S1p receptor modulating compounds and use thereof   

This application is a divisional application of copending U.S. Ser. No. 11/726,351, filed Mar. 21, 2007, which is a continuation-in-part of U.S. Ser. No. 11/491,766, filed Jul. 24, 2006, now U.S. Pat. No. 7,855,193, which claims priority to U.S. Ser. No. 60/739,466, filed Nov. 23, 2005, U.S. Ser. No. 60/753,806, filed Dec. 22, 2005, and U.S. Ser. No. 60/784,549, filed Mar. 21, 2006, and this application also claims the benefit of priority under 35 U.S.C. 119(e) to copending U.S. Provisional Application No. 60/784,549, filed on Mar. 21, 2006, the entire contents of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity.

BACKGROUND OF THE INVENTION

Sphingosine-1-phosphate (S1P) has been demonstrated to induce many cellular effects, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and endothelial cell in vitro angiogenesis. S1P receptors are therefore good targets for therapeutic applications such as wound healing and tumor growth inhibition. S1P signals cells in part via a set of G protein-coupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly called EDG-1, EDG-5, EDG-3, EDG-6, and EDG-8, respectively). These receptors share 50-55% amino acid and cluster identity with three other receptors (LPA1, LPA2, and LPA3 (formerly EDG-2, EDG-4 and EDG-7) for the structurally-related lysophosphatidic acid (LPA).

A conformational shift is induced in the G-Protein Coupled Receptor (GPCR) when the ligand binds to that receptor, causing GDP to be replaced by GTP on the α-subunit of the associated G-proteins and subsequent release of the G-proteins into the cytoplasm. The α-subunit then dissociates from the βγ-subunit, and each subunit can then associate with effector proteins, which activate second messengers leading to a cellular response. Eventually the GTP on the G-proteins is hydrolyzed to GDP, and the subunits of the G-proteins re-associate with each other and then with the receptor. Amplification plays a major role in the general GPCR pathway. The binding of one ligand to one receptor leads to the activation of many G-proteins, each capable of associating with many effector proteins, leading to an amplified cellular response.

S1P receptors make good drug targets, because individual receptors are both tissue- and response-specific. Tissue specificity of the S1P receptors is important, because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the S1P receptors is also important because it allows for development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other things. For example, the response specificity of the S1P receptors could allow for an S1P mimetic that initiates platelet aggregation without affecting cell morphology.

S1P is formed as a metabolite of sphingosine in its reaction with sphingosine kinase, and is abundantly stored in platelet aggregates where high levels of sphingosine kinase exist and sphingosine lyase is lacking. S1P is released during platelet aggregation, accumulates in serum and is also found in malignant ascites. S1P biodegradation most likely proceeds via hydrolysis by ectophosphohydrolases, specifically the sphingosine 1-phosphate phosphohydrolases.

SUMMARY

The present invention relates to the use of new compositions which include S1P modulators, e.g., agonists, partial agonists, inverse agonists and antagonists, and their use in treating, preventing or curing various S1P receptor-related conditions. The invention features compounds which are S1P receptor modulators; in an embodiment, such compounds include those having the formula

and pharmaceutically acceptable salts thereof, wherein R1, Z2, C, B, A, Z1, Y and X are defined herein.

DETAILED DESCRIPTION

In one embodiment, the present invention relates to compounds of formula I.

In formula I, A may be an aryl or heteroaryl group, optionally substituted with one, two or three substituents which may include halogen, hydroxyl, SR2, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino/arylamino/heteroarylamino, C1-6alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy. Optionally two adjacent substituents of A may, taken with Z1 and the ring A to which they are attached, form a fused ring that may optionally contain one or more hetero atoms. R2 may be selected independently from hydrogen, hydroxyl, amino, alkylamino/arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or aryl/heteroaryl. A may desirably be a C5-6 cyclic ring (alicyclic or aromatic) optionally having one or more heteroatoms.

B and C are an at least partially aromatic bicyclic ring system, e.g., bicycloaryl, bicycloheteroaryl, dihydrobicyclic or tetrahydrobicyclic aryl and heteroaryl. The bicyclic ring system may be substituted with 1 to 5 substituents, e.g., C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy.

Z1 and Z2 may be independently selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S, C═N—R3, or a direct bond. R3 may be hydrogen, hydroxyl, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl. R4 and R5 may independently be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen substituted C1-5 alkoxy; aryl or heteroaryl or together form “C═O”; n may be 0, 1, 2 or 3. In an embodiment where Z2 is a direct bond, R3 may be a C3-C6 ring optionally containing a heteroatom.

