Tetralin analogs having sphingosine 1-phosphate agonist activity

A compound of Formula I:

• wherein
• X1, Y1 and Z1 are independently O, CRa, CRaRb, N, NRc, or S;
• R1 and R2 are independently hydrogen, halo, halo(C1-C10)alkyl, cyano, —NRaRb, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C1-C20)alkoxy, (C2-C26)alkoxyalkyl, (C3-C12)cycloalkyl, (C6-C10)aryl, (C7-C30)arylalkyl, (C2-C10)heterocyclic, (C4-C10)heteroaryl, or (C4-C10)heteroaryl(C1-C20)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R1 and R2 independently are optionally perfluorinated or optionally substituted with 1, 2, 3, or 4 groups where the substituent groups are independently hydroxy, halo, cyano, (C1-C10)alkoxy, C6-aryl, (C7-C24)arylalkyl, oxo (═O), or imino (═NRd), wherein one or more of the carbon atoms in the R1 or R2 alkyl groups can be independently replaced with non-peroxide oxygen, sulfur or NRc;
• the alkyl groups of R3 are optionally substituted with 1, or 2 hydroxy groups;
• or
• R2 can be a group having formula II, III, IV, V, or VI;
• wherein each R7, R8, R9, R10, R11, R12, R13, and R14 is independently O, S, C, CR15, CR16R17, C═O, N or NR18;
• each R15, R16 and R17 is independently hydrogen, halo, (C1-C10)alkyl, (C6-C10)aryl, (C1-C10)alkyl substituted with halo, hydroxy, (C1-C10)alkoxy, or cyano;
• and where R18 can be hydrogen or (C1-C10)alkyl;
• wherein Z2 is hydrogen, halo, halo(C1-C10)alkyl, cyano, —NRaRb, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C1-C20)alkoxy, (C2-C26)alkoxyalkyl, (C3-C12)cycloalkyl, (C6-C10)aryl, (C7-C30)arylalkyl, (C2-C10)heterocyclic, (C4-C10)heteroaryl, or (C4-C10)heteroaryl(C1-C20)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of Z2 are optionally perfluorinated or optionally substituted with 1, 2, 3, or 4 groups where the substituent groups are independently hydroxy, halo, cyano, (C1-C10)alkoxy, C6-aryl, (C7-C24)arylalkyl, oxo (═O), or imino (═NRd), wherein one or more of the carbon atoms in the Z2 alkyl groups can be independently replaced with non-peroxide oxygen, sulfur or NRc;
• indicates one or more optional double bonds;
• wherein Y2 is a bond, O, S, C═O, or NRc, CH2;
• W1 is a bond, —CH2— and m is 1, 2, or 3, or W1 is (C═O)(CH2)1-5 and m is 1;
• wherein W1 is optionally interrupted with non-peroxide O, S, C═O, or NRc;
• n is 0, 1, 2, or 3;
• one represents an optional double bond;
• R3 is hydrogen, (C1-C10)alkyl, hydroxy(C1-C10)alkyl or (C1-C10)alkoxy;
• and
• R4 is hydroxyl (—OH), phosphate (—OPO3H2), phosphonate (—CH2PO3H2), or alpha-substituted phosphonate;
• each Ra, Rb, Rc, and Rd is independently hydrogen, CF3 or (C1-C10)alkyl;
• or
• a pharmaceutically acceptable salt or ester thereof.