PATENT ABSTRACT
The present invention relates to novel aromatic thio derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

PATENT DESCRIPTION
RELATED APPLICATION 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/736,732 filed Dec. 13, 2012, the disclosure of which is hereby incorporated in its entirety herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to novel aromatic thio derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors. The invention also 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. 
         [0004]    US Patent Application No. 20130217652 discloses thiobenzyl and sulfinylbenzyl derivatives as S1P modulators of general formula: 
         [0000]    
       
                 
         
             
             
         
       
     
       SUMMARY OF THE INVENTION 
       [0005]    A group of novel compounds which are potent 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 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. 
         [0006]    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. 
         [0007]    In one embodiment of the invention, there are provided compounds having the Formula I below and pharmaceutically accepted salts thereof, its enantiomers, diastereoisomers, tautomers or a pharmaceutically acceptable salt thereof, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein: 
         [0008]    R 1  is S; SO or SO 2 ; 
         [0009]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0010]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0011]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0012]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0013]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0014]    R 7  is N or CR 7a ; 
         [0015]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0016]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0017]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0018]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0019]    R 11  is H, D, F or C 1-4  alkyl; 
         [0020]    R 12  is H, D, F or C 1-4  alkyl; 
         [0021]    R 13  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 14  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0022]    R 14  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 13  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0023]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0024]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0025]    R 17  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 18  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0026]    R 18  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 17  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0027]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 ; 
         [0028]    R 20  is H or C 1-4  alkyl; 
         [0029]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0030]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0031]    R 1  is S; SO or SO 2 ; 
         [0032]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0033]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0034]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0035]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0036]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0037]    R 7  is N or CR 7a ; 
         [0038]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0039]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or 
         [0040]    C(O)R 21 ; 
         [0041]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0042]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0043]    R 11  is H, D, F or C 1-4  alkyl; 
         [0044]    R 12  is H, D, F or C 1-4  alkyl; 
         [0045]    R 13  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 14  can form a 3 to 6 
         [0000]    membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0046]    R 14  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 13  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0047]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0048]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0049]    R 17  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 18  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0050]    R 18  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 17  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0051]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 ; 
         [0052]    R 20  is H or C 1-4  alkyl; 
         [0053]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0054]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0055]    R 1  is S; SO or SO 2 ; 
         [0056]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0057]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0058]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0059]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0060]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0061]    R 7  is CR 7a ; 
         [0062]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0063]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0064]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0065]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0066]    R 11  is H; 
         [0067]    R 12  is H; 
         [0068]    R 13  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 14  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0069]    R 14  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 13  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0070]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0071]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0072]    R 17  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl; 
         [0073]    R 18  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl; 
         [0074]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 ; 
         [0075]    R 20  is H or C 1-4  alkyl; 
         [0076]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0077]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0078]    R 1  is S; SO or SO 2 ; 
         [0079]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0080]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0081]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0082]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0083]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0084]    R 7  is CR 7a ; 
         [0085]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0086]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0087]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0088]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0089]    R 11  is H; 
         [0090]    R 12  is H; 
         [0091]    R 13  is H; 
         [0092]    R 14  is H; 
         [0093]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0094]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0095]    R 17  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0096]    R 18  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0097]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 ; 
         [0098]    R 20  is H or C 1-4  alkyl; 
         [0099]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0100]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0101]    R 1  is S; 
         [0102]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0103]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0104]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0105]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0106]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0107]    R 7  is CR 7a ; 
         [0108]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0109]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0110]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0111]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0112]    R 11  is H; 
         [0113]    R 12  is H; 
         [0114]    R 13  is H; 
         [0115]    R 14  is H; 
         [0116]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0117]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0118]    R 17  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0119]    R 18  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0120]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , R 20  is H or C 1-4  alkyl; 
         [0121]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0122]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0123]    R 1  is S; 
         [0124]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0125]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0126]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0127]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0128]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0129]    R 7  is CR 7a ; 
         [0130]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0131]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0132]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0133]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0134]    R 11  is H; 
         [0135]    R 12  is H; 
         [0136]    R 13  is H; 
         [0137]    R 14  is H; 
         [0138]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0139]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl, or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0140]    R 17  is H; 
         [0141]    R 18  is H; 
         [0142]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , 
         [0143]    R 20  is H or C 1-4  alkyl; 
         [0144]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0145]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0146]    R 1  is S; 
         [0147]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0148]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0149]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0150]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0151]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0152]    R 7  is CR 7a ; 
         [0153]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0154]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0155]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0156]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0157]    R 11  is H; 
         [0158]    R 12  is H; 
         [0159]    R 13  is H; 
         [0160]    R 14  is H; 
         [0161]    R 15  is H; 
         [0162]    R 16  is H; 
         [0163]    R 17  is H; 
         [0164]    R 18  is H; 
         [0165]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , 
         [0166]    R 20  is H or C 1-4  alkyl; 
         [0167]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0168]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0169]    R 1  is S; 
         [0170]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0171]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0172]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0173]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0174]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0175]    R 7  is CR 7a ; 
         [0176]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0177]    R 8  is H; 
         [0178]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0179]    R 10  is H; 
         [0180]    R 11  is H; 
         [0181]    R 12  is H; 
         [0182]    R 13  is H; 
         [0183]    R 14  is H; 
         [0184]    R 15  is H; 
         [0185]    R 16  is H; 
         [0186]    R 17  is H; 
         [0187]    R 18  is H; 
         [0188]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , 
         [0189]    R 20  is H or C 1-4  alkyl; 
         [0190]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0191]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0192]    R 1  is S; 
         [0193]    R 2  is H, D, F; 
         [0194]    R 3  is H, D, F; 
         [0195]    R 4  is H, D, F, 
         [0196]    R 5  is H, D, F; 
         [0197]    R 6  is H, D, F; 
         [0198]    R 7  is CR 7a ; 
         [0199]    R 7a  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0200]    R 8  is H; 
         [0201]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0202]    R 10  is H; 
         [0203]    R 11  is H; 
         [0204]    R 12  is H; 
         [0205]    R 13  is H; 
         [0206]    R 14  is H; 
         [0207]    R 15  is H; 
         [0208]    R 16  is H; 
         [0209]    R 17  is H; 
         [0210]    R 18  is H; 
         [0211]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , 
         [0212]    R 20  is H or C 1-4  alkyl; 
         [0213]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0214]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0215]    R 1  is S; 
         [0216]    R 2  is H, D or F; 
         [0217]    R 3  is H, D or F; 
         [0218]    R 4  is H, D or F; 
         [0219]    R 5  is H, D or F; 
         [0220]    R 6  is H, D or F; 
         [0221]    R 7  is N; 
         [0222]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H or O(C 1-4  alkyl); 
         [0223]    R 9  is H, D or F; 
         [0224]    R 10  is H, D or F; 
         [0225]    R 11  is H; 
         [0226]    R 12  is H; 
         [0227]    R 13  is H or D; 
         [0228]    R 14  is H or D; 
         [0229]    R 15  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0230]    R 16  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0231]    R 17  is H or D; and 
         [0232]    R 18  is H or D. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0233]    R 1  is S; 
         [0234]    R 2  is H, D or F; 
         [0235]    R 3  is H, D or F; 
         [0236]    R 4  is H, D or F; 
         [0237]    R 5  is H, D or F; 
         [0238]    R 6  is H, D or F; 
         [0239]    R 7  is CR 7a ; 
         [0240]    R 7a  is H or D; 
         [0241]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H or O(C 1-4  alkyl); 
         [0242]    R 9  is H, D or F; 
         [0243]    R 10  is H, D or F; 
         [0244]    R 11  is H; 
         [0245]    R 12  is H; 
         [0246]    R 13  is H or D; 
         [0247]    R 14  is H or D; 
         [0248]    R 15  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0249]    R 16  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0250]    R 17  is H or D; and 
         [0251]    R 18  is H or D. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0252]    R 1  is S; 
         [0253]    R 2  is H, D or F; 
         [0254]    R 3  is H, D or F; 
         [0255]    R 4  is H, D or F; 
         [0256]    R 5  is H, D or F; 
         [0257]    R 6  is H, D or F; 
         [0258]    R 7  is CR 7a ; 
         [0259]    R 7a  is H; 
         [0260]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H or O(C 1-4  alkyl); 
         [0261]    R 9  is H, D or F; 
         [0262]    R 10  is H, D or F; 
         [0263]    R 11  is H; 
         [0264]    R 12  is H; 
         [0265]    R 13  is H or D; 
         [0266]    R 14  is H or D; 
         [0267]    R 15  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 16  can form a 3 to 6 membered carbocyclic spiro ring; 
         [0268]    R 16  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 15  can form a 3 to 6 membered carbocyclic spiro ring; 
         [0269]    R 17  is H or D; and 
         [0270]    R 18  is H or D. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0271]    R 1  is S; 
         [0272]    R 2  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0273]    R 3  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0274]    R 4  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0275]    R 5  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0276]    R 6  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, OH, NH 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0277]    R 7  is CR 7a ; 
         [0278]    R 7a  is H; 
         [0279]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 )perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0280]    R 9  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0281]    R 10  is H, D, F, Cl, Br, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, NH 2 , NO 2 , C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H, O(C 1-4  alkyl), CN, SO 2 R 19  or C(O)R 21 ; 
         [0282]    R 11  is H; 
         [0283]    R 12  is H; 
         [0284]    R 13  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 14  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0285]    R 14  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl, or together with R 13  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring; 
         [0286]    R 15  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 16  can form a 3 to 6 membered carbocyclic; 
         [0287]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; or together with R 15  can form a 3 to 6 membered carbocyclic; 
         [0288]    R 17  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0289]    R 18  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0290]    R 19  is H, C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 20 ) 2 , R 20  is H or C 1-4  alkyl; 
         [0291]    R 21  is C 1-4  alkyl, OH, C 1-4  perfluoroalkyl or N(R 22 ) 2 ; and 
         [0292]    R 22  is H or C 1-4  alkyl. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0293]    R 1  is S; 
         [0294]    R 2  is H or F; 
         [0295]    R 3  is H; 
         [0296]    R 4  is H, F, Cl, Br, C 1-4  alkyl or O(C 1-4  alkyl); 
         [0297]    R 5  is H or F; 
         [0298]    R 6  is H or F; 
         [0299]    R 7  is CR 7a ; 
         [0300]    R 7a  is H, F, Cl, Br, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0301]    R 8  is H, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl or O(C 1-4 ) perfluoroalkyl; 
         [0302]    R 9  is H, F, Cl, Br or C 1-4  alkyl; 
         [0303]    R 10  is H or F; 
         [0304]    R 11  is H or F; 
         [0305]    R 12  is H or F; 
         [0306]    R 13  is H; 
         [0307]    R 14  is H; 
         [0308]    R 15  is H, C 1-4  alkyl or together with R 16  can form a 3 to 6 membered carbocyclic spiro ring; 
         [0309]    R 16  is H, C 1-4  alkyl or together with R 15  can form a 3 to 6 membered carbocyclic spiro ring; 
         [0310]    R 17  is H; and 
         [0311]    R 18  is H. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0312]    R 1  is S; 
         [0313]    R 2  is H or F; 
         [0314]    R 3  is H; 
         [0315]    R 4  is H, F, Cl, Br, C 1-4  alkyl or O(C 1-4  alkyl); 
         [0316]    R 5  is H or F; 
         [0317]    R 6  is H or F; 
