8.32 (broad s, 1 H); 8.13(broad s, 1 H); 8.02 (d, 1 H, J = 7.98 Hz); 7.62 (d, 1 H, J = 8.31 Hz); 6.97 (s, 1 H); 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 48
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 H2O (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 H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.32g, 97%), as creamy solid. 1H 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 36, Step B, the similar procedure afforded the title compound in 66% yield, as creamy solid. 1H 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 36, 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 36, 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 36, Step E, the similar procedure afforded the title compound in 49% yield, as creamy solid. 1 H NMR (DMSO-de) 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 49
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 MgSO4 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. 1H NMR (CDCI3) 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 36, Step B, the similar procedure afforded the title compound in 57% yield, as creamy solid. 1H 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 36, Step C, the similar procedure afforded the title compound in 74% yield, as creamy solid. 1H NMR (CDCI3) 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 36, Step D, the similar procedure afforded the title compound in 44% yield, as pale paste. 1H 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 36, Step E, the similar procedure afforded the title compound in 29% yield, as off white solid. 1H NMR (DMSOd6) 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 50
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-propoxybenzaldθhydθ was oxidized by KMnO4, according to the procedure as described in Example 47, 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 36, 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: When 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 36, 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 36, Step E, the similar procedure afforded the title compound in 10% yield, as light yellow solid. 1H 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 51 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 H2O2 (30 %, 0.5 ml) in CH3OH (1 .5 ml) was added I2 (0.2 g, 0.8 mmol) and the mixture was stirred overnight at room temperature. The solvent was distilled off and the residue was diluted to 10 ml with CH2CI2, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give 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) an ice cold solution of NaNO2 (0.1 g, 1 .3 mmol) in H2O (1 ml) was added at O5C, followed by a solution of K- ethylxhanthate, freshly prepared by rapid stirring of a mixture of KOH (0.085 g, 1.5 mmol) and CS2 (0.173 g, 1 .5 mmol) in a mixture of EtOH and H2O (1 ml : 1 .5 ml) for 2.5 h at room temperature. The resulting mixture was stirred for 5 h at 55 5C, than cooled to room temperature and extracted with EtOAc (50 ml). The organic layer was separated, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was diluted to 20 ml with EtOH and KOH (0.5 g, 3.62 mmol) was added. This was stirred for 5 h at reflux and the mixture was evaporated to dryness and the residue was treated with 1 M HCI and extracted with EtOAc (20 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.1 g, 24%), as a yellow paste, which was used as such in next step. 1H 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 with the product of Step B was substituted for 4-(5-(3- chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 24% yield, as white solid. 1H 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, 2H1 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 36, 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 52 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), CF3CO2Ag (0.25 g, 1 mmol) and I2 (0.185 g, 0.73 mmol) in CH2CI2 (10 ml) was stirred for 0.5 h at 0 5C , then for 0.5 h at room temperature. The solution was filtered through Celite bead and washed with CH2CI2 (30 ml). The filtrates were evaporated to dryness 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 with the product of Step A was substituted for 4-(5-(3-chloro- 4-propoxyphenyl)-1 ,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 53% yield, as a light yellow paste. 1H 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 the product of Step B 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-yl- carbamate in Example 36, Step E, the similar procedure afforded the title compound in 51 % yield, 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 53
2-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)acetic acid
Step A: N-Hydroxy-IH-indole-4-carboximidamide: A mixture of A- cyanoindolθ (0.64 g; 4.5 mmol), HCI x H2NOH (1.1 g; 15.8 mmol), and Na2CO3 (0.79 g; 7.43 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6h under N2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3 x 10 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. 1H-NMR (DMSO-d6 + CDCI3 + CD3OD) 7.4 - 7.3 (m, 1 H); 7.2 - 7.12 (m, 2H); 7.01 (t, 1 H, J = 7.8 Hz); 6.74 (d, 1 H, J = 3.1 Hz); 3.68 (HDO); 1 .71 (broad s, H2O).
