SELECTIVE SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS AND COMBINATION THERAPY THEREWITH

1 . A method of treatment of a malcondition in a patient for which activation or agonism of an sphingosine-1-phosphate receptor subtype 1 is medically indicated, comprising administering to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient an effective amount of at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated, in combination with a compound having the structure of Formula I-R or I-S:

or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof

wherein

X is —NR′R″ or —OR″;

Y is —CN, —Cl, or —CF 3 ;

R′ is H, C 1-4 alkyl, n-hydroxy C 1-4 alkyl, —SO 2 —R 1 , or —CO—R 1 ;

R″ is H, —SO 2 —R 3 , C 1-4 alkyl optionally substituted with 1 or more R 2 , or a ring moiety optionally substituted with R 4 wherein such ring moiety is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl;

R′″ is H, C 1-4 alkyl, or —CO—R 1

or R′ and R″ taken together with the nitrogen atom to which they are bound form a 4, 5, or 6 membered saturated heterocyclic ring containing 0 or 1 additional heteroatoms where such additional heteroatom is O or N wherein such heterocycle is optionally singly or multiply substituted with substituents independently selected from the group consisting of —OH, oxo, —NH 2 , n-hydroxy-C 1-4 alkyl, —COOH, —(CH 2 ) m —COOH, —(CH 2 ) m —COOR 1 , —N(R 1 R 1 ), and —(CH 2 ) m —CO—N(R 5 R 5 );

each R 1 is independently C 1-4 alkyl or H;

each R 2 is independently H, halo, OH, oxo, ═NH, NH 2 , —COOH, F, —NHR 1 , —N(R 5 R 5 ), —SO 2 —R′, —SO 2 —N(R 5 R 5 ), —N(R′)—SO 2 —R′, —COOR′, —OCO—R′, —CO—N(R 5 R 5 ), —N(R′)—COR 1 , C 1-3 alkyl, C 1-3 alkoxy, and a ring moiety optionally substituted with R 4 wherein such ring moiety is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl;

each R 3 is independently R 2 , C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 alkyl optionally substituted with 1 or more R 2 ;

each R 4 is independently halo, OH, —NH 2 , —NHR 1 , —N(R 1 R 1 ), —COOH, —COOR 1 , —NHCO—R 1 , each R 5 is independently C 1-4 alkyl or H, or two R 5 taken together with the nitrogen atom to which they are bound form a 4, 5, or 6 membered saturated heterocyclic ring containing 0 or 1 additional heteroatoms where such additional heteroatom is O or N wherein such heterocycle is optionally substituted with —OH, —NH 2 , —N(R 1 R 1 ), n-hydroxy C 1-4 alkyl, —(CH 2 ) m —COOH, —(CH 2 ) m —COOR 1 ;

each m is independently 0, 1, 2, or 3.

2 . The method of claim 1 wherein the compound having the structure of Formula I-R or I-S is administered in combination with laquinimod or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 wherein the compound having the structure of Formula I-R or I-S is administered in combination with dimethyl fumarate or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 where the compound having the structure of Formula I-R or I-S is administered im the same dosage form with laquinimod or dimethyl fumarate or a pharmaceutically acceptable salt thereof.

5 . The method of claim 1 where the compound having the structure of Formula I-R or I-S is administered in separate dosage forms with laquinimod or dimethyl fumarate or a pharmaceutically acceptable salt thereof.

6 . The method of claim 1 where the compound having the structure of Formula I-R or I-S is administered sequentially with laquinimod or dimethyl fumarate or a pharmaceutically acceptable salt thereof.

7 . The method of claim 1 where the compound having the structure of Formula I-R or I-S is administered non-sequentially with laquinimod or dimethyl fumarate or a pharmaceutically acceptable salt thereof.

8 . The method of claim 1 where the compound having the structure of Formula I-R or I-S is administered with laquinimod or dimethyl fumarate or a pharmaceutically acceptable salt thereof in oral dosage form.

9 . The method of claim 1 wherein the compound has the structure of Formula I-R or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

10 . The method of claim 1 wherein the compound has the structure of Formula I-S or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

11 . The method of claim 1 wherein the compound is substantially enantiomerically pure.

12 - 33 . (canceled)

34 . The method of claim 1 wherein the compound is selected from compounds 1-252:

or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

35 . The method of claim 34 selected from the group consisting of compounds 50, 86 and 139:

or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

36 . The method of claim 34 selected from the group consisting of compounds 163 and, 186:

or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

37 . The method of claim 34 selected from the group consisting of compounds 211, 234, and 241:

or a pharmaceutically acceptable salt, ester, prodrug, homolog, hydrate or solvate thereof.

38 . The method of claim 1 wherein the malcondition comprises multiple sclerosis, transplant rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome.

39 . The method of claim 1 wherein the malcondition is multiple sclerosis.

40 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is laquinimod.

41 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is dimethyl fumarate.

42 . The method of claim 1 wherein the at least one medicament adapted for treat treatment ement of a malcondition for which activation of S1P 1 is medically indicated is fingolimod.

43 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is glatiramer acetate.

44 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is daclizumab.

45 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is alemtuzumab.

46 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is natalizumab.

47 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is rituximab.

48 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is teriflunomide.

49 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is ocrelizumab.

50 . The method of claim 1 wherein the at least one medicament adapted for treatment of a malcondition for which activation of S1P 1 is medically indicated is beta interferon.