         [0318]    R 7  is CR 7a ; 
         [0319]    R 7a  is H, F, Cl, Br, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0320]    R 8  is H, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl or O(C 1-4 ) perfluoroalkyl; 
         [0321]    R 9  is H, F, Cl, Br or C 1-4  alkyl; 
         [0322]    R 10  is H or F; 
         [0323]    R 11  is H or F; 
         [0324]    R 12  is H or F; 
         [0325]    R 13  is H; 
         [0326]    R 14  is H; 
         [0327]    R 15  is H, C 1-4  alkyl or together with R 16  can form a 3 to 6 membered carbocyclic spiro ring selected from: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0328]    R 16  is H, C 1-4  alkyl or together with R 15  can form a 3 to 6 membered carbocyclic spiro ring selected from: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0329]    R 17  is H; and 
         [0330]    R 18  is H. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0331]    R 1  is S; 
         [0332]    R 2  is H, D or F; 
         [0333]    R 3  is H, D or F; 
         [0334]    R 4  is H, D or F; 
         [0335]    R 5  is H, D or F; 
         [0336]    R 6  is H, D or F; 
         [0337]    R 7  is CR 7a ; 
         [0338]    R 7a  is H or D; 
         [0339]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H or O(C 1-4  alkyl); 
         [0340]    R 9  is H, D or F; 
         [0341]    R 10  is H, D or F; 
         [0342]    R 11  is H; 
         [0343]    R 12  is H; 
         [0344]    R 13  is H or D; 
         [0345]    R 14  is H or D; 
         [0346]    R 15  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0347]    R 16  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0348]    R 17  is H or D; and 
         [0349]    R 18  is H or D. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0350]    R 1  is S; 
         [0351]    R 2  is H, D or F; 
         [0352]    R 3  is H, D or F; 
         [0353]    R 4  is H, D or F; 
         [0354]    R 5  is H, D or F; 
         [0355]    R 6  is H, D or F; 
         [0356]    R 7  is N; 
         [0357]    R 8  is H, D, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl, O(C 1-4 ) perfluoroalkyl, OCF 2 H, OCF 2 CF 2 H or O(C 1-4  alkyl); 
         [0358]    R 9  is H, D or F; 
         [0359]    R 10  is H, D or F; 
         [0360]    R 11  is H; 
         [0361]    R 12  is H; 
         [0362]    R 13  is H or D; 
         [0363]    R 14  is H or D; 
         [0364]    R 15  is H, D, F, C 1-4  alkyl, C 1-4  perfluoroalkyl or together with R 16  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0365]    R 16  is H, D, F, C 1-4  alkyl or C 1-4  perfluoroalkyl or together with R 15  can form a 3 to 6 membered carbocyclic or heterocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0366]    R 17  is H or D; and 
         [0367]    R 18  is H or D. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0368]    R 1  is S; 
         [0369]    R 7  is CR 7a ; 
         [0370]    R 8  is H; 
         [0371]    R 11  is H; 
         [0372]    R 12  is H; 
         [0373]    R 13  is H; 
         [0374]    R 14  is H; 
         [0375]    R 15  is H; 
         [0376]    R 16  is H; 
         [0377]    R 17  is H; and 
         [0378]    R 18  is H. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0379]    R 1  is S; 
         [0380]    R 2  is H, D, F; 
         [0381]    R 3  is H, D, F; 
         [0382]    R 4  is H, D, F; 
         [0383]    R 5  is H, D, F; 
         [0384]    R 6  is H, D, F; 
         [0385]    R 7  is CR 7a ; 
         [0386]    R 8  is H; 
         [0387]    R 10  is H; 
         [0388]    R 11  is H; 
         [0389]    R 12  is H; 
         [0390]    R 13  is H; 
         [0391]    R 14  is H; 
         [0392]    R 15  is H; 
         [0393]    R 16  is H; 
         [0394]    R 17  is H; and 
         [0395]    R 18  is H. 
         [0000]    In another aspect the invention provides a compound of Formula I, wherein: 
         [0396]    R 1  is S; 
         [0397]    R 2  is H or F; 
         [0398]    R 3  is H; 
         [0399]    R 4  is H, F, Cl, Br, C 1-4  alkyl or O(C 1-4  alkyl); 
         [0400]    R 5  is H or F; 
         [0401]    R 6  is H or F; 
         [0402]    R 7  is CR 7a ; 
         [0403]    R 7a  is H, F, Cl, Br, C 1-4  alkyl or C 1-4  perfluoroalkyl; 
         [0404]    R 8  is H, F, Cl, Br, C 1-4  alkyl, C 1-4  perfluoroalkyl or O(C 1-4 ) perfluoroalkyl; 
         [0405]    R 9  is H, F, Cl, Br or C 1-4  alkyl; 
         [0406]    R 10  is H or F; 
         [0407]    R 11  is H or F; 
         [0408]    R 12  is H or F; 
         [0409]    R 13  is H; 
         [0410]    R 14  is H; 
         [0411]    R 15  is H, C 1-4  alkyl or together with R 16  can form a 3 to 6 membered carbocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0412]    R 16  is H, C 1-4  alkyl or together with R 15  can form a 3 to 6 membered carbocyclic spiro ring selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0413]    R 17  is H; and 
         [0414]    R 18  is H. 
         [0415]    The term “alkyl”, as used herein, refers to saturated, monovalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 4 carbon atoms. One methylene (—CH 2 —) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C 3-6  cycloalkyl. Alkyl groups can be substituted by halogen, amino, hydroxyl, cycloalkyl, amino, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid. 
         [0416]    The term “perfluoroalkyl” groups as used herein, refers to alkyl chains containing 1 to 4 carbon atoms wherein all the hydrogen atoms have been replaced by fluorine atoms on the carbon chain. 
         [0417]    The term “alkylene”, as used herein, refers to saturated, divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 2 to 4 carbon atoms. One methylene (—CH 2 —) group of the alkylene can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl. 
         [0418]    The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl can be substituted by alkyl groups or halogens. 
         [0419]    The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 5 to 8 carbon atoms derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by alkyl groups or halogens. 
         [0420]    The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine or iodine. 
         [0421]    The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 4 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-4  alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups. 
         [0422]    The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 4 carbon atoms, derived from a saturated alkyl, having at least one triple bond. Alkynyl groups can be substituted by alkyl groups. 
         [0423]    The terms “a 3 to 6 membered carbocyclic spiro ring”, as used herein, refers to a structure such as but not limited to: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0424]    The terms “a 3 to 6 membered heterocyclic spiro ring”, as used herein, refers to a structure such as but not limited to: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0425]    The term “hydroxyl” as used herein, represents a group of formula “—OH”. 
         [0426]    The term “carbonyl” as used herein, represents a group of formula “—C═O”. 
         [0427]    The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”. 
         [0428]    The term “sulfonyl” as used herein, represents a group of formula “—SO 2 ”. 
         [0429]    The term “sulfate” as used herein, represents a group of formula “—O—S(O) 2 —O—”. 
         [0430]    The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”. 
         [0431]    The term “sulfoxide” as used herein, represents a group of formula “—S═O”. 
         [0432]    The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”. 
         [0433]    The term “phosphoric acid” as used herein, represents a group of formula “—(O)P(O)(OH) 2 ”. 
         [0434]    The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”. 
         [0435]    The term “amino” as used herein, represents a group of formula “—NH 2 ”. 
         [0436]    The formula “H”, as used herein, represents a hydrogen atom. 
         [0437]    The formula “O”, as used herein, represents an oxygen atom. 
         [0438]    The formula “N”, as used herein, represents a nitrogen atom. 
         [0439]    The formula “S”, as used herein, represents a sulfur atom. 
         [0440]    Compounds of the invention are:
   [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({4-[(5-phenylpentyl)thio]-3-(trifluoromethyl)benzyl}amino)propyl]phosphonic acid;   [3-({4-[(5-phenylpentyl)thio]-2-(trifluoromethyl)benzyl}amino)propyl]phosphonic acid;   [3-({2-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({3-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({4-[(5-phenylpentyl)thio]-3-(trifluoromethoxy)benzyl}amino)propyl]phosphonic acid;   [3-({3-cyano-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   {3-[(4-{[5-(4-fluorophenyl)pentyl]thio}-3-methylbenzyl)amino]propyl}phosphonic acid;   (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   {3-[(4-{[5-(4-methoxyphenyl)pentyl]thio}-3-methylbenzyl)amino]propyl}phosphonic acid;   (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(4-methylphenyl)pentyl]thio}-3 (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   [3-({3-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)-1,1-difluoropropyl]phosphonic acid;   [1,1-difluoro-3-({4-[(5-phenylpentyl)thio]-3-(trifluoromethoxy)benzyl}amino)propyl]phosphonic acid;   [3-({3-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)-1-methylpropyl]phosphonic acid;   [3-({3-methyl-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({3-fluoro-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   {3-[(3-cyano-4-{[5-(4-fluorophenyl)pentyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-methyl-4-{[5-(4-methylphenyl)pentyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-2-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   [3-({2,5-difluoro-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-({2-chloro-5-fluoro-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid;   [3-(3-bromo-4-{[4-(1-phenylcyclohexyl)butyl]thio}phenyl)propyl]phosphonic acid;   3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   {3-[(2,5-difluoro-4-{[4-(1-phenylcyclohexyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-chloro-4-{[4-(1-phenylcyclohexyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   [3-({3-bromo-4-[(5-methyl-5-phenylhexyl)thio]benzyl}amino)propyl]phosphonic acid;   3-((2,5-difluoro-4-((5-(4-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2,5-difluoro-4-((5-(3-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2,5-difluoro-4-((5-(2-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2-bromo-5-fluoro-4-((5-phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((5-fluoro-2-methyl-4-((5-phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((5-chloro-2-fluoro-4-((5-phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((5-bromo-2-fluoro-4-((5-phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2-fluoro-5-methyl-4-((5-phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-(((5-((5-phenylpentyl)thio)pyridin-2-yl)methyl)amino)propyl)phosphonic acid;   (3-(((4-fluoro-5-((5-phenylpentyl)thio)pyridin-2-yl)methyl)amino)propyl)phosphonic acid;   (3-((2-chloro-5-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2-bromo-5-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((5-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)-2-methylbenzyl)amino)propyl)phosphonic acid;   (3-((5-chloro-2-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((5-bromo-2-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)-5-methylbenzyl)amino)propyl)phosphonic acid;   (3-(((4-fluoro-5-((5-(4-fluorophenyl)pentyl)thio)pyridin-2-yl)methyl)amino)propyl)phosphonic acid;   (3-(((5-((5-(4-fluorophenyl)pentyl)thio)pyridin-2-yl)methyl)amino)propyl)phosphonic acid;   (3-((4-((4-(1-phenylcyclohexyl)butyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((4-((5-methyl-5-phenylhexyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((4-((4-(1-phenylcyclopentyl)butyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((4-((4-(3-phenyloxetan-3-yl)butyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2,5-difluoro-4-((5-methyl-5-phenylhexyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2,5-difluoro-4-((4-(1-phenylcyclopentyl)butyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-((2,5-difluoro-4-((4-(3-phenyloxetan-3-yl)butyl)thio)benzyl)amino)propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2,5-difluoro-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid   {3-[(2,5-difluoro-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(2,5-difluoro-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-chloro-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-chloro-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-chloro-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-chloro-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-chloro-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-chloro-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   {3-[(3-chloro-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-chloro-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[4-(1-phenylcyclohexyl)butyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   [3-({4-[(5-methyl-5-phenylhexyl)thio]-3-(trifluoromethoxy)benzyl}amino)propyl]phosphonic acid;   [3-({4-[(5-methyl-5-phenylhexyl)thio]-3-(trifluoromethyl)benzyl}amino)propyl]phosphonic acid;   (3-{[4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-{[4-(1-phenylcyclohexyl)butyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[(4-fluoro-5-{[4-(1-phenylcyclohexyl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   (3-{[(5-{[4-(1-phenylcyclohexyl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   [3-({[4-fluoro-5-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2-yl]methyl}amino) propyl]phosphonic acid;   [3-({[5-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[4-fluoro-5-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[5-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   {3-[({4-fluoro-5-[(5-methyl-5-phenylhexyl)thio]pyridin-2-yl}methyl)amino]propyl}phosphonic acid;   {3-[({5-[(5-methyl-5-phenylhexyl)thio]pyridin-2-yl}methyl)amino]propyl}phosphonic acid;   (3-{[(4-fluoro-5-{[5-(4-fluorophenyl)-5-methylhexyl]thio}pyridin-2-yl)methyl]amino}propyl) phosphonic acid;   (3-{[(5-{[5-(4-fluorophenyl)-5-methylhexyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   (3-{[(4-fluoro-5-{[5-(2-fluorophenyl)-5-methylhexyl]thio}pyridin-2-yl)methyl]amino}propyl) phosphonic acid;   (3-{[(5-{[5-(2-fluorophenyl)-5-methylhexyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   (3-{[(4-fluoro-5-{[4-(3-phenyloxetan-3-yl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   (3-{[(5-{[4-(3-phenyloxetan-3-yl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   [3-({[4-fluoro-5-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[5-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[4-fluoro-5-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[5-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   (3-{[(4-fluoro-5-{[4-(1-phenylcyclopentyl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   (3-{[(5-{[4-(1-phenylcyclopentyl)butyl]thio}pyridin-2-yl)methyl]amino}propyl)phosphonic acid;   [3-({[4-fluoro-5-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[5-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[4-fluoro-5-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   [3-({[5-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2-yl]methyl}amino)propyl]phosphonic acid;   {3-[(3-fluoro-4-{[4-(1-phenylcyclohexyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-fluoro-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-fluoro-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   [3-({3-fluoro-4-[(5-methyl-5-phenylhexyl)thio]benzyl}amino)propyl]phosphonic acid;   {3-[(3-fluoro-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-fluoro-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-fluoro-4-{[4-(3-phenyloxetan-3-yl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-fluoro-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-fluoro-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   {3-[(3-fluoro-4-{[4-(1-phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-fluoro-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-fluoro-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   {3-[(3-bromo-4-{[4-(1-phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-bromo-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-bromo-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   {3-[(3-bromo-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-bromo-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(3-bromo-4-{[4-(3-phenyloxetan-3-yl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[3-bromo-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-bromo-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-bromo-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[3-bromo-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   {3-[(3-chloro-4-{[4-(3-phenyloxetan-3-yl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-{[4-(1-phenylcyclopentyl)butyl]thio}-3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-3-(trifluoromethyl)benzyl]amino}propyl) phosphonic acid;   (3-{[4-{[4-(1-phenylcyclopentyl)butyl]thio}-3-(trifluoromethoxy)benzyl]amino}propyl)phosphonic acid;   [3-({3-chloro-4-[(5-methyl-5-phenylhexyl)thio]benzyl}amino)propyl]phosphonic acid;   {3-[(3-chloro-4-{[4-(1-phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   {3-[(4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   {3-[(4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}benzyl)amino]propyl}phosphonic acid;   (3-{[4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-{[4-(1-phenylcyclohexyl)butyl]thio}-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   [3-({2-fluoro-4-[(5-methyl-5-phenylhexyl)thio]-5-(trifluoromethyl)benzyl}amino)propyl]phosphonic acid;   (3-{[2-fluoro-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-{[4-(1-phenylcyclopentyl)butyl]thio}-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-{[2-fluoro-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid;   (3-((4-((5-(p-tolyl)pentyl)thio)-3-(trifluoromethyl)benzyl)amino)propyl)phosphonic acid;   (3-{[2-fluoro-4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-5-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid.   
 
