Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity

1. A compound of Formula IA, IB, or IC:

wherein W 1 , X 1 , Y 1 and Z 1 are independently O, CR a , CR a R b , N, NR c , or S;

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 )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 ; the alkyl groups of R 3 are optionally substituted with 1, or 2 hydroxyl 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;

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;

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;

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

n is 0, 1, 2, or 3; each represents an optional double bond; and q is 0, 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 ), 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 any of claim 1 , wherein R 2 has Formula III

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 each of X 1 , Y 1 and Z 1 is 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