Abstract:
The present invention relates to alkene derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/763,430 filed Feb. 11, 2013, the disclosure of which is hereby incorporated in its entirety herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to alkene derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of the sphingosine-1-phosphate receptors. The invention relates to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1-phosphate (S1P) receptor modulation. 
       BACKGROUND OF THE INVENTION 
       [0003]    Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases. On the other hand the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation. 
       SUMMARY OF THE INVENTION 
       [0004]    A group of novel alkene derivatives, which are potent and selective sphingosine-1-phosphate modulators has been discovered. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of the sphingosine-1-phosphate receptors. The term “modulator” as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist. 
         [0005]    This invention describes compounds of Formula I, which have sphingosine-1-phosphate receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1P modulation. 
         [0006]    In one aspect, the invention provides a compound having Formula I, or an E geometric isomer, or a Z geometric isomer, or a mixture of an E and a Z geometric isomers, or an enantiomer, or a diastereoisomer, or a tautomer, or a zwitterion, or a pharmaceutically acceptable salt thereof: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein: 
         [0007]    A is optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl or optionally substituted C 3-8  cycloalkenyl; 
         [0008]    B is optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl or optionally substituted C 3-8  cycloalkenyl; 
         [0009]    R 1  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0010]    R 2  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0011]    R 3  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0012]    R 4  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0013]    R 5  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0014]    R 6  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , NR 14 R 15  or hydroxyl; 
         [0015]    R 7  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 14 R 15  or hydroxyl; 
         [0016]    R 8  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 14 R 15  or hydroxyl; 
         [0017]    R 9  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 14 R 15  or hydroxyl; 
         [0018]    R 10  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 13 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 14 R 15  or hydroxyl; 
         [0019]    R 11  is H or optionally substituted C 1-8  alkyl; 
         [0020]    R 12  is OPO 3 H 2 , carboxylic acid, PO 3 H 2 , optionally substituted C 1-6  alkyl, —S(O) 2 H, —P(O)MeOH, —P(O)(H)OH or OR 16 ; 
         [0021]    R 13  is H, OH or optionally substituted C 1-8  alkyl; 
         [0022]    R 14  is H or optionally substituted C 1-8  alkyl; 
         [0023]    R 15  is H or optionally substituted C 1-8  alkyl; 
         [0024]    R 16  is H or optionally substituted C 1-8  alkyl; 
         [0025]    L 1  is O, S, S(O), NH or CH 2 ; 
         [0026]    L 2  is O, S or CH 2 , 
         [0027]    L 3  is O, S or CH 2 ; 
         [0028]    a is 1, 2, 3, 4, 5 or 6; 
         [0029]    b is 0 or 1; and 
         [0030]    c is 0, 1, 2, 3, 4 or 5. 
         [0031]    In another aspect, the invention provides a compound having Formula I wherein the double bond is in the E configuration. 
         [0032]    In another aspect, the invention provides a compound having Formula I wherein the double bond is in the Z configuration. 
         [0033]    In another aspect, the invention provides a compound having Formula I wherein the double bond is in a mixture of E and Z geometric isomers. 
         [0034]    In another aspect, the invention provides a compound having Formula I wherein L 1  is O. 
         [0035]    In another aspect, the invention provides a compound having Formula I wherein L 1  is S. 
         [0036]    In another aspect, the invention provides a compound having Formula I wherein L 1  is S(O). 
         [0037]    In another aspect, the invention provides a compound having Formula I wherein L 2  is CH 2 . 
         [0038]    In another aspect, the invention provides a compound having Formula I wherein L 3  is CH 2 . 
         [0039]    In another aspect, the invention provides a compound having Formula I wherein a is 1, 2 or 3. 
         [0040]    In another aspect, the invention provides a compound having Formula I wherein 
         [0000]    
       
                 
         
             
             
         
       
     
         [0041]    In another aspect, the invention provides a compound having Formula I wherein 
         [0000]    
       
                 
         
             
             
         
       
     
         [0042]    In another aspect, the invention provides a compound having Formula I wherein 
         [0000]    
       
                 
         
             
             
         
       
     
         [0043]    In another aspect, the invention provides a compound having Formula I wherein 
         [0000]    
       
                 
         
             
             
         
       
     
         [0044]    R 1  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0045]    R 2  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0046]    R 3  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0047]    R 4  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0048]    R 5  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0049]    R 6  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0050]    R 7  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0051]    R 8  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0052]    R 9  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0053]    R 10  is H, halogen or optionally substituted C 1-8  alkyl; 
         [0054]    R 11  is H; 
         [0055]    R 12  is carboxylic acid or PO 3 H 2 ; 
         [0056]    L 1  is O, S or S(O); 
         [0057]    L 2  is CH 2 ; 
         [0058]    L 3  is CH 2 ; 
         [0059]    a is 1, 2 or 3; 
         [0060]    b is 1; and 
         [0061]    c is 0 or 1. 
         [0062]    The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 6 carbon atoms, unless otherwise specified. One methylene (—CH 2 —) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, —NH—, carbonyl, carboxyl, sulfonyl, amido, sulfonamido, by a divalent C 3-6  cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can be independently substituted by halogen, hydroxyl, cycloalkyl, amine, heterocyclic, carboxylic acid, —C 2-6  alkenyl, —C 2-6  alkynyl, phosphonic acid, sulphonic acid, phosphoric acid, nitro, amide, sulfonamides, ketone, aldehydes or esters groups. 
         [0063]    The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen, nitro groups, cyano groups, —OC 1-6  alkyl groups, —SC 1-6  alkyl groups, —C 1-6  alkyl groups, —C 2-6  alkenyl groups, —C 2-6  alkynyl groups, C 3-8  cycloalkyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups or hydroxyl groups. 
         [0064]    The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen atoms, nitro groups, cyano groups, —OC 1-6  alkyl groups, —SC 1-6  alkyl groups, —C 1-6  alkyl groups, —C 2-6  alkenyl groups, —C 2-6  alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3-8  cycloalkyl groups or hydroxyl groups. 
         [0065]    The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine. 
         [0066]    The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-6  alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by C 1-8  alkyl. 
         [0067]    The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. 
         [0068]    The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, monocyclic or polycyclic, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S heteroatom can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen, —SC 1-6  alkyl, —S(O) 2 C 1-6  alkyl, —S(O)C 1-6  alkyl, sulfonamide, amide, nitro, cyano, —OC 1-6  alkyl, —C 1-6  alkyl, —C 2-6  alkenyl, —C 2-6  alkynyl, ketone, amine, C 3-8  cycloalkyl, aldehydes, esters, carboxylic acid, phosphonic acid, sulfonic acid or hydroxyl groups. 
         [0069]    The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic. Aryl can be substituted by halogen atoms, nitro groups, cyano groups, —OC 1-6  alkyl groups, —SC 1-6  alkyl groups, —C 1-6  alkyl groups, —C 2-6  alkenyl groups, —C 2-6  alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3-8  cycloalkyl groups or hydroxyl groups. Usually aryl is phenyl. Preferred substitution site on aryl are meta and para positions. 
         [0070]    The term “cyano” as used herein, represents a group of formula “—CN”. 
         [0071]    The term “nitro” as used herein, represents a group of formula “—NO 2 ”. 
         [0072]    The term “amide” as used herein, represents a group of formula “−C(O)NR x R y ,” wherein R x  and R y  can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above. 
         [0073]    The term “amine” as used herein, represents a group of formula “—NR x R y ”, wherein R x  and R y  can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above. 
         [0074]    The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —(CO)R x  wherein R x  can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above. 
         [0075]    The term “aldehyde” as used herein, represents a group of formula “—C(O)H”. 
         [0076]    The term “ester” as used herein, represents a group of formula “—C(O)OR x ”, wherein R x  can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above. 
         [0077]    The term “sulfonamide” as used herein, represents a group of formula “—S(O) 2 NR x R y ” wherein R x  and R y  can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above. 
         [0078]    The term “hydroxyl” as used herein, represents a group of formula “—OH”. 
         [0079]    The term “carbonyl” as used herein, represents a group of formula “—C(O)”. 
         [0080]    The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”. 
         [0081]    The term “sulfonyl” as used herein, represents a group of formula “—SO 2 ”. 
         [0082]    The term “sulfate” as used herein, represents a group of formula “−O—S(O) 2 —O—”. 
         [0083]    The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”. 
         [0084]    The term “sulfoxide” as used herein, represents a group of formula “—S═O”. 
         [0085]    The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”. 
         [0086]    The term “phosphoric acid” as used herein, represents a group of formula “—(O)P(O)(OH) 2 ”. 
         [0087]    The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”. 
         [0088]    The formula “H”, as used herein, represents a hydrogen atom. 
         [0089]    The formula “O”, as used herein, represents an oxygen atom. 
         [0090]    The formula “N”, as used herein, represents a nitrogen atom. 
         [0091]    The formula “S”, as used herein, represents a sulfur atom. 
         [0092]    Compounds of the invention are:
   {3-[(4-{[(5E)-5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]sulfanyl}benzyl)amino]propyl}phosphonic acid;   3-[(4-{[(5E)-5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]sulfanyl}benzyl)amino]propanoic acid;   3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfanyl}benzyl)amino]propanoic acid;   3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzyl)amino]propanoic acid;   3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzyl)amino]propanoic acid;   {3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propyl}phosphonic acid;   3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propanoic acid;   3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propanoic acid;   {3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propyl}phosphonic acid;   3-[(4-{[(3E)-3-(3-Chlorophenyl)-4-(3,4-dimethylphenyl)but-3-en-1-yl]sulfinyl}benzyl)amino]propanoic acid.   
 