Step B: 5-(3,4-Diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole To a solution of 3,4-diethoxybenzoic acid (0.1 1 g; 0.52 mmol), and the product of Step A (0.09 g; 0.51 mmol) in anhydrous THF (2 ml), PyBroP (0.25 g; 0.54 mmol) was added followed by DIPEA (0.21 ml; 1.22 mmol), with stirring, at room temperature under N2. After 2 h of stirring, the mixture was diluted to 15 ml with EtOAc, washed with saturated NH4CI (2 x 5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was suspended in anhydrous toluene (10 ml). To it 1 M TBAF in THF (0.5 ml) was added and the reaction mixture was refluxed for 3 h under N2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H2O (5 ml) and the solid was purified by FCC (SiO2; CH2CI2) to give the title compound (0.06 g; 34%) as colourless solid. 1H-NMR (CDCI3) 8.42 (s, 1 H); 8.06 (dd, 1 H, J = 2, 8.4 Hz); 7.83 (d, 1 H, J = 8.4Hz); 7.74 (d, 1 H, J = 2 Hz); 7.54 (d, 1 H, J = 8.1 Hz); 7.37 - 7.31 (m, 3H); 6.98 (d, 1 H, J = 8.5 Hz); 4.26 - 4.16 (no, 4H); 1 .5 (m, 6H).
Step C: 5-(3,4-Diethoxyphenyl)-3-(indolin-4-yl)-1,2,4-oxadiazole: To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1 M BH3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at O0C with stirring. After the addition was completed (~5 min), the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2 x 2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1 H-NMR (CDCI3) 7.78 (dd, 1 H, J = 1.9, 7.2 Hz); 7.68 (d, 1 H, J = 1 .9 Hz); 7.52 (d, 1 H, J = 7.2 Hz); 7.17 (t, 1 H, J = 7.7); 6.97 (d, 1 H, J = 8.5 Hz); 6.75 (d, 1 H, J = 7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J = 8.9 Hz); 3.45 (tr, 2H, J = 8.9 Hz); 1 .7 (broad s, 1 H + H2O); 1 .49 (m, 6H).
Step D: Ethyl 2-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)acetate: When the product of Step E was substituted for n- octylaniline and ethyl isocyanatoacetate was substituted for ethyl 3- isocyanatopropionate in Example 1 1 , Step A the similar process afforded the title compound in 61 %, as colourless solid. 1H-NMR (CDCI3) 8.1 1 (d, 1 H, J = 7.4 Hz); 7.78 (dd, 2H, J = 2, 7.1 Hz); 7.67 (d, 1 H, J = 2 Hz); 7.31 (t, 1 H, J = 8 Hz); 6.97 (d, 1 H, J = 8.5 Hz); 5.13 (t, 1 H, J = 5.1 Hz); 4.28 - 4.04 (m, 10 H); 3.61 (t, 1 H, J - 8.6 Hz); 1.52 - 1.47 (m, 6H); 1 .32 (t, 3H, J = 7.1 Hz);
Step E: 2-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamidojacetic acid: When the product of Step D was substituted for ethyl 3- (3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B the identical process afforded the title compound in 75 % yield. 1H-NMR (DMSO-d6) 8.03 (d, 1 H, J = 9 Hz); 7.73 (dd, 1 H, J = 2, 8 Hz); 7.61 - 7.59 (m, 2H); 7.29 (t, 1 H, J = 7.9 Hz); 7.17 (d, 1 H, J = 8.6 Hz); 7.09 (broad m, 1 H); 4.17 - 4.0 (m, 4H); 3.98 (t, 2H, J = 5.8 Hz); 3.74 (d, 2H, J = 5.2 Hz); 3.47 (t, 2H, J = 9 Hz); 1.38 - 1.32 (m, 6H).