         [0607]    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. 
         [0608]    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. 
         [0609]    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, such as for example: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl &amp; Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345). 
         [0610]    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. 
         [0611]    In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier. 
         [0612]    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. 
         [0613]    These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1P modulation: not limited to the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds. 
         [0614]    Therapeutic utilities of S1P modulators are ocular diseases, such as but not limited to: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, 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; or systemic vascular barrier related diseases such as but not limited to: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression such as but not limited to: rheumatoid arthritis, Crohn&#39;s disease, Graves&#39; disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases such as but not limited to: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection such as but not limited to: ischemia reperfusion injury and atherosclerosis; or wound healing such as but not limited to: 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 and skin ageing, and prevention of radiation-induced injuries; or bone formation such as but not limited to: treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity such as but not limited to: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer&#39;s disease, age-related neuronal injuries; or in organ transplant such as renal, corneal, cardiac or adipose tissue transplant; inflammatory skin diseases, scleroderma, dermatomyositis, atopic dermatitis, lupus erythematosus, epidermolysis bullosa, and bullous pemphigold. Topical use of S1P (sphingosine) compounds is of use in the treatment of various acne diseases, acne vulgaris, and rosacea. 
         [0615]    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, and individual enantiomers, diastereomers thereof. 
         [0616]    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 disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, 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; or 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; or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn&#39;s disease, Graves&#39; disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection, ischemia reperfusion injury and atherosclerosis; or 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 and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer&#39;s disease, age-related neuronal injuries; or in organ transplant such as renal, corneal, cardiac or adipose tissue transplant; inflammatory skin diseases, scleroderma, dermatomyositis, atopic dermatitis, lupus erythematosus, epidermolysis bullosa, and bullous pemphigoid. 
         [0617]    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. 
         [0618]    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. 
         [0619]    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. 
         [0620]    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. 
         [0621]    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. 
         [0622]    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. 
         [0623]    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. 
         [0624]    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. 
         [0625]    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. 
         [0626]    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. 
         [0627]    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. 
         [0628]    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. 
         [0629]    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 
                 0-10 
               
               
                   
                 buffer 
                 0.01-10   
               
               
                   
                 pH adjustor 
                 q.s. pH 4.5-7.8 
               
               
                   
                 antioxidant 
                 as needed 
               
               
                   
                 surfactant 
                 as needed 
               
               
                   
                 purified water 
                 to make 100% 
               
               
                   
                   
               
             
          
         
       
     
         [0630]    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. 
         [0631]    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 dropwise 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-resealable 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 (microliter). 
         [0632]    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. 
         [0000]    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. 
         [0633]    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. 
         [0634]    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, illustrates how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I. 
         [0635]    In Scheme 1, mercaptobenzaldehydes react with activated (e.g. halogenated) compounds in the presence of a base (such as tertiary amines) to give the corresponding thioether intermediate. This intermediate reacts with 3-aminopropylphosphonic acid to give a derivative of Formula I. 
         [0000]    
       
                 
         
             
             
         
       
     
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0636]      FIG. 1  shows the results obtained from compound [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino) propyl]phosphonic acid, Compound 1, in a lymphopenia model. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0637]    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. 
         [0638]    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. 
         [0639]    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. 
         [0640]    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. 
         [0641]    As will be evident to those skilled in the art, individual diasteroisomeric forms can be obtained by separation of mixtures thereof in conventional manner; chromatographic separation may be employed. 
         [0642]    Compound names were generated with ACDLab version 8.00 or 12.5 and in some cases Chem Bio Draw Ultra version 12.0; and Intermediates and reagent names used in the examples were generated with software such as ACD version 12.05, Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. 
         [0643]    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; or at 60 MHz on a Varian T-60 spectrometer or at 300 MHz on a Varian Inova system. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. 
         [0000]    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, AscentScientific LLC., Fisher, 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.
 
Compounds of the invention were purified according to either of the following methods below:
 
         [0644]    Added amino modified silica gel to organic solution (MeOH/CHCl 3 ) and concentrated. Auto column on a silica gel-amine column with 70% MeOH, 0.5% acetic acid in dichloromethane gave product after removal of solvents, and drying under vacuum. 
         [0645]    Product trituration with methanol, filtered, and washed with methanol to give product after removal of solvents, and drying under vacuum. 
         [0646]    Column chromatography (Auto-column) on a Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise. 
         [0000]    The following abbreviations are used in the examples:
   s, m, h, d second, minute, hour, day   CH 3 CN acetonitrile   PSI pound per square inch   CH 2 Cl 2  dichloromethane   DMF N,N-dimethylformamide   EtOH ethanol   IPA isopropyl alcohol   NaOH sodium hydroxide   NaN 3  sodium azide   MeOH methanol   CD 3 OD deuterated methanol   CF 3 C(O)OD deuterated trifluoroacetic acid   CDCl 3  deuterated chloroform   DMSO-d 6  deuterated dimethyl sulfoxide   NH 3  ammonia   HCl hydrochloric acid   Na 2 SO 4  sodium sulfate   RT or rt room temperature   MgSO 4  magnesium sulfate   EtOAc ethyl acetate   Auto-column automated flash liquid chromatography   TFA trifluoroacetic acid   THF tetrahydrofuran   DMAP 4-dimethylaminopyridine   M molar   PdCl 2 (PPh 3 ) 2  bis(triphenylphosphine)palladium(II) chloride   AcOH acetic acid   K 2 O 3  potassium carbonate   NaCl sodium chloride   CHCl 3  chloroform   D 2 O deuterated water   TsCl p-toluenesulfonyl chloride   Pd(C) palladium on carbon
 
Those skilled in the art will be routinely able to modify and/or adapt the following procedures to synthesize any compound of the invention covered Formula I.
   
 
       Example 1 
     Intermediate 1 
     Diethyl 3-tosyloxy-1,1-difluoro-propylphosphonate 
       [0680]    
       
                 
         
             
             
         
       
     
         [0681]    Diethyl 3-hydroxy-1,1-difluoro-propylphosphonate [1225194-19-3] (4.4 g, 0.019 mol) was dissolved in CH 2 Cl 2  (20 mL) and triethylame (7.7 g) and treated with TsCl (5.4 g, 0.029 mol) followed by DMAP (0.23 g, 0.0019 mol) at rt for 2 h. After 2 h, an additional portion of TsCl (0.6 g) was added. After 30 m, the reaction mixture was partitioned between water and CH 2 Cl 2 . The organic layer was filtered and concentrated in vacuo. The residue was dissolved in 1:1 hexanes:CH 2 Cl 2  (100 mL) and applied to 85 g flash silica gel (topped with Na 2 SO 4  and equilibrated with hexanes). The column was eluted with hexanes-ethyl acetate. The product Intermediate 1 weighed 6.3 g (94%).  1 H NMR (CDCl 3 ) δ: 7.2-7.8 (AB, 4H); 3.9-4.4 (m, 6H); 2.0-3.0 (m, 5H), 1.4 (t, 6H). 
       Example 2 
     Intermediate 2 
     Ethyl hydrogen 3-azido-1,1-difluoro-propylphosphonate 
       [0682]    
       
                 
         
             
             
         
       
