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    • 专利摘要:
    The present invention relates to novel phenoxy derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1- phosphate receptors. Formula (I)
    公开号:AU2013222531A1
    申请号:U2013222531
    申请日:2013-02-20
    公开日:2014-09-18
    发明作者:Ken Chow；Evelyn G. Corpuz；Wenkui K. Fang；Wha Bin Im；Liming Wang
    申请人:Allergan Inc；
    IPC主号:C07F9-6553
    专利说明:
    WO 2013/126428 PCT/US2013/026901 PHENOXY DERIVATIVES AS SPHINGOSINE 1-PHOSPHATE (S1P) RECEPTOR MODULATORS By inventors: Wenkui K. Fang, Liming Wang, Evelyn G. Corpuz, 5 Ken Chow and Wha-Bin Im RELATED APPLICATION This application claims the benefit of U.S. Provisional Application Serial No. 61/601,129, filed February 21, 2012, which is incorporated herein by reference in its 10 entirety. FIELD OF THE INVENTION The present invention relates to phenoxy derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as 15 pharmaceuticals, as modulators of the sphingosine-1 -phosphate receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1-phosphate (S1P) receptor modulation. 20 BACKGROUND OF THE INVENTION 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 25 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 30 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 1 WO 2013/126428 PCT/US2013/026901 interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1 -phosphate metabolism is under active investigation. SUMMARY OF THE INVENTION 5 A group of novel phenoxy derivatives, which are potent and selective sphingosine-1 -phosphate modulators has been discovered. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of the sphingosine-1 -phosphate receptors. The term "modulator" as used herein, includes but is not limited to: receptor agonist, 10 antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist. 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 S1 P modulation. 15 In one aspect, the invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof RR
    R
    3 - A 0aC- / LR11 Nb
    R
    10 R4 ( RS R" j 12 R 20 Formula I wherein: A is optionally substituted C6.10 aryl, optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl or optionally substituted C 3.8 cycloalkenyl; 2 WO 2013/126428 PCT/US2013/026901 B is optionally substituted C610 aryl, optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl or optionally substituted C 3.8 cycloalkenyl;
    R
    1 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    2 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    1 4
    R
    15 or hydroxyl; 5 R3 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    4 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    1 4
    R
    15 or hydroxyl;
    R
    5 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    6 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    7 is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, 10 C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    8 is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R 3 , C6.10 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    9 is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; 15 R 10 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; R" is H or C1.8 alkyl;
    R
    12 is OPO 3
    H
    2 , carboxylic acid, P0 3
    H
    2 , C1.6 alkyl, -S(O) 2 H, -P(O)MeOH, P(O)(H)OH or OR 16 ; 20 R 13 is H, OH or C1.8 alkyl;
    R
    1 4 is H or C1.8 alkyl;
    R
    15 is H or C1.8 alkyl;
    R
    16 is H or C1.8 alkyl;
    L
    1 is 0, S, NH or CH R- 16 25 L2 is O, S or CH R 16 .
    L
    3 is 0, S or CH R- 16 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; c is 1, 2, 3,4 or5. 30 In another aspect, the invention provides a compound having Formula I wherein Ll is CH 2 . 3 WO 2013/126428 PCT/US2013/026901 In another aspect, the invention provides a compound having Formula I wherein
    L
    2 is CH 2 . In another aspect, the invention provides a compound having Formula I 5 wherein a is 1,2 or3. In another aspect, the invention provides a compound having Formula I wherein R 2 R1R R1 R2 R ,1 |
    R
    3
    -
    AR 10 is R 3 , R 3 R1 or RR2 In another aspect, the invention provides a compound having Formula I wherein R 2 R1 R1
    R
    3 - A R2 15 is R3 In another aspect, the invention provides a compound having Formula I wherein 4 WO 2013/126428 PCT/US2013/026901 R 2R1 R1 R 3 A is R3. In another aspect, the invention provides a compound having Formula I wherein 5 R2
    R
    1
    R
    2 S X is In another aspect, the invention provides a compound having Formula I wherein R 4 B R4 R R4& R5 10 R5 is R . In another aspect, the invention provides a compound having Formula I wherein R 2 R1 R1 R3-- A R2 is R 3 ;and R4 B R 6 :&R5 15 R5 is R 6 5 WO 2013/126428 PCT/US2013/026901 In another aspect, the invention provides a compound having Formula I wherein R2 R1 R R1 R2 R3-( R R2 R3 is R3 ,R3 R1 or R2 S 5 R B R 5 is R ;
    R
    1 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl; 10 R 2 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    1 4
    R
    15 or hydroxyl;
    R
    3 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    4 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    1 4
    R
    15 or hydroxyl;
    R
    5 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl;
    R
    6 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13
    NR
    14
    R
    15 or hydroxyl; 15 RT is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    8 is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    9 is H, halogen, -OC1.8 alkyl, C1.
    8 alkyl, CN, C(O)R, C610 aryl, heterocycle, 20 C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    10 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; R" is H or C1.8 alkyl; 6 WO 2013/126428 PCT/US2013/026901
    R
    1 2 is OPO 3
    H
    2 , carboxylic acid, P0 3
    H
    2 , C1.6 alkyl, -S(O) 2 H, -P(O)MeOH, P(O)(H)OH or OR 16 ;
    R
    1 3 is H, OH or C1.8 alkyl;
    R
    1 4 is H or C1.8 alkyl; 5 R 15 is H or C1.8 alkyl;
    R
    16 is H or C1.8 alkyl; Ll is 0, S, NH or CH R- 16
    L
    2 is 0, S or CH R 16 .
    L
    3 is 0, S or CH R- 16 10 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; c is 1, 2, 3,4 or5. In another aspect, the invention provides a compound having Formula I wherein 15 R3 A R 2 R 2 R1R x is R3 or R B R 4
    R
    6 R
    R
    5 is R
    R
    1 is H, C 1
    .
    8 alkyl; 20 R 2 is H, C 1
    .
    8 alkyl;
    R
    3 is H, C 1
    .