Example 54
3-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoic acid
Step A: Ethyl 3-(4-(5-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoate: When the product of Example 16 Step C was substituted for n-octylaniline in Example 11 , Step A the identical process afforded the title compound in 52 % yield. 1H-NMR (CDCI3) 8.1 (d, 1 H, J = 9 Hz); 7.79 - 7.75 (m, 2H); 7.67 (d, 1 H, J = 2 Hz); 7.31 (t, 1 H, J = 8 Hz); 6.97 (d, 1 H, J = 8.5 Hz); 5.38 (tr, 1 H, J = 5.7 Hz); 4.24 - 4.12 (m, 6H); 3.98 (t, 2H, J = 8.6 Hz); 3.63 - 3.55 (m, 4H); 2.61 (t, 2H1 J = 5.9 Hz); 1.27 (t, 3H, J = 9 Hz);
Step B: 3-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoic acid: When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 1 1 , Step B the identical process afforded the title compound in 61 % yield. 1H-NMR (CDCI3) 8.03 (d, 1 H, J = 9 Hz); 7.72 (dd, 1 H, J = 1 .9, 8.4 Hz): 7.59 - 7.56 (m, 2H); 7.27 (t, 1 H, J = 7.9 Hz); 7.16 (d, 1 H, J = 8.6 Hz); 6.76 (t, 1 H, J = 5.3 Hz); 4.04 - 4.16 (m, 4H); 3.92 (t, 2H, J = 8.6 Hz); 3.43 (tr, 2H, J = 8.4 Hz); 3.36 - 3.28 (m, 2H + H2O); 2.48 - 2.42 (m, 2H); 1 .37 - 1 .32 (m, 6H).
Example 55
S1 P receptors activity evaluation
Selected Compounds of the Examples were evaluated at Millipore Corporation, USA , using S1 P1 receptor; [35S]-GTPgamaS binding assay. A [35S]-GTPgamaS binding assay at Millipore was conducted by GPCR Profiler™ Custom Service Laboratory, Temecula, CA, Millipore, Inc. to monitor dose- dependent agonist selectivity for selected Examples against the S1 P1 receptors. The assay was completed with sample compounds subjected to an eight-point, four-fold dose response curve with starting concentration of 10μM. Selectivity was determined upon initial addition of compounds followed by a 30 minute incubation at 305C. Following compound incubation, bounded [35S]-GTPgamaS was determined by filtration and scintillation counting. Percentage activation and inhibition values were determined relative to the reference agonist at S1 P1 and are shown in Table 10.
Independently, selected compounds were evaluated for S1 P1 and S1 P3 agonistic activity. The S1 P1 assay system was GTPgama-S35 binding in membranes from CHO K1 cells, expressing S1 P1 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 μM. 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 10.
Figure imgf000111_0001
NA = no activity; ND = not determined.
Example 56 Lymphopenia Assay
The study was performed at wVoPharm Pty Ltd, Adelaide, Australia, to determine the ability of the compounds of invention to induce lymphopenia in female BALB /c mice. On day 0, 27 female BALB/c mice were randomised based on body weight into nine groups of three mice each. Animals received a single i.p. administration of Test compounds and blood was collected by cardiac puncture either 6 or 24 h after administration. Treatment with 3 mg/kg of Example 40 was shown to decrease lymphocyte counts at both 6 and 24 h, compared to untreated animals (Figure 1 ). Changes to other haematological parameters were not observed.

Claims

CLAIMS:
1. A compound of formula (I):
Figure imgf000113_0001
(I)
wherein G represents an organic substituent comprising in any combination one or more nitrogen, oxygen or sulphur atom(s), Z represents an organic moiety comprising at least one aromatic centre, X and Y separately, or in combination, are alkyl, alkyl-amino, alkoxy, an alkyl chain containing one or more of O, N, S, SO, SO2, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond, carbocycle, heterocycle or a group selected from the following:
R O O
JL ΛΛT N
JVΛ' T" /Λ\
R, O O
wherein R1 is selected from H or alkyl, the asterisk indicating the attachment within formula (I); and wherein the groups J, m and D separately, or in any combination, are selected from hydrogen, deuterium, alkyl, alkoxy, alkylamino, halogen, amino, hydroxy, oxo (=0), imino (=NR), cyano, aryl, heterocycle, carbocycle, alkyl chain of 1 -15 carbon atom optionally containing carbon-carbon multiple bond, carbon- hetero multiple bond wherein one or more carbon atoms can be independently replaced with oxygen, sulphur, SO, S02, NR' (wherein R' is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle), carbocycle and heterocycle.