R1 may be C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl or heteroaryl. R1 may optionally be substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, heteroarylamino groups, and the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents, e.g., hydroxyl, halogen, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, C3-6 cycloalkyl.

X may be WC(O)OR6a, WP(O)R6bR6c, WS(O)2OH, WCONHSO3H or 1H-tetrazol-5-yl. W may be a direct bond, oxygen or C1-4 alkyl with substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C1-4 alkoxy and; R6a may be hydrogen or C1-4alkyl; R6b and R6c may be hydrogen, hydroxyl, C1-4alkyl or halogen substituted C1-4alkyl.

Y may be a residue of formula (a) where the left and right asterisks indicate the point of attachment:

wherein Q may be a direct bond, C═O, C═S, SO2, C═ONR or (CR10R11)m; m may be 0, 1, 2 or 3; R7 and R8 may be independently hydrogen, halogen, amino, C1-5 alkylamino, hydroxyl, cyano, C1-6 alkyl, C1-6 hydroxyalkyl (e.g., hydroxy-terminated alkyl), C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or R7 and R8 may be joined together with the atoms to which they are attached to form a 4 to 7-membered ring, optionally having a hetero atom. R9 may be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy; R10 and R11 may individually be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy.

In another embodiment, the invention includes compounds having the formula

and pharmaceutically acceptable salts thereof. In formula I, A may be a C1-6 cyclic ring (alicyclic or aromatic) that may have one or more heteroatoms. Where A is an aryl or heteroaryl group, A may be optionally substituted with one, two or three substituents which may include halogen, hydroxyl, S, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino/arylamino/heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy. Optionally two adjacent substituents may, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring, e.g. piperidinyl. R2 may be hydrogen, hydroxyl, amino, alkylamino/arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or aryl/heteroaryl.

B and C are an at least partially aromatic bicyclic ring system, e.g., bicycloaryl, bicycloheteroaryl, dihydrobicyclic or tetrahydrobicyclic aryl and heteroaryl. The bicyclic ring system may be substituted with 1 to 5 substituents, e.g., C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy; Z1 and Z2 may be independently selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S, C═N—R3, or a direct bond. R3 may be hydrogen, hydroxyl, S(O)2, C═O, C═S, C═NH, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl. R4 and R5 may independently be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl or together form “C═O”; n may be 0, 1, 2 or 3. R1 may be C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl or heteroaryl. R1 may optionally be substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, heteroarylamino groups, and the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents, e.g., hydroxyl, halogen, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, C3-6 cycloalkyl.

X may be WC(O)OR6a, WP(O)R6bR6c, WS(O)2OH, WCONHSO3H or 1H-tetrazol-5-yl. W may be a direct bond, oxygen or C1-4 alkyl with substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C1-4 alkoxy and COO2H; R4a may be hydrogen or C1-4alkyl; R6b and R6c may be hydrogen, hydroxyl, C1-4alkyl or halogen substituted C1-4alkyl. Y has the formula:

wherein Q may be a direct bond, C═O, C═S, SO2, C═ONR or (CR10R11)m; m may be 0, 1, 2 or 3, and R7-R8 may be hydrogen, halogen, amino, C1-5 alkylamino, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or R7 and R8 may be joined together with the atoms to which they are attached to form a 4 to 7 member ring. R9 may be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy; R10 and R11 may individually be hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy.

In another embodiment, the present invention relates to a compound having the formula

wherein

A is an optionally substituted aryl or heteroaryl group;

B and C are an at least partially aromatic bicyclic ring system;

X is selected from the group consisting of WC(O)OR6a, WP(O)R6bR6c, WS(O)2OH, WCONHSO3H or 1H-tetrazol-5-yl; where W is a direct bond, oxygen or C1-4 alkyl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C1-4 alkoxy and COO2H; R6a is hydrogen or C1-4alkyl; and R6b and R6c are independently hydrogen, hydroxyl, C1-4alkyl or halogen substituted C1-4alkyl;

Y is residue of formula (a) where the left and right asterisks indicate the point of attachment

wherein

Q is selected from C═O, C═S, SO2, C═ONR and (CR10R11)m;

m is 0, 1, 2 or 3;

R7 and R8 are independently selected from the group consisting of hydrogen, halogen, amino, C1-5 alkylamino, hydroxyl, cyano, C1-6 alkyl, C1-6 hydroxyalkyl (e.g., hydroxy-terminated alkyl), C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or R7 and R8 may be joined together with the atoms to which they are attached to form a 4 or 5-membered ring; and

R9 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy;

R10 and R11 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy and

Z1 is selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S and C═N—R3; and Z2 is selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S and C═N—R3; wherein

R3 is selected from the group consisting of hydrogen, hydroxyl, SO2, C═O, C═S, C═NH, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl, or when Z2 is a direct bond, R3 is a C3-C6 ring optionally containing a heteroatom;

R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl or together form C═O; and

n is 0, 1, 2 or 3; and

R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl or heteroaryl.