     
         [0683]    Intermediate 1 (16 g, 0.046 mol) was mixed with NaN 3  (6.0 g, 0.092 mol) and DMF (100 mL) and the mixture was stirred 1 week. The solvent was removed at high vacuum, and the residue was taken up in water (100 mL) and washed with ethyl acetate (100 mL). The aqueous layer was mixed with 1 M HCl (130 mL) and washed with CH 2 Cl 2  (4×100 mL). The aqueous was concentrated to 100 mL volume, and stirred with EtOH (150 mL). The solid was filtered away, and the filtrate was concentrated to 50 mL and stirred with EtOH (100 mL). The solid was filtered away, and the filtrate was concentrated and dried at high vacuum. The 15 g residue was taken on to the next step. 
       Example 3 
     Intermediate 3 
     Ethyl hydrogen 3-amino-1,1-difluoro-propylphosphonate 
       [0684]    
       
                 
         
             
             
         
       
     
         [0685]    Intermediate 2 was mixed with 10% Pd[C] (1.4 g) and EtOH (100 mL), and hydrogenated overnight at 60 psi H 2 . The mixture was filtered, and the residue was triturated with ether (2×100 mL) to leave 14.1 g. 
       Example 4 
     Intermediate 4 
     (3-Amino-1,1-difluoro-propyl)-phosphonic acid 
       [0686]    
       
                 
         
             
             
         
       
     
         [0687]    Intermediate 3 was mixed with 6 M aq. HCl (250 mL) in a flask equipped with a reflux condenser. The mixture was heated overnight at 115° C. and concentrated in vacuo. The residue was reconcentrated twice from water (50 mL) and twice from EtOH (100 mL). The oily residue was triturated with THF. The combined triturates were concentrated and set aside. The residue was stirred with IPA until a free-flowing solid had formed. The solid was collected to yield 4.2 g of Intermediate 4 
         [0688]      1 H NMR (D 2 O) δ: 4.7 (s, 2.3H, —NH 2 , —OH); 3.2 (t, 2H); 2.2-2.5 (m, 2H). 
       Example 5 
     Intermediate 5 
     3-bromo-4-mercaptobenzaldehyde 
       [0689]    
       
                 
         
             
             
         
       
     
         [0690]    A mixture of 3-bromo-4-fluorobenzaldehyde, CAS Registry number: [77771-02-9] (4.70 g, 22.7 mmol), and sodium sulfide nonahydrate [1313-82-2] (7.79 g, 31.8 mmol), in DMF (25 mL) was reacted at rt for ˜18 h. Following an aqueous work up and extraction with 1:1 hexanes:ethyl acetate (2×100 mL) the pooled organic extracts were washed with water (3×) and dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was dissolved in chloroform and concentrated onto silica gel. The material was purified on Auto-column: chromatography on a Teledyne-ISCO CombiFlash with a silica column eluting with 9:1 hexane/EtOAc to give Intermediate 5 3.22 g (66%). 
         [0691]    Intermediate 6 was prepared according to the procedure described in Example 5. The starting materials and the results are tabulated below in Table 1. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Interm. 
                 IUPAC name 
                 Starting 
                   
               
               
                 No. 
                 Structure 
                 materials 
                   1 H NMR δ (ppm) 
               
               
                   
               
             
             
               
                 6 
                 2-chloro-4- mercaptobenzaldehyde                            
 
                 2-chloro-4- fluoro- benzaldehyde CAS [84194-36-5]  
                   1 H NMR (300 MHz, CDCl 3 ) δ: 10.4 (s, 1H), 7.77-7.76 (m, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 7.21-7.19 (m, 1H). 
               
               
                   
               
             
          
         
       
     
       Example 6 
     Intermediate 7 
     3-bromo-4-((5-phenylpentyl)thio)benzaldehyde 
       [0692]    
       
                 
         
             
             
         
       
     
         [0693]    A mixture of Intermediate 5 (0.58 g, 2.34 mmol) 1-bromo-5-phenyl pentane [14469-83-1] (0.64 g, 2.82 mmol) and triethylamine (0.65 mL, 4.66 mmol) in THF (10 mL) was stirred for ˜18 h at rt. After an aqueous work up with 3:1 hexanes/ethyl acetate (200 mL) the crude material was dried and concentrated onto silica gel and purified by Auto-column (9.5 hexanes: 0.5 ethyl acetate) to give 3-bromo-4-((5-phenylpentyl)thio)benzaldehyde Intermediate 7 as a pure product, 0.48 g, (52%). 
         [0694]      1 H NMR (300 MHz, CDCl 3 ): δ 9.87 (s, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.76-7.73 (m, 1H), 7.29-7.16 (series of m, 6H), 2.98 (t, J=7.2 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H), 1.90-1.55 (series of m, 6H). 
       Example 7 
     Intermediate 33 
     1-(4-bromobutyl)cyclohexyl)benzene 
       [0695]    
       
                 
         
             
             
         
       
     
         [0696]    1-Phenyl-cyclohexanebutanoic acid ethyl ester [1356465-13-8] was reduced with a hydride such as LiAlH 4  to produce 4-(1-phenylcyclohexyl)butan-1-ol. 4-(1-Phenylcyclohexyl)butan-1-ol was converted into the bromide with Br 2  and PPh 3  in DMF to produce (1-(4-bromobutyl)cyclohexyl)benzene (Intermediate-33)  1 H NMR (300 MHz, DMSO-d 6 ) δ: 7.31 (d, J=4.0 Hz, 4H), 7.11-7.21 (m, 1H), 3.39 (t, J=6.7 Hz, 2H), 2.02 (br. s., 2H), 1.44-1.67 (m, 8H), 1.20-1.44 (m, 4H), 0.93-1.07 (m, 2H). 
         [0697]    Intermediates 8 through 35 were prepared according to the procedure(s) described in Example 5 and/or Example 6. The fluorobenzaldehyde starting materials were used in both Example 5 and 6. The mercaptobenzaldehydes were used in Example 6. Intermediate 35 was prepared according to the procedure used in Example 7. The starting materials and the results are tabulated below in Table 2. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Interm. 
                 IUPAC name 
                 Starting 
                   
               
               
                 No. 
                 Structure 
                 materials 
                   1 H NMR δ (ppm) 
               
               
                   
               
             
             
               
                  8 
                 4-((5-phenylpentyl)thio)-3- (trifluoromethyl)benzaldehyde                            
 
                 4-fluoro-3- (trifluoromethyl) benzaldehyde CAS [67515-60-0] 
                   1 H NMR (300 MHz, DMSO- d 6 ) δ: 10 (s, 1H), 8.15 (s, 1H), 8.1-7.9 (ser of m, 2H), 7.3-7.1 (m, 5H), 3.2-3.1 (m, 2H), 2.6-2.5 (m, 2H), 1.7- 1.4 (m, 6H) 
               
               
                   
               
               
                  9 
                 4-((5-phenylpentyl)thio)-2- (trifluoromethyl)benzaldehyde                            
 
                 4-fluoro-2- (trifluoromethyl) benzaldehyde CAS [90176-80-0] 
                   1 H NMR (600 MHz, CDCl 3 ) δ: 10.2 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.22-7.09 (m, 5H), 2.96 (t, J = 7.8 Hz, 2H), 2.56 (t, J = 7.8 Hz, 2H), 1.71-1.58 (m, 4H), 1.47-1.42 (m, 2H) 
               
               
                   
               
               
                 10 
                 2-chloro-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 Intermediate 6 
                   1 H NMR (300 MHz, CDCl 3 ) δ: 10.4 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.79-7.16 (m, 7H), 2.98 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.77-1.50 (ser. of m, 6H) 
               
               
                   
               
               
                 11 
                 3-chloro-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 3-chloro-4- fluorobenzaldehyde CAS [34328-61-5] 2M NaOH at 60° C. for 18 h 
                   1 H NMR (300 MHz, CDCl 3 ) δ: 9.89 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.72-7.69 (m, 1H), 7.31-7.16 (m, 6H), 2.99 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 1.85-1.51 (m, 6H) 
               
               
                   
               
               
                 12 
                 4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 4-Mercaptobenzaldehyde CAS [91358-96-2] 2M NaOH at 60° C. for 18 h 
                   1 H NMR (300 MHz, CDCl 3 ) δ: 9.92 (s, 1H), 7.78-7.74 (m, 2H), 7.36-7.15 (m, 7H), 3.00 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.80-1.48 (ser of m, 6H) 
               
               
                   
               
               
                 13 
                 5-formyl-2-((5- phenylpentyl)thio)benzonitrile                            
 
                 2-fluoro-5- formylbenzonitrile CAS [218301-22-5] 
                   1 H NMR (600 MHz, CDCl 3 ) δ: 10.2 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.22-7.09 (m, 5H), 2.96 (t, J = 7.8 Hz, 2H), 2.56 (t, J = 7.8 Hz, 2H), 1.71-1.58 (m, 4H), 1.47-1.42 (m, 2H) 
               
               
                   
               
               
                 14 
                 4-{[5-(4- fluorophenyl)pentyl]thio}-3- (trifluoromethyl)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- fluorobenzene CAS [958257-61-9], 4-mercapto-3- (trifluoromethyl) benzaldehyde CAS [1187874-88-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 10.00 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.24-7.17 (m, 2H), 7.12- 7.02 (m, 2H), 3.19 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.74-1.53 (m, 4H), 1.49-1.37 (m, 2H) 
               
               
                   
               
               
                 15 
                 4-{[5-(4- methoxyphenyl)pentyl]thio}-3- (trifluoromethyl)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- methoxybenzene CAS [14469-84-2], 4-mercapto-3- (trifluoromethyl) benzaldehyde CAS [1187874-88-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 10.00 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.11-7.05 (m, 2H), 6.85- 6.78 (m, 2H), 3.71 (s, 3H), 3.18 (t, J = 7.3 Hz, 2H), 2.54-2.46 (m, 2H), 1.73- 1.61 (m, 2H), 1.61-1.51 (m, 2H), 1.49-1.38 (m, 2H) 
               
               
                   
               
               
                 16 
                 4-{[5-(4- methoxyphenyl)pentyl]thio}-3- methylbenzaldehyde                            
 
                 1-(5- bromopentyl)-4- methoxybenzene CAS [14469-84-2], 4-fluoro-3- methylbenzaldehyde CAS [135427-08-6] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.87 (s, 1H), 7.71- 7.67 (m, 1H), 7.67-7.65 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.10-7.04 (m, 2H), 6.83-6.77 (m, 2H), 3.69 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.52-2.45 (m, 2H), 2.27 (s, 3H), 1.66 (dq, J = 7.6, 7.4 Hz, 2H), 1.60- 1.50 (m, 2H), 1.48-1.36 (m, 2H) 
               
               
                   
               
               
                 17 
                 4-{[5-(4- chlorophenyl)pentyl]thio}-3- (trifluoromethyl)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- chlorobenzene CAS [14491-44-2] 4-mercapto-3- (trifluoromethyl) benzaldehyde CAS [1187874-88-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 10.00 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 8.4, 1.3 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.33-7.28 (m, 2H), 7.24- 7.18 (m, 2H), 3.19 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.63 (tdd, J = 7.6 Hz, 4H), 1.49-1.37 (m, 2H) 
               
               
                   
               
               
                 18 
                 4-{[5-(4- chlorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- chlorobenzene CAS [14491-44-2], 4-fluoro-3- (trifluoromethoxy) benzaldehyde CAS [86256-48-6] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.96 (s, 1H), 7.90 (dd, J = 8.2, 1.8 Hz, 1H), 7.79 (quin, J = 1.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.24- 7.18 (m, 2H), 3.11 (t, J = 7.3 Hz, 2H), 2.55 (d, J = 7.6 Hz, 2H), 1.73-1.53 (m, 4H), 1.49-1.38 (m, 2H) 
               
               
                   
               
               