    8 alkyl;
    R
    4 is H, C 1
    .
    8 alkyl; R 5 is H, C 1
    .
    8 alkyl; R 6 is H, C 1
    .
    8 alkyl; 7 WO 2013/126428 PCT/US2013/026901
    R
    7 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3-8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    8 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C6.10 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; 5 R 9 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    1 0 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; R" is H or C1.8 alkyl; 10 R 12 is carboxylic acid, P0 3
    H
    2 , -P(O)MeOH, or OR 1 6 ;
    R
    1 3 is H, OH or C1.8 alkyl;
    R
    1 4 is H or C1.8 alkyl;
    R
    15 is H or C1.8 alkyl;
    R
    16 is H or C1.8 alkyl; 15 Ll is CH R- 16
    L
    2 is CH R 16 ;
    L
    3 is CH R- 16 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; 20 cis1,2,3,4or5. In another aspect, the invention provides a compound having Formula I wherein R2 R1 R2 S 2
    R
    3 - A 3 3 >K is, R1 or 25 8 WO 2013/126428 PCT/US2013/026901 R 4 B R6 :&R5 R5 is RS R 1 is H, C 1
    .
    8 alkyl;
    R
    2 is H, C 1
    .
    8 alkyl; 5 R3 is H, C 1
    .
    8 alkyl;
    R
    4 is H, C 1
    .
    8 alkyl; R 5 is H, C 1
    .
    8 alkyl; R 6 is H, C 1
    .
    8 alkyl;
    R
    7 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, 10 C 3-8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    8 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C6.10 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl;
    R
    9 is H, halogen, -OC1.8 alkyl, C 1
    .
    8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; 15 R10 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R 3 , C610 aryl, heterocycle, C 3.8 cycloakyl, C 3.8 cycloalkenyl, NR 1 4
    R
    15 or hydroxyl; R" is H or C1.8 alkyl;
    R
    12 is carboxylic acid, P0 3
    H
    2 , -P(O)MeOH, or OR 16 ;
    R
    1 3 is H, OH or C1.8 alkyl; 20 R 1 4 is H or C1.8 alkyl;
    R
    15 is H or C1.8 alkyl;
    R
    16 is H or C1.8 alkyl; L' is CH R- 16
    L
    2 is CH R 16 ; 25 L 3 is CH R- 16 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; c is 1, 2, 3,4 or5. 9 WO 2013/126428 PCT/US2013/026901 The term "alkyl", as used herein, refers to saturated, monovalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 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 3-8 5 cycloalkyl. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amine groups, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamides groups. The term "cycloalkyl", as used herein, refers to a monovalent or divalent group 10 of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen, nitro groups, cyano groups, -OC1.6 alkyl groups, -SC 1
    .
    6 alkyl groups, -C1. 6 alkyl groups, -02-6 alkenyl groups, - C2-6 alkynyl groups , C3-8 cycloalkyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide 15 groups, amine groups, sulfonamide groups or hydroxyl groups. The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen atoms, nitro groups, cyano groups, -OC1.6 20 alkyl groups, -SC 1
    .
    6 alkyl groups, -C 1
    .
    6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C3.8 cycloalkyl groups or hydroxyl groups. The term "halogen", as used herein, refers to an atom of chlorine, bromine, 25 fluorine, iodine. The term "alkenyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by C1.8 alkyl. 10 WO 2013/126428 PCT/US2013/026901 The term "alkynyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. The term "heterocycle" as used herein, refers to a 3 to 10 membered ring, 5 which can be aromatic or non-aromatic, saturated or non-saturated, monocyclic or polycyclic, containing at least one heteroatom selected form 0 or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C=0; the S heteroatom can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be 10 substituted by halogen, nitro groups, cyano groups, -OC1.6 alkyl groups, -SC1.
    6 alkyl groups, -C1.6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C3.8 cycloalkyl groups or hydroxyl groups. The term "aryl" as used herein, refers to an organic moiety derived from an 15 aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic. Aryl can be substituted by halogen atoms, nitro groups, cyano groups, -OC1.6 alkyl groups, -SC1. 6 alkyl groups, -C 1 -6 alkyl groups, -02-6 alkenyl groups, - C2-6 alkynyl groups , carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide 20 groups, amine groups, sulfonamide groups, C3.8 cycloalkyl groups or hydroxyl groups. Usually aryl is phenyl. Preferred substitution site on aryl are meta and para positions. The term "cyano" as used herein, represents a group of formula "-CN". The term "nitro" as used herein, represents a group of formula "-NO 2 ". 25 The term "amide" as used herein, represents a group of formula " C(O)NRxRy," wherein RX and RY can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above. The term "amine" as used herein, represents a group of formula "-NRxRy ",wherein RX and RY can be the same or independently H, alkyl, aryl, cycloalkyl, 30 cycloalkenyl, heterocyle as defined above. 11 WO 2013/126428 PCT/US2013/026901 The term "ketone" as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)RX wherein RX can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above. The term "aldehyde" as used herein, represents a group of formula "-C(O)H". 5 The term "ester" as used herein, represents a group of formula "-C(O)ORX", wherein RX can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above. The term "sulfonamide" as used herein, represents a group of formula "