In another embodiment, the invention includes compounds of formula (II):

wherein A may be an aryl or heteroaryl group; X is —C(O)OR6a, where R6a is hydrogen or C1-4alkyl; Y is a residue of formula (a)

wherein Q is (CR10R11)m is 0, 1, 2, 3 or 4; R7 and R8 may independently be hydrogen, hydroxyl, lower alkyl; or R7 and R8, taken with the atoms to which they are attached, form a ring; R9 is selected from, e.g., hydrogen, halogen, hydroxyl, or cyano; and Z1 and Z2 are independently O or (CR4R5)n, where R4 and R5 are independently hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy; n is 0, 1, 2 or 3; and R1 is selected from, e.g., C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl or heteroaryl; or a pharmaceutically acceptable salts thereof.

The aryl or heteroaryl group may be substituted with one, two or three substituents such as halogen, hydroxyl, S, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino/arylamino/heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, or halogen-substituted C1-5 alkoxy (where R2 is, e.g., of hydrogen, hydroxyl, amino, alkylamino/arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring. R2 may be selected from hydrogen, hydroxyl, amino, alkylamino/arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; or aryl/heteroaryl.

The benzofuranyl ring may be substituted with 1 to 5 substituents, e.g., of C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy. R1 may be C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl or heteroaryl; R1 may optionally substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, arylamino, or heteroarylamino groups. (The aryl and heteroaryl groups may be substituted with one to five substituents such as hydroxyl, halogen, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, and C3-6 cycloalkyl.

The present invention relates, in one embodiment, to compounds according to Formula I. Preferably A is a substituted or unsubstituted aryl or heteroaryl group, which may be one illustrated below, where R12 is hydrogen or C1-6alkyl; and the left and right asterisks indicate the point of attachment in formula (I);

R12 may be hydrogen, hydroxyl, amino, alkylamino or arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy; aryl or heteroaryl; more preferably hydrogen.

B and C preferably are substituted or unsubstituted aryl or heteroaryl, e.g.,

In the groups shown in the two tables directly above, the asterisks indicate that the group depicted may be attached to the molecule as shown, or “inverted”. The groups depicted immediately above this text may desirably be present in the molecule in the orientation illustrated.

wherein R12 is hydrogen or C1-6 alkyl; and the left and right asterisks indicate the point of attachment in formula (I); W1, W2, W3 or W4 may be C, N, C—OH, C—OR13 or C—R13; R13 is hydrogen or C1-6alkyl, C1-5alkylthio, C1-5alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5alkoxy.

Z1 and Z2 are preferably CH2, O, S or a direct bond. R3 is preferably methyl. R4 and R5 are preferably hydrogen or methyl. n is preferably for 2. X may be combined with Y, e.g.,

Optionally, two adjacent substituents on the ring A with Z1 to form a fused ring, that may contain one or more hetero atoms, and wherein X may be combined with Y, e.g.,

In another embodiment of the invention, in conjunction with the above and below embodiments, A is an aryl or heteroaryl group, optionally substituted with one, two or three substituents selected from halogen, hydroxyl, SR2, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino, arylamino, heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy; wherein R2 is selected independently, in each instance, from hydrogen, hydroxyl, amino, alkylamino, arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl, halogen-substituted C1-5 alkoxy, aryl and heteroaryl.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is 1,4-disubstituted phenyl, additionally optionally substituted with one, two or three substituents selected from halogen, hydroxyl, SR2, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino, arylamino, heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy; wherein R2 is selected independently, in each instance, from hydrogen, hydroxyl, amino, alkylamino, arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl, halogen-substituted C1-5 alkoxy, aryl and heteroaryl.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is an aryl or heteroaryl group, optionally substituted with one, two or three halogen atoms.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is an phenyl, optionally substituted with one, two or three halogen atoms.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is an phenyl, optionally substituted with one, two or three fluorine atoms.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is fluorophenyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is

In another embodiment of the invention, in conjunction with the above and below embodiments, A is a heteroaryl group, optionally substituted with one, two or three halogen atoms.

In another embodiment of the invention, in conjunction with the above and below embodiments, A is a heteroaryl group.