                 19 
                 4-{[5-(4- fluorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- fluorobenzene CAS [958257-61-9], 4- fluoro-3- (trifluoromethoxy) benzaldehyde CAS [86256-48-6] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.96 (s, 1H), 7.90 (dd, J = 8.1, 1.6 Hz, 1H), 7.79 (qd, J = 1.5, 1.3 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.25-7.17 (m, 2H), 7.11-7.02 (m, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H), 1.74-1.52 (m, 4H), 1.50-1.37 (m, 2H) 
               
               
                   
               
               
                 20 
                 4-{[5-(4- methylphenyl)pentyl]thio}-3- (trifluoromethoxy)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- methylbenzene CAS [105474-18-8], 4- fluoro-3- (trifluoromethoxy) benzaldehyde CAS [86256-48-6] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.96 (s, 1H), 7.90 (dd, J = 8.2, 1.5 Hz, 1H), 7.79 (qd, J = 1.5, 1.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.06 (s, 4H), 3.11 (t, J = 7.3 Hz, 2H), 2.56-2.48 (m, 2H), 2.25 (s, 3H), 1.73- 1.61 (m, 2H), 1.61-1.52 (m, 2H), 1.49-1.36 (m, 2H) 
               
               
                   
               
               
                 21 
                 4-((5-phenylpentyl)thio)-3- (trifluoromethoxy)benzaldehyde                            
 
                 4-fluoro-3- (trifluoromethoxy) benzaldehyde CAS [86256-48-6] 
                   1 H NMR (300 MHz, CDCl 3 )  δ: 9.92 (s, 1H), 7.74-7.69 (m, 2H), 7.37-7.16 (m, 6H), 2.98 (t, J = 6.6 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 1.82-1.49 (ser. of m, 6H) 
               
               
                   
               
               
                 22 
                 4-{[5-(4- fluorophenyl)pentyl]thio}-3- methylbenzaldehyde                            
 
                 1-(5- bromopentyl)-4- fluorobenzene CAS [958257-61-9], 4- fluoro-3- methylbenzaldehyde CAS [135427-08-6] 
                 (300 MHz, DMSO-d 6 ) δ:  9.89 (s, 1H), 7.73-7.68 (m, 1H), 7.68 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.25- 7.18 (m, 2H), 7.12-7.04 (m, 1H), 3.07 (t, J = 7.3 Hz, 2H), 2.57 (t, J = 7.5 Hz, 1H), 2.29 (s, 3H), 1.75- 1.54 (m, 4H), 1.75-1.53 (m, 3H), 1.52-1.38 (m, 1H) 
               
               
                   
               
               
                 23 
                 3-methyl-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 4-mercapto-3- methylbenzaldehyde CAS [1378380-80-3] (5-bromopentyl) benzene CAS [14469-83-1] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.89 (s, 1H), 7.66- 7.73 (m, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.12-7.30 (m, 5H), 3.08 (t, J = 7.3 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.55- 1.75 (m, 4H), 1.39-1.52 (m, 2H) 
               
               
                   
               
               
                 24 
                 3-fluoro-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 3,4- difluorobenzaldehyde CAS [34036-07-2] 
                 (300 MHz, CDCl 3 ) δ: 9.90  (s, 1H), 7.60-7.15 (series of m, 8H), 2.98 t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.78-1.48 (series of m, 6H) 
               
               
                   
               
               
                 25 
                 2-((5-(4- fluorophenyl)pentyl)thio)-5- formylbenzonitrile                            
 
                 2-fluoro-5- formylbenzonitrile CAS [218301-22-5] 1-(5- bromopentyl)-4- fluorobenzene CAS [958257-61-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.94 (s, 1H), 8.29- 8.32 (m, 1H), 8.06-8.11 (m, 1H), 7.70-7.74 (m, 1H), 7.18-7.26 (m, 2H), 7.03-7.12 (m, 2H), 3.19- 3.26 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H), 1.64-1.75 (m, 2H), 1.53-1.64 (m, 2H), 1.37-1.50 (m, 2H) 
               
               
                   
               
               
                 26 
                 3-methyl-4-((5-(p- tolyl)pentyl)thio)benzaldehyde                            
 
                 4-fluoro-3- methylbenzaldehyde CAS [135427-08-6], 1- (5-bromopentyl)- 4-methylbenzene CAS [105474-18-8] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.89 (s, 1H), 7.66- 7.73 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.06 (s, 4H), 3.07 (t, J = 7.3 Hz, 2H), 2.50-2.56 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.62- 1.74 (m, 2H), 1.52-1.62 (m, 2H), 1.37-1.51 (m, 2H) 
               
               
                   
               
               
                 27 
                 4-((5-(4- fluorophenyl)pentyl)thio)-2- (trifluoromethyl)benzaldehyde                            
 
                 4-fluoro-2- (trifluoromethyl) benzaldehyde CAS [90176-80-0], 1-(5- bromopentyl)-4- fluorobenzene CAS [958257-61-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 10.14-10.17 (m, 1H), 7.98-8.03 (m, 1H), 7.72-7.77 (m, 1H), 7.67- 7.70 (m, 1H), 7.17-7.24 (m, 2H), 7.02-7.11 (m, 2H), 3.17 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.53-1.73 (m, 4H), 1.36-1.49 (m, 2H) 
               
               
                   
               
               
                 28 
                 2,5-difluoro-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 2,4,5- trifluorobenzaldehyde CAS [165047-24-5] 
                 (300 MHz, CDCl 3 ) δ: 10.22  (s, 1H), 7.49-7.44 (m, 1H), 7.31-7.16 (m, 5H), 6.99- 6.94 (m, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.81-1.63 (m, 4H), 1.56-1.49 (m, 2H) 
               
               
                   
               
               
                 29 
                 2-chloro-5-fluoro-4-((5- phenylpentyl)thio)benzaldehyde                            
 
                 2-chloro-4,5- difluorobenzaldehyde CAS [165047-23-4] 
                 (600 MHz, CDCl 3 ) δ: 10.32  (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.28-7.16 (series of m, 6H), 2.98 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.80-1.40 (series of m, 6H) 
               
               
                   
               
               
                 30 
                 3-bromo-4-((4-(1- phenylcyclohexyl)butyl)thio)benzaldehyde                            
 
                 Intermediate 5 (1-(4- bromobutyl)cyclo hexyl)benzene Intermediate 33 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.88 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 3.8 Hz, 4H), 7.10-7.20 (m, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.03 (br. s., 2H), 1.20- 1.61 (m, 12H), 0.99-1.13 (m, 2H) 
               
               
                   
               
               
                 31 
                 4-{[5-(4- methoxyphenyl)pentyl]thio}-3- (trifluoromethoxy)benzaldehyde                            
 
                 1-(5- bromopentyl)-4- methoxybenzene CAS [14469-84-2], 4-fluoro-3- (trifluoromethoxy) benzaldehyde CAS [86256-48-6] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.95 (s, 1H), 7.89 (dd, J = 1.5, 8.2 Hz, 1H), 7.81-7.76 (m, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.70 (s, 3H), 3.10 (t, J = 7.3 Hz, 2H), 2.54-2.45 (m, 2H), 1.73-1.50 (m, 4H), 1.49- 1.34 (m, 2H) 
               
               
                   
               
               
                 32 
                 2,5-difluoro-4-{[4-(1- phenylcyclohexyl)butyl]thio}benzaldehyde                            
 
                 33 2,4,5- trifluorobenzaldehyde CAS [165047-24-5] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 10.07 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 9.6, 5.8 Hz, 1H), 7.38 (dd, J = 10.9, 5.8 Hz, 1H), 7.31 (m, 4H), 7.19-7.11 (m, 1H), 3.00 (t, J = 7.3 Hz, 2H), 2.10-1.98 (m, 2H), 1.60-1.19 (m, 12H), 1.11-0.97 (m, 2H) 
               
               
                   
               
               
                 34 
                 3-chloro-4-{[4-(1- phenylcyclohexyl)butyl]thio}benzaldehyde                            
 
                 33 3-chloro-4- fluorobenzaldehyde CAS [34328-61-5] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.90 (s, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.36-7.27 (m, 4H), 7.20-7.11 (m, 1H), 2.97 (t, J = 7.3 Hz, 2H), 2.10-1.98 (m, 2H), 1.60-1.21 (m, 12H), 1.13-0.99 (m, 2H) 
               
               
                   
               
               
                 35 
                 3-bromo-4-[(5-methyl-5- phenylhexyl)thio]benzaldehyde                            
 
                 5 methyl 5-methyl- 5-phenylhexanoate CAS [121532-74-9] 
                   1 H NMR (300 MHz, DMSO-  d 6 ) δ: 9.88 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.38-7.24 (m, 4H), 7.20-7.11 (m, J = 6.9 HZ, 1H), 3.02 (t, J = 7.2 Hz, 2H), 1.69-1.51 (m, 4H), 1.30-1.12 (m, J = 7.3 Hz, 8H) 
               
               
                   
               
             
          
         
       
     
       Example 8 
     Compound 1 
     [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid 
       [0698]    
       
                 
         
             
             
         
       
     
         [0699]    A mixture of 3-bromo-4-((5-phenylpentyl)thio)benzaldehyde Intermediate 7 (0.48 g, 1.22 mmol), (3-aminopropyl)phosphonic acid [13138-33-5] (0.20 g, 1.44 mmol), and tetrabutyl ammonium hydroxide (3.7 mL of 1.0 M in methanol) in THF (4 mL) and methanol (6 mL) were heated at 60° C. for 30 m followed by 1 h at rt. Sodium borohydride (0.070 g, 1.85 mmol) was added, and the mixture was reacted for ˜18 h at rt. The solvent was removed under vacuum. Water was added followed by 2 M HCl to pH ˜3-4. The mixture was extracted with 3:1 chloroform:isopropanol (2×100 mL). The organic layers were removed under vacuum and the material was purified to give [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid Compound 1, 408 mg (69%). 
         [0700]      1 H NMR (600 MHz, CF 3 C(O)OD): δ 7.56 (d, J=1.2 Hz, 1H), 7.30 (dd, J=1.8, 8.4 Hz, 1H), 7.26 (dd, J=2.4, 8.4 Hz, 1H), 7.20 (t, J=7.2 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.09 (t, J=7.2 Hz, 1H), 4.27 (s, 2H), 3.40 (s, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.26-2.20 (m, 2H), 2.15-2.10 (m, 2H), 1.78-1.73 (m, 2H), 1.69-1.64 (m, 2H), 1.54-1.49 (m, 2H). 
         [0701]    Compounds 2 through 27, 50, and 163 through 165 were prepared according to the procedure described in Example 8 from the corresponding intermediate(s). The starting materials and the results are tabulated below in Table 3. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Comp. 
                   
                 Interm. 
                   