         [0103]    Some compounds of Formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13. 
         [0104]    The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form. 
         [0105]    The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl &amp; Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345). 
         [0106]    The base addition salt form of a compound of Formula I that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, Calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl &amp; Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345). 
         [0107]    Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. 
         [0108]    With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically. 
         [0109]    Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention. 
         [0110]    The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the sphingosine-1-phosphate receptors. 
         [0111]    In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier. 
         [0112]    In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention. 
         [0113]    These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1P modulation. 
         [0114]    Therapeutic utilities of S1P modulators are:
       Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, dry eye, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, retinal vasculitis;   Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury;   Autoimmune and immunosuppression diseases: rheumatoid arthritis, Crohn&#39;s disease, Graves&#39; disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation;   Allergies and other inflammatory diseases: urticaria, bronchial asthma, airway inflammations, pulmonary emphysema and chronic obstructive pulmonary diseases;   Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury;   Wound Healing: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging, skin ageing, prevention of radiation-induced injuries;   Bone formation: treatment of osteoporosis and various bone fractures including hip and ankles;   Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains;   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon;   Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo-skeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains;   CNS neuronal injuries: Alzheimer&#39;s disease, age-related neuronal injuries;   Organ transplants: renal, corneal, cardiac and adipose tissue transplants.       
 
         [0127]    In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.
       The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of   Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, dry eye, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis;   Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury;   Autoimmune and immunosuppression diseases: rheumatoid arthritis, Crohn&#39;s disease, Graves&#39; disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation;   Allergies and other inflammatory diseases: urticaria, bronchial asthma, and other airway inflammations, pulmonary emphysema and chronic obstructive pulmonary diseases;   Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury;   Wound Healing: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging, skin ageing, and prevention of radiation-induced injuries;   Bone formation: treatment of osteoporosis and various bone fractures including hip and ankles;   Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains;   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon;   Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo-skeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains;   CNS neuronal injuries: Alzheimer&#39;s disease, age-related neuronal injuries;   Organ transplants: renal, corneal, cardiac and adipose tissue transplants.       
 
         [0141]    The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient&#39;s general physical condition, the cause of the condition, and the route of administration. 
         [0142]    The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy. 
         [0143]    In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 
         [0144]    Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition. 
         [0145]    Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. 
         [0146]    In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 
         [0147]    The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required. 
         [0148]    Pharmaceutical compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations. 
         [0149]    For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water. 
         [0150]    Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. 
         [0151]    Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. 
         [0152]    In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it. 
         [0153]    The ingredients are usually used in the following amounts: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (% w/v) 
               
               
                   
                   
               
             
             
               
                   
                 active ingredient 
                 about 0.001-5 
               
               
                   
                 preservative 
                     0-0.10 
               
               
                   
                 vehicle 
                 0-40 
               
               
                   
                 tonicity adjustor 
                 1-10 
               
               
                   
                 buffer 
                 0.01-10      
               
               
                   
                 pH adjustor 
                 q.s. pH 4.5-7.8 
               
               
                   
                 antioxidant 
                 as needed 
               
               
                   
                 surfactant 
                 as needed 
               
               
                   
                 purified water 
                 to make 100% 
               
               
                   
                   
               
             
          
         
       
     
         [0154]    The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. 
         [0155]    The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for drop wise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resalable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl. 
         [0156]    Invention compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. 
         [0157]    Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner. 
         [0158]    The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of sphingosine-1-phosphate receptors. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human. 
         [0159]    The present invention concerns also processes for preparing the compounds of Formula I. The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic scheme set forth below, illustrate how compounds according to the invention can be made. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0160]    Those skilled in the art will be able to routinely modify and/or adapt the above scheme to synthesize any compounds of the invention covered by Formula I. 
         [0161]    The following abbreviations are used in Scheme 1 and in the examples: 
         [0000]    CD 3 OD deuterated methanol
 
RT room temperature
 
CDCl 3  deuterated chloroform
 
MPLC medium pressure liquid chromatography
 
NaHCO 3  sodium bicarbonate
 
EtOAc ethyl acetate
 
Na 2 S 2 O 3  sodium thiosulfate
 
MgSO 4  magnesium sulfate
 
NaCl sodium chloride
 
NaBH 4  sodium borohydride
 
Et 2 O ether
 
p-TsOH p-Toluenesulfonic acid
 
LAH lithium aluminium hydride
 
       NMO N-methylmorpholine-N-Oxide 
       [0162]    TPAP tetrapropylammonium perruthenate 
         [0163]    DMSO-d 6  deuterated dimeythylsulfonamide 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0164]    It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. 
         [0165]    It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention. 
         [0166]    The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium  2 H (or D) in place of protium  1 H (or H) or use of  13 C enriched material in place of  12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents. 
         [0167]    The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. 
         [0168]    As will be evident to those skilled in the art, individual diastereomeric forms can be obtained by separation of mixtures thereof in conventional manner, chromatographic separation may be employed. 
         [0169]    Compound names were generated with ACDLab version 12.5, intermediates and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. 
         [0170]    In general, characterization of the compounds is performed according to the following methods: NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. 
         [0171]    All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Ak. Scientific, AmFine Com, Carbocore, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures. 
         [0172]    Usually the compounds of the invention were purified by column chromatography (Auto-column) on an Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise. 
         [0173]    Some compounds of this invention can generally be prepared in one step from commercially available literature starting materials. 
       Example 1 
     Intermediate 1 
     Methyl 4-((4-iodobutyl)thio)benzoate 
       [0174]    
       
                 
         
             
             
         
       
     
         [0175]    A sample of methyl 4-[(4-bromobutyl)thio]benzoate [CAS 1450736-45-4] (5.0 g, 16.5 mmole) and sodium iodide (3.0 g, 1.2 eq) were dissolved in acetone and refluxed at 70° C. for 6 hours. The resulting mixture was cooled to room temperature and concentrated in the rotary evaporator. The concentrate was dissolved in EtOAc and washed with H 2 O (3×50 mL), saturated Na 2 S 2 O 3  (2×50 mL) and brine (1×50 mL). The organic extract was dried with MgSO 4 , filtered, concentrated and purified by MPLC to give 4.77 g (91%) of Intermediate 1. 
         [0176]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.74-1.90 (m, 2H) 1.90-2.08 (m, 2H) 3.01 (t, J=7.00 Hz, 2H) 3.20 (t, J=6.74 Hz, 2H) 3.90 (s, 3H) 7.30 (d, J=8.50 Hz, 2H) 7.93 (d, J=8.79 Hz, 2H). 
       Example 2 
     Intermediate 2 
     Methyl 4-{[5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)-6-oxohexyl]thio}benzoate 
       [0177]    
       
                 
         
             
             
         
       
     
         [0178]    A sample of 2-(3,5-difluorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1450736-61-4] (5.0 g, 19.2 mmole) was dissolved in THF and set to −78° C. Lithium diisopropyl amide (10.6 mL, 1.1 eq.) was added dropwise and the resulting mixture was stirred for 30 minutes. A solution of methyl 4-[(4-bromobutyl)thio]benzoate [CAS 1456736-45-4] (6.4 g, 1.1 eq) in THF was then added dropwise and the reaction mixture was allowed to stir overnight. It was then refluxed at 90° C. for overnight. The reaction mixture was cooled to room temperature, then to 0° C. after which it was quenched with 1M HCl to pH 2. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl, dried with MgSO 4 , filtered, concentrated and purified by MPLC to give 3.76 g (40%) of Intermediate 2. 
         [0179]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.31-1.54 (m, 2H) 1.63-1.91 (m, 3H) 2.09-2.24 (m, 1H) 2.28 (s, 6H) 2.94 (t, J=7.33 Hz, 2H) 3.89 (s, 3H) 4.50 (t, J=7.18 Hz, 1H) 6.57-6.70 (m, 1H) 6.79-6.88 (m, 2H) 7.17 (d, J=7.62 Hz, 1H) 7.24 (d, J=8.79 Hz, 2H) 7.60-7.68 (m, 1H) 7.71 (s, 1H) 7.90 (d, J=8.50 Hz, 2H). 
       Example 3 
     Intermediate 3 
     Methyl 4-{[5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)-6-hydroxyhexyl]thio}benzoate 
       [0180]    
       
                 
         
             
             
         
       
     
         [0181]    A sample of Intermediate 2 (3.76 g, 7.8 mmoles) was dissolved in 2 mL of THF and diluted with MeOH. The resulting solution was cooled to 0° C. and NaBH 4  (295 mg, 1.0 eq) was added. The reaction mixture was stirred at 0° C. for 2 hours. It was then quenched with 1M HCl and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated NaCl, dried with MgSO 4 , filtered, concentrated and purified by MPLC to give 3.48 g (92%) of Intermediate 3. 
         [0182]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.01-1.27 (m, 2H) 1.32-1.66 (m, 4H) 2.25 (s, 6H) 2.68-2.91 (m, 3H) 3.89 (s, 3H) 4.63 (d, J=8.20 Hz, 1H) 6.58-6.82 (m, 3H) 6.95-7.13 (m, 3H) 7.19 (d, J=8.79 Hz, 2H) 7.89 (d, J=8.50 Hz, 2H). 
       Example 4 
     Intermediate 4 
     Methyl 4-{[(5E)-5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]thio}benzoate 
       [0183]    
       
                 
         
             
             
         
       
     
         [0184]    A sample of Intermediate 3 (3.48 g, 7.2 mmoles) was dissolved in toluene. Molecular sieves (200 mg) were added followed by p-TsOH (1.5 g, 1.1 eq). The resulting mixture was refluxed at 110° C. for 3 hours after which it was cooled to room temperature. The solvent was evaporated and the residue was dissolved in Et 2 O. The solution was washed with saturated NaHCO 3  (2×20 mL), H 2 O (1×20 mL) and brine. It was then dried over MgSO 4 , filtered, concentrated and purified by MPLC to give 2.9 g (87%) of Intermediate 4. 
         [0185]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.39-1.61 (m, 2H) 1.64-1.84 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.46 (t, J=7.30 Hz, 2H) 2.97 (t, J=7.18 Hz, 2H) 3.89 (s, 3H) 6.40 (s, 1H) 6.55-6.74 (m, 5H) 6.86 (d, J=7.91 Hz, 1H) 7.26 (d, J=8.79 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H). 
       Example 5 
     Intermediate 5 
     (4-{[(5E)-5-(3,5-Difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]thio}phenyl) methanol 
       [0186]    
       
                 
         
             
             
         
       
     
         [0187]    A sample of Intermediate 4 (2.9 g, 6.22 mmoles) was dissolved in THF and cooled to −30° C. Lithium aluminum hydride (1.0 M, 6.8 mL, 1.1 eq) was added dropwise and the resulting mixture was stirred at −30° C. for 1 hour. Ether and celite were added to the reaction mixture followed by 1M HCl until pH 2-3. The resulting solution was filtered over celite and the filtrate was concentrated and purified by MPLC to give 2.25 g (83%) of Intermediate 5. 
         [0188]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.43-1.79 (m, 4H) 2.10 (s, 3H) 2.17 (s, 3H) 2.38-2.51 (m, 2H) 2.90 (t, J=7.18 Hz, 2H) 4.64 (s, 2H) 6.38 (s, 1H) 6.50-6.75 (m, 5H) 6.86 (d, J=7.91 Hz, 1H) 7.14-7.40 (m, 4H). 
       Example 6 
     Intermediate 6 
     Methyl 4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)-5-oxopentyl]oxy}benzoate 
       [0189]    
       
                 
         
             
             
         
       
     
         [0190]    A mixture of 2-(3-chlorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1275947-05-1] (2.0 g, 7.7 moles), LDA (7.8 mL, 1.5 eq), and 4-(3-iodopropoxylbenzoate) [CAS 152936-91-9] (3.2 g, 1.5 eq) were reacted to give 1.64 g (47%) of Intermediate 6. 
         [0191]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.66-1.88 (m, 2H) 1.90-2.10 (m, 1H) 2.27 (s, 6H) 2.29-2.41 (m, 1H) 3.87 (s, 3H) 4.00 (t, J=6.30 Hz, 2H) 4.60 (t, J=7.33 Hz, 1H) 6.84 (d, J=9.08 Hz, 2H) 7.13-7.24 (m, 4H) 7.32 (br. s, 1H) 7.68 (d, J=7.70 Hz, 1H) 7.73 (s, 1H) 7.95 (d, J=9.08 Hz, 2H). 
       Example 7 
     Intermediate 7 
     Methyl 4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)-5-hydroxypentyl]oxy}benzoate 
       [0192]    
       
                 
         
             
             
         
       
     
         [0193]    A mixture of Intermediate 6 (1.96 g, 4.35 mmoles), NaBH 4  (164 mg, 1.0 eq) were reacted to give quantitative yield of Intermediate 7. 
         [0194]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.42-1.71 (m, 4H) 2.20-2.26 (m, 6H) 2.83-2.92 (m, 1H) 3.76-3.83 (m, 2H) 3.86 (s, 3H) 4.65 (d, J=8.20 Hz, 1H) 6.75 (d, J=8.79 Hz, 2H) 6.93-7.18 (m, 5H) 7.19-7.32 (m, 2H) 7.92 (d, J=8.79 Hz, 2H). 
       Example 8 
     Intermediate 8 
     Methyl 4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzoate 
       [0195]    
       
