Selective heterocyclic sphingosine 1 phosphate receptor modulators

1. A compound of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof:

wherein

a dashed line signifies that a single bond or a double bond can be present, provided that there are two double bonds and three single bonds in the ring comprising A 1 , A 2 , and A 3 ;

A 1 , A 2 , and A 3 each independently is CH or S or N; provided that one of A 1 , A 2 , and A 3 is S;

R 1 is di-substituted phenyl or di-substituted pyridinyl where the phenyl and pyridinyl substituents are each independently selected from the group consisting of halo, nitro, cyano, perfluromethyl, fluorinated methyl, and C 1-4 -alkoxy; provided that if R 1 is di-substituted phenyl, such phenyl is para-substituted with C 1-4 -alkoxy;

R 2 is

wherein a wavy line indicates a point of attachment;

X is —NR′R″ or —OR′″;

R′ is H, C 1-4 alkyl, n-hydroxy C 1-4 alkyl, —SO 2 —R 3 , or —CO—R 3 ;

R″ is H, —SO 2 —R 5 , C 1-4 alkyl optionally substituted with 1 or more R 4 , or a ring moiety optionally substituted with R 6 wherein such ring moiety is pyridinyl, oxazolyl, piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl;

R′″ is H, C 1-4 alkyl, or —CO-R 3

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 3 , —N(R 3 R 3 ), and —(CH 2 ) m —CO—N(R 7 R 7 );

each R 3 is independently C 1-4 alkyl or H;

each R 4 is independently H, halo, OH, oxo, ═NH, NH 2 , —COOH, F, —NHR 3 , —N(R 7 R 7 ), —SO 2 —R 3 , —SO 2 —N(R 7 R 7 ), —N(R 3 )—SO 2 —R 3 , —COOR 3 , —OCO—R 3 , —CO—N(R 7 R 7 ), —N(R 3 )—COR 3 , C 1-3 alkyl, C 1-3 alkoxy, and a ring moiety optionally substituted with R 6 wherein such ring moiety is pyridinyl, oxazolyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl;

each R 5 is independently R 4 , C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 alkyl optionally substituted with 1 or more R 4 ;

each R 6 is independently halo, OH, —NH 2 , —NHR 3 , —N(R 3 R 3 ), —COOH, —COOR 3 , —NHCO—R 3 ; each R 7 is independently C 1-4 alkyl or H, or two R 7 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 3 R 3 ), n-hydroxy C 1-4 alkyl, —(CH 2 ) m —COOH, —(CH 2 ) m —COOR 3 ;

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

2. The compound of claim 1 wherein the structure of Formula I is selected from the group consisting of formulas a-i through a-x:

3. The compound of claim 1 wherein A 1 is S.

4. The compound of claim 1 wherein A 2 is S.

5. The compound of claim 1 wherein A 3 is S.

6. The compound of claim 5 wherein A 1 is N and A 2 is CH or N.

7. The compound of claim 6 wherein A 2 is CH.

8. The compound of claim 6 wherein A 2 is N.

9. The compound of claim 1 wherein R 1 is

R 3 is C 2-4 alkyl; and Y is —CN, —Cl, —O—R 3 , or —CF 3 .

10. The compound of claim 9 wherein R 3 is isopropyl or ethyl.

11. The compound of claim 9 wherein Y is —CN or —O—C 2 H 5 .

12. The compound of claim 1 wherein R 2 is

13. The compound of claim 1 wherein R 2 is

14. The compound of claim 12 wherein R 2 is

15. The compound of claim 13 wherein R 2 is

16. The compound of claim 14 wherein R 2 is

17. The compound of claim 14 wherein R 2 is

18. The compound of claim 15 wherein R 2 is

19. The compound of claim 15 wherein R 2 is

20. The compound of claim 13 having the following formula:

wherein

A 2 is CH or N;

R m is H, —SO 2 —R 5 , or C 1-4 alkyl optionally substituted with 1 or more R 4 ;

each R 4 is independently H, OH, oxo, NH 2 , —COOH, SO 2 —R 3 , —N(R 3 )—SO 2 —R 3 , —COOR 3 , —CO—N(R 7 R 7 ), N(R 7 R 7 ), C 1-3 alkyl, C 1-3 alkoxy; or a ring moiety selected from pyridinyl, oxazolyl, pyrrolidinyl, or imidazolyl.

21. The compound of claim 20 having the following formula:

22. The compound of claim 20 having the following formula:

23. A compound selected from the group consisting of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof.

24. A compound selected from the group consisting of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof.

25. A compound selected from the group consisting of:

or any pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof.

26. A compound selected from the group consisting of:

or any pharmaceutically acceptable salt, ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvate thereof.

27. A pharmaceutical composition comprising a compound of claim 1 and a suitable excipient.

28. A method of activation or agonism of a sphingosine-1-phosphate receptor subtype 1 comprising contacting the receptor subtype 1 with an effective amount of the compound of claim 1 .

29. A method of treatment of a malcondition in a patient having said malcondition, comprising administering an effective amount of the compound of claim 1 to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient, wherein the malcondition is multiple sclerosis, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome.

30. A compound selected from the group consisting of:

31. A method of treatment of a malcondition in a patient, comprising administering an effective amount of the compound of claim 1 to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient, wherein the malcondition is transplant rejection.