               
               
                 No. 
                 IUPAC name 
                 No. 
                   1 H NMR δ (ppm) 
               
               
                   
               
             
             
               
                  2 
                 [3-({4-[(5-phenylpentyl)thio]-3- (trifluoromethyl)benzyl}amino)propyl]phosphonic acid                            
 
                  8 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.84 (s, 1H), 7.65 (s, 2H), 7.25- 7.20 (m, 2H), 7.14 (d, J = 7.2 Hz, 3H), 4.17 (s, 2H), 3.08-3.01 (m, 4H), 2.53 (t, J = 7.5 Hz, 2H), 1.88-1.75 (m, 2H), 1.70- 1.50 (m, 6H), 1.45-1.35 (m, 2H) 
               
               
                   
               
               
                  3 
                 [3-({4-[(5-phenylpentyl)thio]-2- (trifluoromethyl)benzyl}amino)propyl]phosphonic acid                            
 
                  9 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.74- 7.71 (m, 2H), 7.63 (s, 1H), 7.23 (t, J = 7.8 Hz, 2H), 7.20-7.16 (m, 3H), 4.28 (s, 2H), 3.16 (t, J = 7.2 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H), 1.96-1.90 (m, 2H), 1.79-1.73 (m, 2H), 1.69-1.60 (m, 4H), 1.48-1.43 (m, 2H) 
               
               
                   
               
               
                  4 
                 [3-({2-chloro-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 10 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.56 (d, J = 7.8 Hz, 1H), 7.46 (d, J= 1.8 Hz, 1H), 7.37 (dd, J = 1.8, 8.4 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.20-7.16 (m, 3H), 4.25 (s, 2H), 3.12 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 7.8 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 1.94-1.90 (m, 2H), 1.76-1.70 (m, 2H), 1.65-1.59 (m, 4H), 1.47-1.43 (m, 2H) 
               
               
                   
               
               
                  5 
                 [3-({3-chloro-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 11 
                   1 H NMR (600 MHz, CF 3 C(O)OD) δ: 7.40 (t, J = 1.8 Hz, 1H), 7.32 (dd, J = 2.4, 8.4 Hz, 1H), 7.28-7.26 (m, 1H), 7.24-7.21 (m, 2H), 7.16 (d, J = 7.2 Hz, 2H), 7.13-7.10 (m, 1H), 4.30 (s, 2H), 3.41 (d, J = 5.4 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.29-2.22 (m, 2H), 2.17-2.11 (m, 2H), 1.79-1.74 (m, 2H), 1.71- 1.66 (m, 2H), 1.56-1.51 (m, 2H) 
               
               
                   
               
               
                  6 
                 [3-({4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 12 
                   1 H NMR (600 MHz, CF 3 C(O)OD) δ: 7.39- 7.31 (m, 4H), 7.22 (t, J = 7.2 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 4.31 (t, J = 5.4 Hz, 2H), 3.43-3.39 (m, 2H), 2.99 (t, J = 6.6 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H), 2.28-2.33 (m, 2H), 2.17-2.11 (m, 2H), 1.75-1.70 (m, 2H), 1.68- 1.63 (m, 2H), 1.53-1.50 (m, 2H) 
               
               
                   
               
               
                  7 
                 [3-({4-[(5-phenylpentyl)thio]-3- (trifluoromethoxy)benzyl}amino)propyl]phosphonic acid                            
 
                 21 
                   1 H NMR (300 MHz, CF 3 C(O)OD) δ: 7.49- 4.44 (m, 3H), 7.26-7.21 (series of m, 2H), 7.16- 7.13 (series of m, 3H), 4.13 (s, 2H), 3.10 (br s, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.00 (brs 1H), 1.96 (s, 1H), 1.74-1.59 (series of m, 6H), 1.53- 1.46 (series of m, 2H) 
               
               
                   
               
               
                  8 
                 [3-({3-cyano-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 13 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.88 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 2.1, 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.25-7.20 (m, 2H), 7.15-7.09 (m, 3H), 4.13 (s, 2H), 3.09 (t, J = 6.9 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.75-1.53 (m, 6H), 1.46-1.39 (m, 2H) 
               
               
                   
               
               
                  9 
                 {3-[(4-{[5-(4-fluorophenyl)pentyl]thio}-3- methylbenzyl)amino]propyl}phosphonic acid                            
 
                 22 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.10 (br. s, 3H), 7.05-6.94 (m, 2H), 6.93-6.77 (m, 2H), 3.87 (s, 2H), 2.90- 2.69 (m, 4H), 2.42- 2.33 (m, 2H), 2.07 (s, 3H), 1.77-1.58 (m, 2H), 1.58-1.32 (m, 6H), 1.31-1.15 (m, 2H) 
               
               
                   
               
               
                 10 
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 14 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.85 (s, 1H), 7.66 (s, 2H), 7.24- 7.12 (m, 2H), 7.10- 6.97 (m, 2H), 4.18 (s, 2H), 3.14-2.96 (m, 4H), 2.59-2.52 (m, 2H), 1.92-1.78 (m, 2H), 1.75-1.49 (m, 6H), 1.47-1.34 (m, 2H) 
               
               
                   
               
               
                 11 
                 (3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}- 3-(trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 15 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.86 (s, 1H), 7.66 (br. s, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.18 (s, 2H), 3.69 (s, 3H), 3.14-2.97 (m, 4H), 2.55-2.46 (m, 2H), 1.93-1.76 (m, 2H), 1.75-1.48 (m, 6H), 1.46-1.33 (m, 2H) 
               
               
                   
               
               
                 12 
                 {3-[(4-{[5-(4-methoxyphenyl)pentyl]thio}- 3-methylbenzyl)amino]propyl}phosphonic acid                            
 
                 16 
                   1 H NMR (300 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.11 (br. s, 3H), 6.89 (d, J = 7.9 Hz, 2H), 6.63 (d, J = 8.2 Hz, 2H), 3.88 (s, 2H), 3.52 (s, 3H), 2.92- 2.65 (m, 4H), 2.30- 2.24 (m, 2H), 2.09 (s, 3H), 1.80-1.63 (m, 2H), 1.62-1.30 (m, 6H), 1.30-1.13 (m, 2H) 
               
               
                   
               
               
                 13 
                 (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 17 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.82 (br. s., 1H), 7.66-7.58 (m, 2H), 7.28-7.20 (m, 2H), 7.17-7.13 (m, 2H), 4.15 (br. s., 2H), 3.09- 2.94 (m, 4H), 2.54- 2.50 (m, 2H), 1.90- 1.77 (m, 2H), 1.67 (br. s., 2H), 1.61-1.48 (m, 4H), 1.43-1.30 (m, 2H) 
               
               
                   
               
               
                 14 
                 (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 18 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.55- 7.50 (m, 2H), 7.46 (dd, J = 1.8, 8.2 Hz, 1H), 7.33-7.27 (m, 2H), 7.23-7.17 (m, 2H), 4.16 (s, 2H), 3.07-2.97 (m, 4H), 2.55 (t, J = 7.6 Hz, 2H), 1.87-1.78 (m, 2H), 1.71-1.52 (m, 6H), 1.45-1.36 (m, 2H) 
               
               
                   
               
               
                 15 
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 19 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.52- 7.47 (m, 2H), 7.46- 7.41 (m, 1H), 7.19- 7.14 (m, 2H), 7.06- 6.99 (m, 2H), 4.14 (s, 2H), 3.02-2.95 (m, 4H), 2.55-2.50 (m, 2H), 1.86-1.77 (m, 2H), 1.67-1.50 (m, 6H), 1.41-1.34 (m, 2H) 
               
               
                   
               
               
                 16 
                 (3-{[4-{[5-(4-methylphenyl)pentyl]thio}-3 (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 20 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.52- 7.48 (m, 2H), 7.45 (dd, J = 1.3, 8.1 Hz, 1H), 7.03 (s, 4H), 4.15 (s, 2H), 3.07-2.93 (m, 4H), 2.52-2.48 (m, 2H), 2.22 (s, 3H), 1.90-1.80 (m, 2H), 1.74-1.64 (m, 2H), 1.64-1.50 (m, 4H), 1.44-1.36 (m, 2H) 
               
               
                   
               
               
                 17 
                 [3-({3-chloro-4-[(5-phenylpentyl) thio]benzyl}amino)-1,1-difluoropropyl]phosphonic acid                            
 
                 11 and  4 
                   1 H NMR (600 MHz, CF 3 C(O)OD) δ: 7.55 (d, J = 1.2 Hz, 1H), 7.45- 7.41 (m, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 4.44 (t, J = 5.4 Hz, 2H), 3.70 (brs, 2H), 3.10 (t, J = 7.8 Hz, 2H), 2.92-2.82 (m, 2H), 2.74 (t, J = 7.2 Hz, 2H), 1.91-1.86 (m, 2H), 1.84- 1.78 (m, 2H), 1.68-1.64 (m, 2H) 
               
               
                   
               
               
                 18 
                 [1,1-difluoro-3-({4-[(5-phenylpentyl)thio]- 3-(trifluoromethoxy)benzyl}amino)propyl]phosphonic acid                            
 
                 21 and  4 
                   1 H NMR (300 MHz, DMSO-d 6 ) δ: 7.53-7.49 (m, 3H), 7.27-7.13 (series of m, 5H), 4.08 (s, 2H), 3.00 (t, J = 7.5 Hz, 4H), 2.54 (t, J = 7.5 Hz, 2H), 2.38-2.16 (m, 2H), 1.62-1.50 (m, 4H), 1.45-137 (m, 2H) 
               
               
                   
               
               
                 19 
                 [3-({3-chloro-4-[(5-phenylpentyl) thio]benzyl}amino)-1-methylpropyl]phosphonic acid                            
 
                 11 and (3-amino- 1-methyl- propyl)- phosphonic acid CAS [79782-59-5] 
                   1 H NMR (600 MHz, CF 3 C(O)OD/CDCl 3 ) δ: 7.50 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.27-7.25 (m, 2H), 7.17-7.15 (m, 3H), 4.01 (s, 1H), 3.13 (brs, 1H), 2.99 (brs, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.00-1.82 (m, 2H), 1.80-1.71 (m, 3H), 1.70- 1.65 (m, 2H), 1.55-1.53 (m, 2H), 1.22-1.14 (m, 3H) 
               
               
                   
               
               
                 20 
                 [3-({3-methyl-4-[(5-phenylpentyl)thio] benzyl}amino)propyl]phosphonic acid                            
 
                 23 
                 (300 MHz, DMSO-d 6 - CF 3 CO 2 D) δ: 7.28-7.26 (m, 3H), 7.24-7.21 (m, 2H), 7.16-7.13 (m, 3H), 4.05 (s, 2H), 3.02-2.92 (m, 4H), 2.55 (t, J = 7.2 hz, 2H), 2.25 (s, 3H), 1.90-1.77 (m, 2H), 1.72- 1.53 (m, 6H), 1.46-1.34 (m, 2H) 
               
               
                   
               
               
                 21 
                 [3-({3-fluoro-4-[(5-phenylpentyl)thio] benzyl}amino)propyl]phosphonic acid                            
 
                 24 
                 (300 MHz, DMSO-d 6 - CF 3 CO 2 D) δ: 7.42 (t, J = 7.8 Hz, 1H), 7.34-7.19 (m, 4H), 7.14-7.08 (m, 3H), 4.10 (s, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz, 2H), 1.90- 1.80 (m, 2H), 1.75-1.64 (m, 2H), 1.60-1.50 (m, 4H), 1.44-1.36 (m, 2H) 
               
               
                   
               
               
                 22 
                 {3-[(3-cyano-4-{[5-(4-fluorophenyl) pentyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 25 
                 (600 MHz, DMSO-d 6 - a few drops of CF 3 CO 2 D) δ: 7.89 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 1.9, 8.4 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 5.6, 8.5 Hz, 2H), 7.03 (t, J = 9.0 Hz, 2H), 4.15 (s, 2H), 3.11 (t, J = 7.3 Hz, 2H), 3.05- 2.98 (m, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.88- 1.80 (m, 2H), 1.72- 1.53 (m, 6H), 1.45- 1.38 (m, 2H) 
               
               
                   
               
               