                 
         
             
             
         
       
     
         [0196]    A mixture of Intermediate 7 (2.25 g, 5.0 mmoles), molecular sieves (100 mg) and p-TsOH (1.1 g, 1.2 eq) were reacted to give 2.0 g (86%) of Intermediate 8. 
         [0197]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.83-1.93 (m, 2H) 2.07 (s, 3H) 2.14 (s, 3H) 2.65 (t, J=7.18 Hz, 2H) 3.87 (s, 3H) 4.01 (t, J=6.30 Hz, 2H) 6.43 (s, 1H) 6.56-6.60 (m, 1H) 6.69 (s, J=5.89, 5.89 Hz, 1H) 6.78-6.91 (m, 3H) 7.02-7.09 (m, 1H) 7.17-7.26 (m, 3H) 7.93-8.00 (m, 2H). 
       Example 9 
     Intermediate 9 
     (4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}phenyl)methanol 
       [0198]    
       
                 
         
             
             
         
       
     
         [0199]    A mixture of Intermediate 8 (1.6 g, 3.7 mmoles) and LAH (1.0 M, 4.0 mL, 1.1 eq) were reacted to give 1.15 g (77%) of Intermediate 9. 
         [0200]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.84-1.91 (m, 2H) 2.08 (s, 3H) 2.15 (s, 3H) 2.61-2.67 (m, 2H) 3.97 (t, J=6.30 Hz, 2H) 4.60 (d, J=5.27 Hz, 2H) 6.43 (s, 1H) 6.57-6.60 (m, 1H) 6.69-6.71 (m, 1H) 6.82-6.90 (m, 3H) 7.02-7.06 (m, 1H) 7.17-7.29 (m, 5H). 
       Example 10 
     Intermediate 10 
     4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzaldehyde 
       [0201]    
       
                 
         
             
             
         
       
     
         [0202]    A mixture of Intermediate 9 (1.24 g, 3.0 mmoles), 1.0 g of molecular sieves, NMO (714 mg, 2.0 eq) and TPAP (50 mg) were reacted to give 857 mg (70%) of Intermediate 10. 
         [0203]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.86-1.95 (m, 2H) 2.08 (s, 3H) 2.15 (s, 3H) 2.66 (t, J=7.60 Hz, 2H) 4.06 (t, J=6.30 Hz, 2H) 6.44 (s, 1H) 6.54-6.63 (m, 1H) 6.69 (s, 1H) 6.84 (d, J=6.28 Hz, 1H) 6.94-7.01 (m, 2H) 7.03-7.09 (m, 1H) 7.18-7.27 (m, 3H) 7.83 (d, J=7.98 Hz, 2H) 9.88 (s, J=3.23 Hz, 1H). 
       Example 11 
     Intermediate 11 
     Methyl 4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)-5-oxopentyl]oxy}benzoate 
       [0204]    
       
                 
         
             
             
         
       
     
         [0205]    A mixture of 2-(3,5-difluorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1450736-61-4] (2.3 g, 8.8 mmoles), LDA (6.6 mL, 1.5 eq), and methyl 4-(3-iodopropoxy)benzoate [CAS 152936-91-9] (4.25 g, 1.5 eq) were reacted to give 3.7 g (93%) of Intermediate 11. 
         [0206]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.65-1.90 (m, 2H) 1.91-2.04 (m, 1H) 2.25-2.32 (m, 6H) 2.30-2.43 (m, 1H) 3.88 (s, 3H) 4.01 (t, J=6.15 Hz, 2H) 4.61 (t, J=7.18 Hz, 1H) 6.52-6.73 (m, 1H) 6.82-6.90 (m, 4H) 7.17 (d, J=7.91 Hz, 1H) 7.55-7.77 (m, 2H) 7.93-7.98 (m, 2H). 
       Example 12 
     Intermediate 12 
     Methyl 4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)-5-hydroxypentyl]oxy}benzoate 
       [0207]    
       
                 
         
             
             
         
       
     
         [0208]    A mixture of Intermediate 11 (4.06 g, 9.0 mmoles), and NaBH 4  (340 mg, 1.0 eq) were reacted to give 3.17 g (78%) of Intermediate 12. 
         [0209]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.48-1.64 (m, 4H) 2.25 (s, 3H) 2.26 (s, 3H) 3.79-3.86 (m, 2H) 3.87 (s, 3H) 4.59-4.73 (m, 2H) 6.65-6.92 (m, 4H) 6.97-7.14 (m, 4H) 7.91-8.03 (m, 2H). 
       Example 13 
     Intermediate 13 
     Methyl 4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzoate 
       [0210]    
       
                 
         
             
             
         
       
     
         [0211]    A mixture of Intermediate 12 (3.17 g, 7.0 mmoles), molecular sieves (200 mg) and p-TsOH (1.6 g, 1.2 eq) were reacted to give quantitative yield of Intermediate 13. 
         [0212]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.78-2.00 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.52-2.73 (m, 2H) 3.89 (s, 3H) 4.03 (t, J=6.20 Hz, 2H) 6.45 (s, 1H) 6.53-6.64 (m, 1H) 6.67-6.76 (m, 4H) 6.80-6.97 (m, 3H) 7.99 (d, J=8.79 Hz, 2H). 
       Example 14 
     Intermediate 14 
     (4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}phenyl)methanol 
       [0213]    
       
                 
         
             
             
         
       
     
         [0214]    A mixture of Intermediate 13 (3.32 g, 7.6 mmoles) and LAH (1.0 M, 8.4 mL, 1.1 eq) were reacted to give 2.6 g (84%) of Intermediate 14. 
         [0215]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.82-1.92 (m, 2H) 2.10 (s, 3H) 2.16 (s, 3H) 2.51-2.72 (m, 2H) 3.98 (t, J=6.30 Hz, 2H) 4.59-4.63 (m, 2H) 6.46 (s, 1H) 6.54-6.65 (m, 1H) 6.66-6.75 (m, 4H) 6.83-6.90 (m, 3H) 7.24-7.30 (m, 2H). 
       Example 15 
     Intermediate 15 
     4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzaldehyde 
       [0216]    
       
                 
         
             
             
         
       
     
         [0217]    A mixture of Intermediate 14 (2.6 g, 6.4 mmoles), 2.0 g of molecular sieves, NMO (1.5 g, 2.0 eq) and TPAP (100 mg) were reacted to give 2.0 g (77%) of Intermediate 15. 
         [0218]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.76-2.01 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.65 (t, J=7.30 Hz, 2H) 4.06 (t, J=6.15 Hz, 2H) 6.46 (s, 1H) 6.54-6.64 (m, 1H) 6.67-6.77 (m, 4H) 6.87 (d, J=8.20 Hz, 1H) 6.99 (d, J=8.80 Hz, 2H) 7.83 (d, J=8.80 Hz, 2H) 9.89 (s, J=3.22 Hz, 1H). 
       Example 16 
     Intermediate 16 
     Methyl 4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)-5-oxopentyl]thio}benzoate 
       [0219]    
       
                 
         
             
             
         
       
