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Title:
METHOD OF TREATING LUPUS WITH CERAMIDE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2009/117150
Kind Code:
A3
Abstract:
A method of treating lupus in a subject comprises administering to the subject an effective amount of a compound represented by Structural Formula (1): or a pharmaceutically acceptable salt thereof.

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Inventors:
ZHU YUNXIANG (US)
JIANG CANWEN (US)
CHENG SENG H (US)
Application Number:
PCT/US2009/001773
Publication Date:
January 14, 2010
Filing Date:
March 20, 2009
Export Citation:
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Assignee:
GENZYME CORP (US)
ZHU YUNXIANG (US)
JIANG CANWEN (US)
CHENG SENG H (US)
International Classes:
A61K31/36; A61P29/00; A61K31/395; A61K31/397; A61K31/40; A61K31/4025; A61K31/403; A61K31/4035; A61K31/4178; A61K31/4192; A61K31/422; A61K31/4245; A61K31/427; A61K31/428; A61P37/00
Domestic Patent References:
WO2008150486A22008-12-11
WO2008012555A22008-01-31
WO2005123055A22005-12-29
WO2005063275A12005-07-14
WO2008011478A22008-01-24
WO2008011487A22008-01-24
Foreign References:
JPH09169664A1997-06-30
US20020156107A12002-10-24
US20050267094A12005-12-01
Attorney, Agent or Firm:
CARROLL, Alice, O. et al. (Brook Smith & Reynolds, P.C.,530 Virginia Road,P.O. Box 913, Concord MA, US)
Download PDF:
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Claims:

CLAIMS

What is claimed is:

1. A method of treating lupus in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

Y is -H, a hydrolyzable group, or a substituted or unsubstituted alkyl group;

R 2 and R 3 are each independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring;

X is a covalent bond; -(CR 5 R 6 ) m -; -(CR 5 R 6 ) n -Q-; -O-; -S-; or -NR 7 -;

Q is -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR 8 -, -NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NR 8 -, -OC(O)-, -SO 3 -, -SO-, -S(O) 2 -, -SO 2 NR 8 -, or -NR 8 SO 2 -;

When X is -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen; or

When X is other than -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group; and

R 5 and R 6 are each independently -H, -OH, -SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group; each R 7 is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 7 and R 4 taken together with the nitrogen atom OfNR 7 R 4 form a substituted or unsubstituted non-aromatic heterocyclic group; each R 8 is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; n is 1, 2, 3, 4 or 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15; and m is 1, 2, 3, 4 or 5.

2. The method of Claim 1 , wherein R 1 is an aryl group or a heteroaryl group, each of which optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 1 , -OR 30 , -O(haloalkyl), -SR 30 , -NO 2, -CN, -NCS, -N(R 31 ) 2 ,

-NR 31 C(O)R 30 , -NR 31 C(O)OR 32 , -N(R 3I )C(O)N(R 3 I ) 2 , -C(O)R 30 , -C(S)R 30 , -C(O)OR 30 , -OC(O)R 30 , -C(O)N(R 31 ) 2 , -S(O) 2 R 30 , -SO 2 N(R 31 ) 2 , -S(O)R 32 , -SO 3 R 32 , -NR 31 SO 2 N(R 31 ) 2 , -NR 31 SO 2 R 32 , -V 0 -Ar 1 , -V 0 -OR 30 , -V o -O(haloalkyl), -V 0 -SR 30 , -V 0 -NO 2, -V 0 -CN, -V 0 -N(R 31 ) 2 , -V 0 -NR 31 C(O)R 30 , -V 0 -NR 31 CO 2 R 32 , -V 0 -N(R 3 ")C(O)N(R 31 ) 2 , -V 0 -C(O)R 30 ,

-V 0 -C(S)R 30 , -V 0 -CO 2 R 30 , -V 0 -OC(O)R 30 , -V 0 -C(O)N(R 31 ) 2 -, -V 0 -S(O) 2 R 32 , -V 0 -SO 2 N(R 31 ) 2 , -V 0 -S(O)R 32 , -V 0 -SO 3 R 32 , -V 0 -NR 31 SO 2 N(R 31 ) 2 ,

-V 0 -NR 31 SO 2 R 32 , -0-V 0 -Ar 1 , -O-V,-N(R 3 I ) 2 , -S-V 0 -Ar 1 , -S-V,-N(R 31 ) 2 , -N(R 31 )- V 0 -Ar 1 , -N(R 31 )-V,-N(R 31 ) 2 , -NR 31 C(O)-V 0 -N(R 31 ) 2 , -NR 31 C(O)-V 0 -Ar 1 , -C(O)-V 0 -N(R 31 ) 2 , -C(O)-V 0 -Ar 1 , -C(S)-V 0 -N(R 31 ) 2 , -C(S)-V 0 -Ar 1 , -C(O)O-V,-N(R 31 ) 2 , -C(O)O-V 0 -Ar 1 , -0-C(O)-V 1 -N(R 31 ) 2 , -0-C(O)-V 0 -Ar 1 , -C(O)N(R 3 ! )-V, -N(R 31 ) 2 , -C(O)N(R 3 Vv 0 -Ar 1 ,

-S(O) 2 -V O -N(R 31 ) 2 , -S(O) 2 -V 0 -Ar 1 , -SO 2 N(R 31 )-V, -N(R 31 ) 2 , -SO 2 N(R 31 )- V 0 -Ar 1 , -S(O)-V 0 -N(R 31 ) 2 , -S(O)-V 0 -Ar 1 , -S(O) 2 -O-V 1 -N(R 31 ) 2 , -S(O) 2 -O-V 0 -Ar 1 , -NR 31 SO 2 -V 0 -N(R 31 ) 2 , -NR 31 SO 2 -V 0 -Ar 1 , -0-[CH 2 ] p -0-, - S-[CH 2 ]p-S- and -[CH 2 ] q - ; each V 0 is independently a Cl-ClO alkylene group; each Vi is independently a C2-C10 alkylene group; Ar 1 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and each R 3 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and each R 31 is independently R 30 , -CO 2 R 30 , -SO 2 R 30 or -C(O)R 30 ; or

-N(R 31 ) 2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting

of halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1 -C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino; and each R 32 is independently: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; and each p is independently 1 , 2, 3 or 4; and each q is independently 3, 4, 5 or 6.

3. The method of Claim 2, wherein: Y is -H, -C(O)R, -C(O)OR or -C(O)NRR 1 ; and

R and R' are each independently -H; a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; or an aryl group or a heteroaryl group, each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, lower haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group; or R and R' taken together with the nitrogen atom of NRR' form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen;

-OH; -CN; -NCS; -NO 2 ; -NH 2 ; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; and an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group.

The method of Claim 3, wherein:

-N(R 2 R 3 ) is a 5- or 6-membered non-aromatic nitrogen- containing heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, -OR 40 , -O(haloalkyl), -SR 40 , -NO 2 , -CN, -N(R 41 ) 2 , -NR 41 C(O)R 40 , -NR 41 C(O)OR 42 , -N(R 41 )C(O)N(R 41 ) 2 , -C(O)R 40 ,

-C(S)R 40 , -C(O)OR 40 , -OC(O)R 40 , -C(O)N(R 41 ) 2 , -S(O) 2 R 42 , -SO 2 N(R 41 ) 2 , -S(O)R 42 , -SO 3 R 42 , Ar 2 , V 2 -Ar 2 , -V 2 -OR 40 , -V 2 -O(haloalkyl), -V 2 -SR 40 , -V 2 -NO 2 , -V 2 -CN, -V 2 -N(R 41 ) 2 , -V 2 -NR 41 C(O)R 40 , -V 2 -NR 41 CO 2 R 42 , -V 2 -N(R 41 )C(O)N(R 41 ) 2 , -V 2 -C(O)R 40 , -V 2 -C(S)R 40 , -V 2 -CO 2 R 40 , -V 2 -OC(O)R 40 ,

-V 2 -C(O)N(R 41 ) 2 -, -V 2 -S(O) 2 R 42 , -V 2 -SO 2 N(R 41 ) 2 , -V 2 -S(O)R 42 , -V 2 -SO 3 R 42 , -0-V 2 -Ar 2 and -S-V 2 -Ar 2 ; each V 2 is independently a C1-C4 alkylene group;

Ar 2 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 40 is independently i) hydrogen;

ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C 1 -C6 dialkylamino, C 1 -C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C 1 -C6 alkylamino, C 1 -

C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 41 is independently R 40 , -CO 2 R 40 , -SO 2 R 40 or -C(O)R 40 ; or

-N(R 4 ') 2 taken together is an optionally substituted non-aromatic heterocyclic group with one or more substituents selected from the group consisting of halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl-

C6 alkylamino and C1-C6 dialkylamino; and each R 42 is independently: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or ii) an C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-

C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

5. The method of Claim 4, wherein R 5 and R 6 are each independently

-H; -OH; a halogen; or a C1-C6 alkoxy or C1-C6 alkyl group.

6. The method of Claim 5, wherein Y is -H.

7. The method of Claim 5, wherein each of the aliphatic, the aryl and the heteroaryl groups represented by each of R 4 , R 7 and R 8 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , Ar 3 - Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2, -CN, -NCS, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -NR 51 C(O)OR 52 , -N(R 51 )C(O)N(R 51 ) 2 , -C(O)R 50 , -C(S)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -S(O) 2 R 52 , -SO 2 N(R 51 ) 2 , -S(O)R 52 , -SO 3 R 52 , -NR 51 SO 2 N(R 51 ) 2 , -NR 51 SO 2 R 52 ,

-V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2 , -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -NR 51 CO 2 R 52 , -V 4 -N(R 51 )C(O)N(R 51 ) 2 , -V 4 -C(O)R 50 , , -V 4 -C(S)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 5 V, -V 4 -S(O) 2 R 52 , -V 4 -SO 2 N(R 51 ) 2 , -V 4 -S(O)R 52 , -V 4 -SO 3 R 52 , -V 4 -NR 51 SO 2 N(R 51 ) 2 , -V 4 -NR 51 SO 2 R 52 ,

-0-V 4 -Ar 3 , -O-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )- V 4 -Ar 3 , -N(R 51 )-V 5 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(S)-V 4 -N(R 51 ) 2 , -C(S)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 ,

-C(O)N(R 51 )-V 5 -N(R 51 ) 2 , -C(O)N(R 51 )-V 4 - Ar 3 , -S(O) 2 -V 4 -N(R 51 ) 2 , -S(O) 2 -V 4 -Ar 3 , -SO 2 N(R 51 )- V 5 -N(R 51 );,, -SO 2 N(R 51 )- V 4 -Ar 3 , -S(O)-V 4 -N(R 5 I ) 2 , -S(O)-V 4 -Ar 3 , -S(O) 2 -O-V 5 -N(R 5 ') 2 , -S(O) 2 -O-V 4 -Ar 3 , -NR 51 SO 2 -V 4 -N(R 51 ) 2 , -NR 51 SO 2 -V 4 -Ar 3 , -0-[CH 2 V-O-, -S-[CH 2 V-S-, and -[CH 2 ] q - ;

each V 4 is independently a Cl-ClO alkylene group; each V 5 is independently a C2-C10 alkylene group; each Ar 3 is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and each R 50 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and each R 51 is independently R 50 , -CO 2 R 50 , -SO 2 R 50 or -C(O)R 50 ; or

-N(R 51 ) 2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =S, =N(C 1 -C6 alkyl), C 1 -C6 alkyl,

C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl- C6 alkylamino and C1-C6 dialkylamino; and each R 52 is independently: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or two substituents selected from the group consisting of

halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and the non-aromatic heterocyclic group represented by -N(R 4 R 7 ) is optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino; each p' is 1 , 2, 3 or 4; and each q' is 3, 4, 5 or 6.

8. The method of Claim 7, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted aliphatic group.

9. The method of Claim 8, wherein:

R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR 30 , -SR 30 , -N(R 31 ) 2 , Ar 1 , -V 0 -OR 30 , -V O -N(R 31 ) 2 , -V 0 -Ar 1 , -0-V 0 -Ar 1 , -O-V,-N(R 31 ) 2 , -S-V 0 -Ar 1 , -S-V 1 -N(R 31 ) 2 ,

-N(R 31 ^V 0 -Ar 1 , -N(R 31 )-V,-N(R 31 ) 2 , -O-[CH 2 ] P -O-, -S-[CH 2 ] P -S-, and -[CH 2 ] q - ;

Ar 1 is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, Cl- C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, Cl- C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C 1 -C6 alkylcarbonyl and C 1 -C6 haloalkyl; and each R ' is independently R 30 , or -N(R ') 2 is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

10. The method of Claim 9, wherein -N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

1 1. The method of Claim 10, wherein the aliphatic group represented by R 4 is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, Ar 3 , Ar 3 -Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2 , -CN, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -C(O)R 50 ,

-C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -C(O)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 51 ) 2 -, -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )- V 4 -Ar 3 , -N(R 51 )-V 5 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 ,

-C(O)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 , -C(O)N(R 51 )-V 5 -N(R 5l ) 2 , -C(O)N(R 51 )-V 4 -Ar 3 , -0-[CH 2 V-O- and -[CH 2 Jq-.

12. The method of Claim 11 , wherein Y is -H.

13. The method of Claim 12, wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

14. The method of Claim 13, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of -OR 30 , alkyl, and

-0-[CH 2 ] p -0-.

15. The method of Claim 14, wherein the aliphatic group represented by R 4 is optionally substituted with one or more substituents selected from the group

consisting of halogen, cyano, nitro, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ] q -.

16. The method of Claim 15, wherein: Ar 3 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 50 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C 1 -C6 haloalkoxy, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C 1 -C6 haloalkoxy, C 1 -C6 alkoxycarbonyl , C 1 -C6 alkylcarbonyl and C1-C6 haloalkyl.

17. The method of Claim 16, wherein R 4 is an aliphatic group.

18. The method of Claim 17, wherein -N(R 2 R 3 ) is N-pyrrolidinyl or N- morpholinyl.

19. The method of Claim 18, wherein R 1 is 4-hydroxyphenyl or 3,4- ethy lenedioxy- 1 -phenyl .

20. The method of Claim 19, wherein R 4 is a C6 - Cl 8 alkyl group.

21. The method of Claim 20, wherein R 4 is a C6 - C8 alkyl group.

22. The method of Claim 7, wherein: X is -(CR 5 RVQ-; Q is -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-,

-C(S)S-, -C(O)NR 8 -, -NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NR 8 -, -OC(O)-, -SO 3 -, -SO-, -S(O) 2 -, -SO 2 NR 8 -, or -NR 8 SO 2 -; and R 4 is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; or X is -0-, -S- or -NR 7 -; and R 4 is a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; or

X is -(CR 5 R 6 ) m -; and R 4 is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,

-CN, -NCS, -NO 2 or a halogen; or

X is a covalent bond; and R 4 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and n is 1, 2, 3, 4, 5 or 6.

23. The method of Claim 22, wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein R 7 is -H or C1-C6 alkyl.

24. The method of Claim 23, wherein:

R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR 30 , -SR 30 , -N(R 31 ) 2 , Ar 1 , -V 0 -OR 30 , -V O -N(R 31 ) 2 , -V 0 -Ar 1 , -0-V 0 -Ar 1 , -O-V,-N(R 31 ) 2 , -S-V 0 -Ar 1 , -S-V,-N(R 31 ) 2 , -N(R 31 ^V 0 -Ar 1 , -N(R 31 )-V,-N(R 31 ) 2 , -O-[CH 2 ] P -O-, -S-[CH 2 ] P -S-, and

-[CH 2 ] q - ;

Ar is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C 1 -C6 haloalkoxy, C 1 -C6 alkoxycarbonyl , C 1 -C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen,

C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, Cl- C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, Cl- C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 31 is independently R 30 , or -N(R 31 ) 2 is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

25. The method of Claim 24, wherein -N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

26. The method of Claim 25, wherein each of the aliphatic group, the aryl group and the heteroaryl group, represented by each of R 4 , R 7 and R 8 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, Ar 3 , Ar 3 -Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2, -CN, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -C(O)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -C(O)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 51 ) 2 -, -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )- V 4 - Ar 3 , -N(R 51 )-V 5 -N(R 5I ) 2 , -NR 51 C(O)-V 4 -N(R 5 ") 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 , -C(O)N(R 51 )-V 5 -N(R 51 ) 2 , -C(O)N(R 51 )-V 4 - Ar 3 , -O-[CH 2 ]p-O- and -[CH 2 ] q -.

27. The method of Claim 26, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted aryl group or an optionally substituted heteroaryl group.

28. The method of Claim 27, wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

29. The method of Claim 28, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of -OR 30 , alkyl, and

30. The method of Claim 29, wherein:

R 4 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ],,-.

31. The method of Claim 30, wherein:

Ar 3 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 50 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or

iii) an C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

32. The method of Claim 31 , wherein -N(R 2 R 3 ) is N-pyrrolidinyl or N- morpholinyl.

33. The method of Claim 32, wherein m is 1 , 2 or 3.

34. The method of Claim 33, wherein R 4 is a biaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy.

35. The method of Claim 34, wherein the optionally substituted biaryl group is an optionally substituted biphenyl group.

36. The method of Claim 33, wherein -(CH 2 ) m -R 4 is H * , and wherein phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy.

37. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

38. The method of Claim 37, wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

39. The method of Claim 38, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of -OR 30 , alkyl, and -O-[CH 2 ] P -O-.

40. The method of Claim 39, wherein R 4 is: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ] q s or

ii) an aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -0-[CH 2 V-O- and -[CH 2 ] q -.

41. The method of Claim 40, wherein:

Ar is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 50 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

42. The method of Claim 41 , wherein -N(R 2 R 3 ) is W-pyrrolidinyl or N- morpholinyl.

43. The method of Claim 42, wherein R 4 is an optionally substituted alkyl group, or an optionally substituted phenyl group.

44. The method of Claim 43, wherein R 1 is 4-hydroxyphenyl or 3,4- ethylenedioxy- 1 -phenyl.

45. The method of Claim 44, wherein R 4 is an unsubstituted alkyl group, or a phenyl group optionally substituted with one or more substituents selected from the group consisting of -OH, -OCH 3 and -OC 2 H 5 .

46. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

47. The method of Claim 46, wherein R 4 is an aryl group, a heteroaryl group, a lower arylalkyl group or a lower heteroarylalkyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2, -CN, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -C(O)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -C(O)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 51 ) 2 -, -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 5 ") 2 , -N(R 51 )- V 4 - Ar 3 , -N(R 51 )- V 5 -N(R 51 ) 2 , -NR 51 C(O)- V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 , -C(O)N(R 51 )-V 5 -N(R 51 ) 2 , -C(O)N(R 51 )- V 4 - Ar 3 , -0-[CH 2 ] p -0- and -[CH 2 ] q -.

