S1P receptor modulating compounds and use thereof

1. A compound having the formula:

or pharmaceutically acceptable salts thereof;

wherein,

p and q are independently 0, 1, 2, 3 or 4;

Z is O, NR 2 , S, S(O), S(O) 2 , S(O) 2 NR 2 , (CR 3 R 4 ) n , C═O, C═S, or C═N—R 2 ;

n is 1, 2, 3 or 4;

R 1 is aryl or heteroaryl;

R 2 is hydrogen, hydroxyl, S(O) 2 , C═O, C═S, C═NH, C 1-6 alkyl, C 1-5 alkoxy, C 1-5 alkylthio, halo-substituted C 1-6 alkyl, halo-substituted C 1-5 alkoxy, aryl, or heteroaryl;

R 3 and R 4 are independently hydrogen, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-5 alkoxy, C 1-5 alkylthio, halo-substituted C 1-6 alkyl, halo-substituted C 1-5 alkoxy, aryl, or heteroaryl; or R 3 and R 4 , taken together, may form C═O;

X is WC(O)OR 5a , WP(O)R 5b R 5c , WS(O) 2 OH, WS(O) 2 NH 2 , WCONHSO 3 H or 1H-tetrazol-5-yl;

W is a direct bond, O, or C 1-4 alkylene optionally substituted with one or more of halo, hydroxyl, cyano, amino, alkylamino, aryl amino, heteroaryl amino group, C 1-4 alkoxy, or CO 2 H;

R 5a is hydrogen or C 1-4 alkyl;

R 5b and R 5c are independently hydrogen, hydroxyl, C 1-4 alkyl, or halo substituted C 1-4 alkyl;

Y is

Q is a direct bond, C═O, C═S, SO 2 , C(O)NR 9 , or (CR 9 R 10 ) m ;

m is 0 or 1;

R 6 and R 7 are independently hydrogen, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-5 alkylthio, C 1-5 alkoxy, halo-substituted C 1-6 alkyl or halo-substituted C 1-5 alkoxy; or R 6 and R 7 may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring, or R 6 is an alkylene group with the omega end of said alkylene group attached to ring A;

R 8 is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-5 alkylthio, C 1-5 alkoxy, halo-substituted C 1-6 alkyl, or halo-substituted C 1-5 alkoxy;

R 9 and R 10 are independently hydrogen, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-5 alkoxy, C 1-5 alkylthio, halo-substituted C 1-6 alkyl, halo-substituted C 1-5 alkoxy, or —CO 2 R 5a ;

A is aryl or heteroaryl, either of which may optionally be substituted with 1, 2, or 3 substituents selected from the group consisting of halo, hydroxyl, cyano, C 1-6 alkyl, C 1-5 alkylthio, C 1-5 alkoxy, halo-substituted C 1-6 alkyl, and halo-substituted C 1-5 alkoxy;

B has the formula:

in which, the asterisks indicate the point of attachment in formula I;

r is 1;

U is CH 2 , C(H)CH 3 , C(CH 3 ) 2 , C(H)(CF 3 ) or C(CF 3 ) 2 ; and

V is C(═O) or C(═S).

2. The compound of claim 1 , wherein Z is (CR 3 R 4 ) n .

3. The compound of claim 1 , wherein X is WC(O)OR 5a .

4. The compound of claim 1 , wherein Y is

Q is (CR 9 R 10 ) m , and

R 6 and R 7 are joined together with the atoms to which they are attached to form a 4- to 7-membered ring.

5. The compound of claim 1 , wherein Y is

Q is (CR 9 R 10 ) m , and R 6 and R 7 are joined together with the atoms to which they are attached to form a 4- to 7-membered ring.