     
         [0220]    A sample of 2-(3,5-difluorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1450736-61-4] (5.0 g, 19.2 mmole) was dissolved in THF and cooled to −78° C. Lithium diisopropyl amide (10.6 mL, 1.1 eq.) was added dropwise and the resulting mixture was stirred for 30 minutes. A solution of methyl 4-[(3-bromopropyl)thio]benzoate [CAS 134520-57-3] (6.1 g, 1.1 eq) in THF was then added dropwise and the reaction mixture was allowed to stir overnight. It was then refluxed at 90° C. overnight. The reaction mixture was cooled to room temperature, then to 0° C. after which it was quenched with 1M HCl to pH 2. The resulting mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl, dried with MgSO 4 , filtered, concentrated and purified by MPLC to give 4.28 g (48%) of Intermediate 16. 
         [0221]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.53-1.78 (m, 2H) 1.86-2.11 (m, 1H) 2.28 (s, 6H) 2.31-2.38 (m, 1H) 2.89-3.06 (m, 2H) 3.89 (s, 3H) 4.51 (t, J=7.33 Hz, 1H) 6.57-6.71 (m, 1H) 6.78-6.88 (m, 2H) 7.14-7.29 (m, 3H) 7.62-7.66 (m, 1H) 7.69-7.72 (m, 1H) 7.90 (d, J=7.66 Hz, 2H). 
       Example 17 
     Intermediate 17 
     Methyl 4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)-5-hydroxypentyl]thio}benzoate 
       [0222]    
       
                 
         
             
             
         
       
     
         [0223]    A sample of Intermediate 16 (4.28 g, 9.1 mmoles) was dissolved in 5 mL of THF and diluted with MeOH. The resulting solution was cooled to 0° C. and NaBH 4  (346 mg, 1.0 eq) was added. The reaction mixture was stirred at 0° C. for 2 hours. It was then quenched with 1M HCl and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated NaCl, dried with MgSO 4 , filtered, concentrated and purified by MPLC to give 3.73 g (87%) of Intermediate 17. 
         [0224]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.31-1.50 (m, 2H) 1.53-1.72 (m, 2H) 2.26 (s, 6H) 2.70-2.90 (m, 3H) 3.89 (s, 3H) 4.63 (d, J=8.20 Hz, 1H) 6.56-6.85 (m, 3H) 6.90-7.05 (m, 2H) 7.07-7.21 (m, 3H) 7.83-7.89 (m, 2H). 
       Example 18 
     Intermediate 18 
     Methyl 4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]thio}benzoate 
       [0225]    
       
                 
         
             
             
         
       
     
         [0226]    A mixture of Intermediate 17 (880 mg, 1.9 mmoles), molecular sieve (50 mg) and p-TsOH (392 mg, 1.1 eq) were reacted to give 685 mg (81%) of Intermediate 18. 
         [0227]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.62-1.86 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.55-2.73 (m, 2H) 3.00 (t, J=7.18 Hz, 2H) 3.90 (s, 3H) 6.44 (s, 1H) 6.53-6.77 (m, 5H) 6.87 (d, J=7.91 Hz, 1H) 7.26 (d, J=8.50 Hz, 2H) 7.91 (d, J=8.50 Hz, 2H). 
       Example 19 
     Intermediate 19 
     (4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]thio}phenyl)methanol 
       [0228]    
       
                 
         
             
             
         
       
     
         [0229]    A mixture of Intermediate 18 (685 mg, 1.5 mmoles) and LAH (1.0 M, 1.7 mL, 1.1 eq) were reacted to give 550 mg (86%) of Intermediate 19. 
         [0230]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.61-1.80 (m, 2H) 2.10 (s, 3H) 2.16 (s, 3H) 2.58 (t, J=7.30 Hz, 2H) 2.92 (t, J=7.18 Hz, 2H) 4.55-4.72 (m, 2H) 6.42 (s, 1H) 6.48-6.77 (m, 5H) 6.86 (d, J=7.91 Hz, 1H) 7.17-7.38 (m, 4H). 
       Example 20 
     Intermediate 20 
     4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]thio}benzaldehyde 
       [0231]    
       
                 
         
             
             
         
       
     
         [0232]    A mixture of Intermediate 19 (550 mg, 1.3 mmoles), oxalyl-Cl (121 μL, 1.1 eq), DMSO (202 μL, 2.2 eq) and triethylamine (904 μL, 5.0 eq) were reacted to give 78.5 mg (14%) of Intermediate 20. 
         [0233]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.59-1.89 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.62 (t, J=7.00 Hz, 2H) 3.02 (t, J=7.33 Hz, 2H) 6.46 (s, 1H) 6.54-6.76 (m, 5H) 6.87 (d, J=7.91 Hz, 1H) 7.32 (d, J=8.50 Hz, 2H) 7.74 (d, J=8.79 Hz, 2H) 9.92 (s, 1H). 
       Example 21 
     Intermediate 21 
     Methyl 4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)-5-oxopentyl]thio}benzoate 
       [0234]    
       
                 
         
             
             
         
       
     
         [0235]    A mixture of 2-(3-chlorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1275947-05-1] (3.8 g, 14.7 mmoles) was dissolved in THF and cooled to −78° C. Lithium diisopropyl amide (16.2 mL, 1.5 eq) were added dropwise and the resulting mixture was stirred for 30 minutes. A solution of methyl 4-[(3-bromopropyl)thio]benzoate [CAS134520-57-3] (6.1 g, 1.1 eq) in THF was then added dropwise and the reaction mixture was allowed to stir overnight. It was then refluxed at 90° C. for overnight. The reaction mixture was cooled to room temperature, then to 0° C. after which it was quenched with 1M HCl to pH 2. The resulting mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl, dried with MgSO 4 , filtered, concentrated and purified by MPLC give 3.7 g (93%) of Intermediate 21. 
         [0236]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.58-1.81 (m, 3H) 1.82-2.01 (m, 1H) 2.27 (s, 6H) 2.79-3.10 (m, 2H) 3.89 (s, 3H) 4.50 (t, J=7.33 Hz, 1H) 7.12-7.32 (m, 7H) 7.65 (d, J=7.91 Hz, 1H) 7.71 (s, 1H) 7.89 (d, J=8.50 Hz, 2H). 
       Example 22 
     Intermediate 22 
     Methyl 4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)-5-hydroxypentyl]thio}benzoate 
       [0237]    
       
                 
         
             
             
         
       
     
         [0238]    A mixture of Intermediate 21 (2.67 g, 5.72 mmoles), and NaBH 4  (216 mg, 1.0 eq) were reacted to give 2.25 g (84%) Intermediate 22. 
         [0239]      1 H NMR (300 MHz, d 6 -DMSO) δ ppm 1.22-1.39 (m, 2H) 1.43-1.55 (m, 1H) 1.57-1.75 (m, 1H) 2.15 (s, 6H) 2.61-3.02 (m, 2H) 3.80 (s, 3H) 4.43-4.63 (m, 1H) 5.05 (d, J=4.40 Hz, 1H) 6.85-6.92 (m, 1H) 6.95-7.02 (m, 2H) 7.05-7.10 (m, 1H) 7.13-7.30 (m, 5H) 7.76 (d, J=8.50 Hz, 2H). 
       Example 23 
     Intermediate 23 
     Methyl 4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]thio}benzoate 
       [0240]    
       
                 
         
             
             
         
       
     
         [0241]    A mixture of Intermediate 22 (2.25 g, 4.8 mmoles), triethyl silane (1.15 mL, 1.5 eq) and trifluoroacetic acid (925 μL, 2.5 eq) were reacted to give 1.3 g (60%) of Intermediate 23. 
         [0242]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.39-1.73 (m, 3H) 1.73-1.96 (m, 1H) 1.97-2.11 (m, 1H) 2.19 (s, 3H) 2.27 (s, 3H) 2.70-2.95 (m, 2H) 3.06-3.17 (m, 1H) 3.90 (s, 3H) 5.86 (d, J=9.00 Hz, 1H) 6.77-6.82 (m, 1H) 6.92-7.07 (m, 3H) 7.07-7.26 (m, 5H) 7.83-7.90 (m, 2H). 
       Example 24 
     Intermediate 24 
     (4-{[4-(3-Chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]thio}phenyl)methanol 
       [0243]    
       
                 
         
             
             
         
       