48. The method of Claim 47, wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

49. The method of Claim 48, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of -OR 30 , alkyl, and

-O-[CH 2 ]p-O-.

50. The method of Claim 49, wherein R 4 is an optionally substituted aryl or an optionally substituted heteroaryl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -0-[CH 2 ] P -O- and -[CH 2 ] r .

51. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein:

k is 1, 2, 3, 4, 5 or 6; and R 10 Is i) -H, or ii) an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, and haloalkyl, or iii) a C1-C6 alkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of with one or more substituents selected from the group consisting of halogen, cyano, nitro, Cl-ClO alkyl, Cl-ClO haloalkyl, amino, Cl-ClO alkylamino, Cl-ClO dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, Cl-10 alkoxy, -O- [CH 2 ] P -O- or -[CH 2 ],,-.

52. The method of Claim 51 , wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

53. The method of Claim 52, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of -OR 30 , alkyl, and -O-[CH 2 ]p-O-.

54. The method of Claim 53, wherein R 10 is a C1-C6 alkyl group; an optionally substituted phenyl group; or an optionally substituted, monocyclic or bicyclic heteroaryl group.

55. The method of Claim 26, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

56. The method of Claim 55, wherein -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

57. The method of Claim 56, wherein: the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of —OR 30 , alkyl, and

58. The method of Claim 57, wherein each of the aryl and the heteroaryl groups represented by R 4 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ],-.

59. The method of Claim 58, wherein:

Ar 3 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R 50 is independently i) hydrogen;

ϋ) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

60. The method of Claim 59, wherein -N(R 2 R 3 ) is N-pyrrolidinyl or N- morpholinyl.

61. The method of Claim 60, wherein R 1 is 4-hydroxyphenyl or 3,4- ethylenedioxy- 1 -phenyl.

62. The method of Claim 1, wherein the compound is selected from the group consisting of:

wherein each ring A independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl and alkoxy.

63. The method of Claim 1, wherein the lupus is systemic lupus erythematosus.
Description:

METHOD OF TREATING LUPUS WITH CERAMIDE DERIVATIVES

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/070,145, filed on March 20, 2008, the entire teachings of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Lupus is an autoimmune disease that can affect various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. There are several types of lupus, including discoid (or cutaneous) lupus erythematosus, systemic lupus erythematosus (SLE), drug-induced lupus erythematosus and Neonatal lupus. Inflammation characterized by pain, heat, redness, swelling and loss of function, either on the inside or on the outside of the body (or both) is considered the primary feature of lupus. For most people, lupus is a mild disease affecting only a few organs. For others, it may cause serious and even life-threatening problems. In particular, systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can be fatal.

The cause(s) of lupus is currently unknown, but there are environmental and genetic factors involved. In particular, it is generally believed that abnormal T-cell receptor (TCR)-mediated signal transduction pathways may be involved in SLE, which lead to B cell hyper-responsiveness, increased apotosis, skewed cytokine production, and breakdown of immunological tolerance. For example, it has been observed that mice deficient in genes encoding Lyn, CD22, Fcγ receptor type lib, or CD72, all of which function as negative regulators of B cell receptor (BCR) signaling, produce anti-double-stranded DNA (anti-dsDNA) autoantibodies and develop lupus. It is also generally believed that, in the antigen-mediated T cell signaling events, a rapid increase in protein tyrosine phosphorylation by recruitment of proximal protein tyrosine kinases (PTKs), Src family kinases, and syk/Zap-70 kinases, are responsible for the initiation and amplification of the activation signal.

During antigen presentation, the engagement of TCRs and accessory molecules on the T-cells and antigen presentation cells are believed to induce the formation of a large molecular complex (called the immune synapse), wherein lipid raft clustering and reorganization play a crucial role in complex formation and propagation of intracellular signals.

Generally, the course of lupus is unpredictable, with periods of illness (called flares) alternating with remission. Currently, there is no known cure for SLE, and treatment has been restricted to reducing the severity and duration of its symptoms, when they occur.

Thus, there is a need for agents and methods for treating lupus, especially SLE.

SUMMARY OF THE INVENTION

Applicants have now discovered that certain ceramide derivatives are effective in treating lupus in an animal model. Based upon this discovery, a method of treating lupus with the ceramide derivatives is disclosed herein.

In one embodiment, the invention is directed to a method of treating lupus in a subject, comprising administering to the subject an effective amount of a compound represented by Structural Formula (1):

or a pharmaceutically acceptable salt thereof.

R 1 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.

Y is -H, a hydrolyzable group, or a substituted or unsubstituted alkyl group.

R 2 and R 3 are each independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring. X is a covalent bond; -(CR 5 R 6 V; -(CR 5 R 6 ) n -Q-; -O-; -S-; or -NR 7 -;

Q is -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR 8 -, -NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NR 8 -, -OC(O)-, -SO 3 -, -SO-, -S(O) 2 -, -SO 2 NR 8 -, or -NR 8 SO 2 -.

When X is -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen.

When X is other than -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group.

R 5 and R 6 are each independently -H, -OH, -SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group.

Each R 7 is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 7 and R 4 taken together with the nitrogen atom OfNR 7 R 4 form a substituted or unsubstituted non-aromatic heterocyclic group.

Each R 8 is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. n is 1, 2, 3, 4 or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. m is 1 , 2, 3, 4 or 5.

Also, included in the present invention is the use of ceramide derivatives disclosed herein for treating lupus in a subject.

The present invention also includes the use of ceramide derivatives disclosed herein for the manufacture of a medicament for treating a subject having lupus. The present invention has many advantages. In particular, the present invention provides a treatment for lupus that addresses the underlying disease state, rather than simply ameliorating symptoms that are associated with lupus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing GMl levels, as detected by cholera toxin B subunit labeled with AlexaFluor-488 (CTB) and FACS analysis, in Jurkat T cells treated with Compound C9 ("+ C9") and in Jurkat T cells without the C9 Compound treatment ("-C9"), and in the control ("-CTB").

FIG. 2 shows a graph showing CD3 levels in Jurkat T cells treated with Compound C9 for 3 days or mock treated without Compound C9, which indicates no substantial change in the CD3 levels. FIG. 3 shows reduction of phosphorylation of various proximal signaling molecules of the TCR, Lck, Zap-70, and Lat. GAPDH was used as control for protein loading, after activation of two groups of Jurkat T cells by anti-CD3/CD28 dynal beads, one with and the other without pretreatment with Compound 9 ("+C9" indicates pretreatment with Compound C9; "-C9" indicates without pretreatment with Compound C9).

FIG. 4 is a graph showing calcium ratios over time after activation of two groups of Jurkat T cells, one with and the other without pretreatment with Compound C9 ("+C9" indicates pretreatment with Compound C9; "-C9" indicates without pretreatment with Compound C9), the data of which indicates Ca 2+ response in the T cells during early phase of T cell activation.

FIG. 5 is a graph showing the content of IL-2 secreted into culture media from isolated primary human T cells from pheripheral blood with and without pretreatment of Compound C9 ("+C9" indicates pretreatment with Compound C9; "- C9" indicates without pretreatment with Compound C9) for 3 days. FIG. 6 is a graph showing cumulative proteinuria of three groups of NZB/W

Fl mice, which are a model of lupus: a first group treated with vehicle only (daily oral gavage of sterile water, filled diamond); a second group treated with Compound C9 (daily oral gavage of 75 mg/kg of Compound C9 divided into two doses of 37.5 mg/kg each, BID, filled square), and a third group treated with cyclophosphamide as

a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle).

FIG. 7 is a graph showing the percentage of animals survival observed in three groups of NZB/W Fl mice over time: a first group treated with vehicle only (daily oral gavage of sterile water, filled diamond); a second group treated with

Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled square); and a third group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle).

FIG. 8 is a graph showing the average proteinuria levels observed in three groups of NZB/W Fl mice over time: a first group treated with vehicle only (daily oral gavage of sterile water, filled diamond); a second group treated with Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled square); and a third group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle). FIG. 9 is a graph showing the average albuminuria levels observed in three groups of NZB/W Fl mice over time: a first group treated with vehicle only (daily oral gavage of sterile water, filled diamond); a second group treated with Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled square), and a third group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle).

FIG. 10 is a graph showing glomeruli scores of the kidneys of three groups of NZB/W Fl mice: a first group treated with vehicle only ("Water": daily oral gavage of sterile water); a second group treated with Compound C9 ("C9 BID": daily oral gavage of 2 x 37.5 mg/kg of Compound C9); and a third group treated with cyclophosphamide as a positive control ("CYC": weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide).

FIG. 1 1 is graph showing protein cast scores of the kidneys of three groups NZB/W Fl mice: a first group treated with vehicle only ("Water": daily oral gavage of sterile water); a second group treated with Compound C9 ("C9 BID": daily oral gavage of 2 x 37.5 mg/kg of Compound C9); and a third group treated with cyclophosphamide as a positive control ("CYC": weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide).

FIG. 12 is a graph showing spleen/body ratios observed in three groups of NZB/W Fl mice: a first group treated with vehicle only ("Water": daily oral gavage of sterile water, filled diamond), a second group treated with Compound C9 ("C9 BID": daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled square), and a third group treated with cyclophosphamide as a positive control ("CYC": weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle).

FIG. 13 is a graph showing anti-dsDNA titer levels observed in three groups of NZB/W Fl mice over time: a first group treated with vehicle only (daily oral gavage of sterile water, filled diamond), a second group treated with Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled square), and a third group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle).

FIG. 14 shows reduction of infiltration of inflammatory lymphocyctes (shown with CD4 and CD8 T cells) in the kidneys of NZB/W Fl mice treated with vehicle control (Water), Compound C9 (C9 BID) and cyclophosphamide (CYC) .

FIG. 15 are graphs showing the levels of certain GSLs, ceramide, GLl, GL3, GM3 and GMl, observed in purified B and T cells of three groups of NZB/W Fl mice: a first subgroup treated with vehicle only ("Water/PU-", PU- stands for animals without proteinuria); a second subgroup treated with vehicle only (Water/PU+, PU+ stands for animals with proteinuria, and a third group treated with Compound C9 ("C9/PU-": daily oral gavage of 2 x 37.5 mg/kg. C9/PU- stands for C9 treated animals without proteinuria).

FIG. 16 is a graph showing GL3 levels of three groups of NZB/W Fl mice: a first subgroup treated with vehicle only ("Water/PU-", PU- stands for animals without proteinuria); a second subgroup treated with vehicle only (Water/PU+, PU+ stands for animals with proteinuria, and a third group treated with Compound C9 ("C9/PU-": daily oral gavage of 2 x 37.5 mg/kg. C9/PU- stands for C9 treated animals without proteinuria).

FIG. 17 is a graph showing the concentrations of IL-2 secreted from T cells isolated from the spleens of three groups of NZB/W Fl mice ex vivo: a first subgroup treated with vehicle only ("Water/PU-", PU- stands for animals without proteinuria); a second subgroup treated with vehicle only (Water/PU+, PU+ stands

for animals with proteinuria, and a third group treated with Compound C9 ("C9/PU- ": daily oral gavage of 2 x 37.5 mg/kg. C9/PU- stands for C9 treated animals without proteinuria).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method of treating lupus that comprises administering an effective amount of a ceramide derivative disclosed herein to a subject with lupus. As shown in the examples, Applicants have discovered that Compound C9, a ceramide derivative, shows several beneficial effects for treating and/or alleviating symptoms of lupus in a murine model of lupus, such as increased animal survival, reduced proteinuria and albuminuria, reduced T cell infiltration in the kidneys, alleviated kidney pathology assessed by both glomerular and protein cast scores, decreased spleen size, normalized GSL levels in T cells and B cells isolated from the spleen, and reduced T cell activation. Applicants have also discovered that these benefits can be achieved with minimal effects on the content of anti-dsDNA titers.

In one embodiment, the ceramide derivative is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is -H, a hydrolyzable group, or a substituted or unsubstituted alkyl group. Examples of hydrolyzable groups include -C(O)R, -C(O)OR, -C(O)NRR', C(S)R, -C(S)OR, -C(O)SR or -C(S)NRR'. Specific examples of hydrolyzable groups include an acetyl, -C(=O)(CH 2 )CH 3 and -C(=O)-(1 -lower alkyl- 1 ,4-dihydropyridin- 4-yl. In a specific embodiment, Y is -H, a hydrolyzable group, or an alkyl group. In another specific embodiment, Y is -H, -C(O)R, -C(O)OR or -C(O)NRR'. In yet another specific embodiment, Y is -H.

X is a covalent bond; -(CR 5 R 6 ) n -Q-; -0-; -S-; or -NR 7 -.

Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR 8 -, -NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NR 8 -, -OC(O)-, -SO 3 -, -SO-, -S(O) 2 -, -SO 2 NR 8 -, or

-NR 8 SO 2 -. In a specific embodiment, Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR 8 -, -NR 8 C(O)NR 8 -, or -OC(O)-. In yet another specific embodiment, Q is -O- , -S-, -C(O)-, -C(S)-, -NR 8 (C0)- or -C(O)NR 8 -. In yet another specific embodiment, Q is -0-, -S-, -C(O)- or -C(S)-. In yet another specific embodiment, Q is -O- or -C(O)-.

R 1 is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In a specific embodiment, R 1 is a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. In

another specific embodiment, R is where r is 1 , 2, 3 or 4, preferably 1 or 2.

Suitable substituents for each of the aryl and heteroary groups represented by R 1 include halogen, alkyl, haloalkyl, Ar 1 , -OR 30 , -O(haloalkyl), -SR 30 , -NO 2 , -CN, -NCS, -N(R 31 ) 2 , -NR 31 C(O)R 30 , -NR 31 C(O)OR 32 , -N(R 31 )C(O)N(R 31 ) 2 , -C(O)R 30 , -C(S)R 30 , -C(O)OR 30 , -OC(O)R 30 , -C(O)N(R 31 ) 2 , -S(O) 2 R 30 , -SO 2 N(R 31 ) 2 , -S(O)R 32 , -SO 3 R 32 , -NR 31 SO 2 N(R 31 ) 2 , -NR 31 SO 2 R 32 , -V 0 -Ar 1 , -V 0 -OR 30 , -V 0 -O(haloalkyl), -V 0 -SR 30 , -V 0 -NO 2, -V 0 -CN, -V 0 -N(R 31 ) 2 , -V 0 -NR 31 C(O)R 30 , -V 0 -NR 31 CO 2 R 32 , -V 0 -N(R 31 )C(O)N(R 31 ) 2 , -V 0 -C(O)R 30 , -V 0 -C(S)R 30 , -V 0 -CO 2 R 30 , -V 0 -OC(O)R 30 , -V 0 -C(O)N(R 31 ) 2 -, -V 0 -S(O) 2 R 32 , -V 0 -SO 2 N(R 31 ) 2 , -V 0 -S(O)R 32 , -V 0 -SO 3 R 32 , -V 0 -NR 31 SO 2 N(R 31 ) 2 , -V 0 -NR 31 SO 2 R 32 , -0-V 0 -Ar 1 , -O-V,-N(R 31 ) 2 , -S-V 0 -Ar 1 , -S- V, -N(R 31 ) 2 , -N(R 31 )-V 0 -Ar 1 , -N(R 31 )-V,-N(R 31 ) 2 , -NR 31 C(O)-V 0 -N(R 31 ) 2 , -NR 31 C(O)-V 0 -Ar 1 , -C(O)-V 0 -N(R 31 ) 2 , -C(O)-V 0 -Ar 1 , -C(S)-V 0 -N(R 31 ) 2 , -C(S)-V 0 -Ar 1 , -C(O)O-V 1 -N(R 31 ) 2 , -C(O)O-V 0 -Ar 1 , -0-C(O)-V, -N(R 31 ) 2 , -0-C(O)-V 0 -Ar 1 , -C(O)N(R 31 )- V, -N(R 31 ) 2 , -C(O)N(R 31 ^V 0 -Ar 1 , -S(O) 2 -V 0 -N(R 31 ) 2 , -S(O) 2 -V 0 -Ar 1 , -SO 2 N(R 31 )-V,-N(R 31 ) 2 , -SO 2 N(R 31 )-V o -Ar', -S(O)-V 0 -N(R 31 ) 2 , -S(O)-V 0 -Ar 1 , -S(O) 2 -O-V 1 -N(R 31 ) 2 , -S(O) 2 -O-V 0 -Ar 1 , -NR 31 SO 2 -V 0 -N(R 31 ) 2 , -NR 31 SO 2 -V 0 -Ar 1 , -0-[CH 2 ] p -0-, -S-[CH 2 ] P -S-, or -[CH 2 ] q - . Certain specific substituents for each of the aryl and heteroary groups represented by R include halogen, cyano, nitro, alkyl, haloalkyl, -OR 30 , -SR 30 , -N(R 31 ) 2 , Ar 1 , -V 0 -OR 30 , -V 0 -N(R 31 ) 2 , -V 0 -Ar 1 , -0-V 0 -Ar 1 , -O-V,-N(R 31 ) 2 , -S-V 0 -Ar 1 , -S-V 1 -N(R 31 ) 2 ,

-N(R 31 )-V 0 -Ar', -N(R 31 )-Vi-N(R 31 ) 2 , -O-[CH 2 ] P -O-, -S-[CH 2 ] P -S-, or -[CH 2 ] q -. Alternatively, certain specific substituents for each of the aryl and heteroary groups represented by R 1 include halogen, cyano, nitro, alkyl, haloalkyl, alkylamino, dialkylamino, aryl, aryloxy, -OH, alkoxy, -O-[CH 2 ] P -O-, and -[CH 2 ] q -. Alternatively, certain specific substituents for each of the aryl and heteroary groups represented by R 1 include -OR 30 (e.g., -OH, -OCH 3 , -OC 2 H 5 ), alkyl, (e.g., C1-C6 alkyl), or -O-[CH 2 ] P -O-.

R 2 and R 3 are each independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, or R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring. In a specific embodiment, R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a 5- or 6-membered, optionally- substituted non-aromatic heterocyclic ring . In another specific embodiment, -N(R 2 R 3 ) is an optionally substituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group. In another specific embodiment, -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, preferably an unsubstituted pyrrolidinyl group.

