Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity

A compound of Formula XVII:

• wherein:
• SEM represents a selectivity enhancing moiety;
• rings B, C, D are independently selected from the group consisting of substituted or unsubstituted carbocyclic rings and substituted or unsubstituted heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated;
• B1, B2, B3, C1, C2, C3, D1, D2, and D3 are each independently selected from the group consisting of hydrogen, halogen, cyano, straight chain or branched aliphatic, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, carboxy-alkyl, alkyl-SO2 alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OH, —C(O)-alkyl, —C(O)-halo-alkyl, —C(O)O-alkyl, —C(O)O-halo-alkyl, —CONH2, —CONH-alkyl, —CON-dialkyl, —CONH-halo-alkyl, —CON-halo-dialkyl, -alkyl-CONH-alkyl, -alkyl-CON-dialkyl, halo-alkyl-CONH- alkyl, halo-alkyl-CONH-halo-alkyl, alkyl-CONH-halo-dialkyl, -alkyl-hydroxyl, -alkyl-hydroxyl-alkyl, -halo-alkyl-hydroxyl-alkyl, -alkyl-hydroxyl-halo-alkyl, -halo-alkyl-hydroxyl-halo-alkyl, substituted or unsubstituted alkyl-OR14, substituted or unsubstituted haloalkyl-OR4, —OR14, and N(R)R′;
• or taken together RZ and B3 may form a substituted or unsubstituted carbocyclic ring or substituted or unsubstituted heterocyclic ring, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or taken together C2 and D2 may form a substituted or unsubstituted carbocyclic ring or substituted or unsubstituted heterocyclic ring, which may contain one or more heteroatoms and may be saturated or unsaturated;
• R and R′ are each independently selected from the group consisting of hydrogen, cyano, straight chain or branched alkyl, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, and carboxy-alkyl;
• or taken together R and R′ may form a substituted or unsubstituted carbocyclic ring or substituted or unsubstituted or heterocyclic ring, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or taken together with the N to which they are attached R and R′ may form a moiety selected from the group consisting of substituted straight chain or cyclic guanyl, straight chain or cyclic guanidine, straight chain or cyclic urea, straight chain or cyclic thiourea, straight chain or cyclic carbamate, and straight chain or cyclic thiocarbamate;
• Z is independently selected from the group consisting of C or N;
• R′ is a phosphate derivative, a phosphate mimic or a phosphate precursor;
• R2 and R3 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, straight chain or branched alkyl, alkyl-OR9, halo-alkyl-OR9, alkoxy-OR9, alkyl-OC(O)R9, halo-alkyl-OC(O)R9, alkoxy-OC(O)R9, carbocyclic rings, heterocyclic rings which may contain one or more heteroatoms, alkyl-NR9R10, halo-alkyl-NR9R10, and alkoxy-NR9R10, all of which may be optionally substituted with OH, halogen, NHR9, NR9R10, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, or carboxy-alkyl;
• or taken together R2 and R3 may form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or taken together R2 and RZ may form a substituted or unsubstituted C4-C10 fused carbocyclic ring or substituted or unsubstituted C4-C10 fused heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated;
• R9 and R10 are independently selected from the group consisting of hydrogen, halogen, cyano, straight chain or branched alkyl, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain and branched halo-alkoxy, —C(O)alkyl, —C(O)NH-alkyl, —C(O)N-dialkyl, —C(O)aryl, —C(O)NH-aryl, —C(O)N-alkyl-aryl, —C(O)N-diaryl, —C(O)heteroaryl, —C(O)NH-heteroaryl, —C(O)N-carbocycle, substituted or unsubstituted carbocyclic rings, and substituted or unsubstituted heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or taken together R9 and R10 may form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, which may contain one or more heteroatoms and may be saturated or unsaturated;
• Y is independently selected from the group consisting of (CR11R12)n and (CR11R12)nNR13;
• R11, R12, and R13 are independently selected from the group consisting of hydrogen, halogen, cyano, and straight chain or branched alkyl, all of which may be optionally substituted with OH, halogen, straight chain or branched alkoxy, straight chain or branched halo-alkyl, and straight chain and branched halo-alkoxy;
• or R13 may form a 3-8-membered ring together with either R11 or R12 and the atom to which they are attached;
• n is an integer from 0 to 3;
• X is selected from the group consisting of
• wherein each m is independently selected from an integer between 0 and 6;
• each p is independently selected from 0 or 1;
• each X1 is independently selected from the group consisting of CR14R15, NR14, S, and O, —S(O), —S(O)2, —OS(O)2, —OS(O)2O—, —C(O), C(OH), —C(O)O—, a substituted or unsubstituted aromatic, a substituted or unsubstituted heteroaromatic, and any combination thereof, in any orientation;
• each Ra and Rb are independently selected from the group consisting of hydrogen, cyano, halogen, alkyl, halo-alkyl, —OH, —CO—, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, -alkyl-hydroxyl, -alkyl-hydroxyl-alkyl, -halo-alkyl-hydroxyl-alkyl, -alkyl-hydroxyl-halo-alkyl, -halo-alkyl-hydroxyl-halo-alkyl, carboxy-alkyl, alkyl-SO2, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, all of which may be optionally substituted with OH, halogen, e.g., fluoro, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain and branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, carboxy-alkyl, substituted or unsubstituted carbocyclic rings, and substituted or unsubstituted heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or each Ra and Rb may form a 3-10-membered ring together with the carbon to which they are both attached;
• each R1a and R2a are independently selected from the group consisting of hydrogen, cyano, halogen, alkyl, halo-alkyl, —OH, —CO—, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, -alkyl-hydroxyl, -alkyl-hydroxyl-alkyl, -halo-alkyl-hydroxyl-alkyl, -alkyl-hydroxyl-halo-alkyl, -halo-alkyl-hydroxyl-halo-alkyl, carboxy-alkyl, alkyl-SO2, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, all of which may be optionally substituted with OH, halogen, e.g., fluoro, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain and branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, carboxy-alkyl, substituted or unsubstituted carbocyclic rings, and substituted or unsubstituted heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated;
• or each Ria and R2a may form a 3-10-membered ring together with the carbon to which they are both attached;
• each R14 and R15 is independently selected from the group consisting of hydrogen, halogen, cyano, straight chain or branched alkyl, straight chain or branched alkoxy, straight chain or branched halo-alkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, alkyl-SO2, and carboxy-alkyl;
• or each R14 or R15 may form a 3-8-membered ring together with B1, Ra, Rb, R1a, or R2a and the atoms to which they are attached;
• and
• RZ selected from the group consisting of hydrogen, cyano, straight chain or branched alkyl, cycloalkyl, straight chain or branched alkoxy, straight chain or branched halo-alkyl, halo-cycloalkyl, straight chain or branched halo-alkoxy, alkoxy-alkyl, hydroxyl-alkyl, alkyl-SO2, and carboxy-alkyl;
• or RZ may form a 3-8-membered ring together with B1, R2 or R3 and the atoms to which they are attached.