     
         [0244]    A mixture of methyl Intermediate 23 (1.0 g, 2.2 mmoles) and LAH (1.0 M, 2.4 mL, 1.1 eq) were reacted as outlined in Scheme 8 to give 830 mg (88%) of Intermediate 24. 
         [0245]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.28-1.49 (m, 2H) 1.51-1.74 (m, 3H) 1.74-1.97 (m, 1H) 2.20 (d, J=3.52 Hz, 3H) 2.27 (s, 3H) 2.60-2.90 (m, 3H) 4.63 (s, 2H) 6.81-6.93 (m, 1H) 6.94-7.33 (m, 10H). 
       Example 25 
     Intermediate 25 
     4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzaldehyde 
       [0246]    
       
                 
         
             
             
         
       
     
       Intermediate 26 
     4-{[4-(3-Chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]sulfinyl}benzaldehyde 
       [0247]    
       
                 
         
             
             
         
       
     
         [0248]    A mixture of Intermediate 24 (830 mg, 1.9 mmoles), 400 mg of molecular sieves, NMO (458 mg, 2.0 eq) and TPAP (40 mg) were reacted to give 168 mg (20%) of Intermediate 25 and 300 mg of Intermediate 26. 
         [0249]    Intermediate 25:  1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.40-1.83 (m, 2H) 1.85-2.10 (m, 1H) 2.26 (s, 6H) 2.28-2.43 (m, 1H) 2.91-3.05 (m, 2H) 4.52 (t, J=7.33 Hz, 1H) 7.12-7.22 (m, 4H) 7.27-7.31 (m, 3H) 7.63-7.74 (m, 4H) 9.90 (s, 1H). 
         [0250]    Intermediate 26:  1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.37-1.79 (m, 5H) 2.26 (s, 6H) 2.66-3.04 (m, 3H) 4.63 (d, J=8.20 Hz, 1H) 6.97-7.03 (m, 1H) 7.04-7.15 (m, 3H) 7.15-7.29 (m, 5H) 7.64-7.76 (m, 2H) 9.90 (s, 1H). 
       Example 26 
     Intermediate 27 
     4-{[(5E)-5-(3,5-Difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]thio}benzaldehyde 
       [0251]    
       
                 
         
             
             
         
       
     
         [0252]    A solution of oxalyl chloride (240 μL, 1.1 eq) in 5.0 mL of CH 2 Cl 2  was cooled to −78° C. Dimethylsulfoxide (401 μL, 2.2 eq) was added and the resulting mixture was stirred for 30 minutes. A solution of Intermediate 5 (1.125 g, 2.6 mmoles) in 5 mL CH 2 Cl 2  was added and the reaction mixture was stirred at −78° C. for 2 hours. Triethylamine (1.8 mL, 5.0 eq) was added and the resulting mixture was stirred for 30 minutes. Water was added to quench the reaction mixture and stirring was continued until the solution is at room temperature. The layers were isolated and the organic layer was washed with brine, dried with MgSO 4 , filtered, concentrated and purified by MPLC to give Intermediate 27 (866 mg). 
         [0253]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.46-1.62 (m, 2H) 1.68-1.85 (m, 2H) 2.10 (s, 3H) 2.17 (s, 3H) 2.48 (t, J=7.03 Hz, 2H) 3.00 (t, J=7.33 Hz, 2H) 6.41 (s, 1H) 6.54-6.75 (m, 5H) 6.86 (d, J=7.91 Hz, 1H) 7.33 (d, J=8.50 Hz, 2H) 7.75 (d, J=8.79 Hz, 2H) 9.91 (s, 1H). 
       Example 27 
     Intermediate 28 
     4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzaldehyde 
       [0254]    
       
                 
         
             
             
         
       
     
         [0255]    A mixture of Intermediate 19 (440 mg, 1.03 mmoles), oxalyl-Cl (96 μL, 1.1 eq), DMSO (162 μL, 2.2 eq) and triethylamine (720 μL, 5.0 eq) were reacted to give 286 mg (65%) of Intermediate 28. 
         [0256]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.55-1.82 (m, 2H) 1.89-2.03 (m, 2H) 2.28 (s, 6H) 2.78-3.12 (m, 2H) 4.52 (t, J=7.33 Hz, 1H) 6.55-6.71 (m, 1H) 6.78-6.88 (m, 2H) 7.17 (d, J=7.91 Hz, 1H) 7.31 (d, J=8.50 Hz, 2H) 7.60-7.67 (m, 1H) 7.68-7.79 (m, 3H) 9.78-10.03 (m, 1H). 
       Example 28 
     Intermediate 29 
     Methyl 4-{[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)-4-oxobutyl]thio}benzoate 
       [0257]    
       
                 
         
             
             
         
       
     
         [0258]    A mixture of 2-(3-chlorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1275947-05-1] (3.9 g, 15 mmoles), LDA (8.4 mL, 1.5 eq), methyl 4-[(2-bromoethyl)thio]benzoate [CAS 14184-32-8] (5.38 g, 1.1 eq) were reacted to give 1.02 g (15%) of Intermediate 29. 
         [0259]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.09-2.20 (m, 1H) 2.26 (s, 6H) 2.46-2.64 (m, 1H) 2.91-3.02 (m, 2H) 3.85-3.93 (m, 3H) 4.77 (t, J=7.18 Hz, 1H) 7.08-7.17 (m, 2H) 7.17-7.22 (m, 2H) 7.24-7.30 (m, 3H) 7.61-7.67 (m, 1H) 7.68-7.73 (m, 1H) 7.90 (d, J=8.79 Hz, 2H). 
       Example 29 
     Intermediate 30 
     Methyl 4-{[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)-4-hydroxybutyl]thio}benzoate 
       [0260]    
       
                 
         
             
             
         
       
     
         [0261]    A mixture of Intermediate 29 (1.02 g, 2.25 mmoles) and NaBH 4  (85 mg, 1.0 eq) were reacted to give 830 g (81%) Intermediate 30. 
         [0262]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.66-1.92 (m, 2H) 2.23 (s, 3H) 2.24 (s, 3H) 2.48-2.59 (m, 1H) 2.64-2.84 (m, 1H) 3.00-3.09 (m, 1H) 3.89 (s, 3H) 4.64 (d, J=8.50 Hz, 1H) 6.96-7.09 (m, 5H) 7.12-7.20 (m, 1H) 7.22-7.36 (m, 3H) 7.81 (d, J=8.20 Hz, 2H). 
       Example 30 
     Intermediate 31 
     Methyl 4-{[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butyl]thio}benzoate 
       [0263]    
       
                 
         
             
             
         
       
     
         [0264]    A mixture of Intermediate 30 (830 mg, 1.8 mmoles), triethyl silane (440 μL, 1.5 eq) and trifluoroacetic acid (352 μL, 2.5 eq) were reacted to give 680 mg (85%) of Intermediate 31. 
         [0265]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.62-1.78 (m, 1H) 1.80-1.99 (m, 1H) 2.12-2.20 (m, 1H) 2.22 (s, 3H) 2.24 (s, 3H) 2.48-2.67 (m, 1H) 2.81 (d, J=8.20 Hz, 1H) 3.32-3.43 (m, 1H) 3.90 (s, 3H) 5.85 (d, J=9.67 Hz, 1H) 6.82 (s, 1H) 7.00-7.08 (m, 4H) 7.10-7.17 (m, 1H) 7.18-7.31 (m, 3H) 7.80-7.88 (m, 2H). 
       Example 31 
     Intermediate 32 
     (4-{[3-(3-Chlorophenyl)-4-(3,4-dimethylphenyl)butyl]thio}phenyl)methanol 
       [0266]    
       
                 
         
             
             
         
       