Suitable substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R 3 , and suitable substituents for the non-aromatic heterocyclic ring represented by N(R 2 R 3 ) each independently include halogen, alkyl, haloalkyl, -OR 40 , -O(haloalkyl), -SR 40 , -NO 2, -CN, -N(R 4 ') 2 , -NR 41 C(O)R 40 , -NR 41 C(O)OR 42 , -N(R 41 )C(O)N(R 41 ) 2 , -C(O)R 40 , -C(S)R 40 , -C(O)OR 40 , -OC(O)R 40 , -C(O)N(R 41 ) 2 , -S(O) 2 R 42 , -SO 2 N(R 41 ) 2 , -S(O)R 42 , -SO 3 R 42 , Ar 2 , V 2 -Ar 2 , -V 2 -OR 40 , -V 2 -O(haloalkyl), -V 2 -SR 40 , -V 2 -NO 2 , -V 2 -CN, -V 2 -N(R 41 ) 2 , -V 2 -NR 41 C(O)R 40 , -V 2 -NR 41 CO 2 R 42 , -V 2 -N(R 41 )C(O)N(R 41 ) 2 , -V 2 -C(O)R 40 , -V 2 -C(S)R 40 , -V 2 -CO 2 R 40 , -V 2 -OC(O)R 40 , -V 2 -C(O)N(R 4 V, -V 2 -S(O) 2 R 42 , -V 2 -SO 2 N(R 41 ) 2 , -V 2 -S(O)R 42 , -V 2 -SO 3 R 42 , -0-V 2 -Ar 2 and -S-V 2 -Ar 2 .

Certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R 3 , and for the non-aromatic heterocyclic ring represented by N(R 2 R 3 ) each independently include halogen, alkyl, haloalkyl, -OR 40 , -O(haloalkyl), -SR 40 , -NO 2 , -CN, -N(R 41 ) 2 , -C(O)R 40 , -C(S)R 40 , -C(O)OR 40 , -OC(O)R 40 , -C(O)N(R 41 ) 2 , Ar 2 , V 2 -Ar 2 , -V 2 -OR 40 , -V 2 -O(haloalkyl), -V 2 -SR 40 , -V 2 -NO 2, -V 2 -CN, -V 2 -N(R 4 ') 2 ,

-V 2 -C(O)R 40 , -V 2 -C(S)R 40 , -V 2 -CO 2 R 40 , -V 2 -OC(O)R 40 , -0-V 2 -Ar 2 and -S-V 2 -Ar 2 . Alternatively, certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R 3 , and for the non-aromatic heterocyclic ring represented by N(R 2 R 3 ) each independently include halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, -0(C 1 -C 10 alkyl), -O(phenyl), -0(C 1 -C 10 haloalkyl), -S(C 1 -C 10 alkyl), -S(phenyl), -S(Cl-ClO haloalkyl), -NO 2, -CN, -NH(Cl-ClO alkyl), -N(Cl-ClO alkyl) 2 , -NH(Cl-ClO haloalkyl), -N(Cl-ClO haloalkyl) 2 , -NH(phenyl), -N(phenyl) 2 , -C(O)(C 1 -C 10 alkyl), -C(O)(C 1 -C 10 haloalkyl), -C(O)(phenyl), -C(S)(C 1 -C 10 alkyl), -C(S)(Cl-ClO haloalkyl), -C(S)(phenyl), -C(O)O(Cl-ClO alkyl), -C(O)O(C 1 -C 10 haloalkyl), -C(O)O(phenyl), phenyl, -V 2 -phenyl, -V 2 -O-phenyl, -V 2 -O(Cl-ClO alkyl), -V 2 -O(Cl-ClO haloalkyl), -V 2 -S-phenyl, -V 2 -S(Cl-ClO alkyl), -V 2 -S(Cl-ClO haloalkyl), -V 2 -NO 2, -V 2 -CN, -V 2 -NH(Cl-ClO alkyl), -V 2 -N(Cl-ClO alkyl) 2 , -V 2 -NH(Cl-ClO haloalkyl) , -V 2 -N(Cl-ClO haloalkyl) 2, -V 2 -NH(phenyl), -V 2 -N(phenyl) 2 , -V 2 -C(O)(Cl-ClO alkyl), -V 2 -C(O)(Cl-ClO haloalkyl), - V 2 -C(O)(phenyl), -V 2 -C(S)(C 1 -C 10 alkyl), -V 2 -C(S)(C 1 -C 10 haloalkyl), -V 2 -C(S)(phenyl), -V 2 -C(O)O(Cl-ClO alkyl), -V 2 -C(O)O(Cl-ClO haloalkyl), -V 2 -C(O)O(phenyl), -V 2 -OC(O)(Cl-ClO alkyl), -V 2 -OC(O)(Cl-ClO haloalkyl), -V 2 -OC(O)(phenyl), -O-V 2 -phenyl and -S-V 2 -phenyl. Alternatively, certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R 3 , and for the non-aromatic heterocyclic ring represented by N(R 2 R 3 ) each independently include halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxy, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl, C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

When X is -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen, or alternatively when X is other than -(CR 5 R 6 ) m , R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group. Specifically, R 4 is a substituted or unsubstituted aliphatic group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group.

In a specific embodiment, R 4 is an optionally substituted aliphatic group, such as an optionally substituted alkyl group. In one aspect of this specific

embodiment, the optionally substituted aliphatic group, including the optionally substituted alkyl group, is acyclic. In a more specific embodiment, R 4 is an alkyl group. In another more specific embodiment, R 4 is a C6-C 18 alkyl group, such as a C6, C7, C8, C9 or ClO alkyl group. In one aspect of these more specific embodiments, the alkyl group, including the C6, C7, C8, C9 or ClO alkyl group, is acyclic.

In another specific embodiment, R 4 is an optionally substituted aryl, an optionally substituted heteroaryl group, or an optionally substituted alkyl group.

In yet another specific embodiment, R 4 is an optionally substituted phenyl group or an optionally substituted alkyl group, such as Cl-ClO alkyl group, or C6- C8 alkyl group.

In yet another specific embodiment, R 4 is an aryl group, a heteroaryl group, a lower arylalkyl group or a lower heteroarylalkyl group, or alterantively, R is an optionally substituted aryl or an optionally substituted heteroaryl group. In a more specific embodiment, the aryl, the heteroaryl, the lower arylalkyl and the lower heteroaryl groups represented by R 4 are selected from the group consisting of:

wherein each of rings A-Z5 is optionally and independently substituted; and each x is independently 0 or 1, specifically x is 0. Even more preferably, R 4 is an

optionally substituted group. Alternatively, R 4 is an optionally substituted phenyl group. Alternatively, R 4 is an aryl group or a heteroaryl group, each indepenently optionally substituted with Ar 3 , such as a phenyl group optionally substituted with Ar 3 . It is noted that, as shown above, rings A-Z5 can be attached to variable "X" of Structural Formula (I) through -(CH 2 ) X - at any ring carbon of rings A-Z5 which is not at a position bridging two aryl groups. For example, R 4

represented by means that R 4 is attached to variable "X" through either ring J or ring K.

Suitable substituents for each of the aliphatic, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl, the heteroarylalkyl group and rings A-Z5, include halogen, alkyl, haloalkyl, Ar 3 , Ar 3 -Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2, -CN, -NCS, -N(R 5I ) 2 , -NR 51 C(O)R 50 , -NR 51 C(O)OR 52 , -N(R 51 )C(O)N(R 51 ) 2 , -C(O)R 50 , -C(S)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -S(O) 2 R 52 , -SO 2 N(R 51 ) 2 , -S(O)R 52 , -SO 3 R 52 , -NR 51 SO 2 N(R 51 ) 2 , -NR 51 SO 2 R 52 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -NR 51 CO 2 R 52 , -V 4 -N(R 51 )C(O)N(R 51 ) 2 , -V 4 -C(O)R 50 , , -V 4 -C(S)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 51 ) 2 -,

-V 4 -S(O) 2 R 52 , -V 4 -SO 2 N(R 51 ) 2 , -V 4 -S(O)R 52 , -V 4 -SO 3 R 52 , -V 4 -NR 51 SO 2 N(R 51 ) 2 , -V 4 -NR 51 SO 2 R 52 , -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )- V 4 -Ar 3 , -N(R 51 )-V 5 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(S)-V 4 -N(R 51 ) 2 , -C(S)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 ,

-C(O)N(R 51 )-V 5 -N(R 51 ) 2 , -C(O)N(R 51 )-V 4 -Ar 3 , -S(O) 2 -V 4 -N(R 51 ) 2 , -S(O) 2 -V 4 -Ar 3 , -SO 2 N(R 51 )-V 5 -N(R 51 ) 2 , -SO 2 N(R 5I )-V 4 -Ar 3 , -S(O)-V 4 -N(R 51 ) 2 , -S(O)-V 4 -Ar 3 , -S(O) 2 -O-V 5 -N(R 51 ) 2 , -S(O) 2 -O-V 4 -Ar 3 , -NR 51 SO 2 -V 4 -N(R 51 ) 2 , -NR 51 SO 2 -V 4 -Ar 3 , -0-[CH 2 ]p-0-, -S-[CH 2 ]p'-S-, and -[CH 2 ] q - . Certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroaryl alky 1 group and rings A-Z5, include halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, Ar 3 , Ar 3 -Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2, -CN, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -C(O)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -C(O)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 51 ) 2 , -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )- V 4 - Ar 3 , -N(R 51 )-V 5 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 5 ') 2 , -0-C(O)-V 4 -Ar 3 , -C(O)N(R 51 )- V 5 -N(R 51 ) 2 , -C(O)N(R 51 )- V 4 -Ar 3 , -0-[CH 2 ] p -0- and -[CH 2 ] q -. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, nitro, Cl-ClO alkyl, Cl-ClO haloalkyl, amino, Cl-ClO alkylamino, Cl-ClO dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -0(C 1 -C 10 haloalkyl), -V 4 -O(C 1 -C 10 haloalkyl), -O- V 4 - Ar 3 ,

-0-[CH 2 ] p -0- and-[CH 2 ] q -. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, nitro, Cl-ClO alkyl, Cl-ClO haloalkyl, amino, Cl-ClO alkylamino, Cl-ClO dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, Cl-IO alkoxy, -0-[CH 2 ] p -0- or -[CH 2 ] q -. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 ,

including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, amino, nitro, Ar 3 , C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, hydroxy and C1-C6 haloalkoxy. Alternatively certain specific substituents each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include -OH, -OCH 3 , -OC 2 H 5 and -O-[CH 2 ] P -O-. Specifically, when R 4 is an optionally substituted phenyl ring A, at least one of the optional substituents of ring A is at the para position.

R 5 and R 6 are each independently -H, -OH, -SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. Specifically, R 5 and R 6 are each independently -H; -OH; a halogen; or a lower alkoxy or lower alkyl group. More specifically, R 5 and R 6 are each independently -H, -OH or a halogen. Even more specifically, R 5 and R 6 are each independently -H. Each of R 7 and R 8 independently is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. Alternatively, R 7 and R 4 taken together with the nitrogen atom of -NR 7 R 4 form a substituted or unsubstituted non-aromatic heterocyclic group. In some specific embodiments, each of R and R independently is -H, an optionally substituted aliphatic group or an optionally substituted phenyl group. In some specific embodiments, each of R 7 and R 8 independently is -H, an optionally substituted alkyl group or an optionally substituted phenyl group. In other specific embodiments, each of R 7 and R 8 independently is -H or a C1-C6 alkyl group, phenyl or benzyl. Examples of suitable substituents, including specific examples, for the aliphatic, the aryl and the heteroaryl groups represented by each of R 7 and R 8 independently are as described above for variable R 4 . Examples of suitable substituents for the non-aromatic heterocyclic group represented by -NR 7 R 4 include halogen, =0, =S, =N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C 1 -C6 haloalkoxy, amino, (C 1 -C6 alkyl)amino and (C 1 -C6 dialkyl)amino. Certain specific substituents for the non-aromatic heterocyclic group represented by -NR 7 R 4 include halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy,

C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino. n is i, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15. Specifically, n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10. Alternatively, n is 1, 2, 3, 4, 5 or 6. Alternatively, n is 5, 6, 7, 8, 9 or 10. Alternatively, n is 1, 2, 3 or 4. Alternatively, n is 2, 3, 4 or 5. m is 1, 2, 3, 4, or 5, specifically 1, 2, 3 or 4.

Each p is independently 1, 2, 3 or 4, specifically 1 or 2.

Each q is independently 3, 4, 5 or 6, specifically 3 or 4.

Each p' is independently 1, 2, 3 or 4, specifically 1 or 2. Each q' is independently 3, 4, 5 or 6, specifically 3 or 4.

Each V 0 is independently a Cl-ClO alkylene group, specifically C1-C4 alkylene group.

Each Vi is independently a C2-C10 alkylene group, specifically C2-C4 alkylene group. Each V 2 is independently a C1-C4 alkylene group.

Each V 4 is independently a Cl-ClO alkylene group, specifically a C1-C4 alkylene group.

Each V 5 is independently a C2-C10 alkylene group, specifically a C2-C4 alkylene group. Each Ar 1 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Specifically, Ar 1 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl- C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More specifically, Ar 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl- C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each Ar 2 is an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C 1 -C6 haloalkoxy, amino, C 1 -C6 alkylamino and C 1 -C6 dialkylamino.

Each Ar 3 is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Specifically, each Ar 3 is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, hydroxy, Cl-ClO alkoxy, nitro, cyano, Cl-ClO alkoxycarbonyl, Cl-ClO alkylcarbonyl, Cl-ClO haloalkoxy, amino, Cl-ClO alkylamino and Cl-ClO dialkylamino. Even more specifically, each Ar 3 is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino. Each R 30 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Specifically, each R 30 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1 -C6 alkylamino, C1-C6 dialkylamino, C1 -C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl; or iii) a Cl-ClO alkyl group optionally substituted with one or more

substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-Cl dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More specifically, each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl; or iii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-Cl dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R 31 is independently R 30 , -CO 2 R 30 , -SO 2 R 30 or -C(O)R 30 ; or -N(R 31 ) 2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R 31 is independently R °, or -N(R 31 ) 2 is an optionally substituted non-aromatic heterocyclic group. Suitable substituents for the non- aromatic heterocyclic group represented by -N(R ) 2 include halogen, =0, =S, -N(Cl-Co alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino. Certain specific substituents for the non-aromatic heterocyclic group represented by -N(R 31 ) 2 include halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino.

Each R 32 is independently i) an aryl group or a heteroaryl group, each of which independently is optionally substituted optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Specifically, each R 32 is independently i) an aryl group or a heteroaryl group, each of which independently is

optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or ii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-Cl dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More specifically, each R 32 is independently i) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; or ii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-Cl dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C 1 -C6 alkylcarbonyl.

Each R 40 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or iii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R 41 independently is R 40 , -CO 2 R 40 , -SO 2 R 40 or -C(O)R 40 ; or -N(R 4 ') 2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R 41 independently is R 40 , or -N(R 4I ) 2 is an optionally substituted non-aromatic heterocyclic group. Suitable exemplary substituents, including specific exemplary substituents, for the non-aromatic heterocyclic group represented by -N(R 4 ') 2 are as described above for the non-aromatic heterocyclic group represented by -N(R 31 ) 2

Each R 42 independently is i) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, Cl- C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or ii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Each R 50 independently is i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Specifically, each R 5 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or iii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C 1 -C6 alkoxy, nitro, cyano, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R 51 independently is R 50 , -CO 2 R 50 , -SO 2 R 50 or -C(O)R 50 , or -N(R 51 ) 2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R 51 independently is R5°, or -N(R 51 ) 2 is an optionally substituted non-aromatic heterocyclic group. Suitable exemplary substituents, including specific exemplary substituents, for the non-aromatic heterocyclic group

represented by -N(R 51 ) 2 are as described above for the non-aromatic heterocyclic group represented by -N(R 31 ) 2

Each R 52 independently is i) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Specifically, each R 52 independently is i) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl- C6 alkylamino and C1-C6 dialkylamino; or ii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. R and R are each independently i) -H; ii) a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; or iii) an aryl or a heteroaryl group, each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, C 1 -C6 aliphatic group and C1-C6 haloaliphatic group. Alternatively, R and R' taken together with the nitrogen atom of NRR' form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH; -CN; -NCS; -NO 2 ; -NH 2 ; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; and an aryl or a

heteroaryl group, each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group. In a specific embodiment, R and R' are each independently i) -H; ii) a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1 -C6 haloalkoxy, aryl and heteroaryl; or iii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group. Alternatively, R and R' taken together with the nitrogen atom of NRR' form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH; -CN; -NCS; -NO 2 ; -NH 2 ; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; and a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group. In another specific embodiment, R and R' are each independently -H; a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and benzyl; phenyl; or benzyl. Specific examples of each R and R 1 include -H, C1-C4 alkyl, phenyl and benzyl. A second set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is -H, -C(O)R, -C(O)OR or -C(O)NRR 1 , preferably -H. R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, for the aryl and the heteroaryl groups represented by R 1 are as described in the first set of values for the variables of Structural Formula (I).

R and R taken together with the nitrogen atom of N(R R ) form a 5- or 6- membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents, including specific substituents, for the non-aromatic heterocyclic ring represented by -NR 2 R 3 are as described in the first set of values for the variables of Structural Formula (I).

Values and preferred values for the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A third set of values for the variables in Structural Formula (I) is provided in the following paragraphs: Y is -H, -C(O)R, -C(O)OR or -C(O)NRR 1 , preferably -H.

R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, for the aryl and the heteroaryl groups represented by R 1 are as described in the first set of values for the variables of Structural Formula (I). R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a 5- or 6- membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents, including specific substituents, for the non-aromatic heterocyclic ring represented by -NR 2 R 3 are as described in the first set of values for the variables of Structural Formula (I). R 5 and R 6 are each independently -H, -OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A fourth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Each of Y, R 1 , R 2 , R 3 , R 5 and R 6 independently is as described above for the third set of values.

X is -(CR 5 RVQ-; Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR 8 -, -NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NR 8 -, -OC(O)-, -SO 3 -, -SO-, -S(O) 2 -, -SO 2 NR 8 -, or -NR 8 SO 2 -; and R 4 is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Alternatively, X is -0-, -S- or -NR 7 -; and R 4 is a substituted or unsubstituted

aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Alternatively, X is -(CR 5 R 6 ) m -; and R 4 is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen. Alternatively, X is a covalent bond; and R 4 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. n is 1, 2, 3, 4, 5 or 6.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

In a second embodiment, the ceramide derivative is represented by Structural Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV):

or a pharmaceutically acceptable salt thereof. A first set of values for the variables of Structural Formulas (II) - (XIV) is provided in the following paragraphs: Y in Structural Formula (II) is -H, -C(O)R, -C(O)OR or -C(O)NRR', preferably -H.

R 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, for the aryl and the heteroaryl groups represented by R 1 are as described in the first set of values for the variables of Structural Formula (I).

