Heterobicyclic sphingosine 1-phosphate analogs

A method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired, comprising administering to said mammal an effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• A1 is —C(X1)═;
• A2 is —C(X2)═;
• A3 is —C(X3)(X3)—;
• A4 is C(X4)(X4′)—;
• A5 is C(X5)(X5)—;
• A6 is —C(X6)═;
• X1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X3′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X4′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X5′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• X6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
• Y is —ORf, —(CRfRg)ORf, —(CRfRg)2ORf, —O—P(O)(ORf)ORg, —OC(O)Rc, —C(O)ORc, —(CRfRg)—P(O)(ORf)ORg, —(C(OH)Rf)—P(O)(ORf)ORg, —S—P(O)(ORf)ORg, tetrazole, —SO2NHRf, —SO3, —CONHRf, —Si(OH)2, or —B(OH)2;
• W is —CRfRg—, —O—, —S—, —SO—, or —SO2—;
• Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
• wherein Cy is optionally substituted by 1-6 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, haloalkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl;
• L1 is —CH2—, —CHF—, or —CF2—;
• Z4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —ORf;
• or Z4 is —CH2— bound to the carbon atom to which Y is bound;
• or L1, Z4, Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
• Ra is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
• wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
• Rb is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
• wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
• or Rb and Z4 are taken to together to form —C(O)O— or ═C(Rf)O—;
• Rc is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCORc is a good leaving group;
• each Rf, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
• wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
• and
• each Rg, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
• wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl.