Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity

1. A compound of Formula IA or IB:

wherein

X 1 and Y 1 are independently, CR a or CR a R b ;

R 1 and R 2 are independently hydrogen, halo, halo(C 1 -C 10 )alkyl, cyano, —NR a R b , (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkoxy, (C 2 -C 26 )alkoxyalkyl, (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 30 )arylalkyl, (C 2 -C 10 )heterocyclic, (C 4 -C 10 )heteroaryl, or (C 4 -C 10 )heteroaryl(C 1 -C 20 )alkyl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R 1 and R 2 independently are optionally perfluorinated or optionally substituted with 1, 2, 3, or 4 groups where the substituent groups are independently hydroxy, halo, cyano, (C 1 -C 10 )alkoxy, C 6 -aryl, (C 7 -C 24 )arylalkyl, oxo (═O), or imino (═NR d ), wherein one or more of the carbon atoms in the R 1 or R 2 alkyl groups can be independently replaced with non-peroxide oxygen, sulfur or NR c ; and the alkyl groups of R 3 are optionally substituted with 1, or 2 hydroxy groups; or

R 2 can be a group having formula II, III, IV, V, or VI;

wherein each R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently O, S, C, CR 15 , CR 16 R 17 , C═O, N or NR 18 ;

each R 15 , R 16 and R 17 is independently hydrogen, halo, (C 1 -C 10 )alkyl, (C 6 -C 10 )aryl, (C 1 -C 10 )alkyl substituted with halo, hydroxy, (C 1 -C 10 )alkoxy, or cyano; and where R 18 can be hydrogen or (C 1 -C 10 )alkyl;

where Z 2 is hydrogen, halo, halo(C 1 -C 10 )alkyl, cyano, —NR a R b , (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkoxy, (C 2 -C 26 )alkoxyalkyl, (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 30 )arylalkyl, (C 2 -C 10 )heterocyclic, (C 4 -C 10 )heteroaryl, or (C 4 -C 10 )heteroaryl(C 1 -C 20 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of Z 2 are optionally perfluorinated or optionally substituted with 1, 2, 3, or 4 groups where the substituent groups are independently hydroxy, halo, cyano, (C 1 -C 10 )alkoxy, C 6 -aryl, (C 7 -C 24 )arylalkyl, oxo (═O), or imino (═NR d ), wherein one or more of the carbon atoms in the Z 2 alkyl groups can be independently replaced with non-peroxide oxygen, sulfur or NR c ;

indicates one or more optional double bonds;

wherein Y 2 is a bond, O, S, C═O, or NR c , CH 2 ; W 1 is a bond, —CH 2 — and m is 1, 2, or 3, or W 1 is (C═O)(CH 2 ) 1-5 and m is 1; wherein W 1 is optionally interrupted with non-peroxide O, S, C═O, or NR c ;

n is 0, 1, 2, or 3; represents an optional double bond;

q is 1, 2, or 3;

R 3 is hydrogen, (C 1 -C 10 )alkyl, hydroxy(C 1 -C 10 )alkyl or (C 1 -C 10 )alkoxy; and

R 4 is hydroxyl (—OH), phosphate (—OPO 3 H 2 ), phosphonate (—CH 2 PO 3 H 2 ), or alpha-substituted phosphonate;

each R a , R b , R c , and R d is independently hydrogen, CF 3 or (C 1 -C 10 )alkyl; or a pharmaceutically acceptable salt or ester thereof.

2. The compound of claim 1 , wherein R 1 is hydrogen, fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl substituted with, alkoxy or cyano, alkyl-substituted aryl, aryl-substituted alkyl, or aryl-substituted arylalkyl.

3. The compound of claim 2 , wherein R 1 is hydrogen, trifluoro-methyl, or —CH 2 CF 3 .

4. The compound of claim 2 , wherein R 1 is benzyl, phenylethyl, or benzyl substituted with methyl.

5. The compound of claim 1 , wherein R 2 is

6. The compound of claim 1 , wherein R 2 is:

wherein Z 2 is (CH 3 ) 3 C—, CH 3 CH 2 (CH 3 ) 2 C—, CH 3 CH 2 CH 2 —, CH 3 (CH 2 ) 2 CH 2 —, CH 3 (CH 2 ) 4 —CH 2 —, (CH 3 ) 2 CHCH 2 —, (CH 3 ) 3 CCH 2 —, CH 3 CH 2 O—, (CH 3 ) 2 CHO—, or CF 3 CH 2 CH 2 — or a group having the formula:

7. The compound of claim 6 , wherein R 2 is:

8. The compound of claim 6 , wherein R 2 is:

9. The compound of claim 8 , wherein R 2 is

10. The compound of claim 1 , wherein R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, or octoxy.

11. The compound of claim 1 , wherein X 1 and Y 1 are both CH 2 .

12. The compound of claim 1 , wherein R 3 is hydrogen, methyl, hydroxymethyl, ethyl, or hydroxyethyl.

13. The compound of claim 1 , having the formula

14. A method for 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 claim 1 wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, or altering of lymphocyte trafficking.

15. The method of claim 14 , wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, or multiple sclerosis.

16. The method of claim 15 , wherein the pathological condition or symptom is multiple sclerosis.

17. The method of claim 14 , wherein the pathological condition or symptom is altering of lymphocyte trafficking.

18. The method of claim 17 , wherein altering lymphocyte .trafficking provides prolonged allograft survival.

19. A method for treatment of a pathological condition or symptom in a mammal, wherein the activity S1P lyase is implicated and inhibition of the S1P lyase is desired, comprising administering to said mammal an effective amount of a compound of claim 1 wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, or altering of lymphocyte trafficking.