R 2 and R 3 taken together with the nitrogen atom OfN(R 2 R 3 ) form a 5- or 6- membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents, including specific substituents, for the non-aromatic

heterocyclic ring represented by -NR 2 R 3 are as described in the first set of values for the variables of Structural Formula (I).

For Structural Formula (II), in one specific embodiment, R 4 is an optionally substituted aliphatic group. In another specific embodiment, R 4 is an an optionally substituted aliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen. In one further aspect of this another specific embodiment, R 4 is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, for the aliphatic, the aryl and the heteroaryl groups represented by R 4 are as described in the first set of values for the variables of Structural Formula (I).

Each R 4 in Structural Formulas (IV), (V), (VI), (VII), (X), (XI) and (XII) is independently an optionally substituted aliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group. Specifically, for Structural Formulas (VI) and (VII), each R 4 independently is an an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted lower arylalkyl group or an optionally substituted heteroarylalkyl group. Examples of suitable substituents, including specific substituents, for the aliphatic, the aryl and the heteroaryl groups represented by R 4 are as described in the first set of values for the variables of Structural Formula (I).

Each of R 5 and R 6 in Structural Formulas (III), (IV) and (V) are each independently -H, -OH, a halogen, a C1-C6 alkoxy group or a C1-C6 alkyl group.

Each R 4 in Structural Formulas (III) and (VIII) independently is an optionally substituted cyclic alkyl (e.g., C3-C8) group, an optionally substituted cyclic alkenyl (e.g., C3-C8) group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen. Specifically, R 4 is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, for the alkyl, the alkenyl, the aryl and the heteroaryl groups represented by R 4 are as described in the first set of values for the variables of Structural Formula (I).

Each R 7 in Structural Formulas (VII) and (XII) is independently -H or Cl- C6 alkyl.

For Structural Formula (IV), values and preferred values of each of Q and R 8 independently are as described above in the first set of values for Structural Formula (I). In a specific embodiment of Structural Formula (IV), Q is -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -NR 8 (C0)-, -C(O)NR 8 - or -OC(O)-; and R 8 is optionally -H, an optionally substituted aliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group. In another specific embodiment of Structural Formula (IV), Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -NR 8 (C0)-, -C(O)NR 8 - or -OC(O)-; and R 8 is optionally -H, an optionally substituted aliphatic group or an optionally substituted phenyl group. In yet another specific embodiment of Structural Formula (IV), Q is -O- , -S-, -C(O)-, -C(S)-, -NR 8 (C0)- or -C(O)NR 8 -; and R 8 is optionally -H, an optionally substituted aliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group. In yet another specific embodiment of Structural Formula (IV), Q is -O- , -S-, -C(O)-, -C(S)-, -NR 8 (C0)- or -C(O)NR 8 -; and R 8 is optionally -H, an optionally substituted aliphatic group or an optionally substituted phenyl group. In yet another specific embodiment of Structural Formula (IV), Q is -O- , -S-, -C(O)-, -C(S)-, -NR 8 (C0)- or -C(O)NR 8 -; and R 8 is optionally -H, an optionally substituted aliphatic group or an optionally substituted phenyl group; and R is -H or a C1-C6 alkyl group, phenyl or benzyl. Examples of suitable substituents, including specific substituents, for the alkyl, the alkenyl, the aryl and the heteroaryl groups represented by R 8 are as described in the first set of values for the variables of Structural Formula (I).

Each R 10 in Structural Formulas (XIII) and (XIV) independently is i) -H; ii) an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, and haloalkyl; or iii) a C1-C6 alkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of with one or more substituents selected from the group consisting of halogen, cyano, nitro, Cl- ClO alkyl, Cl-ClO haloalkyl, amino, Cl-ClO alkylamino, Cl-ClO dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, Cl-IO alkoxy, -O-[CH 2 ] P -O- or -[CH 2 ],-.

Each k in Structural Formulas (XIII) and (XIV) independently is 1, 2, 3, 4, 5 or 6.

Each n in Structural Formulas (IV) and (V) independently is 1, 2, 3, 4, 5 or 6.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables of Structural Formulas (II) - (XIV) is provided in the following paragraphs:

Each of Y, Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 independently is as described above for the first set of values for the variables of Structural Formulas (II) - (XIV).

R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR 30 , -SR 30 , -N(R 3 I ) 2 , Ar 1 , -V 0 -OR 30 , -V O -N(R 31 ) 2 , -V 0 -Ar 1 , -0-V 0 -Ar 1 , -O-V,-N(R 31 ) 2 , -S-V 0 -Ar 1 , -S-V,-N(R 31 ) 2 , -N(R 31 )-V 0 -Ar 1 , -N(R 31 )-V,-N(R 31 ) 2 , -O-[CH 2 ] P -O-, - S-[CH 2 ]p-S-, or -[CH 2 ] q -. Specifically, R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, alkylamino, dialkylamino, aryl, aryloxy, -OH, alkoxy, -0-[CH 2 ] p -0- and -[CH 2 ] q -. Specifically, the "alkyl" referred to in the the alkyl, alkoxy, haloalkyl, alkylamino and dialkylamino groups of the exemplaryl substitutents independently is C1-C6 alkyl.

Ar 1 is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl- C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar 1 is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl- C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6

alkylcarbonyl and C1-C6 haloalkyl; or iii) a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C 1-C6 haloalkyl.

Each R 31 is independently R 30 , or -N(R 31 ) 2 is an optionally substituted non- aromatic heterocyclic group. Examples of suitable substituents, including specific substituents, for the non-aromatic heterocyclic ring represented by -NR 2 R 3 are as described in the first set of values for the variables of Structural Formula (I). Values and preferred values of the remainder of the variables of Structural

Formulas (H)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (H)-(XIV) is provided in the following paragraphs: Each of Y, Q, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 and Ar 1 independently is as described above for the second set of values for the variables of Structural Formulas (II) - (XIV).

Each -N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, Cl- C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

Values and preferred values of the remainder of the variables of Structural Formulas (H)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas (H)-(XIV) is provided in the following paragraphs:

Each of Y, Q, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 and Ar 1 independently is as described above for the third set of values for values for the variables of Structural Formulas (II) - (XIV).

Each -N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A fifth set of values for the variables in Structural Formulas (II)-(XIII) is provided in the following paragraphs:

Each of Y, Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 and Ar 1 independently is as described above for the fourth set of values for the variables of Structural Formulas (II) - (XIV).

R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of -OR 30 (e.g., -OH, -OCH 3 , -OC 2 H 5 ), alkyl

(e.g., Cl-ClO alkyl) and -O-[CH 2 ] P -O-. Specifically, R 1 is 4-hydroxyphenyl or 3,4- ethy lenedioxy- 1 -phenyl .

Values and preferred values of the remainder of the variables of Structural Formulas (H)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A sixth set of values for the variables in Structural Formulas (II)-(XIV) is provided in the following paragraphs:

Each of Y, Q, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 and Ar 1 independently is as described above for the fifth set of values for the variables of Structural Formulas (II) - (XIV).

Each R 4 for Structural Formulas (II), (IV) - (VII), (IX) and (X) is independently i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] p -O- and -[CH 2 ] q -; or ii) an aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ] q .-.

Each R 4 for Structural Formulas (XI) and (XII) is independently an aryl group, a heteroaryl group, a lower arylalkyl group or a lower heteroaryl group, each

of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , -OR 50 , -O(haloalkyl), -SR 50 , -NO 2 , -CN, -N(R 51 ) 2 , -NR 51 C(O)R 50 , -C(O)R 50 , -C(O)OR 50 , -OC(O)R 50 , -C(O)N(R 51 ) 2 , -V 4 -Ar 3 , -V-OR 50 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V 4 -NO 2, -V 4 -CN, -V 4 -N(R 51 ) 2 , -V 4 -NR 51 C(O)R 50 , -V 4 -C(O)R 50 , -V 4 -CO 2 R 50 , -V 4 -OC(O)R 50 , -V 4 -C(O)N(R 5 V, -0-V 4 -Ar 3 , -0-V 5 -N(R 51 ) 2 , -S-V 4 -Ar 3 , -S-V 5 -N(R 51 ) 2 , -N(R 51 )-V 4 -Ar 3 , -N(R 51 )-V 5 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -N(R 51 ) 2 , -NR 51 C(O)-V 4 -Ar 3 , -C(O)-V 4 -N(R 51 ) 2 , -C(O)-V 4 -Ar 3 , -C(O)O-V 5 -N(R 51 ) 2 , -C(O)O-V 4 -Ar 3 , -0-C(O)-V 5 -N(R 51 ) 2 , -0-C(O)-V 4 -Ar 3 , -C(O)N(R 51 )-V 5 -N(R 51 ) 2 , -C(O)N(R 51 )- V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ] q -. Specifically, R 4 is an optionally substituted aryl or an optionally substituted heteroaryl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -0-[CH 2 ] p -0- and -[CH 2 ] q -.

Each R 4 for Structural Formulas (III) and (VIII) independently is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -0-[CH 2 ] r 0- and -[CH 2 ] q -. Values and preferred values of the remainder of the variables of Structural Formulas (H)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

A seventh set of values for the variables in Structural Formulas (H)-(XIV) is provided in the following paragraphs:

Each of Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 and Ar 1 independently is as described above for the sixth set of values for the variables of Structural Formulas (II) - (XIV).

Each Ar 3 is independently a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano,

hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl.

Each R 50 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C 1-C6 haloalkyl.

Values and preferred values of the remainder of the variables of Structural Formulas (H)-(XIV) are each independently as described above in the first set of values for Structural Formula (I). An eighth set of values for the variables in Structural Formulas (H)-(XIV) is provided in the following paragraphs:

Each of Y, Q, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 10 , R 30 , R 31 , R 50 , Ar 1 and Ar 3 independently is as described above for the seventh set of values for the variables of Structural Formulas (II) - (XIV). Each -N(R 2 R 3 ) is independently N-pyrrolidinyl or N-morpholinyl.

R 4 for Structural Formula (II) is an aliphatic group. Specifically, R 4 is a C6- C18 alkyl group or a C6-C8 alkyl group (e.g., C6, C7, C8, C9 or ClO alkyl group).

Each R 4 for Structural Formulas (IX) and (X) is independently an alkyl group, or an optionally substituted phenyl group. Specifically, each R 4 is an unsubstituted alkyl group (e.g., Cl-ClO alkyl), or a phenyl group optionally substituted with one or more substituents selected from the group consisting of -OH, -OCH 3 and -OC 2 H 5 .

Each R 4 for Structural Formulas (XI) and (XII) is an optionally substituted aryl or an optionally substituted heteroaryl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar 3 , -V 4 -Ar 3 , -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -0-V 4 -Ar 3 , -O-[CH 2 ] P -O- and -[CH 2 ] q -.

Specifically, the "alkyl" referred to in the the alkyl, alkoxy, haloalkyl, alkylamino and dialkylamino groups of the exemplaryl substitutents independently is Cl-ClO alkyl, or, alterantively, C1-C6 alkyl.

R 4 for Structural Formula (III) or (VIII) is a biaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy. Specifically, the optionally substituted biaryl group is an optionally substituted

biphenyl group. Alternatively, -(CH 2 ) n -R is , wherein phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy.

Each R 10 for Structural Formulas (XIII) and (XIV) is independently a C1-C6 alkyl group; an optionally substituted phenyl group; or an optionally substituted, monocyclic or bicyclic heteroaryl group. Suitable substituents, incluidng specific substituents, for each of the alkyl, phenyl and the heteroaryl groups are as described in the first set of values for R 4 of Structural Formula (I). Specifically, exemplary substituents for each of the alkyl, phenyl and the heteroaryl groups are as described above in the seventh set of values for R 8 for Structural Formulas (XIII) and (XIV). For Structural Formulas (III) and (VIII), m is 1, 2 or 3. For Structural Formulas (IX) and (X), each n is independently 1, 2, 3, 4 or 5.

Specifically, for Structural Formula (IX), n is 1, 2, 3 or 4. Specifically, for Structural Formula (X), n is 3, 4 or 5.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

In a ninth set, values and preferred values of each of Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 30 , R 31 , R 32 , R 40 , R 41 , R 42 , R 50 , R 51 , R 52 , Ar 1 , Ar 2 , and Ar 3 of Structural Formulas (H)-(XIV) independently are as described above for the first set, second set, third set or fourth set of values for the variables of Structural Formula (I).

Values and preferred values of the remaining variables of Structural Formulas (II)- (XIV) each independently are as described above for the first set, second set, third set, fourth set, fifth set, six set, seventh set or an eighth set of values for the variables of Structural Formulas (H)-(XIV).

Certain specific examples of ceramide derivatives that can be employed in the invention are as follows:

or a pharmaceutically acceptable salt thereof, wherein each ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl and alkoxy.

In a third embodiment, the compound of the invention is represented by Structural Formula (XXI):

(XXI)

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formula (XXI) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. k' is 0, 1 or 2. k" is 0, 1 or 2. Preferably, k" is 0 or 1. More preferably k" is 1. m' is 0, 1 or 2. Preferably, m 1 is 1.

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

Y is -H, -C(O)R, -C(O)OR or -C(O)NRR', preferably -H.

Values and preferred values for A, B, k', k" and m' are each independently as described above in the first set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

R 30 is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl ; or a C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R 30 is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl; or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, R 30 is independently hydrogen; or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C 1 -C6 haloalkoxy, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylcarbonyl and C1-C6 haloalkyl. Even more preferably, R 30 is independently hydrogen, or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy. Values and preferred values for A, B, Y, k 1 , k" and m' are each independently as described above in the second set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

Y is -H.

Values and preferred values for R 30 , A, B, k', k" and m' are each independently as described above in the third set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

In a fourth embodiment, the compound of the invention is represented by Structural Formula (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI):

(XXII)

(XXIII)

(XXIV)

(XXV)

(XXVI)

(XXVIII)

(XXXI) or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XXII) - (XXXI) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Each R 30 is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl; or a Cl-ClO alkyl group optionally substituted with one or more

substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R 30 is independently hydrogen; or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, R 30 is independently hydrogen, or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy and hydroxy.

Each k' is independently 0, 1 or 2.

Each k" is independently 0, 1 or 2.

Each m' is independently 0, 1 or 2. Preferably, each m' is 1.

Each n is independently 1 , 2, 3, 4, 5 or 6. Preferably, each n in Structual Formulas (XXV) and (XXVI) is independently 1 , 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII) - (XXXI) are each independently as described above in the first set of values for Structural Formula (I). A second set of values for the variables in Structural Formulas (XXII) -

(XXXI) is provided in the following paragraphs:

Each R 4 in Structural Formulas (XXII) -(XXVIII) is independently an aliphatic or aryl group each optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I). Preferably, each R 4 in Structural Formulas (XXII) -(XXVIII) is independently an optionally substituted aryl or an optionally substituted lower arylalkyl group. Examples of suitable substituents are as described in the first set of values for Structural Formula

(I). Each R 4 in Structural Formulas (XXIX) -(XXXI) is independently an aryl group optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R 5 and R 6 in Structural Formulas (XXII), (XXIII), (XV) and (XXIX) are each independently -H, -OH, a halogen, a C1-C6 alkoxy group or a C1-C6 alkyl group.

For Structural Formula (XXVIII), R 7 is -H or C1-C6 alkyl, preferably -H. Values and preferred values for A, B, R 30 , k', k", m' and n are each independently as described above in the first set of values for the variables in Structural Formulas (XXII) - (XXXI). Preferably, each n in Structual Formulas (XXV) and (XXVI) is independently 1 , 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5. Values and preferred values for the remainder of the variables of Structural

Formulas (XXII) - (XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (XXII) - (XXXI) is provided in the following paragraphs: Each R 4 in Structural Formulas (XXII) -(XXVIII) is independently an optionally substituted aryl or an optionally substituted lower arylalkyl group. Example of suitable substituents are as described in the first set of values for Structural Formula (I). Each R 4 in Structural Formulas (XXIX) -(XXXI) is independently an aryl group optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R 5 and R 6 for Structural Fomrulas (XXII), (XXIII), (XXV) and (XXIX) are each independently -H, -OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (XXVIII), R 7 is -H . Q in Structural Formula (XXII) is -O- , -S-, -C(O)-, -C(S)-, -NR 7 (CO)- or

-C(O)NR 7 -.

Values and preferred values for A, B, R 30 , k', k", m' and n are each independently as described above in the first set of values for the variables in Structural Formulas (XXII) - (XXXI). Preferably, each n in Structual Formulas (XXV) and (XXVI) is independently 1 , 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas (XXII) - (XXXI) is provided in the following paragraphs:

Each R 4 in Structural Formulas (XXII) -(XXVIII) is independently selected from the group consisting of:

wherein each x is independently 0 or 1, and each of rings A-Z5 is optionally and independently substituted.

Each R 4 in Structural Formulas (XXIX) -(XXXI) is independently selected from the group consisting of:

wherein each of rings A-Z5 is optionally and independently substituted. Preferably, each R 4 in Structural Formulas (XXII) - (XXXI) is independently monocyclic.

Example of suitable substituents for rings A-Z5 are as described in the first set of values for Structural Formula (I).

Preferably, in Structural Formulas (XXIX) - (XXXI), each of rings A-Z5 is optionally and independently substituted with one or more substituents selected from Ar 3 and Ar 3 -Ar 3 wherein values and preferred values of Ar 3 are as described above for the first set of values for Structural Formula (I). Preferably, Ar 3 is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-ClO alkyl, Cl-ClO haloalkyl, hydroxy, Cl-ClO alkoxy, nitro, cyano, Cl-ClO alkoxycarbonyl, Cl-ClO alkylcarbonyl, Cl-ClO haloalkoxy,

amino, Cl-ClO alkylamino and Cl-ClO dialkylamino. More preferably, Ar 3 is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C 1 -C4 alkoxycarbonyl, C 1 -C4 alkylcarbonyl, C 1 -C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Values and preferred values for R 5 , R 6 , R 7 , R 30 , Q, k\ k", m' and n are each independently as described above in the third set of values for the variables in Structural Formulas (XXII) - (XXXII). Preferably, each n in Structual Formulas (XXV) and (XXVI) is independently 1 , 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII) - (XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A fifth set of values for the variables in Structural Formulas (XXII) - (XXXI) is provided in the following paragraphs:

Each R 4 in Structural Formulas (XXII) -(XXVIII) is independently

wherein x is 0 or 1.

Each R 4 in Structural Formulas (XXIX) - (XXXI) is independently

Each ring A is optionally substituted. Example of suitable substituents for rings A are as described in the first set of values for Structural Formula (I). Perferably, ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

Ar 3 is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Values and preferred values for A, B 5 R 5 , R 6 , R 7 , R 30 , Q, k', k", nϊ and n are each independently as described above in the fourth set of values for the variables in Structural Formulas (XXII) - (XXXI).

Values and preferred values for the remainder of the variables of Structural Formulas (XXII) - (XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A sixth set of values for the variables other than A, B, k', k" and m' in Structural Formulas (XXII) - (XXXI) is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for the varibales for Structural Formula (I), and values and preferred values for A, B, k', k" and m' are each independently as described above in the first set of values for the variables in Structural Formulas (XXII) - (XXXI).

In an fifth embodiment, the compound of the invention is represented by Structural Formula (XXXII) or (XXXIII ):

(XXXIII)

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XXXII) - (XXXIII) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C 1 -C6 alkoxy or C 1 -C6 haloalkoxy.

Each R 30 is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl- C6 haloalkyl; or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R 30 is independently hydrogen; or a Cl-ClO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C 1 -C6 haloalkyl. More preferably, R 30 is independently hydrogen, or a C 1 -C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy. Each k 1 is independently 0, 1 or 2. Each k" is independently 0, 1 or 2. Each m' is independently 0, 1 or 2. Each q is independently 0, 1, 2, 3, 4, 5 or 6. Each R 8 independently is -H, or an optionally substituted aryl or an optionally substituted lower alkyl group. Examples of suitable substituents are as described for the first set of values for Structural Formula (I). Preferably, each R independently is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted. Examples of suitable substituents for R 8 are as provided above in the first set of values for R 4 in

Structural Formula (I). More preferably, each R 8 is independently a group. Alternatively, each R 8 is independently an aryl group substituted with Ar 3 , such as a phenyl group substituted with Ar 3 , where values and preferred values of Ar 3 are as described above in Structural Formula (I).

Values and preferred values for the remainder of the variables of Structural Formulas (XXXII) - (XXXIII) are each independently as described above in the first set of values for Structural Formula (I).

In one preferred embodiment, each k' in Structural Formulas (XXI) - (XXXIII) is independently 0 or 1. Preferably, when k 1 is 1 , each A independently is positioned at a meta position of the phenyl ring.

In another perferred embodiment, each k" in Structural Formulas (XXI) - (XXXIII) is independently 0 or 1 , more preferably 1.

In yet another perferred embodiment, each m' in Structural Formulas (XXI) - (XXXIII) is independently 1.

In yet another preferred embodiment, each k 1 in Structural Formulas (XXI) - (XXXHI) is independently 0 or 1 ; and each k" in Structural Formulas (XXI) - (XXXIII) is independently 0 or 1 , more preferably 1.

In yet another preferred embodiment, in Structural Formulas (XXI) - (XXXIII):

Each R 30 is independently hydrogen or a C1-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, nitro, cyano, hydroxy, C1-C3 haloalkoxy, C1-C3 alkoxycarbonyl and C1-C3 alkylcarbonyl; each k 1 in Structural Formulas (XXI) - (XXXIV) is independently 0 or 1. Preferably, when k' is 1, each A independently is positioned at a meta position of the phenyl ring; and each k" in Structural Formulas (XXI) - (XXXIV) is independently 0 or 1, preferably 1.

In yet another preferred embodiment, in Structural Formulas (XXI) - (XXXIII): Each -OR 30 is independently -OH or -O-C 1 -C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3 C1-C3 alkoxy, hydroxy and C1-C3 haloalkoxy; each k' in Structural Formulas (XXI) - (XXXIII) is independently 0 or 1. Preferably, when k' is 1 , each A is independently positioned at a meta position of the phenyl ring; and each k" in Structural Formulas (XXI) - (XXXIII) is independently 0 or 1 , preferably 1.

In one more preferred embodiment, the compound of the invention is represented by Structural Formula (XVIA) or (XVIB):

or a pharmaceutically acceptable salt thereof, wherein: Q is -O- , -C(O)- or -NH, specifically, -O- or -C(O)-; r and s are each independently 1, 2, 3 or 4; each n independently is 1, 2, 3, 4, 5 or 6; and R 4 has values and preferred values provided above in the fist set of values for Structural Formula (I).

In another more preferred embodiment, the compound of the invention is represented by Structural Formula (XVIC) or (XVID):

or a pharmaceutically acceptable salt thereof, wherein:

Q is -O- , -C(O)- or -NH, specifically, -O- or -C(O)-; r and s are each independently 1, 2, 3 or 4; each n independently is 1 , 2, 3, 4, 5 or 6;

R 4 has values and preferred values provided above in the fist set of values for Structural Formula (I); and

B is is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. Preferably, B is halogen, hydroxy, C1-C5 alkoxy or C1-C5 haloalkoxy.

In another more preferred embodiment, the compound of the invention is represented by Structural Formula (XVII), (XVIII), (XIX) or (XX):

(XVII)

(XVIII)

XIX or

or a pharmaceutically acceptable salt thereof, wherein phenyl ring A is optionally substituted; each n is 1, 2, 3, 4, 5, or 6; and k is 0, 1 or 2. Values and preferred values of suitable substituents of phenyl ring A are as described above in the first set of values for Structural Formula (I).

In all of the embodiments described above for Structural Formulas (XXI) - (XXXIII) and (XVIC) - (XVID), the heterocyclic ring represented by

can be replaced with a bridged heterobicyclic ring comprising 5- 12 ring carbon atoms and 1 or 2 nitrogen atoms. The invention also includes compounds represented by Structural Formulas (XXI) - (XXXIII) and (XVIC) -

(XVID) with this replacement of with a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms. Values, including preferred values, for the variables other than B, k" and m' in Structural

Formulas (XXI) - (XXXIII) and (XVIC) - (XVID) are as defined above with respect to Structural Formulas (XXI) - (XXXIIII) and (XVIC) - (XVID).

Similary, in all of the embodiments described above for Structural Formulas (I) - (XX), the non-aromatic heterocyclic ring represented by -NR 2 R 3 can be a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms.

Examples of bridged eterobicyclic ring comprising 5-12 ring carbon atoms

and 1 or 2 nitrogen atoms include and

The bridged bicyclic ring carbon atoms can be optionally subsituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, -OH, -SH, -O(C1-C6 alkyl), -S(Cl-CO alkyl), -O(C1-C6 haloalkyl), -S(Cl-CO haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring carbon atoms can be optionally subsituted with one or more substituents selected from the group consisting of halogen, -OH, -0(C 1 -C6 alkyl) and -0(C 1 -C6 haloalkyl). The bridged bicyclic ring nitrogen atoms can be optionally subsituted with one or more substituents selected from the group consisting of C1-C6 alkyl and phenyl, the alkyl being optionally substituted with halogen, cyano, nitro, -OH, -SH, -O(C1-C6 alkyl), -S(Cl-Co alkyl), -O(C1-C6 haloalkyl), -S(Cl-Co haloalkyl), phenyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino, and the phenyl being optionally substituted with halogen, cyano, nitro, -OH, -SH, -O(C1-C6 alkyl), -S(Cl-Co alkyl), -O(C1-C6 haloalkyl), -S(Cl-Co haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring nitrogen atoms can be optionally subsituted with C1-C6 alkyl that is optionally substituted with halogen, -OH, -0(C 1 -C6 alkyl) and -O(C 1 -C6 haloalkyl).

In another embodiment, the compound of the invention is represented by a structural formula selected from Structural Formulas (I) - (VIII) and (XI) - (XV), wherein values, including preferred values, of the variables in the structural

formulas, other than R 30 , R 31 and R 32 for the substituents of R 1 , are independently as defined in each embodiment described above for Structural Formulas (I) - (VIII) and (XI) - (XV). In this embodiment, each R 30 is independently: i) hydrogen; ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each R 31 is independently R 30 , -CO 2 R 30 , -SO 2 R 30 or -C(O)R 30 ; or -N(R 31 ) 2 taken together is an optionally substituted non- aromatic heterocyclic group. Each R is independently: i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each of the phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl for the substituents of the alkyl group respresented by R 30 and R 32 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C5 alkylamino, C1-C5 dialkylamino, (C1-C5 alkoxy)carbonyl and (C1-C5 alkyl)carbonyl. Each of the alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl for the substituents of the alkyl group respresented by R 30 and R 32 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, phenyl, C1-C5 alkoxy, C1-C5 haloalkoxy, phenylamino, C1-C5 alkylamino, C1-C5 dialkylamino, diphenylamino, (C1-C5 alkoxy)carbonyl, (C1-C5 alkyl)carbonyl, benzoyl and phenoxycarbonyl.

Specific examples of the compounds of the invention are shown below:

E(25) and pharmaceutically acceptable salts thereof.

Other specific examples of the compounds of the invention include compounds shown in Tables 1, 2 and 3 and those exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

The ceramide derivatives disclosed herein that contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. When the ceramide derivatives are depicted or named herein without indicating the stereochemistry, it is to be understood that stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed. For example, the compound represented by Structural Formula (I) below has chiral centers 1 and 2. Accordingly, the ceramide derivatives depicted by Structural Formula (I) include the (IR, 2R), (IR, 2S), (IS, 2R) or (I S, 2S) stereoisomer and mixtures thereof.

In some specific embodiments, the ceramide derivatives represented by Structural Formula (I) are (IR, 2R) stereoisomers.

As used herein, a racemic mixture means 50% of one enantiomer and 50% of its corresponding enantiomer relative to all chiral centers in the molecule. Enantiomeric and diastereomeric mixtures can be resolved into their

component enantiomers or stereoisomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enatiomer over the weight of the enantiomer plus the weight of its optical isomer.

Pharmaceutically acceptable salts of the ceramide derivatives can be used in the methods disclosed herein. The ceramide derivatives that include one or more basic amine groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic, and tartaric acids). The ceramide derivatives that include one or more acidic groups, such as carboxylic acids, can form pharamceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo. An "aliphatic group" is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic. When

straight chained or branched, an aliphatic group typically contains between 1 and 20 carbon atoms, typically between 1 and 10 carbon atoms, more typically between 1 and 6 atoms. When cyclic, an aliphatic group typically contains between 3 and 10 carbon atoms, more typically between about 3 and 7 carbon atoms. A "substituted aliphatic group" is substituted at any one or more "substitutable carbon atom". A "substitutable carbon atom" in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms. One or more hydrogen atoms can be optionally replaced with a suitable substituent group. A "haloaliphatic group" is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group.

The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", "arylalkyl", "alkylamine", "cycloalkyl", "dialkyamine", "alkylamino", "dialkyamino" "alkylcarbonyl", "alkoxycarbonyl" and the like, as used herein means saturated straight-chain, cyclic or branched aliphatic group. As used herein, a Cl- C6 alkyl group is referred to "lower alkyl." Similarly, the terms "lower alkoxy", "lower haloalkyl", "lower arylalkyl", "lower alkylamine", "lower cycloalkylalkyl", "lower dialkyamine", "lower alkylamino", "lower dialkyamino" "lower alkylcarbonyl", "lower alkoxycarbonyl" include straight and branched saturated chains containing one to six carbon atoms, and cyclic saturated chains containing three to six carbon atoms.

The term "alkoxy" means -O-alkyl; "hydroxyalkyl" means alkyl substituted with hydroxy; "aralkyl" means alkyl substituted with an aryl group; "alkoxyalkyl" mean alkyl substituted with an alkoxy group; "alkylamine" means amine substituted with an alkyl group; "cycloalkylalkyl" means alkyl substituted with cycloalkyl; "dialkylamine" means amine substituted with two alkyl groups; "alkylcarbonyl" means -C(O)-R*, wherein R* is alkyl; "alkoxycarbonyl" means -C(O)-OR*, wherein R* is alkyl; and where alkyl is as defined above.

The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F.

The term "acyl group" means -C(O)R + , wherein R* is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.

An "alkylene group" is represented by -[CH 2 ] Z -, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.

An "alkenylene group" is an alkylene in which at least a pair of adjacent methylenes are replaced with -CH=CH-.

An "alkynylene group" is an alkylene in which at least a pair of adjacent methylenes are replaced with -C≡C-. The term "aryl group" used alone or as part of a larger moiety as in

"arylalkyl", "arylalkoxy", or "aryloxyalkyl", means carbocyclic aromatic rings. The term "carbocyclic aromatic group" may be used interchangeably with the terms "aryl", "aryl ring" "carbocyclic aromatic ring", "aryl group" and "carbocyclic aromatic group". An aryl group typically has 6-14 ring atoms. A "substituted aryl group" is substituted at any one or more substitutable ring atom. The term "C 6-I4 aryl" as used herein means a monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthracenyl, 1,2-dihydro naphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. The term "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group", used alone or as part of a larger moiety as in "heteroarylalkyl" or "heteroarylalkoxy", refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1 - 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. The term "5-14 membered heteroaryl" as used herein means a monocyclic, bicyclic or tricyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteroatoms independently selected from N, NH, N(C 1-6 alkyl), O and S.

Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3- furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),

isoxazolyl( e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2- oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3-thienyl. Examples of monocyclic six-membered nitrogen-containing heteraryl groups include pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

Typically, the aryl and heteroaryl groups are C6-C14 aryl and 5-14 membered heteroaryl groups, respectively. Specific examples of the aryl and heteroaryl groups include:

wherein each of rings A-Z5 is optionally and independently substituted. Suitable substituents for rings A-Z5 are as described above. In a specific embodiment, the aryl and heteroaryl groups include monocyclic rings A, B, E, F, G, H, I, N, O, V, and W, wherein each ring is optionally and independently substituted. The aryl and heteroaryl groups can be optionally substituted. In certain embodiments, the aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, amino, C 1-20 alkylamino, C 1-20 dialkylamino, C 1-20 alkoxy, (C 1-10 alkoxy)Ci. 20 alkyl, C 1-20 haloalkoxy, (C 1-10 haloalkoxy)C 1-20 alkyl and C 1-20 haloalkyl. More specific substituents for the aryl and heteroaryl groups include halogen, nitro, cyano, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, amino, C 1-10 alkylamino, C 1-10 dialkylamino, C 1-10 alkoxy, (C 1-6 alkoxy)C M O alkyl, C 1-10 haloalkoxy, (C 1-6 haloalkoxy)C MO alkyl and C 1-10 haloalkyl. More pecific substituents include C 1-10 alkyl, -OH, C 1-10 alkoxy, C 1-10 haloalkyl, halogen, C 1-10 haloalkoxy,amino, nitro and cyano.

The term "non-aromatic heterocyclic group", used alone or as part of a larger moiety as in "non-aromatic heterocyclylalkyl group", refers to non-aromatic ring systems typically having five to twelve members, preferably five to seven, in which one or more ring carbons, preferably one or two, are each replaced by a heteroatom such as N, O, or S. A non-aromatic heterocyclic group can be monocyclic or fused bicyclic. A "nitrogen-containing non-aromatic heterocyclic group" is a non- aromatic heterocyclic group with at least one nitrogen ring atom.

Examples of non-aromatic heterocyclic groups include (tetrahydrofuranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), [1,3]- dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, tetrahydrothienyl (e.g., 2- tetrahydrothienyl, 3-tetrahydrothieneyl), azetidinyl (e.g., N-azetidinyl, 1-azetidinyl, 2-azetidinyl), oxazolidinyl (e.g., N-oxazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5- oxazolidinyl), morpholinyl (e.g., N-morpholinyl, 2-morpholinyl, 3-morpholinyl), thiomorpholinyl (e.g., N-thiomorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl), pyrrolidinyl (e.g., N-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) piperazinyl (e.g., N- piperazinyl, 2-piperazinyl), piperidinyl (e.g., N-piperidinyl), 2-piperidinyl, 3-

piperidinyl, 4-piperidinyl), thiazolidinyl (e.g., 4-thiazolidinyl), diazolonyl and N- substituted diazolonyl. The designation 'W on N-morpholinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-piperazinyl, iV-piperidinyl and the like indicates that the non- aromatic heterocyclic group is attached to the remainder of the molecule at the ring nitrogen atom.

The ceramide derivatives disclosed herein can be prepared by processes disclosed in the art, for example, in U.S. 5,849,326; U.S. 5,916,91 1 ; U.S.6,255,336; U.S. 7,148,251 ; U.S. 6,855,830; U.S. 6,835,831 ; and U.S. Provisional Application No. 60/932,370, filed May 31, 2007, the entire teachings of which are incorporated herein by reference. It is noted that the definitions of terms provided herein prevail over those of the references incorporated herein by reference.

The ceramide derivatives disclosed herein or salts thereof can be administered by an appropriate route. Suitable routes of administration include, but are not limited to, orally, intraperitoneally, subcutaneously, intramuscularly, intradermally, transdermally, rectally, sublingually, intravenously, buccally or via inhalation. Typically, the compounds are administered orally or intravenously.

As used herein a "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, such as a companion animal (e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep, pigs, horses, and the like) or a laboratory animal (e.g., rats, mice, guinea pigs, and the like). Subject and patient are used interchangeably.

"Treatment" or "treating" refers to both therapeutic and prophylactic treatment.

An effective amount of a disclosed ceramide derivative depends, in each case, upon several factors, e.g., the health, age, gender, size and condition of the subject to be treated, the intended mode of administration, and the capacity of the subject to incorporate the intended dosage form, among others. An effective amount of an active agent is an amount sufficient to have the desired effect for the condition being treated, which can either be treatment of an active disease state or prophylactically inhibiting the active disease state from appearing or progessing. For example, an effective amount of a compound for treating lupus is the quantity of compound that

results in a slowing in the progression of lupus, a reversal of the state of lupus, and/or a reduction in the severity of the symptoms associated with lupus.

Typically, the ceramide derivatives disclosed herein are administered for a sufficient period of time to achieve the desired therapeutic or prophylactic effect. Effective amounts of the disclosed ceramide derivatives typically range between 0.001 mg/kg per day and 500 mg/kg per day, such as between 0.1 and 500 mg/kg body weight per day, between 0.1 and 100 mg/kg body weight per day or between 0.01 mg/kg per day and 50 mg/kg per day. The disclosed ceramide derivatives may be administered continuously or at specific timed intervals. For example, the ceramide derivatives may be administered 1, 2, 3, or 4 times per day, such as, e.g., a once-daily or twice-daily dosage regimen. Commercially available assays may be employed to determine optimal dose ranges and/or schedules for administration. For example, assays for measuring blood glucose levels are commercially available (e.g., OneTouchrUItra , Lifescan, Inc. Milpitas, CA). Kits to measure human insulin levels are also commercially available (Linco Research, Inc. St. Charles, MO).

Additionally, effective doses may be extrapolated from dose- response curves obtained from animal models (see, e.g., Comuzzie et al, Obes. Res. 11 (1 ):75 (2003); Rubino et al., Ann. Surg. 240(2):389 (2004); Gill-Randall et al, Diabet. Med. 21 (7):759 (2004), the entire teachings of which are incorporated herein by reference). Therapeutically effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219 (1996), the entire teachings of which are incorporarted herein by reference) and Table A below for equivalent surface area dosage factors.