In another embodiment of the invention, in conjunction with the above and below embodiments, B and C together are bicycloheteroaryl optionally substituted with 1 to 5 substituents selected from C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments, B and C together are a bicycloheteroaryl selected from:

any of which are optionally substituted with 1 to 5 substituents selected from C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments, B and C together are a bicycloheteroaryl selected from:

any of which are substituted with 1 to 5 substituents selected from C1-6 alkyl, halogen, and halogen-substituted C1-6alkyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, B and C together are a bicycloheteroaryl selected from:

In another embodiment of the invention, in conjunction with the above and below embodiments, B and C together are a bicycloheteroaryl selected from:

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl and heteroaryl; any of which are optionally substituted with hydroxyl, halogen, cyano, amino, alkylamino, arylamino or heteroarylamino, wherein the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy and C3-6 cycloalkyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is selected from phenyl and heteroaryl; both of which are optionally substituted with halogen.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is phenyl optionally substituted with halogen.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is heteroaryl optionally substituted with halogen.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is phenyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is heteroaryl.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is 5- or 6-membered unsaturated ring including one atom selected from N, O and S, and 0, 1, 2 or 3 additional N atoms.

In another embodiment of the invention, in conjunction with the above and below embodiments, R1 is selected from pyridinyl, pyrimidine, thiazolyl, oxazolyl, furanyl and thiophenyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, X is WC(O)OR6a, WP(O)R6bR6c, WS(O)2OH, WCONHSO3H or 1H-tetrazol-5-yl. W is a direct bond, oxygen or C1-4 alkyl with substituents independently selected from halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino and C1-4 alkoxy; and R6a is hydrogen or C1-4alkyl; R6b and R6c are independently selected from hydrogen, hydroxyl, C1-4alkyl and halogen substituted C1-4alkyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, X is CO2H.

In another embodiment of the invention, in conjunction with the above and below embodiments, Y is

wherein R9 is selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments, Y is

wherein R9 is selected from hydrogen, halogen and hydroxyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, R9 is hydrogen.

In another embodiment of the invention, in conjunction with the above and below embodiments, R9 is hydroxyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, Z1 is CR4R5; wherein R4 and R5 are independently hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments, Z1 is CR4R5; wherein R4 and R5 are independently hydrogen, halogen, C1-6 alkyl or halogen-substituted C1-6 alkyl.

In another embodiment of the invention, in conjunction with the above and below embodiments, Z1 is CH2.

In another embodiment of the invention, in conjunction with the above and below embodiments,

Z2 is selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S, and C═N—R3;

R3 is hydrogen, hydroxyl, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy;

R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy, or together form “C═O”; and

n is 1, 2 or 3.

In another embodiment of the invention, in conjunction with the above and below embodiments,

Z2 is selected from O, NR3, S, S(O), S(O)2, S(O)2NR3, CR4R5, C═O, C═S, and C═N—R3;

R3 is hydrogen, hydroxyl, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy; and

R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments Z2 is selected from O, NR3, S, CR4R5, C═O, C═S, and C═N—R3;

R3 is hydrogen, hydroxyl, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl or halogen-substituted C1-5 alkoxy; and

R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy.

In another embodiment of the invention, in conjunction with the above and below embodiments Z2 is selected from O, S, CH2, C═O, C═S and C═N—OH.

The specification and claims contain listing of species using the language “selected from . . . and . . . ” and “is . . . or . . . ” (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual elements or subgroups as needed.

In one aspect, the present invention provides methods for modulating S1P-1 receptor mediated biological activity. The present invention also provides methods for using S1P-1 modulators (i.e., agonists or antagonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostate cancer; acute lung diseases, adult respiratory distress syndrome (“ARDS”), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury such as transcorneal freezing or cutaneous burns, and cardiovascular diseases such as ischemia in a subject in need of such treatment or prevention.

In another aspect, the invention provides methods for using S1P-1 modulators in treating or preventing disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn\'s disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behçet\'s disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner\'s granuloma.

In still another aspect, the invention provides methods for using S1P-1 modulators to treat or prevent a disease or disorder in a subject, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of an S1P-1 modulator, e.g., an agonist, that stimulates the immune system. In certain embodiments, the subject is afflicted by an infectious agent. In other embodiments, the subject is immunocompromised.

In still another aspect, the present invention provides a method of modulating an S1P-1 receptor-mediated biological activity in a cell. A cell expressing the S1P-1 receptor is contacted with an amount of an S1P-1 receptor modulator sufficient to modulate the S1P-1 receptor mediated biological activity.