2. The compound of claim 1 wherein G is a group selected from the following:
Figure imgf000114_0001
HO
NH2 NH O ••^ NH Nx^R VΛ ^s-#O
V_J •0 *-N>kN^R
HO
Figure imgf000114_0002
Figure imgf000114_0003
wherein R is independently selected from H, deuterium, CN, amino, alkylamino, CH2OH, alkoxy, CF3, an alkyl chain optionally containing one or more of deuterium, O, NR'R" (wherein R' and R" are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle) S, SO, SO2, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond or a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, sulphonamide, hydroxyl, -CH2COOH, COOH, - OPO3H2, -PO3H2, cyclic phosphate, cyclic phosphonates and/or salts, tetrazole, and n is 0-4, with the proviso that if an amino group is present on the same carbon atom as R in group G, R is not hydroxyl, -'' ->> represents an optional bridging group; the asterisks indicating the attachment within formula (I).
3. The compound of claims 1 or 2 wherein X, Y and Z separately, or in any combination, are selected from the following:
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
wherein the asterisks indicate the attachment within formula (I), R2 is selected from halogen, H, deuterium, CN, amino, alkylamino, alkoxy, CF3, an alkyl chain (up to 20 carbon atoms) optionally containing one or more of deuterium, O, NR'R" (wherein R' and R" are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle) S, SO, SO2, halogen, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-heteroatom double bond or a carbon-hetero atom triple bond, carbocycle, heterocycle, amide, sulphonamide and A represents one or more ring atoms or groups independently selected from the group consisting of C, N, O, S, CO, C=NR, SO or SO2, R3 may be a linking group or alkyl, aryl, heterocycle or an optionally substituted alkyl chain.
4. The compound of claims 1 or 2 wherein Z and G, in combination, are selected from the following groups:
Figure imgf000116_0001
wherein R is as defined for group G in claim 1 , wherein A is defined as in claim 3 and X is selected from the group consisting of heteroatom or heteroatom containing species such as O, N, S, SO, S02, CO or C=NR and R2 is as defined in claim 3, the asterisks indicating the attachment within formula (I),
Figure imgf000116_0002
wherein A is as defined in claim 3 and X and Y are independently selected from the group consisting of heteroatom or heteroatom containing species such as O, N, S, SO, S02, CO or C=NR and R2 is as defined as in claim 3, the asterisks indicating the attachment within formula (I).
5. The compound of any one of claims 1 to 4 wherein the group J is selected from H, alkyl or one of the following groups:
Figure imgf000117_0001
wherein A is as defined in claim 3, n is 0-10, R4 is halogen, CN, amino, alkylamino, alkoxy, CF3, an alkyl chain containing one or more of O, N, S, SO, SO2, a carbon-carbon double bond, a carbon-carbon triple bond, a carbon- heteroatom double bond or a carbon-hetero atom triple bond.
6. The compound of any one of claims 1 to 5 wherein the group D is selected from H, deuterium, alkyl, aryl, heterocycle or cycloalkyl.
7. The compound of any one of claims 1 to 6 wherein the group m, is selected from unsubstituted or substituted aryl, carbocycle or heterocycle.