    S(O)
    2 NRxR" wherein RX and RY can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above. 10 The term "hydroxyl" as used herein, represents a group of formula "-OH". The term "carbonyl" as used herein, represents a group of formula "-C(O)". The term "carboxyl" as used herein, represents a group of formula "-C(0)0-". The term "sulfonyl" as used herein, represents a group of formula "-SO 2 ". The term "sulfate" as used herein, represents a group of formula "-O-S(0) 2 -0 15 The term "carboxylic acid" as used herein, represents a group of formula C(O)OH". The term "sulfoxide" as used herein, represents a group of formula "-S=O". The term "phosphonic acid" as used herein, represents a group of formula 20 P(O)(OH) 2 ". The term "phosphoric acid" as used herein, represents a group of formula
    (O)P(O)(OH)
    2 ". The term "sulphonic acid" as used herein, represents a group of formula
    S(O)
    2 0H". 25 The formula "H ", as used herein, represents a hydrogen atom. The formula "0 ", as used herein, represents an oxygen atom. The formula "N ", as used herein, represents a nitrogen atom. The formula "S ", as used herein, represents a sulfur atom. Compounds of the invention are: 30 3-[(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy}benzyl) amino]propanoic acid; 12 WO 2013/126428 PCT/US2013/026901 3-({4-[3-(3-chlorophenyl)-4-(3,4 dimethylphenyl)butoxy]benzyl}amino)propanoic acid; {3-[(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy} benzyl)amino] propyl} phosphonic acid; 5 [3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl] phosphonic acid; 3-[(4-{[4-(3,5-d ifluorophenyl)-5-(3,4-d imethylphenyl)pentyl]oxy}benzyl) amino]propanoic acid; 3-[(4-{[4-(3-chlorophenyl)-5-(3,4-d imethylphenyl)pentyl]oxy}benzyl) 10 amino]propanoic acid; {3-[(4-{[4-(3,5-d ifluorophenyl)-5-(3,4-d imethylphenyl)pentyl]oxy}benzyl)am ino] propyl}phosphonic acid; {3-[(4-{[4-(3-chlorophenyl)-5-(3,4 dimethylphenyl)pentyl]oxy}benzyl)amino]propyl} phosphonic acid; 15 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl)amino]propanoic acid; 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl) amino]propyl} phosphonic acid; and 3-[(4-{[4-(2,3-d ifluorophenyl)-5-(3,4-d imethylphenyl)pentyl]oxy}benzyl) 20 amino]propanoic acid. 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. 25 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. 30 The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric 13 WO 2013/126428 PCT/US2013/026901 acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, 5 ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- ZOrich, 2002, 329-345). The base addition salt form of a compound of Formula I that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an 10 inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, Calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- ZOrich, 2002, 329-345). 15 Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and 20 mixtures thereof unless the particular isomeric form is referred to specifically. Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention. The compounds of the invention are indicated for use in treating or preventing 25 conditions in which there is likely to be a component involving the sphingosine-1 phosphate receptors. In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier. 14 WO 2013/126428 PCT/US2013/026901 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 5 of at least one compound of the invention. These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1 P modulation. Therapeutic utilities of S1 P modulators are ocular diseases, such as but not 10 limited to: Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, dry eye, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced 15 fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; 20 Autoimmune diseases and immnuosuppression: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation ; 25 Allergies and other inflammatory diseases: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury 15 WO 2013/126428 PCT/US2013/026901 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 ; 5 Bone formation: treatment of osteoporosis and various bone fractures including hip and ankles; Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; 10 Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon; Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo skeletal pains, visceral pain, pain associated with diabetic neuropathy, 15 rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries; Organ transplants: renal, corneal, cardiac and adipose tissue transplants. In still another embodiment of the