     
         [0267]    A mixture of Intermediate 31 (680 mg, 1.6 mmoles) and LAH (1.0 M, 1.7 mL, 1.1 eq) were reacted to give 422 mg (66%) of Intermediate 32. 
         [0268]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.53-1.88 (m, 4H) 2.16-2.27 (m, 6H) 2.42-2.57 (m, 1H) 2.57-2.86 (m, 1H) 3.02-3.16 (m, 1H) 4.54-4.68 (m, 2H) 7.02-7.10 (m, 4H) 7.11-7.19 (m, 4H) 7.20-7.29 (m, 3H). 
       Example 32 
     Intermediate 33 
     4-{[(3E)-3-(3-Chlorophenyl)-4-(3,4-dimethylphenyl)but-3-en-1-yl]sulfinyl}benzaldehyde 
       [0269]    
       
                 
         
             
             
         
       
     
       Intermediate 34 
     4-{[3-(3-Chlorophenyl)-4-(3,4-dimethylphenyl)butyl]sulfinyl}benzaldehyde 
       [0270]    
       
                 
         
             
             
         
       
     
         [0271]    A mixture Intermediate 32 (422 mg, 1.03 mmoles), 200 mg of molecular sieve, NMO (240.6 mg, 2.0 eq) and TPAP (25 mg) were reacted to give 43 mg (20%) of Intermediate 33 and 188 mg of Intermediate 34. 
         [0272]    Intermediate 33:  1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.07-2.21 (m, 1H) 2.23-2.28 (m, 6H) 2.51-2.63 (m, 1H) 2.98 (t, J=7.30 Hz, 2H) 4.76 (t, J=7.18 Hz, 1H) 7.08-7.24 (m, 4H) 7.26-7.39 (m, 3H) 7.63-7.76 (m, 4H) 9.90 (s, 1H) 
         [0273]    Intermediate 34:  1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.77-1.95 (m, 3H) 2.12-2.32 (m, 6H) 2.52-2.66 (m, 1H) 2.67-2.89 (m, 1H) 3.00-3.11 (m, 1H) 4.65 (d, J=8.20 Hz, 1H) 6.96-7.12 (m, 4H) 7.13-7.22 (m, 2H) 7.25-7.33 (m, 3H) 7.65 (d, J=8.50 Hz, 2H) 9.89 (s, 1H). 
       Example 33 
     Compound 1 
     {3-[(4-{[(4E)-4-(3-Chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propyl}phosphonic acid 
       [0274]    
       
                 
         
             
             
         
       
     
         [0275]    A mixture of Intermediate 10 (385 mg, 0.95 mmoles), (3-aminopropyl)phosphonic acid [CAS 13138-33-5] (120 mg, 0.9 eq), Bu 4 NOH (950 μL, 1.0 eq) and NaCNBH 3  (60.0 mg, 1 eq) were reacted to give Compound 1. 
         [0276]      1 H NMR (300 MHz, CD 3 OD) δ ppm 1.56-1.77 (m, 2H) 1.77-2.03 (m, 4H) 2.05 (s, 3H) 2.14 (s, 3H) 2.68 (t, J=7.03 Hz, 2H) 3.07 (t, J=6.30 Hz, 2H) 3.91-4.08 (m, 4H) 6.47 (br. s, 1H) 6.56 (d, J=7.62 Hz, 1H) 6.65 (br. s, 1H) 6.81 (d, J=6.00 Hz, 1H) 6.96 (d, J=9.00 Hz, 2H) 7.05-7.13 (m, 1H) 7.13-7.18 (m, 1H) 7.22-7.31 (m, 2H) 7.38 (d, J=9.00 Hz, 2H). 
       Example 34 
     Compound 2 
     3-[(4-{[(4E)-4-(3-Chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propanoic acid 
       [0277]    
       
                 
         
             
             
         
       
     
         [0278]    A mixture of Intermediate 10 (236 mg, 0.58 mmoles), β-alanine (52 mg, 1.0 eq), HOAc (10 drops) and NaCNBH 3  (36.7 mg, 1 eq) were reacted to give Compound 2. 
         [0279]      1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.79-1.91 (m, 2H) 2.05 (s, 3H) 2.14 (s, 3H) 2.48 (t, J=6.45 Hz, 2H) 2.69 (t, J=6.89 Hz, 2H) 3.13 (t, J=6.30 Hz, 2H) 4.02 (t, J=6.30 Hz, 2H) 4.12 (br. s, 2H) 6.47 (s, 1H) 6.56 (d, J=7.62 Hz, 1H) 6.65 (s, 1H) 6.81 (d, J=7.91 Hz, 1H) 6.95-7.00 (m, 2H) 7.07-7.12 (m, 1H) 7.15-7.18 (m, 1H) 7.23-7.30 (m, 2H) 7.33-7.49 (m, 2H). 
       Example 35 
     Compound 3 
     3-[(4-{[(4E)-4-(3,5-Difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propanoic acid 
       [0280]    
       
                 
         
             
             
         
       
     
         [0281]    A mixture of Intermediate 15 (220 mg, 0.54 mmoles), β-alanine (48.3 mg, 1.0 eq), HOAc (10 drops) and NaCNBH 3  (34 mg, 1 eq) were reacted to give Compound 3. 
         [0282]      1 H NMR (300 MHz, CD 3 OD) δ ppm 1.80-1.90 (m, 2H) 2.08 (s, 3H) 2.15 (s, 3H) 2.48 (t, J=6.45 Hz, 2H) 2.69 (t, J=7.18 Hz, 2H) 3.12 (t, J=6.45 Hz, 2H) 4.03 (t, J=6.01 Hz, 2H) 4.10 (s, 2H) 6.51 (s, 1H) 6.59 (d, J=8.20 Hz, 1H) 6.68 (s, 1H) 6.71-6.89 (m, 4H) 6.95-7.00 (m, 2H) 7.34-7.40 (m, 2H). 
       Example 36 
     Compound 4 
     {3-[(4-{[(4E)-4-(3,5-Difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)amino]propyl}phosphonic acid 
       [0283]    
       
                 
         
             
             
         
       
     
         [0284]    A mixture of Intermediate 15 (463 mg, 1.14 mmoles), (3-aminopropyl)phosphonic acid (143 mg, 0.9 eq), Bu 4 NOH (1.1 mL, 1.0 eq) and NaCNBH 3  (72.0 mg, 1 eq) were reacted to give Compound 4. 
         [0285]      1 H NMR (300 MHz, CD 3 OD) δ ppm 1.57-1.74 (m, 2H) 1.76-2.00 (m, 4H) 2.07 (s, 3H) 2.15 (s, 3H) 2.67 (t, J=7.30 Hz, 2H) 3.04 (t, J=6.20 Hz, 2H) 3.79-4.07 (m, 4H) 6.50 (s, 1H) 6.58 (d, J=6.20 Hz, 1H) 6.64-6.87 (m, 5H) 6.95 (d, J=8.79 Hz, 2H) 7.40 (d, J=8.50 Hz, 2H). 
       Example 37 
     Compound 5 
     3-[(4-{[(4E)-4-(3-Chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzyl)amino]propanoic acid 
       [0286]    
       
                 
         
             
             
         
       
     
         [0287]    A mixture of Intermediate 25 (168 mg, 0.40 mmoles), β-alanine (35.4 mg, 1.0 eq), HOAc (8 drops) and NaCNBH 3  (25 mg, 1 eq) were reacted as outlined is Scheme 1 to give Compound 5. 
         [0288]      1 H NMR (300 MHz, CD 3 OD) δ ppm 1.42-1.76 (m, 2H) 2.12-2.25 (m, 1H) 2.28 (s, 6H) 2.48 (t, J=6.30 Hz, 2H) 2.93-3.03 (m, 2H) 3.14 (t, J=6.45 Hz, 2H) 4.14 (s, 2H) 4.72 (t, J=7.30 Hz, 1H) 7.16-7.28 (m, 5H) 7.30-7.38 (m, 5H) 7.69-7.76 (m, 2H). 
       Example 38 
     Compound 6 
     3-[(4-{[(3E)-3-(3-Chlorophenyl)-4-(3,4-dimethylphenyl)but-3-en-1-yl]sulfinyl}benzyl)amino]propanoic acid 
       [0289]    
       