                 23 
                 {3-[(3-methyl-4-{[5-(4-methylphenyl) pentyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 26 
                 (600 MHz, DMSO-d 6 - a few drops of CF 3 CO 2 D) δ: 7.33-7.25 (m, 3H), 7.08-7.01 (m, 4H), 4.05 (s, 2H), 3.03- 2.91 (m, 4H), 2.52-2.50 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.88- 1.79 (m, 2H), 1.69- 1.52 (m, 6H), 1.44- 1.37 (m, 2H) 
               
               
                   
               
               
                 24 
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-2-(trifluoromethyl) benzyl]amino}propyl)phosphonic acid                            
 
                 27 
                 (600 MHz, CF 3 CO 2 D) δ: 7.68 (br. s., 1H), 7.54- 7.46 (m, 2H), 7.13- 7.06 (m, 2H), 6.91- 6.84 (m, 2H), 4.51 (br. s., 2H), 3.51 (br. s., 2H), 3.06-2.96 (m, 2H), 2.66-2.55 (m, 2H), 2.38-2.25 (m, 2H), 2.23-2.12 (m, 2H), 1.81-1.71 (m, 2H), 1.72-1.61 (m, 2H), 1.57-1.46 (m, 2H) 
               
               
                   
               
               
                 25 
                 [3-({2,5-difluoro-4-[(5-phenylpentyl) thio]benzyl}amino)propyl]phosphonic acid                            
 
                 28 
                 (600 MHz, DMSO-d 6 - CF 3 CO 2 D) δ: 7.40 (dd, J = 9.6, 6.0 Hz, 1H), 7.31 (dd, J = 10.0, 6.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.14-7.10 (m, 3H), 4.12 (s, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 6.6 Hz, 2H), 2.53 (j. 7.2 Hz, 2H), 1.90- 1.80 (m, 2H), 1.70-1.64 (m, 2H), 1.62-1.53 (m, 4H), 1.42-1.37 (m, 2H) 
               
               
                   
               
               
                 26 
                 [3-({2-chloro-5-fluoro-4-[(5-phenylpentyl) thio]benzyl}amino)propyl]phosphonic acid                            
 
                 29 
                 (600 MHz, DMSO-d 6 - CF 3 CO 2 D) δ: 7.50-7.47 (m, 2H), 7.21 (t, J = 7.8 Hz, 2H), 7.13-7.09 (m, 3H), 4.20 (s, 2H), 3.08 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.8 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 1.92- 1.85 (m, 2H), 1.75-1.69 (m, 2H), 1.62-1.54 (m, 4H), 1.42-1.37 (m, 2H) 
               
               
                   
               
               
                 27 
                 [3-(3-bromo-4-{[4-(1-phenylcyclohexyl) butyl]thio}phenyl)propyl]phosphonic acid                            
 
                 30 
                 (600 MHz, DMSO-d 6  &amp; drop(s) TFA) δ: 7.72 (s, 1H), 7.41 (dd, J = 1.8, 8.2 Hz, 1H), 7.33-7.25 (m, 5H), 7.16-7.09 (m, 1H), 4.08 (s, 2H), 2.99 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.03 (br. s., 2H), 1.88-1.77 (m, 2H), 1.71-1.62 (m, 2H), 1.56-1.46 (m, 6H), 1.44-1.21 (m, 6H), 1.09-0.99 (m, 2H) 
               
               
                   
               
               
                 163 
                 (3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 31 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.54- 7.51 (m, 2H), 7.46 (dd, J = 1.8, 8.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.16 (s, 2H), 3.70 (s, 3H), 3.05-2.98 (m, 2H), 2.50-2.47 (m, 2H), 1.89-1.80 (m, 2H), 1.71-1.58 (m, 4H), 1.58-1.51 (m, 2H), 1.44-1.37 (m, 2H) 
               
               
                   
               
               
                 50 
                 {3-[(2,5-difluoro-4-{[4-(1-phenylcyclohexyl) butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 32 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.41- 7.36 (m, 1H), 7.31- 7.20 (m, 5H), 7.15- 7.09 (m, 1H), 4.13 (s, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.91-2.83 (m, 2H), 2.01 (br. s., 2H), 1.90- 1.80 (m, 2H), 1.73- 1.63 (m, 2H), 1.55- 1.44 (m, 6H), 1.42- 1.30 (m, 4H), 1.30- 1.22 (m, 2H), 1.05- 0.97 (m, 2H) 
               
               
                   
               
               
                 164 
                 {3-[(3-chloro-4-{[4-(1-phenylcyclohexyl) butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 34 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.56 (d, J = 1.8 Hz, 1H), 7.38- 7.34 (m, 1H), 7.33- 7.25 (m, 5H), 7.15- 7.10 (m, 1H), 4.09 (s, 2H), 2.99 (t, J = 7.5 Hz, 2H), 2.88-2.82 (m, 2H), 2.02 (br. s., 2H), 1.88- 1.79 (m, 2H), 1.71- 1.63 (m, 2H), 1.55- 1.45 (m, 6H), 1.44- 1.32 (m, 4H), 1.30- 1.22 (m, 2H), 1.07- 1.00 (m, 2H) 
               
               
                   
               
               
                 165 
                 [3-({3-bromo-4-[(5-methyl-5-phenylhexyl) thio]benzyl}amino)propyl]phosphonic acid                            
 
                 35 
                   1 H NMR (600 MHz, DMSO-d 6  &amp; CF 3 C(O)OD) δ: 7.73 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 1.8, 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 3H), 7.31-7.26 (m, 2H), 7.17-7.13 (m, 1H), 4.10 (s, 2H), 3.00 (t, J = 7.5 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 1.88- 1.78 (m, 2H), 1.69- 1.58 (m, 4H), 1.55- 1.48 (m, 2H), 1.25 (s, 6H), 1.20-1.12 (m, 2H) 
               
               
                   
               
             
          
         
       
     
         [0702]    Compounds 28 through 162 are prepared according to the procedures described above. The compounds are tabulated below in Table 3.1. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 3.1 
               
               
                   
               
               
                 Comp. 
                 Compound name 
               
               
                 No. 
                 Structure 
               
               
                   
               
             
             
               
                 28 
                 (3-((2,5-difluoro-4-((5-(4- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 29 
                 (3-((2,5-difluoro-4-((5-(3- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 30 
                 (3-((2,5-difluoro-4-((5-(2- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 31 
                 (3-((2-bromo-5-fluoro-4-((5- phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 32 
                 (3-((5-fluoro-2-methyl-4-((5- phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 33 
                 (3-((5-chloro-2-fluoro-4-((5-phenylpentyl)thio)benzyl)amino) propyl)phosphonic acid                            
 
               
               
                   
               
               
                 34 
                 (3-((5-bromo-2-fluoro-4-((5- phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 35 
                 (3-((2-fluoro-5-methyl-4-((5- phenylpentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 36 
                 (3-(((5-((5-phenylpentyl)thio)pyridin-2-yl)methyl)amino) propyl)phosphonic acid                            
 
               
               
                   
               
               
                 37 
                 (3-(((4-fluoro-5-((5-phenylpentyl)thio)pyridin-2- yl)methyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 38 
                 (3-((2-chloro-5-fluoro-4-((5-(4- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 39 
                 (3-((2-bromo-5-fluoro-4-((5-(4- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 40 
                 (3-((5-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)-2- methylbenzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 41 
                 (3-((5-chloro-2-fluoro-4-((5-(4- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 42 
                 (3-((5-bromo-2-fluoro-4-((5-(4- fluorophenyl)pentyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 43 
                 (3-((2-fluoro-4-((5-(4-fluorophenyl)pentyl)thio)-5- methylbenzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 44 
                 (3-(((4-fluoro-5-((5-(4-fluorophenyl)pentyl)thio)pyridin-2- yl)methyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 45 
                 (3-(((5-((5-(4-fluorophenyl)pentyl)thio)pyridin-2- yl)methyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 46 
                 (3-((4-((4-(1-phenylcyclohexyl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 47 
                 (3-((4-((5-methyl-5-phenylhexyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 48 
                 (3-((4-((4-(1-phenylcyclopentyl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 49 
                 (3-((4-((4-(3-phenyloxetan-3-yl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 50 
                 (3-((2,5-difluoro-4-((4-(1- phenylcyclohexyl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 51 
                 (3-((2,5-difluoro-4-((5-methyl-5- phenylhexyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 52 
                 (3-((2,5-difluoro-4-((4-(1- phenylcyclopentyl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 53 
                 (3-((2,5-difluoro-4-((4-(3-phenyloxetan-3- yl)butyl)thio)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
               