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 N-(1 H-Tetrazol-5-yl)methyl-4-octylbenzylamine N-((1 H-Tetrazol-5-yl)methyl)-4-n-octylaniline 2-(4-Octylphenylamino)propane-1 ,3-diol 2-((4-n-Octylbenzylamino)methyl)propane-1 ,3-diol 2-((Methyl(4-octylbenzyl)amino)methyl)propane-1 ,3-diol 4,4-Bis(hydroxymethyl)-1 -(4-octylphenyl)imidazolidin-2-one 2-(4-(4-n-Octylphenyl)piperazin-1-yl)acetic acid 2-(4-Octylphenethyl)propane-1 ,2,3-triol 3-(3-(4-n-Octylphenyl)ureido)propanoic acid 3-(3-Methyl-3-(4-octylphenyl)ureido)propanoic acid 3-(3-(4-Octylphenyl)-2-oxoimidazolidin-1 -yl)propanoic acid 2-(3-(4-Octylbenzyl)ureido)acetic acid 2-(3-(4-Octylbenzyl)-2-oxoimidazolidin-1 -yl)acetic acid 2-(1 -(4-Octylbenzyl)hydrazine-carboxamido)acetic acid 3-(5-Octylindoline-1 -carboxamido)propanoic acid 4-(4-(N-(6,6-Dimethylbicyclo[3.1.1 ]heptan-2-yl)sulfamoyl)phenyl)butyl- dihydrogen phosphate:
4-(4-(3-(3-(2,2,2-trifluoroacetyl)-1 H-indol-1 -yl)propyl)phenyl)butyl- dihydrogen phosphate
4-(4-(2-(6,6-Dimethylbicyclo[3.1.1 ]heptan-2-yl)ethoxy)phenyl)butyl- dihydrogen phosphate
2-(4-(2-(6-Methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)ethanol 2-((4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2-yl)benzyl) (methyl) amino)ethanol
2-(4-(5-(((4-Fluorophenyl)(isopropyl)amino)methyl)thiophen-2- yl)benzylamino) propane-1 ,3-diol
2-(4-(3-((4-Fluorophenyl)(isopropyl)amino)propyl)benzylamino)propane-1 ,3- diol hydrochloride
1 -((4'-(N-(3-methoxyphenyl)-N-methylsulfamoyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid 2-(((4'-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl)(methyl) amino)acetic acid 1 -((4p-(((4-Fluorophenyl)(isopropyl)amino)methyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid:
1 -(4-(4-Oxo-4-(3,4,5-trimethoxyphenyl)but-2-en-2-yl)benzyl)azetidine-3- carboxylic acid
1 -((4'-(3-(3-(Trifluoromethyl)phenyl)but-2-enoyl)biphenyl-4- yl)methyl)azetidine-3-carboxylic acid:
1 -(4-(4-Oxo-2-phenyl-4H-chromen-6-yl)benzyl)azetidine-3-carboxylic acid: 3'-(1 -Admantanyl)-4'methoxybiphenyl-4-yl)methyl)azetidine-3-carboxylic acid:
1 -(4-(3-(1 -Admantnyl)-4-methoxybenzyloxy)benzyl)azetidine-3-carboxylic acid: 1 -(4-(2-(6,6-Dimethylbicyclo[3.1.1 ]heptan-2-yl)ethoxy)benzyl)azetidine-3- carboxylic acid:
1 -(4-(12-Oxo-i 2H-chromeno[2,3-b]quinolin-2-yl)benzyl)azetidine-3- carboxylic acid:
1 -(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylic acid 2-Amino-2-(5-(5-(3-chloro-4-propoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol
(E)-2-Amino-2-(5-(5-(4-methylstyryl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol
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-(3,4-diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)benzofuran-2- yl)propane-1 ,3-diol
2-Amino-2-(5-(5-(4-propoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol
5-(3,4-Diethoxyphenyl)-3-(2-methylbenzofuran-5-yl)-1 ,2,4-oxadiazole 2-Amino-2-(5-(5-(6-methoxybenzofuran-2-yl)-1 ,2,4-oxadiazol-3- yl)benzofuran-2-yl)propane-1 ,3-diol
2-Amino-2-(5-(5-(4-propylphenyl)-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
5-(3-(2-(2-Amino-1 ,3-dihydroxypropan-2-yl)benzofuran-5-yl)-1 ,2,4- oxadiazol-5-yl)-2-propoxybenzonitrile
2-Amino-2-(5-(5-(3-bromo-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-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)acetic acid
3-(4-(5-(3,4-Diethoxyphenyl)-1 ,2,4-oxadiazol-3-yl)indoline-1 - carboxamido)propanoic acid
9. A compound as claimed in any one of claims 1 to 8 wherein the compound modulates S1 P receptor activity and/or expression.