                 
         
             
             
         
       
     
         [0290]    A mixture of Intermediate 33 (43 mg, 0.11 mmoles), β-alanine (9.4 mg, 1.0 eq), HOAc (3 drops) and NaCNBH 3  (6.6 mg, 1 eq) were reacted to give Compound 6. 
         [0291]      1 H NMR (300 MHz, CD 3 OD) δ ppm 1.92-2.15 (m, 1H) 2.27 (s, 6H) 2.48 (t, J=6.30 Hz, 2H) 2.90 (d, J=7.62 Hz, 2H) 3.14 (t, J=6.30 Hz, 2H) 4.14 (s, 2H) 4.92 (t, J=7.00 Hz, 1H) 7.10-7.31 (m, 6H) 7.31-7.44 (m, 4H) 7.67-7.75 (m, 2H). 
       Example 39 
     Compound 7 
     3-[(4-{[(4E)-4-(3,5-Difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzyl)amino]propanoic acid 
       [0292]    
       
                 
         
             
             
         
       
     
         [0293]    A mixture of Intermediate 28 (143 mg, 0.34 mmoles), β-alanine (30 mg, 1.0 eq), HOAc (7 drops) and NaCNBH 3  (21.2 mg, 1 eq) were reacted to give Compound 7. 
         [0294]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.30-1.60 (m, 2H) 1.79-1.92 (m, 1H) 2.16 (s, 1H) 2.23 (s, 6H) 2.28 (t, J=6.59 Hz, 1H) 2.71 (t, J=6.50 Hz, 2H) 2.85-3.07 (m, 1H) 3.71 (s, 2H) 4.92 (t, J=7.60 Hz, 1H) 6.95-7.11 (m, 3H) 7.16-7.28 (m, 6H) 7.79 (s, 2H). 
       Example 40 
     Compound 8 
     3-[(4-{[(4E)-4-(3,5-Difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]thio}benzyl)amino]propanoic acid 
       [0295]    
       
                 
         
             
             
         
       
     
         [0296]    A mixture of Intermediate 20 (78.5 mg, 0.19 mmoles), β-alanine (17 mg, 1.0 eq), HOAc (3 drops) and NaCNBH 3  (12 mg, 1 eq) were reacted to give Compound 8. 
         [0297]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.49-1.67 (m, 2H) 2.03 (s, 3H) 2.09 (s, 3H) 2.17-2.23 (m, 1H) 2.28 (t, J=6.59 Hz, 2H) 2.58 (t, J=7.33 Hz, 1H) 2.66-2.83 (m, 2H) 2.93 (t, J=7.33 Hz, 2H) 3.73 (s, 2H) 6.44 (s, 1H) 6.53 (d, J=7.91 Hz, 1H) 6.71 (s, 1H) 6.76-6.89 (m, 3H) 7.17-7.33 (m, 5H). 
       Example 41 
     Compound 9 
     3-[(4-{[(5E)-5-(3,5-Difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]thio}benzyl)amino]propanoic acid 
       [0298]    
       
                 
         
             
             
         
       
     
         [0299]    A mixture of Intermediate 27 (100 mg, 0.23 mmoles), β-alanine (20.4 mg, 1.0 eq), HOAc (5 drops) and NaCNBH 3  (14.4 mg, 1.0 eq) were reacted as outlined is Scheme 1 to give Compound 9. 
         [0300]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.31-1.47 (m, 2H) 1.48-1.64 (m, 2H) 2.03 (s, 3H) 2.09 (s, 3H) 2.17-2.32 (m, 3H) 2.38-2.57 (m, 1H) 2.66-2.77 (m, 2H) 2.88-2.96 (m, 2H) 3.72 (s, 2H) 6.43 (s, 1H) 6.52 (d, J=7.62 Hz, 1H) 6.69 (s, 1H) 6.75-6.88 (m, 3H) 7.14-7.37 (m, 5H). 
       Example 42 
     Compound 10 
     {3-[(4-{[(5E)-5-(3,5-Difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]thio}benzyl)amino]propyl}phosphonic acid 
       [0301]    
       
                 
         
             
             
         
       
     
         [0302]    A mixture of Intermediate 27 (386 mg, 0.89 mmoles), (3-aminopropyl)phosphonic acid (100 mg, 0.9 eq), Bu 4 NOH (800 μL, 1.0 eq) and NaCNBH 3  (50.33 mg, 1.0 eq) were reacted to give Compound 10. 
         [0303]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.24-1.36 (m, 5H) 1.55 (br. s., 4H) 2.09 (s, 3H) 2.02 (s, 3H) 2.63 (br. s., 2H) 2.86-2.97 (m, 1H) 3.09-3.18 (m, 3H) 3.72 (br. s., 1H) 6.42 (s, 1H) 6.52 (d, J=7.33 Hz, 1H) 6.69 (s, 1H) 6.75-6.88 (m, 3H) 7.09 (d, J=8.79 Hz, 1H) 7.22 (d, J=8.20 Hz, 2H) 7.32 (d, J=8.20 Hz, 2H). 
       Biological Data 
       [0304]    Compounds were synthesized and tested for S1P1 activity using the GTP γ 35 S binding assay. These compounds may be assessed for their ability to activate or block activation of the human S1P1 receptor in cells stably expressing the S1P1 receptor. GTP γ 35 S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCl 2  10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP γ 35 S, and 5 μg membrane protein in a volume of 150 μl. Test compounds were included in the concentration range from 0.08 to 5,000 nM unless indicated otherwise. Membranes were incubated with 100 μM 5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP γ 35 S and continued for 30 min at 25° C. Reaction mixtures were filtered over Whatman GF/B filters under vacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4, MgCl 2  10 and NaCl 100). Filters were dried and mixed with scintillant, and counted for  35 S activity using a β-counter. Agonist-induced GTP γ 35 S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a non-linear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1P in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM. 
         [0000]    Table 1 shows activity potency: S1P1 receptor from GTP γ 35 S: nM, (EC 50 ).
 
Activity potency: S1P1 receptor from GTP γ 35 S: nM, (EC 50 ),
 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                   
                 S1P1 
               
               
                   
                 IUPAC name 
                 EC 50  (nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 3-[(4-{[(5E)-5-(3,5-difluorophenyl)-6-(3,4- 
                 639.19 
               
               
                   
                 dimethylphenyl)hex-5-en-1- 
               
               
                   
                 yl]sulfanyl}benzyl)amino]propanoic acid 
               
               
                   
                 3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4- 
                 10.19 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]sulfanyl}benzyl)amino]propanoic acid 
               
               
                   
                 3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4- 
                 110.99 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]sulfinyl}benzyl)amino]propanoic acid 
               
               
                   
                 3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4- 
                 449.99 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]sulfinyl}benzyl)amino]propanoic acid 
               
               
                   
                 {3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4- 
                 7.84 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]oxy}benzyl)amino]propyl}phosphonic acid 
               
               
                   
                 3-[(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4- 
                 51.92 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]oxy}benzyl)amino]propanoic acid 
               
               
                   
                 3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4- 
                 73.24 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]oxy}benzyl)amino]propanoic acid 
               
               
                   
                 {3-[(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4- 
                 9.65 
               
               
                   
                 dimethylphenyl)pent-4-en-1- 
               
               
                   
                 yl]oxy}benzyl)amino]propyl}phosphonic acid