invention, there are provided methods for 20 treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof. 25 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 16 WO 2013/126428 PCT/US2013/026901 Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, dry eye, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced 5 fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; 10 Autoimmune diseases and immnuosuppression: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation ; 15 Allergies and other inflammatory diseases: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury 20 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 ; Bone formation: treatment of osteoporosis and various bone fractures including 25 hip and ankles; Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; 17 WO 2013/126428 PCT/US2013/026901 Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon; Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo 5 skeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries; Organ transplants: renal, corneal, cardiac and adipose tissue transplants. 10 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's general physical condition, the cause of the condition, and the route of administration. 15 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 20 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. In another embodiment of the invention, there are provided pharmaceutical 25 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. Pharmaceutical compositions of the present invention can be used in the form 30 of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and 18 WO 2013/126428 PCT/US2013/026901 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, 5 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 10 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. Pharmaceutical compositions containing invention compounds may be in a 15 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 20 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 25 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 30 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. 19 WO 2013/126428 PCT/US2013/026901 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 5 or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 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 10 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 15 vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required. 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 20 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. 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 25 of the practitioner. 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 30 embodiments of the invention, there are provided methods for treating a disorder associated with modulation of sphingosine-1 -phosphate receptors. Such methods 20 WO 2013/126428 PCT/US2013/026901 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 5 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. The present invention concerns also processes for preparing the compounds 10 of Formula 1. 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 schemes set forth below, illustrate how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the 15 following scheme to synthesize any compounds of the invention covered by Formula 1. The following abbreviations are used in the general scheme description and in the examples: AcCN acetonitrile 20 DCM dichloromethane MeOH methanol
    CD
    3 0D deuterated methanol CDCl 3 deuterated chloroform DMSO-d 6 deuterated dimethyl sulfoxide 25 TEA triethylamine RT or rt room temperature M molar AcOH acetic acid MPLC Medium Pressure Liquid Chromatography 30 NMO 4-Methylmorpholine N-oxide TPAP Tetrapropylammonium perruthenate NaBH 4 Sodium borohydride NaCNBH 3 Sodium cyanoborohydride 21 WO 2013/126428 PCT/US2013/026901
    R
    2
    R
    1 R R 1
    R
    7
    R
    8 R 3 A General R- A R 0 procedureA 0 -aa R1 is OH L L R9 L 4 R R
    R
    1 R General RL 3 A procedure B B 2 R(
    R
    12 is -COOH R6 /12 12 ~ R--LR Nb General
    LL
    3 procedure C B
    R
    12 is -P(O)(OH)2 RR 12 L2 R 1 1 / Nb ~ HN L3 is or HN (/c (HO) 2 O)P COOH 5 General procedure A The alcohol intermediate (0.61 mmol) was mixed with NMO (1 5.4mmol), molecular sieve (500mg) in AcCN (6mL) and DCM (30mL). A catalytic amount of TPAP (35mg) was added. The resulting reaction mixture was stirred at RT for 1 hour and evaporated to dryness. The aldehyde compound was purified by MPLC using 0-10% 10 ethyl acetate in hexane. 22 WO 2013/126428 PCT/US2013/026901 General procedure B The aldehyde (0.66mmol), azetidine acid (0.86mmol)and TEA (0.7mmol) were mixed with MeOH (1Oml). Upon stirring at 600C for 90 min, the reaction solution was cooled to RT. NaBH 4 (50mg, mmol) was added and stirred at RT for 2 hour. The 5 reaction was quenched with 0.5 mL of water and concentrated to minimal amount. The final compound was isolated by reverse phase MPLC using 0 to 90% H 2 0 in AcCN. General procedure C: 10 The aldehyde (0.69mmol), 3-aminopropylphosphonic acid (0.69mmol)and tetra-n butylammonium hydroxide (1.0M/MeOH, 0.69mmol) were mixed with MeOH (10ml). Upon stirring at 500C for 30 min, NaBH 3 CN (0.69mmol) was added and stirred at 500C for 3 hour. The reaction was quenched with 0.5mL of water and concentrated to minimal amount. The final compound was isolated by MPLC using 10 to 90% 15 MeOH in EtOAc. DETAILED DESCRIPTION OF THE INVENTION It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not 20 restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. 