Typically, the pharmaceutical compositions of the ceramide derivatives disclosed herein can be administered before or after a meal, or with a meal. As used herein, "before" or "after" a meal is typically within two hours, preferably within one hour, more preferably within thirty minutes, most preferably within ten minutes of commencing or finishing a meal, respectively.

In one embodiment, the method of the present invention is a mono-therapy where the disclosed ceramide derivatives are administered alone. Accordingly, in this embodiment, the ceramide derivative is the only pharmaceutically active ingredient being administered for the treatment lupus.

In another embodiment, the method of the invention is a co-therapy with other therapeutically active drug(s). The disclosed ceramide derivatives are coadministered simultaneously as a single dosage form, simultaneously as separate dosage forms, or consecutively as separate dosage forms, with other agents that ease the symptoms and/or complications associated with lupus. Lupus is an autoimmune disease that can affect various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. There are several types of lupus, including discoid (or cutaneous) lupus erythematosus, systemic lupus erythematosus (SLE), drug- induced lupus erythematosus and Neonatal lupus. The common initial and chronic symptoms associated with lupus include fever, malaise, joint pains, myalgias and fatigue. Other signs and symptoms associated with lupus includes dermatological manifestations (e.g., rash), musculoskeletal manifestations (e.g., joint pain), hematological manifestations (e.g., anemia and iron deficiency), cardiac manifestations (e.g., inflammation of various parts of the heart, such as pericarditis, myocarditis and endocarditis), pulmonary manifestations (e.g., pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse interstitial lung disease, etc.), hepatic involvement, renal involvement (e.g., hematuria, proteinuria, membranous glomerulonephritis with 'wire loop 1 abnormalties, or acute or chronic renal impairment), neurological manifestations (e.g., seizures or psychosis), and T-cell abnormalties (e.g., deficiency in CD45 phosphatase, or increased expression of CD40 ligand). Other additional abnormalities associated with lupus include increased expression of FcεRIγ, increased and sustained calcium levels

in T cells, moderate increase in inositol triphosphate, reduction in PKC phosphorylation and reduction in Ras-MAP kinase signaling. Examples of the agents that can be co-administered with the compounds of the invention include, but are not limited to, anti-inflammatory drugs, hypolipidemic agents, immuno suppressive agents, over-the counter pain medications, antibiotics, antimicrobials, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin II antagonists such as losartan, and calcium channel blockers such as diltiazem. Examples of pain medications include acetaminophen, aspirin, naproxen, ibuprofen and COX-2 selective inhibitors such as rofecoxib, celecoxib and valdecoxib. Examples of antibiotics and antimicrobials include cephalosporins, penicilin derivatives, aminoglycosidesm ciprofloxacin, erythromycin, chloramphenicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofloxacin, streptomycin, rifamycin, amphotericin B, griseofulvin, cephalothin, cefazolin, fluconazole, clindamycin, erythromycin, bacitracin, vancomycin and fusidic acid Examples of thiazide diuretics include bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone and trichlormethiazide. Examples of angiotensin-converting enzyme inhibitors include benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. Examples of anti-inflammation drugs include corticosteroids and nonsteroidal anti-inflammation drugs (e.g., aspirin, naproxen sodium and ibuprofen). Examples of immunosuppressive agents include azathiopine (Imuran), cyclophosphamide (Cytoxan), methotrexate (Rheumatrex), chlorambucil (Leukeran), cyclosporine (Neoral, Sandimmune) and mycophenolate mofetil (CellCept). Examples of hypolipidemic agents include HMG-CoA reductase inhibitors, such as statins. Some specific examples of statins include Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin and Simvastatin.

In one specific embodiment, the ceramide derivatives disclosed herein are co- administered with one or more drugs chosen from nonsteroidal anti-inflammation drugs, antimalarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids and immunosuppressive medications. In another specific embodiment, the ceramide

derivatives described herein are co-administered with one or more of hypolipidemic agents, such as HMG-CoA reductase inhibitors (e.g., statins).

Pharmaceutical compositions of the disclosed ceramide derivatives optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). The carriers, diluents and/or excipients are "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. The pharmaceutical compositions can conveniently be presented in unit dosage form and can be prepared by any suitable method known to the skilled artisan. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the compounds disclosed herein with the carriers, diluents and/or excipients and then, if necessary, dividing the product into unit dosages thereof.

The pharmaceutical compositions of the disclosed ceramide derivatives can be formulated as a tablet, sachet, slurry, food formulation, troche, capsule, elixir, suspension, syrup, wafer, chewing gum or lozenge. A syrup formulation will generally consist of a suspension or solution of the compounds of the invention described herein or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent. Where the composition is in the form of a tablet, one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose. Where the composition is in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Though the above description is directed toward routes of oral administration of pharmaceutical compositions consistent with embodiments of the invention, it is understood by those skilled in the art that other modes of administration using vehicles or carriers conventionally employed and which are inert with respect to the compounds of the invention may be utilized for preparing and administering the pharmaceutical compositions. For example, the pharmaceutical compositions of the invention may also be formulated for rectal administration as a suppository or retention enema, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Also, the pharamceutical compositions of the invention can be formulated for injection, or for transdermal or trnasmucosal administration. Illustrative of various modes of administration methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18 th ed. (1990), the disclosure of which is incorporated herein by reference.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION

Example 1. : General Methods for the Preparation of Compounds of the Invention

A general method for the synthesis of final compounds is depicted in Scheme 1. A general method for the preparation of the compounds of the invention involves the reaction of the amine of type EVII with the appropriate reagent. The amine type EVII, such as (IR, 2R)-2-amino-(2,3-dihydrobenzo [β][1,4[dioxin-6-yl)-3- (pyrrolidin-1-yl) propan-1-ol, can be prepared according to the preparation of intermediate 4 of US patent 6,855,830 (the entire teachings of which are incorporated herein by reference), or by using the general synthetic procedures depicted in schemes 2-5. Final amide compounds, EIX can be prepared by reaction of the amine EVII with the corresponding acylating agent using standard reaction conditions for the formation of an amide. The urea compounds, EIIX can be prepared by reaction of the amine EVII with the corresponding isocyanate. The

carbamates, EX can be prepared by reaction of the amine EVII with the corresponding chloroformate.

Example IA. Synthesis of the Compounds of the Invention: General Methods for the Preparation of Amide Analogs

Method 1

A mixture of Compound EVII (1 mmol), such as (IR, 2R)-2-amino-1-(2,3- dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan- 1-ol, prepared according to the preparation of intermediate 4 of US patent 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, an acid (1.2 mmol), DCC

(dicyclohexylcarbodiimide, 1.2 mmol) and HOBT (1 -hydroxy benzotriazole, 1.2 mmol) was dissolved in CH 2 Cl 2 (5 ml). The mixture was stirred at room temperature and monitored by TLC (thin liquid chromatography) for completion.

After completion the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH 2 Cl 2 /MeOH/NH 4 OH).

Method 2

A mixture of Compound EVII (1 mmol), such as (IR, 2R)-2-amino-1-(2,3- dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrτolidin-1-yl)propan -1-ol, prepared according to the preparation of intermediate 4 of US patent 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, an acid (1.2 mmol) and DCC

(dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CHCl 3 (5 ml). The mixture was placed in the microwave reactor (T = 120 °C, time = lmin) and it was then filtered and purified by column chromatography using, for example, a mixture of (CH 2 Cl 2 /MeOH/NH 4 OH).

Method 3

A mixture of Compound EVII (1 mmol), such as (IR, 2R)-2-amino-1-(2,3- dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan- 1-ol, prepared according to the preparation of intermediate 4 of US patent 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, (1.2 mmol) and K 2 CO 3 (2 mmol) was suspended in THF (5 ml). The mixture was stirred at room temperature and monitored by TLC for completion. After completion, the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH 2 Cl 2 ZMeOHZNH 4 OH).

Method 4

Compound EVII, such as (IR, 2R)-2-amino-1-(2,3-dihydro-benzo[l ,4] dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol, prepared according to the preparation of intermediate 4 of US patent 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, was coupled with a variety of N-hydroxysuccinamide esters in methylene chloride under an atmosphere of nitrogen, for example, for 18 to 24 hours depending on the ester used.

Preparation of N-hydroxysuccinamide esters

Various mono- and di-keto acids were coupled with N-hydroxysuccinamide in the presence of N, N '-dicyclohexylcarbodiimide in ethyl acetate under an

atmosphere of nitrogen for 18 hours. The products were filtered to remove the dicyclohexylurea. The identity of these esters was confirmed by 1 H NMR and the crude material was then used in the preparation of amide analogs without further purification.

Example IB. Alternative Synthetic Method for the Prepartion of Intermediate EVIL Synthetic Route 1

An alternative general synthesis of Compound EVII is depicted in Scheme 2. Treatment of (R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid with EDCI and N,O-dimethylhydroxyamine gave the weinreb amide EI in excellent yield. The primary alcohol was protected as the TBDMS ether EII in excellent yield by reaction with TBDMSCl in DMF. Reaction of EII with a grignard at low temperature gave EIII in good to excellent yields. Steroselective reduction of EIII and with L-selectride at -70C gave EIV in good to excellent yield and selectivity. Compound EV was obtained in good to excellent yields after deprotection with acetic acid. Reaction with mesylate chloride and a suitable amine produced EVI in good to excellent yield. Finally, deprotection to the primary amine EVII was done in the microwave oven using NaOH aqueous solution in methanol at 150 °C for one to three minutes depending on the specific compound.

Scheme 2

Example IB. Alternative Synthetic Method for the Prepartion of Intermediate EVIL Synthetic Route 2:

An alternative general synthesis of Compound EVII is depicted in Scheme 3. Intermediate AI was obtained with excellent diastereoselectivity (96:4) by reduction of compound A with LiA1H 4 followed by reaction with an aldehyde in the presence of CuI and Me 2 S. Mesylate intermediate AIII was obtained by reaction with Amberlyst 15 followed by reaction with MsCl in pyridine. The final compound EVII was obtained by reaction with pyrrolidine and removal of the CBz by hydrogenation.

Example IB. Alternative Synthetic Method for the Prepartion of Intermediate EVII. Synthetic Route 3

A general alternative route for synthesis of compound EVII is depicted in Scheme 4. Intermediate EIV was obtain as shown in Scheme 4 was cycled into oxazolidinone B using sodium hydride in a DMF/THF solution. Deprotection of the primary alcohol by reaction with nBi^NF, followed by formation of the tosylate by reaction with tosyl chloride in pyridine, finally, displacement of the tosylate by an appropriate amine afforded compound Bl in good to excellent yield. Hydrolysis of the oxazolidinone with LiOH in a water ethanol mixture gave compound EVIL

Example IB. Alternative Synthetic Method for the Prepartion of Intermediate EVIL Synthetic Route 4

An alternative general synthesis of Compound EVII is depicted in Scheme 5. An aldehyde (2 equiv) is condensed with the chiral morpholinone in toluene with removal of water to provide the fused cycloadduct 2. Treatment of 2 with hydrogen chloride in an alcohol solvent such as methanol provides amino acid 3. Removal of the N-benzyl functionality can be accomplished with hydrogen in the presence of a palladium catalyst to afford 4. Cyclization of 4 with triphosgene and base provides ester 5. The ester functionality can be reduced with sodium borohydride, and the resulting alcohol converted to an appropriate leaving group (i.e. tosylate or iodide). Reaction of 6 with a suitable amine in the presence of excess base (e.g. K 2 CO 3 ) in a polar solvent (e.g. DMSO or CH 3 CN) affords 7. Final deprotection under basic conditions affords Compound EVII analogs suitable for conversion to the desired amide final products.

Example 1C. Preparation of Compound EVII using Scheme 2.

Preparation of EII: (R)-benzyl 3,8,8.9,9-pentamethyl-4-oxo-2.7-dioxa-3-aza-8- siladecan-5-ylcarbamate

Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3- hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert- butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chlroride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). 1 H NMR (400 MHz, CDCl 3 ) δ= 0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).

Preparation of EIII: (R)-benzyl 3-(tert-butyldimethylsilyloxy)- l-(23- dihydrobenzo[βl [ 1 ,4]dioxin-6-yl ' )- 1 -oxopropan-2-ylcarbamate.

(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)magnesium bromide (26 g, 78 mmol) dissolved in 40 mL of THF (tetrahydrofuran) under a nitrogen atmosphere was cooled down to -70 °C and (R)-benzyl 3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza- 8-siladecan-5-ylcarbamate (12.3 g, 31mmol) dissolved in THF (13 ml) were added dropwise. The reaction mixture was allowed to warm up to -15 °C and left to react for 12 hrs followed by stirring at room temperature for 2 hrs. After cooling the reaction mixture to -40 °C it was quenched using aqueous ammonium chloride and the aqueous layer was extracted with EtOAc dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography using 25% EtOAc-hexanes to give pure product (13 g, 88% yield). 1 H NMR (400 MHz, CDCl 3 ) δ= 0 (d, 6H), 0.9 (s, 9H), 4.0-4.2 (m, 2H), 4.4 (s, 2H), 4.5 (s, 2H), 5.2 (s, 2H), 5.4 (m, 1H), 6.1 (d, 1H), 7 (d, 1H), 7.4-7.7 (m, 7H).

Preparation of EIV: benzyl (IR, 2R)-3-(tert-butyldimethylsilyloxy)-l-(2.3- dihvdrobenzorβiri.41dioxin-6-yl)-1-hvdroxypropan-2-ylcarbam ate.

(R)-benzyl 3-(tert-butyldimethylsilyloxy)- 1 -(2,3- dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (3.1g, 6.6 mmol) were dissolved in THF (25 ml) and cooled down to -70 °C under nitrogen atmosphere. L Selectride (13.2 ml of IM solution in THF, 13mmol) was added dropwise while keeping the temperature at -70 °C. After 1 hour, the reaction was quenched with a IM aqueous solution of potassium tartrate (13 ml) and extracted with EtOAc. The organic layer was evaporated down and the product was purified by column chromatography using 2.5%EtOAc-2%acetone-methylene chloride. The desired diastereomer was obtained in 80% yield (2.5 g ). 1 H NMR (400 MHz, CDCl 3 ) δ= 0 (d, 6H), 0.9 (s, 9H), 3.5 (broad s, 1H), 3.7-3.9 (m, 2H), 4.2 (s, 4H), 4.9 (broad s, 1H), 5.0 (d, 2H), 5.4 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

Preparation of EV: benzyl (IR, 2RH-(2.3-dihvdrobenzorβ1IT.41dioxin-6-yl)-1.3- dihydroxypropan-2-ylcarbamate. Benzyl (lR,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3- dihydrobenzo[β][l ,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate (0.5g) was dissolved in a 4 ml mixture of Acetic acid/THF/ water (3/1/1) and left to stir over night. The crude was evaporated down and the product azeotropically dried with EtOAc (10 ml). The crude product was purified by column chromatography using 50%EtOAc-hexane. The pure product was obtained in 74% yield (0.28 g). 1 H NMR (400 MHz, CDCl 3 ) δ= 3.4-3.8 (m, 4H), 4.1 (broad s, 4H), 4.8 (s, 1H), 4.9 (broad s, 2H), 5.7 (broad s, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

General procedure for preparation of EVI and EVII Benzyl (IR, 2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3- dihydroxypropan-2-ylcarbamate was dissolved in excess pyridine, cooled to -15 °C and one equivalent of methanosulfonyl chloride was added to the mixture. Mixture was stirred about half an hour, and ten equivalents of the amine were added. The reaction mixture was allowed to warm up to room temperature and then heated at 50 °C overnight. The crude was evaporated down and the product was purified by column chromatography using a mixture of methanol/methylene

chloride/ammonium hydroxide. The pure compound EVI was then de-protected by hydrolysis in the microwave, using aqueous NaOH (40%in weight)/methanol solution as solvent and heating the mixture to 150 °C for about 15 minutes to give the free amines of the type EVI. The final product was purified by silica-gel column chromatography using a mixture of methanol/methylene chloride/ammonium hydroxide.

Examples of EVlI compounds

\) HR, 2R)-2-amino-1-(2.3-dihvdrobenzorβiπ .41dioxin-6-vn-3- morpholinopropan- 1 -ol.

1 H NMR (400 MHz, CDCl 3 ) δ= 2.3 (dd, 2H), 2.4 (dd, 2H), 2.5-2.6 (m, 2H), 3.2 (m, 1H), 3.6-3.7 (m, 4H), 4.2 (s, 4H), 4.4 (d, 1H), 6.5-6.9 (m, 3H); MS for C 5 H 22 N 2 O 4 m/z 294.8 [M+H].

HU IR. 2R)-2-amino-1-f2,3-dihvdrobenzorβiπ.41dioxin-6-vn-3-(piper idin- l-yl)propan-1-ol.

1H NMR (400 MHz, CDCl 3 ) δ= 1.4 (broad s, 2H), 1.7 (m, 4H), 2.2-2.6 (m, 6H), 3.2 (m, 1H), 4.2 (s, 4H), 4.5 (s, 1H), 6.7-6.9 (m, 3H).

Example ID. Preparation of Substituted Phenoxy Propionic Acids

Example IDl : Preparation of 3 -(4-methoxyphenoxy)propionic acid. i) 3 -(4-methoxyphenoxy)propionitrile

A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in

methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78 °C for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-buty\ methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 3-(4-methoxyphenoxy)propionitrile as white crystals (Yield: 89.48 %). 1 H NMR (450 MHz, CDCl 3 ): δ = 2.72 (t, 2 H; CH 2 CN); δ = 3.83 (s, 3 H; OCH 3 ); δ = 4.05 (t, 2H; OCH 2 ); δ = 6.70 (m, 4H; Ar-H); 13 C NMR (112.5 MHz, CDCl 3 ): d = 18.843 (CH 2 CN); 55.902 (OCH 3 ); 63.699 (OCH 2 ); 114.947 (CH 3 OCCH); 116.183 (CH 2 OCCH); 1 17.716 (CN); 151.983 (CH 3 OC); 154.775 (CH 2 OQ. ii) 3-(4-methoxyphenoxy)propionic acid. A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile) was charged to a 22 L round bottom flask equipped with an overhead stirrer under N 2 . To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H 2 O. The reaction mixture was heated to 100 °C for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10 °C by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 3-(4-methoxyphenoxy)propionic acid. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH = 9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 3-(4-methoxyphenoxy)propionic acid as a white solid (Yield: 86.04 %). 1 H NMR (450 MHz, CDCl 3 ); <5 = 2.78 (t, 2H; CH 2 COOH); 3.70 (s, 3H; OCH 3 ); 4.18 (t, 2H; OCH 2 ); 6.78 (m, 4 H; Ar-H); 13 C NMR (1 12.5 MHz, CDCl 3 ): δ = 34.703 (CH 2 COOH); 55.925 (OCH 3 ); 64.088 (OCH 2 ); 1 14.855 (CH 3 OCCH); 1 15.984 (CH 2 OCCH); 152.723 (CH 3 OC); 154.302 (CH 2 OC); 177.386 (COOH).