                 54 
                 (3-{[2,5-difluoro-4-({4-[1-(2- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 55 
                 (3-{[2,5-difluoro-4-({4-[1-(4- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 56 
                 (3-{[2,5-difluoro-4-({4-[1-(2- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 57 
                 (3-{[2,5-difluoro-4-({4-[1-(4- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 58 
                 (3-{[2,5-difluoro-4-({4-[3-(2-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 59 
                 (3-{[2,5-difluoro-4-({4-[3-(4-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 60 
                 {3-[(2,5-difluoro-4-{[5-(2-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 61 
                 {3-[(2,5-difluoro-4-{[5-(4-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 62 
                 (3-{[3-chloro-4-({4-[1-(2- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 63 
                 (3-{[3-chloro-4-({4-[1-(4- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 64 
                 (3-{[3-chloro-4-({4-[1-(2- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 65 
                 (3-{[3-chloro-4-({4-[1-(4- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 66 
                 (3-{[3-chloro-4-({4-[3-(2-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 67 
                 (3-{[3-chloro-4-({4-[3-(4-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 68 
                 {3-[(3-chloro-4-{[5-(2-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 69 
                 {3-[(3-chloro-4-{[5-(4-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 70 
                 (3-{[4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 71 
                 (3-{[4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 72 
                 (3-{[4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 73 
                 (3-{[4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 74 
                 (3-{[4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 75 
                 (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 76 
                 (3-{[4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 77 
                 (3-{[4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 78 
                 (3-{[4-{[4-(1-phenylcyclohexyl)butyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 79 
                 [3-({4-[(5-methyl-5-phenylhexyl)thio]-3- (trifluoromethoxy)benzyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 80 
                 [3-({4-[(5-methyl-5-phenylhexyl)thio]-3- (trifluoromethyl)benzyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 81 
                 (3-{[4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 82 
                 (3-{[4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 83 
                 (3-{[4-{[4-(1-phenylcyclohexyl)butyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 84 
                 (3-{[(4-fluoro-5-{[4-(1-phenylcyclohexyl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 85 
                 (3-{[(5-{[4-(1-phenylcyclohexyl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 86 
                 [3-({[4-fluoro-5-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 87 
                 [3-({[5-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 88 
                 [3-({[4-fluoro-5-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 89 
                 [3-({[5-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 90 
                 {3-[({4-fluoro-5-[(5-methyl-5-phenylhexyl)thio]pyridin-2- yl}methyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 91 
                 {3-[({5-[(5-methyl-5-phenylhexyl)thio]pyridin-2- yl}methyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 92 
                 (3-{[(4-fluoro-5-{[5-(4-fluorophenyl)-5-methylhexyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 93 
                 (3-{[(5-{[5-(4-fluorophenyl)-5-methylhexyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 94 
                 (3-{[(4-fluoro-5-{[5-(2-fluorophenyl)-5-methylhexyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 95 
                 (3-{[(5-{[5-(2-fluorophenyl)-5-methylhexyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 96 
                 (3-{[(4-fluoro-5-{[4-(3-phenyloxetan-3-yl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 97 
                 (3-{[(5-{[4-(3-phenyloxetan-3-yl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 98 
                 [3-({[4-fluoro-5-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 99 
                 [3-({[5-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 100 
                 [3-({[4-fluoro-5-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 101 
                 [3-({[5-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 102 
                 (3-{[(4-fluoro-5-{[4-(1-phenylcyclopentyl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 103 
                 (3-{[(5-{[4-(1-phenylcyclopentyl)butyl]thio}pyridin-2- yl)methyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 104 
                 [3-({[4-fluoro-5-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)pyridin- 2-yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 105 
                 [3-({[5-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 106 
                 [3-({[4-fluoro-5-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 107 
                 [3-({[5-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)pyridin-2- yl]methyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 108 
                 {3-[(3-fluoro-4-{[4-(1- phenylcyclohexyl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 109 
                 (3-{[3-fluoro-4-({4-[1-(4-fluorophenyl) cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 110 
                 (3-{[3-fluoro-4-({4-[1-(2- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 111 
                 [3-({3-fluoro-4-[(5-methyl-5-phenylhexyl)thio]benzyl} amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 112 
                 {3-[(3-fluoro-4-{[5-(4-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 113 
                 {3-[(3-fluoro-4-{[5-(2-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 114 
                 {3-[(3-fluoro-4-{[4-(3-phenyloxetan-3- yl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 115 
                 (3-{[3-fluoro-4-({4-[3-(4-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 116 
                 (3-{[3-fluoro-4-({4-[3-(2-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 117 
                 {3-[(3-fluoro-4-{[4-(1- phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 118 
                 (3-{[3-fluoro-4-({4-[1-(4- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 119 
                 (3-{[3-fluoro-4-({4-[1-(2- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 120 
                 {3-[(3-bromo-4-{[4-(1- phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 121 
                 (3-{[3-bromo-4-({4-[1-(4- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 122 
                 (3-{[3-bromo-4-({4-[1-(2- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 123 
                 {3-[(3-bromo-4-{[5-(4-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 124 
                 {3-[(3-bromo-4-{[5-(2-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 125 
                 {3-[(3-bromo-4-{[4-(3-phenyloxetan-3- yl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 126 
                 (3-{[3-bromo-4-({4-[3-(4-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 127 
                 (3-{[3-bromo-4-({4-[3-(2-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 128 
                 (3-{[3-bromo-4-({4-[1-(4- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 129 
                 (3-{[3-bromo-4-({4-[1-(2- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 130 
                 (3-{[4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 131 
                 (3-{[4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 132 
                 (3-{[4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 133 
                 (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 134 
                 (3-{[4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 135 
                 {3-[(3-chloro-4-{[4-(3-phenyloxetan-3- yl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 136 
                 (3-{[4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 137 
                 (3-{[4-{[4-(1-phenylcyclopentyl)butyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 138 
                 (3-{[4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 139 
                 (3-{[4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 140 
                 (3-{[4-{[4-(1-phenylcyclopentyl)butyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 141 
                 [3-({3-chloro-4-[(5-methyl-5-phenylhexyl) thio]benzyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 142 
                 {3-[(3-chloro-4-{[4-(1- phenylcyclopentyl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 143 
                 (3-{[4-({4-[1-(2- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 144 
                 (3-{[4-({4-[1-(4- fluorophenyl)cyclohexyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 145 
                 {3-[(4-{[5-(2-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 146 
                 {3-[(4-{[5-(4-fluorophenyl)-5- methylhexyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
               
               
                   
               
               
                 147 
                 (3-{[4-({4-[1-(2- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 148 
                 (3-{[4-({4-[1-(4- fluorophenyl)cyclopentyl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 149 
                 (3-{[4-({4-[3-(2-fluorophenyl)oxetan- 3-yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 150 
                 (3-{[4-({4-[3-(4-fluorophenyl)oxetan-3- yl]butyl}thio)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 151 
                 (3-{[2-fluoro-4-({4-[1-(2-fluorophenyl)cyclohexyl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 152 
                 (3-{[2-fluoro-4-({4-[1-(4-fluorophenyl)cyclohexyl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 153 
                 (3-{[2-fluoro-4-{[4-(1-phenylcyclohexyl)butyl]thio}-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 154 
                 (3-{[2-fluoro-4-{[5-(2-fluorophenyl)-5-methylhexyl]thio}-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 155 
                 (3-{[2-fluoro-4-{[5-(4-fluorophenyl)-5-methylhexyl]thio}-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 156 
                 [3-({2-fluoro-4-[(5-methyl-5-phenylhexyl)thio]-5- (trifluoromethyl)benzyl}amino)propyl]phosphonic acid                            
 
               
               
                   
               
               
                 157 
                 (3-{[2-fluoro-4-({4-[1-(2-fluorophenyl)cyclopentyl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 158 
                 (3-{[2-fluoro-4-({4-[1-(4-fluorophenyl)cyclopentyl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 159 
                 (3-{[2-fluoro-4-{[4-(1-phenylcyclopentyl)butyl]thio}-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 160 
                 (3-{[2-fluoro-4-({4-[3-(2-fluorophenyl)oxetan-3-yl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 161 
                 (3-{[2-fluoro-4-({4-[3-(4-fluorophenyl)oxetan-3-yl]butyl}thio)-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 162 
                 (3-{[2-fluoro-4-{[4-(3-phenyloxetan-3-yl)butyl]thio}-5- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
               
               
                   
               
               
                 166 
                 (3-((4-((5-(p-tolyl)pentyl)thio)-3- (trifluoromethyl)benzyl)amino)propyl)phosphonic acid                            
 
               
               
                   
               
             
          
         
       
     
       Biological Examples 
     In Vitro Assay 
       [0703]    Compounds were 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. 
         [0704]    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 5, 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 5 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 8-counter. Agonist-induced GTP γ 35 5 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 4 
               
             
             
               
                   
               
               
                 Activity potency: S1P1 receptor from GTP y 35 S: nM, (EC 50 ) 
               
             
          
           
               
                 IUPAC name 
                 S1P1 
               
               
                 Structure 
                 EC 50  (nM) 
               
               
                   
               
               
                 [3-({3-bromo-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 1.8 
               
               
                   
               
               
                 [3-({4-[(5-phenylpentyl)thio]-2- (trifluoromethyl)benzyl}amino)propyl]phosphonic acid                            
 
                 13.6 
               
               
                   
               
               
                 [3-({2-chloro-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 2.2 
               
               
                   
               
               
                 [3-({3-chloro-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 1.5 
               
               
                   
               
               
                 [3-({4-[(5-phenylpentyl)thio] benzyl}amino)propyl]phosphonic acid                            
 
                 3.3 
               
               
                   
               
               
                 [3-({4-[(5-phenylpentyl)thio]-3-(trifluoromethoxy) benzyl}amino)propyl]phosphonic acid                            
 
                 0.6 
               
               
                   
               
               
                 [3-({3-cyano-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 6.1 
               
               
                   
               
               
                 {3-[(4-{[5-(4-fluorophenyl)pentyl]thio}-3- methylbenzyl)amino]propyl}phosphonic acid                            
 
                 27.2 
               
               
                   
               
               
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 5.4 
               
               
                   
               
               
                 (3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 60.6 
               
               
                   
               
               
                 (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 4.6 
               
               
                   
               
               
                 (3-{[4-{[5-(4-chlorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 7.9 
               
               
                   
               
               
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 1.6 
               
               
                   
               
               
                 (3-{[4-{[5-(4-methylphenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 3.5 
               
               
                   
               
               
                 [3-({3-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)-1,1- difluoropropyl]phosphonic acid                            
 
                 4.8 
               
               
                   
               
               
                 [1,1-difluoro-3-({4-[(5-phenylpentyl)thio]-3- (trifluoromethoxy)benzyl}amino)propyl]phosphonic acid                            
 
                 13.6 
               
               
                   
               
               
                 [3-({3-chloro-4-[(5-phenylpentyl)thio]benzyl}amino)-1- methylpropyl]phosphonic acid                            
 
                 8.8 
               
               
                   
               
               
                 [3-({3-methyl-4-[(5- phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 3.2 
               
               
                   
               
               
                 [3-({3-fluoro-4-[(5-phenylpentyl)thio]benzyl} amino)propyl]phosphonic acid                            
 
                 0.3 
               
               
                   
               
               
                 {3-[(3-cyano-4-{[5-(4- fluorophenyl)pentyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 2.4 
               
               
                   
               
               
                 {3-[(3-methyl-4-{[5-(4- methylphenyl)pentyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 41.4 
               
               
                   
               
               
                 (3-{[4-{[5-(4-fluorophenyl)pentyl]thio}-2- (trifluoromethyl)benzyl]amino}propyl)phosphonic acid                            
 
                 8.7 
               
               
                   
               
               
                 (3-{[4-{[5-(4-methoxyphenyl)pentyl]thio}-3- (trifluoromethoxy)benzyl]amino}propyl)phosphonic acid                            
 
                 67.9 
               
               
                   
               
               
                 {3-[(2,5-difluoro-4-{[4-(1-phenylcyclohexyl) butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 0.9 
               
               
                   
               
               
                 {3-[(3-chloro-4-{[4-(1- phenylcyclohexyl)butyl]thio}benzyl)amino]propyl}phosphonic acid                            
 
                 2.0 
               
               
                   
               
               
                 [3-({3-bromo-4-[(5-methyl-5- phenylhexyl)thio]benzyl}amino)propyl]phosphonic acid                            
 
                 13.1 
               
               
                   
               
             
          
         
       
     
       In Vivo Assay 
     Lymphopenia Assay in Mice 
       [0705]    Test drugs are prepared in a solution containing 3% (w/v) 2-hydroxy propyl β-cyclodextrin (HPBCD) and 1% DMSO to a final concentration of 1 mg/ml, and subcutaneously injected to female C57BL6 mice (CHARLES RIVERS) weighing 20-25 g at the dose of 0.5 to 10 mg/Kg. Blood samples are obtained by puncturing the submandibular skin with a Goldenrod animal lancet at 5, 24, 48, 72, and 96 hrs post drug application. Blood is collected into microvettes (SARSTEDT) containing EDTA tripotassium salt. Lymphocytes in blood samples are counted using a HEMAVET Multispecies Hematology System, HEMAVET HV950FS (Drew Scientific Inc.). 
         [0000]    (Hale, J. et al Bioorg.&amp; Med. Chem. Lett. 14 (2004) 3351). 
         [0706]    A lymphopenia assay in mice; as previously described, was employed to measure the in vivo blood lymphocyte depletion after dosing with the test compound: [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid Compound-1. This S1P1 modulator, [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid Compound-1 is useful for S1P-related diseases and exemplified by the lymphopenia in vivo response. Test compound, was prepared in a solution containing 3% (w/v) 2-hydroxy propyl β-cyclodextrin (HPBCD) and 1% DMSO to a final concentration of 1 mg/ml, and subcutaneously injected to female C57BL6 mice (CHARLES RIVERS) weighing 20-25 g at the dose of 10 mg/Kg. Blood samples were obtained by puncturing the submandibular skin with a Goldenrod animal lancet at different time intervals such as: 24, 48, 72, and 96 h post drug application. Blood was collected into microvettes (SARSTEDT) containing EDTA tripotassium salt. Lymphocytes in blood samples were counted using a HEMAVET Multispecies Hematology System, HEMAVET HV950FS (Drew Scientific Inc.). Results are shown in the  FIG. 1  that depicts lowered lymphocyte count after 5 hours (&lt;1 number of lymphocytes 10 3 /μL blood). The positive control, [3-({3-bromo-4-[(5-phenylpentyl)thio]benzyl}amino)propyl]phosphonic acid is an S1P1 modulator.