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. 25 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. 30 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 2H (or 23 WO 2013/126428 PCT/US2013/026901 D) in place of protium 1H (or H) or use of 13 C enriched material in place of 12C and the like. Similar substitutions can be employed for N, 0 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) 5 of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents. 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 10 can be made without exceeding the spirit or scope of the invention. As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed. 15 Compound names were generated with ACD version 12.0 and intermediates and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. In general, characterization of the compounds is performed using NMR spectra, which were recorded on 300 and/or 600 MHz Varian and acquired at room 20 temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, 25 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. Usually the compounds of the invention were purified by column chromatography (Auto-column) on an Teledyne-ISCO CombiFlash with a silica 30 column, unless noted otherwise. 24 WO 2013/126428 PCT/US2013/026901 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 1. 5 Example 1 Intermediate 1 4-[3-(3-ch lorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzaldehyde CI 0 CHO The corresponding alcohol intermediate (2.43g, 0.61 mmol) was mixed with 10 NMO (1.79g, 15.4mmol), molecular sieve (500mg) in AcCN (6mL) and DCM (30mL). A catalytic amount of TPAP (35mg) was added. The resulting reaction mixture was stirred at RT for 1 hour and evaporated to dryness. The title aldehyde compound was purified by MPLC using 0-10% ethyl acetate in hexane. 1 H NMR (300 MHz, CD 3 OD) 5 ppm 1.98 - 2.10 (m, 1 H) 2.12 - 2.28 (m, 7 H) 15 2.80-2.90 (m, 2H) 3.08-3.18 (m, 1 H) 3.76-3.85 (m, 1 H) 3.90-3.98 (m, 1 H) 6.75-6.82 (m, 2H) 6.88-6.95 (m, 3H) 7.05 - 7.25 (m, 4H) 7.80 (d, J=8.79 Hz, 2 H) 9.79 (s, 1 H). Intermediates 2 through 7 were prepared according to the procedure described in Example 1 from the corresponding alcohol. The results for intermediates 2 and 3 are tabulated below in Table 1. 20 25 WO 2013/126428 PCT/US2013/026901 Table 1 Interm. IUPAC name 'H NMR 6 (ppm) No. 2 4-{[4-(3-chlorophenyl)-5-(3,4- 1 H NMR (600 MHz, CD 3 OD) dimethylphenyl)pentyl]oxy}benzaldehy 5 ppm 1.59- 1.66 (m, 2 H) de 1.70 - 1.82 (m, 1 H) 1.82 CI 1.94 (m, 1 H) 2.14(s, 3H) CHO 2.16(s, 3 H) 2.70 - 2.96 (m, 3 H) 3.97 (t, J=6.31 Hz, 2 H) 6.73 (d, J=7.63 Hz, 1 H) 6.79 (s, 1 H) 6.91 (d, J=7.63 Hz, 1 H) 6.94 - 7.00 (m, 2 H) 7.07 (d, J=7.34 Hz, 1 H) 7.11 7.17 (m, 2 H) 7.19 - 7.29 (m, 1 H) 7.82 (d, J=8.51 Hz, 2 H) 9.81 (s, 1 H) 3 4-{[5-(3-chlorophenyl)-6-(3,4- 1 H NMR (300 MHz, CD 3 OD) dimethylphenyl)hexyl]oxy}benzaldehyd 5 ppm 1.25 - 1.39 (m, 2 H) e 1.55 - 1.88 (m, 4 H) 2.14 (s, CI 3 H) 2.15 (s, 3H) 2.69 - 2.91 (m, 3 H) 3.94 (t, J=6.45, 2 H) 0 6.62 - 6.82 (m, 2 H) 6.84 CHO 7.07 (m, 4 H) 7.08 - 7.21 (m, 3 H) 7.81 (d, J=8.87Hz, 2 H) 9.80 (s, 1 H) 4 4-{[4-(2,3-difluorophenyl)-5-(3,4- 1 H NMR (300 MHz, CDCI 3 ) 5 dimethylphenyl)pentyl]oxy}benzaldehy ppm 1.60 - 1.74 (m, 2 H) de 1.75 - 1.97 (m, 2 H) 2.19 (d, F J=3.22 Hz, 6 H) 2.72 - 2.91 F (m, 2 H) 3.20 - 3.39 (m, 1 H) 3.94 (t, J=6.30 Hz, 2 H) 6.61 - 6.70 (m, 1 H) 6.72 - 6.82 'C'CHO (m, 1 H) 6.85 (br. s, 1 H) 6.87 - 7.03 (m, 5 H) 7.80 (d, J=7.81 Hz, 2 H) 9.87 (s, 1 H) 5 4-{[5-(3,4-dimethylphenyl)-4-(3- 1 H NMR (300 MHz, CDCI 3 ) 5 thienyl)pentyl]oxy}benzaldehyde ppm 1.57 - 1.78 (m, 3 H) S 1.78 - 1.93 (m, 1 H) 2.19 (s, 3 H) 2.20 (s, 3 H) 2.82 (t, J=8.06 Hz, 2 H) 2.93 - 3.07 O ,5 (m, 1 H) 3.80 - 3.98 (m, 2 H) CHO 6.76 (d, J=7.33 Hz, 1 H) 6.81 CHO (br. s, 1 H) 6.84 - 7.02 (m, 5 H) 7.26 (dd, J=4.98, 2.93 Hz, 1 H) 7.80 (d, J=7.80 Hz, 2 H) 9.86 (s, 1 H) 26 WO 2013/126428 PCT/US2013/026901 6 4-((4-(3,5-difluorophenyl)-5-(3,4- 'H NMR (600 MHz, CD 3 OD) dimethylphenyl)pentyloxy)benzaldehyd 5 ppm 1.58- 1.70 (m, 2 H) e 1.72 - 1.82 (m, 1 H) 1.85 1.95 (m, 1 H) 2.16 (s, 3H) F 2.17 (s, 3 H) 3.72 - 3.78 (m, CHO 1 H) 3.82-3.88 (m, 1 H) 3.90 3.98 (m, 1 H) 4.10 (t, J=6.15 F O Hz, 2 H) 6.65-6.82 (m, 5 H) 6.92 (d, J=7.70 Hz, 1 H) 7.00 (d, J=8.50 Hz, 2 H) 7.83 (d, J=8.5OHz, 2 H) 9.81 (s, 1 H) 7 4-{[4-(3,4-difluorophenyl)-5-(3,4- 'H NMR (300 MHz, CDCI 3 ) 5 dimethylphenyl)pentyl]oxy}benzaldehy ppm 1.54 - 1.77 (m, 3 H) de 1.78 - 1.98 (m, 1 H) 2.19 (br F s, 6 H) 2.68 - 2.92 (m, 3 H) F CHO 3.93 (t, J=5.86 Hz, 2 H) 6.56 - 6.76 (m, 1 H) 6.75 - 6.86 (m, 2 H) 6.85 - 7.12 (m, 5 H) O 7.80 (d, J=8.20 Hz, 2 H) 9.87 (s, 1 H) Example 2 Compound 1 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl] oxy}benzyl)amino] 5 propanoic acid S 0 H N N CO2H A mixture of Intermediate 5 (150 mg, 0.40 mmoles), p-alanine (35.4 mg, 1.0 eq), HOAc (7 drops) and NaCNBH 3 (25 mg, 1.0 eq) were reacted as outlined is Scheme 10 1 to give Compound 1. 