Example 1D2: Preparation of 3-(4-(3-oxobutyl)phenoxy * )propanoic acid

Step 1 : a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B (400 μL), acrylonitrile (4 mL) and MeOH (0.8 mL) was heated at 70 °C for 20 hours. The mixture was cooled to room temperature and the solvent was removed to dryness. 3-(4-(3-oxobutyl)phenoxy)propanenitrile was obtained as a white solid (0.572 g) after purification by column chromatography using ethyl acetate/hexane. Step 2: 3-(4-(3-oxobutyl)phenoxy)propanenitrile (0.478g ) was suspended in

HCl (37%, 5 mL) and placed in the microwave reactor (T= 1 10 °C, 5 min). The mixture was poured onto iced water (20 g), filtered, and the solid was washed with water (2 X 5 mL). After column chromatography purification using a mixture of methylene chloride/methanol, 3-(4-(3-oxobutyl)phenoxy)propanoic acid was obtained as a white solid (0.3 g). 1 H NMR (CDCl 3 , 400 mHz, ppm); 2.2 (s, 3H), 2.7 (t, 2H), 2.85 (m, 4H), 4.25 (t, 2H), 6.8 (d, 2H), 7.1 (d, 2H).

Example 1D3: Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid

Step 1 : a mixture of 4-(2-methoxy ethyl) phenol (1.547g, 10.3 mmol), propiolic acid tert-butyl ester (1.367g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH 2 Cl 2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO 2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/ (Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g).

Step2: (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (0.57 g) was suspended in a mixture of THF (5 mL)/HCl (2 M, 5 mL) and placed in the microwave reactor (T = 100 °C, 15 sec). THF was removed by rotary evaporation

and the mixture was extracted with CH 2 Cl 2 (10 mL). (E)/(Z)-3-(4-(2- methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification by column chromatography using a mixture of hexane/ethyl acetate.

Step 3: (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5 %, degussa type ElOl, 40 mg) was added. The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). 1 H NMR (CDCl 3 , 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s, 3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).

Example 1D4: Preparation of 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid

Step 1 : 3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH (12 mL) and H 2 SO 4 (18 M, 3 drops) was added. The mixture was place in the microwave reactor (T: 140 °C, t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N, 20 mL). The organic phase was dried over MgSO 4 , filtered, and evaporated to give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).

Step 2: aluminum chloride (1.1 g, 8.34 mmol) was added to a cold solution (0 0 C) solution of methyl 3-phenoxypropanoate (1.0 g, 5.56 mmol) and tert- butylacetyl chloride (1.25 mL, 8.34 mmol) in CH 2 Cl 2 (9 mL) and the reaction mixture was stirred overnight. The mixture was evaporated and the residue was diluted with EtOAc (30 mL) and then washed with water (2 X 20 mL). The organic phase was removed and purified with silica chromatography using of a gradient hexanes/EtOAc (100:0— » 0:100) to give methyl 3-phenoxypropanoate (600 mg, 2.27 mmol, 40%).

Step 3: a solution of methyl 3-phenoxypropanoate (200 mg, 0.76 mmol) in 2 mL of HCl (37%) was placed in a microwave reactor (T: 120 0 C, t: 5 min). The mixture was poured into iced water (2g) and washed with EtOH (3 XlO mL). The organic phase was combined and evaporated. The crude product was purified with silica gel chromatography using of a gradient hexanes/EtOAc (100:0— > 0: 100) to give 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid (120 mg, 0.48 mmol, 63%).

Example 2. Preparation of Compounds of the Invention

The exemplary compounds shown in Example 2 and Tables 1 -3 can be prepared by following scheme 1 described above, Detailed synthetic description of certain compounds also are described below as examples.

Example 2El. Preparation of Hemi -Hydrate of Compound 163 N-[2-Hydroxy-2- r2.3-dihvdrobenzorβiri.41dioxin-6-yl)-l-pyrrolidin-1-ylmeth yl-ethyll-3-(4- methoxy-phenoxy)-propionamide

(Scheme IA)

Compound 163 was prepared by following Scheme IA above. 3-(4- methoxyphenoxy)propanoic acid (see Example IDl, 34.47g, 169mmol, 96% purity by HPLC), DCC (34.78g, 169 mmol) and N-hydroxysuccinimide (19.33, 169mmol) were combined as dry powders and methylene chloride (50OmL) was added. The suspension was mechanically stirred overnight, ambient temperature, under a nitrogen atmosphere. HPLC analysis showed complete conversion of the acid to the NHS ester (N-hydroxy succinyl ester). To the mixture was added (IR, 2R)-2- amino- 1 -(2,3-dihydro-benzo[ 1 ,4] dioxin-6-yl)-3-pyrrolidin- 1 -yl-propan- 1 -ol (5Og, 169mmol) and stirring continued for 2.5 hours. HPLC showed conversion to the product and loss of both the NHS ester and step 5 amine. The reaction mixture was vacuum filtered on a Bϋchner funnel to remove DCC urea. The solid urea was washed with 50OmL of methylene chloride. The organic layers were combined, placed in a separatory funnel, and treated with 50OmL of 1.0M NaOH. The layers

were separated, and the cloudy organic layer was recharged into a separatory runnel and treated with a 6% HCl solution (adjusted to pH=0.03-0.34, 10OmL of solution). Two clear layers formed. The resultant biphasic solution was poured into an Erlenmeyer flask and cautiously neutralized to a pH of 7.2-7.4 with a saturated solution of sodium bicarbonate (approx 20OmL of solution). The organic layer was separated from the aqueous layer, dried over sodium sulfate and evaporated to yield 83.6g of yellow oil (theoretical yield: 77.03g). The oil was dissolved in isopropyl alcohol (50OmL) with heating and transferred to a IL round bottom flask equipped with a mechanical stirrer and heating mantel. The solution was heated to 50°C and the mechanical stirrer was set to a rate of 53-64 rpm. Tartaric acid (25.33g, 168mmol) was dissolved in deionized water (5OmL) and added to the stirred solution at 50°C. Once the solution turned from milky white to clear, seed crystals were added to the mixture and crystallization immediately began (temperature jumped to 56°C). After 20 minutes, the mixture was set to cool to a temperature of 35 °C (cooling took 1.15 hours). Heating was removed and the solution was allowed to stir for 12 hours. The resulting thick slurry was filtered on a Bϋchner funnel. Any remaining solid in the flask was washed onto the funnel using ice-cold isopropyl alcohol (10OmL). The material was transferred to a drying tray and heated to 48°C under vacuum for 3 days (after two days the material weighed 76g and after three days it weighed 69.3g). The solid was analyzed by LC and shown to be 98.1% pure (AUC), the residual solvent analysis showed the material to possess 3472 ppm of isopropyl alcohol, and the DSC (differnetial scaaning calroimetery) showed a melting point of 134.89°C. A total of 69.3g of white solid was collected (65.7% overall yield). 1 H NMR (400 MHz, CDCl 3 ) δ= 1.8 (M, 4H), 2.4-2.6 (m, 4H), 2.6 (m, 1H), 2.85 (m, 2H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 (m, 2H), 3.86 (2, 2H), 4.18 (br s, 5H), 4.6 (s, 1H), 6.6-6.8(m 5 7 H), 7.8 (d, 1H); MS for C 29 H 40 N 2 Oi 3 m/z 457.3 [M+H] for main peak (free-base).

Example 2E2. Preparation of Compound 247: N-((1R, 2R)-I -hydroxy- 1 -(4- methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy ' )propanarnide.

Compound 247 was prepared by reaction of ( 1 R, 2R)-2-amino- 1 -(4- methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as the amine, prepared according to scheme 3 with 3-(4-methylphenoxy)propionic acid using method 1.

Preparation of A : (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate

N,O-dimethylhydroxylamine hydrochloride (45 g, 0.46 mmol, 1.5 eq) and N- methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly to a cold (-15 °C) suspension of d-CBz serine (73.0 g, 0.305 mol) in CH 2 Cl 2 (560 mL) keeping the temperature below -5 °C. The mixture was cooled back to ~ -15 °C and EDCI (62 g, 0.323 mol, 1.05 eq) was added. The mixture was stirred for 5 hours keeping the temperature below 5 °C. The solvent was removed by rotary evaporation and the mixture was partitioned between HCl (1 M, 300 mL)and EtOAc (500 mL).The organic layer was separated and washed with HCl (1 M, 2X 100 mL) and then sat. NaHCO 3 (2 X 150 mL). The mixture was dried over MgSO 4 , filtered and then the solvent was removed by rotary evaporation. (R)-benzyl 3-hydroxy-1- (methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate was re-dissolved in a mixture of acetone (375 mL) and 2,2-dimethoxy propane (375 mL) and boron trifluoride ethereate (3 mL) was added. The mixture was stirred at room temperature for 5 hours and then triethyl amine (3 mL) was added. The solvent was removed to dryness and (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3- carboxylate was obtained as a white solid (73.0 g, 74 % yield from both steps) after purification by column chromatography using a mixture of hexane/EtOAc/acetone. 1H NMR (CDCl 3 , 400 mHz, ppm); 1.5 (s, 2 H), 1.6 (s, 3H), 1.7 (s, 2H), 1.75

(s, 3H), 3.14 (s, 3 H), 3.24 (2 H), 3.4 (3 H), 3.76 (s, 2 H), 4.0 (m, 1.7 H), 4.16 (m, 1

H), 4.2 (m, 1.7), 4.78 (m, 1 H), 4.88 (m, 0.6 H), 5.06 (q, 2 H), 5.18 (q, 1 H), 7.4 (m, 8 H).

Preparation of Al: (R)-benzyl 4-((R)-hydroxyC4-methoxyphenv0methyl>2,2- dimethyloxazolidine-3-carboxylate

A solution Of LiALH 4 (1 M, 20 mL, 20 mmol) was added dropwise to a cold (-15 °C) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2- dimethyloxazolidine-3-carboxylate (12.2 g, 37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0 °C. A saturated solution Of KHSO 4 (100 mL) was added slowly to the mixture and it was warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92 % yield) after purification by column chromatography (SiO 2 , using a mixture of hexane/EtOAc). 1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (m, 6 H), 4.15 (m, 2H), 4.4 (m, 1H), 5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 1H). 1 ,2-dibromoethane (0.2 mL) was added slowly to a hot (65 °C) solution of magnesium turnings (0.91 g, 37 mmol) in THF (14 mL), followed by the dropwise addition of a solution of 4-bromo anisole (4 mL, 32 mmol) in THF (14 mL). The mixture was refluxed for 2 hours and then cooled to room temperature. The grignard solution was added dropwise to a suspension of CuI (6.8 g, 36 mmol) in a mixture Of Me 2 S (20 mL)/THF (100 mL) at -78 °C. The mixture was warmed slowly to -45 °C and stirred for 30 min keeping the temperature between -45 to - 35 °C. The mixture was cooled back to -78 °C , and a solution of the Garner's

aldehyde [(R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate ](3.20 g, 12.6 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at low temperature overnight (15 h, T max = 10 °C). The reaction mixture was quenched with NH 4 Cl (sat. 100 mL) and extracted with EtOAc (50 mL). The solvent was removed to dryness and the mixture was purified by column chromatography (SiO 2 , using a mixture of hexane/EtOAc/acetone)and the product was obtained as a colorless oil (1.697 g, 36 % yield).

Preparation of All: benzyl (IR, 2R)-1,3-dihydroxy-1-(4-methoxyphenv0propan-2- ylcarbamate

A mixture of benzyl 4-(hydroxy-(4-methoxyphenyl)methyl)-2,2- dimethyloxazolidine-3-carboxylate (1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOH (20 mL) was stirred at room temperature for 2 days. The mixture was centrifuged and the solid was washed with MeOH (2 X 40 mL). The solvent was removed to dryness and after purification by column chromatography (SiO 2 using a mixture of CH 2 Cl 2 /Et0Ac) the product was obtained as a white solid (1.26 g, 84 % yield).

Preparation of AlV: Synthesis of Compound 289: benzyl (IR. 2R)-1 -hydroxy- 1 -(4- methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate

Mesityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (-10 °C) solution of benzyl (IR, 2R)-1 ,3-dihydroxy-l -(4-methoxyphenyl)propan-2- ylcarbamate (1.07 g, 3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min and then pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. The mixture was heated to 45 °C for 6 hours and then the solvent was removed to dryness. After purification by column chromatography (SiO 2 , using a mixture of CH 2 Cl 2 , MeOH, NH 4 OH), the product was obtained as a clear oil (0.816 g, 66 % yield).

Preparation of EVH:( 1 R, 2R)-2-amino- 1 -(4-methoxyphenyl)-3 -(pyrrolidin-1- yl)propan-1-ol as the amine was prepared by the procedures described below:

A mixture of benzyl (IR, 2R)-I -hydroxy- l-(4-methoxyphenyl)-3- (pyrrolidin- 1 -yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5 %, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was

filtered over celite and the solvent was removed to dryness. The product was obtained as a colorless oil (63.5 mg, 85 % yield).

Preparation of Compound 247: N-(ClR, 2Ryi-hvdroxy-1-(4-methoxyphenyl)-3- (pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide.

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H), 2.85 (m, 2H), 3.75 (s, 3H), 4.1 (m, 2H), 4.25 (m, 1H), 5.05 (sd, 1H), 6.5 (br, 1H), 6.8 (m, 4H), 7.1 (d, 2H), 7.2 (d, 2H). M/Z for C 24 H 32 N 2 O 4 [M-H]- = 413.

Example 2E3. Preparation of Compound 251: N-((1R. 2R)- 1 -hydroxy- 1 -(4- methoxyphenyl)-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-(4- (trifluoromethvθphenyl)acetamide.

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.5 (s, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 5.05 (sd, 1H), 5.8 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 7.55 (d, 2H). M/Z for C 23 H 27 F 3 N 2 O 3 [M-H]- = 437.

Example 2E4. Preaparation of Compound 5: N-((1R, 2R)-I -(2.3- dihydrobenzo[βl \ 1.4]dioxin-6-yl)- 1 -hvdroxy-3-(pyπOlidin- 1 -yl)propan-2- vPbenzorblthiophene-2-carboxamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.45 (m, 1H), 5.05 (sd, 1H), 6.6 (br, 1H), 6.85 (s, 2H), 6.95 (s, 1H), 7.4 (m, 2H), 7.7 (s, 1H), 7.85 (m, 2H). M/Z for C 24 H 26 N 2 O 4 S [M-H]- - 439.

Example 2E5. Preparation of Compound 11: N-((1R. 2R)- 1 -(2.3- dihydrobenzo[β][ 1 ,41dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-2- (phenylthio)acetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (br, 2H), 3.6 (q, 2H), 4.1.5 (m, 1H), 4.2 (s, 4H), 5.9 (sd, 1H), 6.7 (m, 2H), 6.8 (s, 1H), 7.2 (m, 7H). M/Z for C 23 H 28 N 2 O 4 S [M-H]- = 429.

Example 2E6. Preparation of Compound 12: N-((1R. 2R)-1-(2.3- dihvdrobenzo[β][1.4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2- yl)biphenyl-4-carboxamide

1H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H),

4.25 (s, 4H), 4.4 (br, 1H), 5.05 (sd, 1H), 6.6 (sd, 1H), 6.85 (m, 2H), 6.95 (s, 1H), 7.45 (m, 3H), 7.6 (m, 4H), 7.75 (m, 2H). M/Z for C 28 H 30 N 2 O 4 [M-H]- = 459.

Example 2E7. Preparation of Compound 19: N-((1R. 2R)-l -(2,3- dihydrobenzo[βl [ 1 ,4]dioxin-6-yl )- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2- vObenzorblthiophene-5-carboxamide

1H NMR (d 6 -dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (m, 1H),

4.15 (s, 4H), 4.25 (m, 1H), 4.75 (sd, 1H), 5.6 (br, 1H), 6.7 (m, 3H), 7.5 (sd, 1H), 7.7 (sd, 1H), 7.8 (sd, I H), 7.85 (sd, I H), 8.0 (sd, 1H), 8.2 (s, 1H). M/Z for C 24 H 26 N 2 O 4 S [M-H]- = 439.

Example 2E8. Preparation of Compound 23: 2-(biphenyl-4-yl)-N-((lR. 2R)- l -(2.3- dihvdrobenzo[βl[1,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2- vPacetamide

II 1 H 11 NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (d, 2H), 3.55 (s, 2H), 4.2 (m, 5H), 4.85 (sd, 1H), 5.95 (br, 1H), 6.6 (m, 1H), 6.75 (m, 2H), 7.2 (sd, 2H), 7.4 (m, 1H), 7.5 (st, 2H), 7.6 (m, 4H). M/Z for C 29 H 32 N 2 O 4 [M-H]- = 473

Example 2E9. Preparation of Compound 24: N-(ClR. 2R)- 1 -(2,3- dihydrobenzo[βl [ 1 ,4]dioxin-6-yl)- 1 -hvdroxy-3-(pynOlidin- 1 -yl)propan-2-yl)-2-(4- phenoxyphenyPacetamide

1H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H),

3.45 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.9 (br, 1H), 6.6 (m, 1H), 6.7 (s, 1H), 6.8 (m, 1H), 7.15 (m, 7H), 7.4 (m, 2H). M/Z for C 29 H 32 N 2 O 5 [M-H] ' - 489.

Example 2E10. Preparation of Compound 25: CS)-N-CClR. 2R)- 1-C2.3- dihvdrobenzorβl[l ,4]dioxin-6-yl)-l -hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- hydroxy-3-phenylpropan amide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 7H), 3.1 (dd, 2H), 4.2 (m, 6H), 4.8 (sd, 1H), 6.6 (m, 1H), 6.8 (m, 3H), 7.3 (m, 5H). M/Z for C 24 H 30 N 2 O 5 [M-H]- = 427.

Example 2El 1. Preparation of Compound 27: N-((1R. 2R)- l-(2,3- dihvdroben2θ[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl)-3- phenoxypropanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 2.9 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 1H), 6.75 (s, 1H), 6.85 (m, 3H), 6.95 (t, 1H), 7.2 (m, 3H). M/Z for C 24 H30N 2 O 5 [M-H]- = 427.

