Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis

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, an effective amount of a compound having the structure of Formula I-R or I-S or a pharmaceutically acceptable salt, ester, 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;

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 );

R′″ is H, C 1-4 alkyl, or —CO—R 1 ;

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 1 , —SO 2 —N(R 5 R 5 ), —N(R 1 )—SO 2 —R 1 , —COOR 1 , —OCO—R 1 , —CO—N(R 5 R 5 ), —N(R 1 )—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 ; and

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

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

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

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

5. The method of claim 1 wherein Y is Cl.

6. The method of claim 1 wherein Y is CF 3 .

7. The method of claim 1 wherein Y is CN.

8. The method of claim 1 wherein X is —NR′R″.

9. The method of claim 1 wherein X is —OR′″.

10. The method of claim 9 wherein X is —OH.

11. The method of claim 9 wherein X is —OCO—R 1 .

12. The method of claim 11 wherein R 1 is C 1-3 alkyl.

13. The method of claim 8 wherein R′ is H.

14. The method of claim 8 wherein R′ is —COR 1 .

15. The method of claim 8 wherein R′ is —SO 2 —R 1 .

16. The method of claim 8 wherein R″ is H.

17. The method of claim 8 wherein R″ is —SO 2 —R 3 .

18. The method of claim 8 wherein R″ is C 1-4 alkyl optionally substituted with 1 or more R 2 .

19. The method of claim 8 wherein R″ is —(CR a R b ) n —R 2 ; each R a and each R b is independently selected from the group consisting of H, hydroxyl and methyl or R a and R b bound to the same carbon taken together are oxo; and n is 0, 1, 2, or 3.

20. The method of claim 19 wherein n is 2.

21. The method of claim 20 wherein R 2 is —OH, —NH 2 , —NHR 1 , —N(R 5 R 5 ), or —COOH.

22. The method of claim 17 wherein R 3 is C 1-4 alkyl optionally substituted with 1 or more R 2 .

23. The method of claim 17 wherein Y is CN.

24. The method of claim 22 wherein R 3 is —C 2 H 5 —N((R 5 R 5 ) or —CH 2 —CO—N(R 5 R 5 ).

25. The method of claim 23 wherein R 3 is C 2 H 5 —O—R 1 .

26. The method of claim 7 wherein X is —NH—CO—N(R 5 R 5 ).

27. The method of claim 1 wherein the compound is selected from the group consisting of:

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

28. The method of claim 27 wherein the compound is selected from the group consisting of:

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

29. The method of claim 1 wherein the compound is administered to the patient in the form of a pharmaceutical composition comprising the compound and a suitable excipient.

30. The method of claim 1 wherein the compound is administered to the patient in the form of a pharmaceutical combination comprising the compound and a second medicament.

31. The method of claim 30 wherein the second medicament is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome.

32. 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 a compound having the structure of Formula I-R or I-S or a pharmaceutically acceptable salt, ester, 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,

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 );

R′″ is H, C 1-4 alkyl, or —CO—R 1 ;

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 1 , —SO 2 —N(R 5 R 5 ), —N(R 1 )—SO 2 —R 1 , —COOR 1 , —OCO—R 1 , —CO—N(R 5 R 5 ), —N(R 1 )—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 ; and

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

33. The method of claim 32 wherein the compound activates or agonizes the sphingosine-1-phosphate receptor subtype 1 to a greater extent than the compound activates or agonizes a sphingosine-1-phosphate receptor subtype 3.

34. The method of claim 32 wherein the sphingosine-1-phosphate receptor subtype 1 is disposed within a living mammal.

35. The method of claim 1 wherein selective activation or agonism of an S1P subtype 1 receptor with respect to other subtypes of S1P receptor is medically indicated.

36. 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.