27 WO 2013/126428 PCT/US2013/026901 'H NMR (300 MHz, DMSO-d 6 ) 5 ppm 1.44-1.74 (m, 4 H) 2.11 (s, 6 H) 2.23 (t, J=6.59 Hz, 2 H) 2.68 - 2.81 (m, 4 H) 2.89 - 3.12 (m, 1 H) 3.73 (s, 2 H) 3.77 - 3.87 (m, 2 H) 6.72 - 6.87 (m, 4 H) 6.92 (d, J=7.62 Hz, 1 H) 7.02 (d, J=4.69 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.21 (d, J=8.50 Hz, 2 H) 7.38-7.45 (m, 1 H). 5 Compounds 2 through 6 were prepared according to the procedure described in Example 2 from the corresponding aldehyde. The starting materials and the results are tabulated below in Table 2. Table 2 Comp. iupac name Interm. 'H NMR 6 (ppm) No. No. 2 3-[(4-{[4-(2,3-difluorophenyl)-5-(3,4- 1 H NMR (300 MHz, dimethylphenyl)pentyl]oxy}benzyl)am 4 DMSO-d 6 ) 5 ppm 1.41 ino]propanoic acid 1.59 (m, 2 H) 1.61 IF 1.84 (m, 2 H) 2.02 F 2.13 (m, 6 H) 2.24 (t, J=6.45 Hz, 2 H) 2.69 SH 2.82 (m, 3 H) 2.84-2.94 N, 'CO 2 H (m, 1 H) 3.16 - 3.40 (m, 1 H) 3.73 (s, 2 H) 3.85 (br. s., 2 H) 6.71 - 6.87 (m, 4 H) 6.89 - 6.99 (m, 2 H) 7.07 - 7.25 (m, 4 H). 3 3-[(4-{[5-(3-chlorophenyl)-6-(3,4- 3 1 H NMR (600 MHz, dimethylphenyl)hexyl]oxy}benzyl)ami CD 3 OD) 5 ppm 1.23 no] propanoic acid 1.31 (m, 2 H) 1.54 cl 1.84 (m, 4 H) 2.14(s, 3 H) 2.15(s, 3H) 2.42 (t, o J=6.75 Hz, 2 H) 2.69 H 2.77 (m, 1 H) 2.77 0 N OH 2.83 (m, 2 H) 2.87 (t, o J=6.75 Hz, 2 H) 3.76 (s, 2 H) 3.79 - 3.89 (m, 2 H) 6.71 (dd, J=7.63, 1.47 Hz, 1 H) 6.74 6.83 (m, 3 H) 6.90 (d, J=7.63 Hz, 1 H) 7.02 (dt, J=7.63, 1.32 Hz, 1 H) 7.08 - 7.15 (m, 2 H) 7.16-7.20(m, 1H) 7.24 (d, J=8.8OHz,2 H) 28 WO 2013/126428 PCT/US2013/026901 4 3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4- 6 'H NMR (300 MHz, dimethylphenyl)pentyl]oxy}benzyl)am CD 3 OD)5 ppm 1.49 ino] propanoic acid 1.65 (m, 2 H) 1.81 F 0 1.89 (m, 2 H) 2.15 (s, - N OH 3H) 2.17 (s, 3H) 2.42 (t, H J=6.74Hz, 2 H) 2.72 F O 2.93 (m, 5H) 3.74 (s, 2 H) 3.85 (t, J=6.15 Hz, 2 H) 6.57 - 6.84 (m, 7 H) 6.92 (d, J=7.62 Hz, 1 H) 7.24 (d, J=8.50 Hz, 2 H) 5 3-[(4-{[4-(3-chlorophenyl)-5-(3,4- 2 'H NMR (300 MHz, dimethylphenyl)pentyl]oxy}benzyl)am CD 3 OD ppm 1.48 ino] propanoic acid 1.64 (m, 2 H) 1.67 cl 0 1.96 (m, 2 H) 2.15 (s, 3 N OH H) 2.17 (s, 3H) 2.41 (t, H J=6.74 Hz, 2 H) 2.67 0 2.94 (m, 5 H) 3.70 (s, 2 H) 3.85 (t, J=6.30 Hz, 2 H) 6.67 - 6.83 (m, 4 H) 6.91 (d, J=7.62 Hz, 1 H) 7.00 - 7.09 (d, J=7.6Hz, 1 H) 7.10 - 7.29 (m, 5 H) 6 3-({4-[3-(3-chlorophenyl)-4-(3,4- 1 1 H NMR (600 dimethylphenyl)butoxy]benzyl}amino) MHz,CD 3 OD) 5 ppm propanoic acid 1.93 - 2.03 (m, 1 H) C1 2.15 (s, 3H) 2.16 (s, 3H) 2.17 - 2.24 (m, 1 H), 2.46 (t, J=6.46 Hz, o H 2 H) 2.78 - 2.94 (m, 2 N OH H) 3.08- 3.16 (m, 3 H) 3.71 (m, 1 H) 3.83 (m, 1 0 H) 4.08 (s, 2 H) 6.75 (dd, J=7.63, 1.76 Hz, 1 H) 6.78 - 6.86 (m, 3 H) 6.91 (d, J=7.63Hz, 1 H) 7.05 (d, J=7.72Hz, 1 H) 7.10 - 7.23 (m, 3 H) 7.31 (d. J=8.86Hz, 2 H) 29 WO 2013/126428 PCT/US2013/026901 Example 3 Compound 7 {3-[(4-{[5-(3,4-Dimethylphenyl)-4-(3-th ienyl)pentyl]oxy}benzyl)am ino] 5 propyl}phosphonic acid S 0 H H -~N OH A mixture of Intermediate 5 (440 mg, 1.16 mmoles), (3 aminopropyl)phosphonic acid (146 mg, 0.9 eq), Bu 4 NOH (1.2 mL, 1.0 eq) and 10 NaCNBH 3 (73.14 mg, 1.0 eq) were reacted as outlined is Scheme 2 to give Compound 7. 'H NMR (300 MHz, DMSO-d 6 ) 5ppm 1.25 - 1.42 (m, 4 H) 1.47 - 1.59 (m, 3 H) 2.11 (s, 6 H) 2.68-2.82 (m, J=7.60 Hz, 4 H) 3.10 - 3.18 (m, 2 H) 3.74 - 3.85 (m, 4 H) 15 6.73 - 6.86 (m, 4 H) 6.92 (d, J=7.62 Hz, 1 H) 7.02 (d, J=5.27 Hz, 1 H) 7.06-7.09 (m, 1 H) 7.32 (d, J=8.79 Hz, 2 H) 7.41 (dd, J=4.69, 3.22 Hz, 1 H). Compounds 8 through 11 were prepared according to the procedure 20 described in Example 3 from the corresponding Intermediate. The starting materials and the results are tabulated below in Table 2. 30 WO 2013/126428 PCT/US2013/026901 Table 2 Comp. IUPAC name Interm. H NMR 6 (ppm) No. No. 8 {3-[(4-{[5-(3-chlorophenyl)-6-(3,4- 1H NMR (300 dimethylphenyl)hexyl]oxy}benzyl)ami 3 MHz,CD 3 OD) 5 ppm no]propyl} phosphonic acid 1.22 - 1.38 (m, 2 H) CI 1.54 - 1.79 (m, 6 H) 1.85 - 2.06 (m, 2 H) O 2.15 (m, 3H) 2.17 (m, H OH 3H) 2.66 - 2.90 (m, 3 OH H) 3.06 (t, J=6.30 Hz, 2 H) 3.87 (t, J=6.59 Hz, 2 H) 4.04 (s, 2 H) 6.67 - 6.80 (m, 2 H) 6.83 - 6.95 (m, 3 H) 7.00 - 7.26 (m, 4 H) 7.32 - 7.41 (m, 2 H) 9 {3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4- 6 1 H NMR (600 MHz, dimethylphenyl)pentyl]oxy}benzyl)am CD 3 OD) 5 ppm 1.55 ino] propyl} phosphonic acid 1.62 (m, 2 H) 1.63 F O 1.70 (m, 2 H) 1.72 r OH 1.80 (m, 1 H) 1.85 F| H H1.92 (m, 1 H) 1.93 1.99 (m, 2 H) 2.16 (s, 3 H) 2.7 (s, 3H) 2.71 2.79 (m, 1 H) 2.81 2.88 (m, 1 H) 2.92 (br. s., 1 H) 3.05 (t, J=6.46 Hz, 2 H) 3.90 (t, J=6.16 Hz, 2 H) 4.04 (s, 2 H) 6.69 (t, J=9.10 Hz, 1 H) 6.71 6.77 (m, 3 H) 6.80 (s, 1 H) 6.85 - 6.98 (m, 3 H) 7.37 (d, J=8.51 Hz, 2 H) 10 {3-[(4-{[4-(3-chlorophenyl)-5-(3,4- 2 1 H NMR (600 MHz, dimethylphenyl)pentyl]oxy}benzyl)am METHANOL-d 4 ) 5 ino]propyl} phosphonic acid ppm 1.54 - 