In yet another aspect, the present invention provides a method for modulating an S1P-1 receptor mediated biological activity in a subject. In such a method, an amount of a modulator of the S1P-1 receptor effective to modulate an S1P-1 receptor-mediated biological activity is administered to the subject.

In yet another aspect, the present invention provides a method for treating, preventing or ameliorating an S1P-1 receptor mediated condition in a subject. In such a method, an amount of a modulator of the S1P-1 receptor effective to modulate an S1P-1 receptor-mediated biological activity is administered to the subject. The S1P-1 receptor mediated condition may be, e.g., transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn\'s disease; acute and chronic lymphocytic leukemias and lymphomas.

The features and other details of the invention will now be more particularly described. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.

For convenience, certain terms used in the specification and examples are collected here.

“Treating”, includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.

“Alkyl” includes saturated aliphatic groups, e.g., straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; branched-chain alkyl groups (e.g., isopropyl, tert-butyl, and isobutyl); cycloalkyl (alicyclic) groups like cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); alkyl-substituted cycloalkyl groups; and cycloalkyl-substituted alkyl groups.

“Alkyl” groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound.

Straight or branched alkyl groups may have six or fewer carbon atoms in their backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and more preferably four or fewer. Preferred cycloalkyl groups have from three to eight carbon atoms in their ring structure, and more preferably five or six carbons in the ring structure. “C1-C6” includes alkyl groups containing one to six carbon atoms.

“Substituted alkyls” refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, or heterocyclyl.

“Aryl” includes groups with aromaticity, including 5- and 6-membered unconjugated (i.e., single-ring) aromatic groups that may include from zero to four heteroatoms, as well as conjugated (i.e., multicyclic) systems having at least one ring that is aromatic. Examples of aryl groups include benzene, phenyl, tolyl and the like. Multicyclic aryl groups include tricyclic and bicyclic systems, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine, tetralin, and methylenedioxyphenyl.

Aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”; e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine. The aromatic ring can be substituted at one or more ring positions with, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl group (e.g., phenylmethyl(benzyl)).

“Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl), branched-chain alkenyl groups, cycloalkenyl groups such as cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl; alkyl or alkenyl-substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl-substituted alkenyl groups.

“Alkenyl” groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound.

Straight or branched alkenyl groups may have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain.) Preferred cycloalkenyl groups have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. The term “C2-C6” includes alkenyl groups containing two to six carbon atoms.

“Substituted alkenyls” refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, or heterocyclyl.

“Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.

“Alkynyl” groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound

Straight or branched chain alkynyls group may have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms.

“Substituted alkynyls” refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, or heterocyclyl.

Unless the number of carbons is otherwise specified, “lower alkyl” includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.

“Acyl” includes compounds and moieties which contain the acyl radical (CH3CO—) or a carbonyl group. “Substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

“Acylamino” includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. “Alkylamino” includes moieties wherein an alkyl moiety is bonded to an amino group; “dialkylamino”, “arylamino”, “diarylamino”, and “alkylarylamino” are analogously named. In some embodiments, “amino” may include acylamino and/or alkylamino groups.

“Alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.

“Alkoxy” includes alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of “substituted alkoxy” groups include halogenated alkoxy groups. Substituted alkoxy groups can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, or heterocyclyl substituents. Examples of halogen-substituted alkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

The terms “heterocyclyl” or “heterocyclic group” include closed ring structures, e.g., 3- to 10-, or 4- to 7-membered rings which include one or more heteroatoms. Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperizine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.

Heterocyclic rings may be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

The term “ether” includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes “alkoxyalkyl” which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.

The term “ester” includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above.

The term “thioether” includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” and alkthioalkynyls” refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O−.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc. The term “perhalogenated” generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.

“Heteroatom” includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.

“At least partially aromatic bicyclic ring system”, means a bicyclic ring system where either or both of the rings forming the bicycle are aromatic.

It will be noted that the structure of some of the compounds of the invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate.

“Combination therapy” (or “co-therapy”) includes the administration of a S1P receptor modulator of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

An “anionic group,” as used herein, refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof. “Functional equivalents” of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents. Classical and non-classical bioisosteres are known in the art (see, e.g., Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp. 19-23). A particularly preferred anionic group is a carboxylate.

The term “heterocyclic group” is intended to include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, or oxygen or sulfur. Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, —CF3, —CN, or the like.

An “S1P-modulating agent” includes compound or compositions capable of inducing a detectable change in S1P receptor activity in vivo or in vitro, e.g., at least 10% increase or decrease in S1P activity as measured by a given assay such as the bioassay described hereinbelow.