6. The compound of claim 1 , wherein V is C(═O) and Z is (CR 3 R 4 ) n .

7. A compound having the formula II:

or a pharmaceutically acceptable salt thereof;

wherein,

A 1 is H, C 1-8 alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —OR 2 , —SR 2 , —S(O)R 2 , —S(O) 2 R 2 ; —C(O)R 2 , —CO 2 R 2 , or —C(R 3 ) 2 R 2 ;

, each of which may optionally be substituted with a halogen, trifluoromethyl, or alkoxy;

p and q represent independently 0, 1, 2, 3 or 4;

Z is (CR 3 R 4 ) n or C(O);

n is 1, 2, 3 or 4;

R 1a is H or C 1-6 alkyl;

R 2 is alkyl, aryl, heteroaryl, or aralkyl;

R 3 and R 4 represent independently for each occurrence hydrogen, halo, hydroxyl, C 1-6 alkyl, C 1-5 alkoxy, or aryl;

X is WC(O)OR 5 or WS(O) 2 NH 2 ;

R 5 is hydrogen or C 1-4 alkyl;

W is a direct bond, oxygen or C 1-4 alkylene;

Y is

Q is a direct bond, C═O or (CR 9 R 10 ) m ;

m is 1;

R 6 and R 7 each represent independently hydrogen, halo, hydroxyl, C 1-6 alkyl, or C 1-5 alkoxy; or R 6 and R 7 may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring;

R 8 is hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl, or C 1-5 alkoxy; and

R 9 and R 10 each independently represent hydrogen, halo, C 1-6 alkyl, or —CO 2 R 5 .

8. The compound of claim 7 , wherein A 2 is

A 3 is

and Y is

9. The compound of claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, succinate, tartarate, mesylate, sodium, potassium, magnesium, and calcium salts.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of

1-(4-(3-(4-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(4-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(3-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(2-oxo-3-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(4-benzylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(biphenyl-4-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(3-benzylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid, and 1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid, or pharmaceutically acceptable salts thereof.

11. A compound selected from the group consisting of

1-(4-(3-(3-benzoylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carbo-xylic acid;

1-(4-(2-oxo-3-(3-(1-phenylethyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(hydroxy(phenyl)methyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(difluoro(phenyl)methyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)-azetidine-3-carboxylic acid;

1-(4-(2-oxo-3-(3-phenoxyphenyl)imidazolidin-1-yl)benzyl)azetidine-3-carbo-xylic acid;

1-(4-(3-(3-(cyclobutylmethoxy)phenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(cyclopropylmethoxy)phenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;

1-(4-(3-(4-cyclohexylpyridin-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,

1-(4-(3-(5-cyclohexylpyridin-3-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(2-cyclohexylpyridin-4-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(2-oxo-3-(3-(phenylsulfonyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(2-oxo-3-(3-(phenylsulfinyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(2-oxo-3-(3-(phenylthio)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(2-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(3-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(4-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(4-cyclohexyloxazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexyl-1,2,4-thiadiazol-5-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-(cyclohexyloxymethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(5-methylbenzo[d]thiazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(4-cyclohexylfuran-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(4-cyclohexylthiazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)pyrrolidine-3-carboxylic acid;

2-amino-3-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)propanoic acid;

3-amino-1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)-3-hydroxyazetidine-3-carboxylic acid;

1-(4-((3-(2H-tetrazol-5-yl)azetidin-1-yl)methyl)phenyl)-3-(3-cyclohexylphenyl)imidazolidin-2-one;

3-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)propanoic acid;

4-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)butanoic acid;

3-((4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)(methyl)amino)propanoic acid;

4-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)-4-oxobutanoic acid;

2-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)succinic acid;

3-(6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid;

2-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)ethanesulfonamide;

1-((6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)methyl)-azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)pyridin-2-yl)methyl)-azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-methoxybenzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-2-fluorobenzyl)azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)thiazol-2-yl)methyl)azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzo[d]thiazol-2-yl)methyl)azetidine-3-carboxylic acid;

1-((6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;

1-((6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)oxazolo[5,4-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)furo[2,3-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;

1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzofuran-2-yl)methyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexyl-4-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-5-methyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-4-methyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-5,5-dimethyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;

1-(4-(3-(3-cyclohexylphenyl)-2-oxo-5-(trifluoromethyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid; and

1-(4-(3-(3-cyclohexylphenyl)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid; and pharmaceutically acceptable salts thereof.