1.61 (m, 2 ci O H) 1.66 (m, 2 H) 1.72 - 1.81 (m, 1 H) 1.82 HO 2.01 (m, 3 H) 2.15 (s, 3 H) 2.17(s, 3H) 2.73 2.79 (m, 1 H) 2.81 2.92 (m, 2 H) 3.01 (t, J=6.16 Hz, 2 H) 3.88 31 WO 2013/126428 PCT/US2013/026901 (t, J=6.31 Hz, 2 H) 4.00 (s, 2 H) 6.73 (d, J=7.92 Hz, 1 H) 6.78 (s, 1 H) 6.84 - 6.89 (m, 2 H) 6.91 (d, J=7.63 Hz, 1 H) 7.06 (d, J=7.63 Hz, 1 H) 7.11 - 7.16 (m, 2 H) 7.19 - 7.25 (m, 1 H) 7.35 (d, J=8.51 Hz, 2 H) 11 [3-({4-[3-(3-chlorophenyl)-4-(3,4- 1 1 H NMR (300 MHz, dimethylphenyl)butoxy]benzyl}amino) CD 3 OD 5 ppm 1.60 propyll] phosphonic acid 1.75 (m, 2 H) 1.85 CI 2.09 (m, 3 H) 2.09 2.25 (m, 7 H) 2.78 2.95 (m, 2 H) 2.98 H 0 3.06 (m, 2 H) 3.06 N, '-OH 3.18 (m, 1 H) 3.68 OH 3.78 (m, 1 H) 3.80 3.90 (m, 1 H) 4.01 (s, 2 H) 6.68 - 6.75 (m, 1 H) 6.78 - 6.87 (m, 3 H) 6.92 (d, J=7.61 Hz, 1 H) 7.04 (d, J=7.61Hz, 1H) 7.10 7.21 (m, 3 H) 7.34 (d, J=8.79Hz, 2 H) Biological Data Compounds were synthesized and tested for S1 P1 activity using the GTP y 35 S binding assay. These compounds may be assessed for their ability to activate 5 or block activation of the human S1 P1 receptor in cells stably expressing the S1 P1 receptor. GTP y 35 S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCl 2 10, NaCI 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP y 35 S, and 5 pg membrane protein in a volume of 150 pl. Test compounds were included in 10 the concentration range from 0.08 to 5,000 nM unless indicated otherwise. Membranes were incubated with 100 pM 5'-adenylylimmidodiphosphate for 30 min, 32 WO 2013/126428 PCT/US2013/026901 and subsequently with 10 pM GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP y 35 S and continued for 30 min at 25 OC. 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, 5 MgCl 2 10 and NaCI 100). Filters were dried and mixed with scintillant, and counted for 35S activity using a p-counter. Agonist-induced GTP y 35 S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a non-linear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1P in the presence of test antagonist at concentrations ranging 10 from 0.08 to 5000 nM. Table 1 shows activity potency: S1 P1 receptor from GTP y 35 S: nM, (EC 5 o). Activity potency: S1 P1 receptor from GTP y 35 S: nM, (EC 5 o), Table 1 S1 P1 IUPAC name
    EC
    5 o (nM) {3-[(4-{[4-(3-chlorophenyl)-5-(3,4- 0.23 d imethylphenyl)pentyl]oxy}benzyl)am ino]propyl}phosphon ic acid {3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4- 0.01 d imethylphenyl)pentyl]oxy}benzyl)am ino]propyl}phosphon ic acid 3-({4-[3-(3-chlorophenyl)-4-(3,4- 96.95 dimethylphenyl)butoxy]benzyl}amino)propanoic acid [3-({4-[3-(3-chlorophenyl)-4-(3,4- 7.44 d imethylphenyl)butoxy]benzyl}amino)propyl]phosphon ic acid 3-[(4-{[5-(3-chlorophenyl)-6-(3,4- 134.46 dimethylphenyl)hexyl]oxy}benzyl)amino]propanoic acid {3-[(4-{[5-(3-chlorophenyl)-6-(3,4- 17.10 d imethylphenyl)hexyl]oxy}benzyl)amino]propyl}phosphon ic acid 3-[(4-{[4-(3-chlorophenyl)-5-(3,4- 59.50 33 WO 2013/126428 PCT/US2013/026901 dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid 3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4- 17.78 dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3- 14.04 thienyl)pentyl]oxy}benzyl)amino]propanoic acid 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3- 2.08 thienyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid 3-[(4-{[4-(2,3-difluorophenyl)-5-(3,4- 0.85 dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid 34
    权利要求:
    Claims (13)
    [1] 1. A compound having Formula I, its enantiomers, diastereoisomers, hydrates, solvates, crystal forms and individual isomers, tautomers or a pharmaceutically acceptable salt thereof, RR R 3 - A 0 L N R 1 Nb LiR0 R9 L B R4(<C RS R12 5 R 5 Formula I wherein: A is C610 aryl, heterocycle, C 3-8 cycloalkyl or C 3.8 cycloalkenyl; 10 B is C610 aryl, heterocycle, C 3.8 cycloalkyl or C 3.8 cycloalkenyl; R 1 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 2 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 3 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 4 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; 15 R5 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 6 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 7 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R 8 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, 20 C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R 9 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R 10 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; 35 WO 2013/126428 PCT/US2013/026901 R" is H or C1.8 alkyl; R 1 2 is OPO 3 H 2 , carboxylic acid, P0 3 H 2 , C1.6 alkyl, -S(O) 2 H, -P(O)MeOH, P(O)(H)OH or OR 16 ; R 1 3 is H, OH or C1.8 alkyl; 5 R 14 is H or C1.8 alkyl; R 15 is H or C1.8 alkyl; R 16 is H or C1.8 alkyl; L' is 0, S, NH or CH R- 16 L 2 is 0, S or CH R 16 . 10 L3 is O, S or CH R- 16 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; c is 1, 2, 3,4 or5.
    [2] 2. A compound according to claim 1 wherein L' is CH 2 . 15
    [3] 3. A compound according to claim 1 wherein L 2 is CH 2 .
    [4] 4. A compound according to claim 1 wherein a is 1, 2 or 3.