10. A pharmaceutical preparation, 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).
1 1 . A process for the preparation of a compound as claimed in any one of claims 1 to 8.
12. 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 thereof in any ratio for the production of a pharmaceutical for the modulation of S1 P receptor activity and/or expression.
13. 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 thereof in any ratio for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression such as autoimmune disease.
14. 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 or physiologically tolerable and/or therapeutically effective salts or mixtures thereof in any ratio for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity and/or expression.
15. 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 thereof in any ratio for the treatment and/or immunotherapy of cancer, solid tumours, haematological disorders, infections, immunological and immune mediated disorders, pain, vascular, cardiovascular, liver disease/injury, lung pathologies/injury, hypoxia and/or allograft or autograft rejection.
16. 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 thereof in any ratio for the mobilization of progenitor/stem cells for regeneraration of tissue and/or organs.
17. 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 thereof in any ratio as adjuvant for vaccination/immunization.
18. 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 thereof in any ratio for the treatment of infection and/or infectious diseases.
19. 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 thereof in any ratio for the immunotherapy of pathogens other than viral, bacterial or fungal infections such as prions and parasites
20. A method of modulation of S1 P receptor activity and/or expression 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 or derivative thereof, to a subject in need.
21 . A method for the treatment of diseases and/or conditions caused by or associated with inappropriate S1 P receptor modulating activity or expression 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 thereof, to a subject in need.
22. A method of treating immunological disorders and/or immune mediated disorders or transplant/allograft/autograft 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 thereof, to a subject in need.
23. A method of prevention and/or treatment and/or immunotherapy of cancer 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 thereof, to a subject in need.
24. A method of prevention and/or prophylaxis and/or treatment and/or immunotherapy of viral, bacterial or fungal infections 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 thereof, to a subject in need.
25. A method of prevention and/or prophylaxis and/or treatment and/or immunotherapy of pathogens other than viral, bacterial or fungal infections such as prions and parasites 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 thereof, to a subject in need.
26. A method of prevention and/or prophylaxis and/or treatment and/or immunotherapy of proliferative and vascular pathologies/injury, cardiovascular pathologies/injuries, liver pathologies/injuries, lung pathologies/injuries, hypoxia and pain, 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 thereof, to a subject in need.
27. A method of boosting the action of immunization/vaccination 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 thereof, to a subject in need.
28. A method of improving drug delivery to a target organ 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 thereof, to a subject in need.
29. A modulator of an S1 P receptor activity and/or expression according to any one of claims 1 to 8.
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ES09820119.7T ES2590904T3 (en) 2008-10-17 2009-10-19 Modulators of S1P receptors and their use
AU2009304598A AU2009304598B2 (en) 2008-10-17 2009-10-19 S1P receptors modulators and their use thereof
JP2011531305A JP2012505836A (en) 2008-10-17 2009-10-19 S1P receptor modulators and their use
CA2740484A CA2740484C (en) 2008-10-17 2009-10-19 S1p receptors modulators and their use thereof
EP09820119.7A EP2344484B1 (en) 2008-10-17 2009-10-19 S1p receptors modulators and use thereof
NZ592748A NZ592748A (en) 2008-10-17 2009-10-19 2-Amino-(oxadiazol-3-yl)-benzofuran derivatives and their use as S1P receptor modulators
CN200980141188.9A CN102186845B (en) 2008-10-17 2009-10-19 S1P receptor modulators and their purposes
US14/066,276 US9193716B2 (en) 2008-10-17 2013-10-29 S1P receptors modulators and their use thereof
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