    [5] 5. A compound according to claim 1 wherein R 1 R 1 R 3 - A R2 is R3 20
    [6] 6. A compound according to claim 1 wherein R 4 B B~R 4 R 6& R5 R 5 is R
    [7] 7. A compound according to claim 1 wherein 36 WO 2013/126428 PCT/US2013/026901 R R 1 R 1 R 3 - A R2 is R3 ;and B R 45 6 R R 5 is R
    [8] 8. A compound according to claim 1 selected from: 5 3-[(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy}benzyl) amino]propanoic acid; 3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethyl phenyl)butoxy]benzyl}am ino)propanoic acid; {3-[(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy} benzyl)amino] 10 propyl} phosphonic acid; [3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl] phosphonic acid; 3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl) amino]propanoic acid; 15 3-[(4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl) amino]propanoic acid; {3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)amino] propyl}phosphonic acid; {3-[(4-{[4-(3-chlorophenyl)-5-(3,4 20 dimethylphenyl)pentyl]oxy}benzyl)amino]propyl} phosphonic acid; 3-[(4-{[5-(3,4-d imethylphenyl)-4-(3-th ienyl)pentyl]oxy}benzyl)am ino]propanoic acid; 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl) amino]propyl} phosphonic acid; and 25 3-[(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl) amino]propanoic acid. 37 WO 2013/126428 PCT/US2013/026901
    [9] 9. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier.
    [10] 10. A pharmaceutical composition according to claim 9 wherein the compound is 5 selected from: 3-[(4-{[5-(3-chlorophenyl)-6-(3,4-d methyl phenyl)hexyl]oxy}benzyl) amino]propanoic acid; 3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethyl phenyl)butoxy]benzyl}am ino)propanoic acid; 10 {3-[(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy} benzyl)amino] propyl} phosphonic acid; [3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl] phosphonic acid; 3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl) 15 amino]propanoic acid; 3-[(4-{[4-(3-chlorophenyl)-5-(3,4-d methyl phenyl)pentyl]oxy}benzyl) amino]propanoic acid; {3-[(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)amino] propyl}phosphonic acid; 20 {3-[(4-{[4-(3-chlorophenyl)-5-(3,4 dimethylphenyl)pentyl]oxy}benzyl)amino]propyl} phosphonic acid; 3-[(4-{[5-(3,4-d imethylphenyl)-4-(3-th ienyl)pentyl]oxy}benzyl)am ino]propanoic acid; 3-[(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl) amino]propyl} 25 phosphonic acid; and 3-[(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl) amino]propanoic acid.
    [11] 11. A method of treating a disorder associated with sphingosine-1 -phosphate receptor modulation, which comprises administering to a mammal in need thereof, a 30 pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula 1 38 WO 2013/126428 PCT/US2013/026901 R2R R R R 3 - A 0 L N R11 Ll Nb L1R10 R9 L RS R12 R5 Formula I wherein: 5 A is C610 aryl, heterocycle, C 3-8 cycloalkyl or C 3.8 cycloalkenyl; B is C610 aryl, heterocycle, C 3.8 cycloalkyl or C 3.8 cycloalkenyl; R 1 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 2 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 1 4 R 15 or hydroxyl; R 3 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; 10 R 4 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 1 4 R 15 or hydroxyl; R 5 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 6 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, 13 NR 14 R 15 or hydroxyl; R 7 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; 15 R 8 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R 9 is H, halogen, -OC1.8 alkyl, C1. 8 alkyl, CN, C(O)R, C610 aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R 1 0 is H, halogen, -OC1.8 alkyl, C1.8 alkyl, CN, C(O)R, C610 aryl, heterocycle, 20 C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 1 4 R 15 or hydroxyl; R" is H or C1.8 alkyl; R 12 is OPO 3 H 2 , carboxylic acid, P0 3 H 2 , C1.6 alkyl, -S(0) 2 H, -P(O)MeOH, P(O)(H)OH or OR 16 ; R 13 is H, OH or C1.8 alkyl; 25 R 1 4 is H or C1.8 alkyl; 39 WO 2013/126428 PCT/US2013/026901 R 15 is H or C1.8 alkyl; R 16 is H or C1.8 alkyl; L' is 0, S, NH or CHR 1 6 L 2 is 0, S or CHR 1 6 . 5 L 3 is O, S or CHR 1 6 a is 1, 2, 3, 4, 5 or 6; b is 0 or 1; c is 1, 2, 3,4 or5.
    [12] 12. A method of claim 11, wherein the pharmaceutical composition is 10 administered to the mammal to treat ocular diseases, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, dry eye, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory 15 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's disease, Graves' disease, 20 inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, 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 25 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 30 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. 40 WO 2013/126428 PCT/US2013/026901
    [13] 13. The method of claim 12 wherein the mammal is a human. 41
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JP5218737B2|2006-02-06|2013-06-26|大正製薬株式会社|Sphingosine-1-phosphate binding inhibitor|
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    WO2015026914A1|2013-08-21|2015-02-26|Allergan, Inc.|Azetidine derivatives as sphingosine-1 phosphate receptors modulators|
    WO2015073547A1|2013-11-13|2015-05-21|Allergan, Inc.|Disubstituted phenoxy azetidine derivatives as sphingosine-1-phosphatereceptor modulators|
    WO2015073556A1|2013-11-13|2015-05-21|Allergan, Inc.|Disubstituted phenoxy derivatives as sphingosine-1-phosphatereceptor modulators|
    WO2015085174A1|2013-12-06|2015-06-11|Allergan, Inc.|Phenoxy derivatives as sphingosine 1-phosphatereceptor modulators|
    EP3466944A4|2016-05-23|2020-03-11|Institute of Materia Medica, Chinese Academy of Medical Sciences|Nicotinyl alcohol ether derivative, preparation method therefor, and pharmaceutical composition and uses thereof|
    WO2021047528A1|2019-09-09|2021-03-18|中国医学科学院药物研究所|Maleate of nicotinyl alcohol ether derivative, crystal form thereof, and application thereof|
    法律状态:
    2016-08-18| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|
    优先权:
    申请号 | 申请日 | 专利标题
    US201261601129P| true| 2012-02-21|2012-02-21||
    US61/601,129||2012-02-21||
    PCT/US2013/026901|WO2013126428A1|2012-02-21|2013-02-20|Phenoxy derivatives as sphingosine 1-phosphatereceptor modulators|
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