Example 2E12. Preparation of Compound 31: N-(ClR. 2R)-H2.3- dihydrobenzo[βiπ .41dioxin-6-yl)- 1 -hvdroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-oxo- 2-phenylacetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.8 (br, 4H), 3.0 (m, 2H), 4.2 (s, 4H), 4.3 (m, 1H), 5.05 (sd, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.35 (m, 1H), 7.45 (t, 2H), 7.6 (t, 1H) 8.2 (d, 2H). M/Z for C 23 H 26 N 2 O 5 [M-H]- = 41 1.

Example 2E13. Preparation of Compound 32: N-((1R. 2R)-1-C2.3- dihvdrobenzorβlf lλldioxin-ό-yl)-1-hvdroxy-S-Cpyrrolidin-1-yl)propan^-vπ-S -

(phenylthio)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.4 (t, 2H), 2.7 (br, 4H), 2.8 (m, 2H), 3.1 (m, 2H), 4.2 (m, 5H), 4.9 (sd, 1H), 5.95 (br, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.3 (m, 3H). M/Z for C 24 H 30 N 2 O 4 S [M-H]- = 443.

Example 2E14. Preparation of Compound 35: N-(ClR. 2R)-1-C2.3- dihydrobenzo [β] [ 1.4] dioxin-6-yl)- 1 -hydrox v-3 -(pyrrolidin- 1 -yl)propan-2-yl)-2-o- tolylacetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.1 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.8 (sd, 1H), 5.75 (br, 1H), 6.5 (d, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 7.1 (d, 1H), 7.2 (m, 3H). M/Z for C 24 H 30 N 2 O 4 [M-H]- = 411.

Example 2E15. Preparation of Compound 36: N-((1R. 2R)-l-(2,3- dihydrobenzo[b] [ 1.4]dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-2-m- tolylacetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.55 (d, 1H), 6.75 (m, 2H), 6.9 (d, 2H), 7.1 (sd, 1H), 7.2 (m, 1H). M/Z for C 24 H 30 N 2 O 4 [M-H]- = 41 1.

Example 2E16. Preparation of Compound 39: 2-(benzylthio)-N-(YlR. 2R)-1-(Z3- dihydrobenzo [β] [ 1 ,4]dioxin-6-yl)- 1 -hvdroxy-3-(pynOlidin- 1 -yl)propan-2- yl)acetamide

1 IIH,, NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 2.9 (m, 2H), 3.0 (m, 2H), 3.3 (d, 1H), 3.55 (d, 1H), 4.2 (m, 5H), 5.05 (sd, 1H), 6.85 (s, 2H), 6.9 (s, 1H), 7.1 (sd, 2H), 7.3 (m, 3H). M/Z for C 24 H 30 N 2 O 4 S [M-H] ' = 443.

Example 2El 7. Preparation of Compound 47: N-((1R. 2R)- 1 -(2.3- dihvdrobenzo[β1[1,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)-2-(4- (pyridin-3 - yl)phenyl)acetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.85 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.25 (d, 3H), 7.4 (m, 1H), 7.6 (sd, 2H), 7.9 (sd, 1H), 8.6 (sd, 1H), 8.85 (s, 1H). M/Z for C 28 H 31 N 3 O 4 [M-H]- = 474.

Example 2El 8. Preparation of Compound 48: 2-(4'-chlorobiphenyl-4-yl)-N-((lR, 2R)- 1 -(23-dihydrobenzo[β] [ 1 ,4]dioxin-6-vP- 1 -hvdroxy-3-(pyrrolidin- 1 -yl)propan- 2-yl)acetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, I H), 4.2 (s, 4H), 4.85 (sd, I H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.55 (sd, 4H). M/Z for C 29 H 31 ClN 2 O 4 [M-H] ' = 508.

Example 2E19. Preparation of Compound 51: N-((1R. 2R)-1-(2.3- dihydrobenzo[β] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-(3- (trifluoromethyl)phenyl)acetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.55 (sd, 1H). M/Z for C 24 H 27 F 3 N2O 4 [M-H]- = 465.

Example 2E20. Preparation of Compound 53: N-((1R, 2R)-I -(2,3- dihydrobenzo[β1 [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-(3- fluorophenvPacetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.50 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 1H), 7.0 (t, 1H), 7.3 (sq, 1H). M/Z for C 23 H 27 FN 2 O 4 [M-H] ' = 415.

Example 2E21. Preparation of Compound 54: N-((1R. 2R)-l-(2.3- dihydrobenzo[β] [ 1 ,41dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-(3- methoxyphenoxy)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.65 (br, 6H), 2.85 (m, 2H), 3.80 (s, 3H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 4H), 6.75 (s, 2H), 6.85 (s, 1H), 7.2 (t, 1 H). M/Z for C 25 H 32 N 2 O 6 [M-H]- = 457.

Example 2E22. Preparation of Compound 55: 3-(2,5-dichlorophenoxy)-N-((lR, 2R)- 1 -(2,3-dihydrobenzo[β][ 1.41dioxin-6-vP- 1 -hydroxy-3-(pyrrolidin- 1 -vOpropan- 2-yl)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.1 (m, 1H), 4.25 (m, 6H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.75 (s, 2H), 6.8 (s, 1H), 6.9 (m, 2H), 7.25 (m, 1H). M/Z for C 24 H 28 Cl 2 N 2 O 5 [M-H]- = 496.

Example 2E23. Preparation of Compound 57: 3-(4-chlorophenoxy)-N-((1R. 2R)-I-

(2,3-dihydrobenzo[β][ 1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.8 (m, 5H), 7.2 (m, 2H). M/Z for C 24 H 29 ClN 2 O 5 [M-H]- = 461.

Example 2E24. Preparation of Compound 58: N-((1R. 2R)-l-(2.3- dihvdrobenzo[β][ 1,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3 -(4- fluorophenoxy)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.4 (br, 1H), 6.8 (m, 5H), 7.0 (m, 2H). M/Z for C 24 H 29 FN 2 O 5 [M-H]- = 445.

Example 2E25. Preparation of Compound 59: N-(QR, 2R)- 1 -(2,3- dihvdrobenzo[βiπ,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2-yl)-3-(p- tolyloxy)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H),

2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.75 (m, 4H), 6.85 (s, 1H), 7.1 (m, 2H). M/Z for C 25 H 32 N 2 O 5 [M-H]- = 441.

Example 2E26. Preparation of Compound 60: N-(QR. 2R)- 1 -(2,3- dihvdrobenzo[β1[1,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2-yl)-3-(2- fluorophenoxy)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.35 (br, 1H), 6.7 (s, 2H), 6.85 (s, 1H), 6.95 (m, 2H), 7.05 (m, 2H). M/Z for C 24 H 29 FN 2 O 5 [M-H]- = 445.

Example 2E27. Preparation of Compound 61: N-(ClR. 2R)- 1 -(2.3- dihydrobenzo|-βl[1.41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1 -yl)propan-2-yl)-3-(4- methoxyphenoxy)propan amide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.2 (br, 5H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.8 (m, 7H). M/Z for C 25 H 32 N 2 O 6 [M-H] ' = 457.

Example 2E28. Preparation of Compound 188: N-((1R. 2R)- 1 -(2.3- dihvdrobenzo[b][1,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-y l)propan-2-yl)-3-(4- ethylphenoxy)propanamide (2R, 3R)-2,3-dihydroxysuccinate

1 H NMR (D 2 O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.35 (q, 2H), 2.4 (br, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C 26 H 34 N 2 O 5 C 4 H 6 O 6 [M- H] ' = 454.

Example 2E29. Preparation of Compound 189: N-(QR, 2R)-1-(2,3- dihydrobenzo [b] [ 1 ,4] dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 - yl)propan-2- yl)-3 -(4- propionylphenoxy)propanamide (2R, 3R)-2,3-dihydroxysuccinate

1 H NMR (D 2 O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.8 (q, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, I H), 6.5 (d, 1H), 6.5 (d, 2H), 6.7 (d, 2H), 7.7 (d, 2H). M/Z for C 27 H 34 N 2 O 6 C 4 H 6 O 6 [M-H]- = 483.

Example 2E30. Preparation of Compound 193: N-((1R, 2R)-l-(2,3- dihydrobenzo [b] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3 -(4- (3-oxobutyl)phenoxy ' )propanamide (2R, 3R)-2.3-dihydroxysuccinate

1 H NMR (D 2 O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 1.94 (s, 3H), 2.45 (br, 2H), 2.6 (m, 4H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C 28 H 36 N 2 O 6 C 4 H 6 O 6 [M- H]- = 497.

Example 2E31. Preparation of Compound 202: N-((1R, R)-l-(2,3- dihvdrobenzo[β][1,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2-yl)-3-(4- (2-methoxyethyl)phenoxy)propanamide (2R, R)-2,3-dihydroxysuccinate

1 H NMR (D 2 O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.62 (t, 2H), 2.9 (br, 2H), 3.1 (s, 3H), 3.25 (m, 2H), 3.4 (br, 4H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C 27 H 36 N 2 O 6 C 4 H 6 O 6 [M-H]- = 485.

Example 2E32. Preparation of Compound 63: N-((1R. 2R)-l-(2,3- dihydrobenzo[β]|-L41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)-2-(3'- methoxybiphenyl-4-yl)acetamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (br, 2H), 3.9 (sd, 3H), 4.2 (m, 5H), 4.95 (sd, I H), 5.9 (br, 1H), 6.5-7.6 (m, 1 1H). M/Z for C 30 H 34 N 2 O 5 [M-H]- = 503.

Example 2E33. Preparation of Compound 127: N-(QR, 2R)-1-(2,3- dihydrobenzo Tb] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-4-(4- ethoxyphenyl)-4-oxobutanamide

1H NMR (CDCl 3 , 400 mHz, ppm); 1.4 (t, 3H), 1.8 (br, 4H), 2.7 (br, 6H), 3.2

(m, 2H), 4.05 (q, 2H), 4.2 (m, 2H), 4.25 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C 27 H 34 N 2 O 6 [M-H] ' = 483.

Example 2E34. Preparation of Compound 154: N-((1R, 2R)-I -(2,3- dihydrobenzoFb] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-4-(4- methoxyphenvP-4-oxobutanamide

1 H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 1H), 3.45 (s, 3H), 3.9 (s, 3 H), 4.2 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C 26 H 32 N 2 O 6 [M-H]- = 469.

Example 2E35. Preparation of Compound 181: N-((1R, 2R)-1-C2.3- dihydrobenzo[bl [ 1 ,4]dioxin-6-yl)- 1 -hvdroxy-3-(pyrrolidin- 1 -v0propan-2-yl)-6-(4- isopropoxyphenyl)-6-oxohexanamide

1H NMR (CDCl 3 , 400 mHz, ppm); 1.4 (d, 6H), 1.8 (br, 8H), 2.15 (br, 2H),

2.8 (br, 10H), 4.25 (m, 5H), 4.65 (m, 1H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C 30 H 40 N 2 O 6 [M-H] * = 525.

Example 2E36. Preparation of Compound 191: N-(QR. 2R)-H2.3- dihydrobenzof β] [ 1.4]dioxin-6-vO- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-5-(4- methoxyphenyl)-5-oxopentanamide (2R.3R)-2,3-dihydroxysuccinate

1 H NMR (D 2 O, 400 mHz, ppm); 1.40 (br, 1H), 1.53 (br, 1H), 1.75 (br, 2H), 1.91 (br, 2H), 1.98 (m, 1H), 2.15 (m, 1H) 2.45 (m, 2H), 2.95 (m, 2H), 3.35 (dd, 2H), 3.4 (m, 2H), 3.68 (br, 5H), 3.77 (br, 2H), 4.3 (br, 3H), 4.68 (br, 1H), 6.47 (d, 1H), 6.65 (d, 2H), 6.85 (d, 2H), 7.63 (d, 2H). M/Z for C 27 H 34 N 2 O 6 C 4 H 6 O 6 [M-H] = 483

Example 2E37. Preparation of Compound 265: N-((1R, 2R)-1-

(benzo[δ] [ 1 ,3]dioxol-5-yl )- 1 -hvdroxy-3-(pyrrolidin- 1 -v0propan-2-y0-5-(4- isopropoxyphenyl)-5-oxopentanamide (2S, 3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 1.30 (sd, 6H), 1.70-1.85 (m, 2H), 2.04 (br, 4H), 2.09-2.26 (m, 2H), 2.64-2.82 (m, 2H), 3.31-3.48 (m, 5H), 4.37 (s, 2H), 4.43 (br, 1H), 4.68 (m, 1H), 4.71 (sd, 1H), 5.76 (s, 2H), 6.66 (d, 1H), 6.82-6.95 (m, 4H), 7.84 (d, 2H); MS for C 28 H 36 N 2 O 6 C 4 H 6 O 6 : [M-H]- 645.

Example 2E38. Preparation of Compound 267: N-((1R, 2R)-l -

(benzo[δl[1,31dioxol-5-yl)-1-hvdroxy-3-(pyrrolidin-1-yl) propan-2-yl)-6-(4- methoxyphenvO-6-oxohexanamide (2S. 3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 1.49 (br, 4H), 2.03 (br, 4H), 2.89 (t, 2H), 3.33-3.46 (m, 6H), 3.84 (s, 3H), 4.37 (s, 2H), 4.43 (d, 1H), 4.76 (br, 1H), 5.81 (s, 2H), 6.68 (d, 1H), 6.81 (d, 1H), 6.88 (s, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C 27 H 34 N 2 O 6 C 4 H 6 O 6 : [M-H]- 633.

Example 2E39. Preparation of Compound 268: N-((1R. 2R)-1-

(benzofδl I- 1 ,3]dioxol-5-yl )- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-7-(4- isopropoxyphenyl)-7-oxoheptanamide (2S, 3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 1.15-1.18 (m, 2H), 1.30 (d, 6H), 1.40-1.45 (m, 2H), 1.57-1.65 (m, 2H), 2.03 (br, 4H), 2.12-2.17 (m, 2H), 2.88 (t, 2H), 3.33-3.48 (m, 5H), 4.38 (s, 2H), 4.42 (d, 1H), 4.67 (m, 1H), 4.78 (d, 1H), 5.83 (d, 2H), 6.71 (d, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 6.92 (d, 2H), 7.90 (d, 2H); MS for C 30 H 40 N 2 O 6 -C 4 H 6 O 6 : [M-H]- 675.

Example 2E40. Preparation of Compound 197: N-(QR. 2R)-H2.3- dihydrobenzo [β] [1,4] dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 - yl)propan-2-y 1 )-4-(4- methoxyphenoxy)butanamide (2S. 3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 1.78-1.91 (m, 2H), 2.00 (br, 4H), 2.32 (t, 2H), 3.33-3.47 (m, 6H), 3.69 (s, 3H), 3.72 (t, 2H), 4.1 1 (br, 4H), 4.37 (s, 2H), 4.41 (d, 1H), 4.72 (d, 1H), 6.69-6.86 (m, 7H); MS for C 26 H 34 N 2 O 6 C 4 H 6 O 6 : [M-H]- 621.

Example 2E41. Preparation of Compound 187: N-((1R. 2R)-H2.3- dihydrobenzo[β] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-(4- (3-methylbutanoyl)phenoxy)propanamide (2S, 3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 0.95 (d, 6H), 2.00 (br, 4H), 2.17 (m, 2H), 2.66 (t, 2H), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40 (s, 2H), 4.45 (d, 1H), 4.73 (sd, 1H), 6.67 (d, 1H), 6.79 (d, 1H), 6.86 (s, 1H), 6.93 (d, 2H), 7.91 (d, 2H); MS for C 29 H 38 N 2 O 6 - C 4 H 6 O 6 : [M-H]- 661.

Example 2E42. Preparation of Compound 83: 2-(4-chlorophenoxy)-N-((lR,2R)-1-

(2,3-dihvdrobenzo[β][1,4]dioxin-6-yl)-1-hvdroxy-3-(pyrro lidin-1-yl)propan-2- yPacetamide

1 H NMR (400MHz, CDCl 3 ) δ 1.76 (br, 4H), 2.63 (br, 4H), 2.78 (dd, 1H), 2.89 (dd, 1H), 4.24 (s, 4H), 4.27 (br, 1H), 4.36 (q, 2H), 4.94 (d, 1H), 6.71 (d, 1H), 6.77-6.82 (m, 4H), 6.86 (d, 1H), 7.24 (s, 1H); MS for C 23 H 27 ClN 2 O 5 : [M-H]- 447.

Example 2E43. Preparation of Compound 87: 2-(3.4-dichlorophenoxy)-N-((lR,2R)- l-(23-dihvdrobenzo[βiri,41dioxin-6-yl)-1-hvdroxy-3-(pyrroli din-1-yl)propan-2- vOacetamide

1 H NMR (400MHz, CDCl 3 ) δ 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd, 1H), 2.92 (dd, 1H), 4.25 (br, s, 5H), 4.35 (q, 2H), 4.95 (d, 1H), 6.71-6.84 (m, 5H), 7.01 (d, 1H), 7.34 (d, 1H); MS for C 23 H 26 Cl 2 N 2 O 5 : [M-H]- 482.

Example 2E44. Preparation of Compound 86: N-(Cl R,2R>1 -(2,3- dihydrobenzo Tb][1 , 4]dioxin-6-viyi-hvdroxy-3-(pyrrolidin-1-yl)propan-2-v0-2-(3- phenoxyphenyl)acetamide

1 H NMR (400MHz, CDCl 3 ) δ 1.72 (br, 4H), 2.57 (br, 4H), 2.75-2.80 (m, 2H), 3.45 (s, 2H), 4.1 1-4.13 (m, 1H), 4.23 (s, 4H), 4.84 (d, 1H), 5.86 (d, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.74 (d, 1H), 6.80 (br, 1H), 6.85 (dd, 1H), 6.92 (dd, 1H), 6.98 (d, 1H), 7.14 (t, 1H), 7.28-7.36 (m, 2H); MS for C 29 H 32 N 2 O 5 : [M-H]- 489.

Example 2E45. Preparation of Compound 280: 2-(3.4-difluorophenvn-N-((lR.2R)- l-(2,3-dihvdrobenzo[β][1,41dioxin-6-yl)-1-hydroxy-3-(pyrrol idin-1-yl)propan-2- yl)acetamide

1 H NMR (400MHz, CDCl 3 ) δ 1.80 (br, 4H, 2.68 (br, 4H), 2.84 (d, 2H), 3.45 (s, 2H), 4.17 (m, 1H), 4.25 (s, 4H), 4.88 (d, 1H), 5.88 (d, 1H), 6.65 (d, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 6.95 (t, 1H), 7.13 (q, 1H); MS for C 23 H 26 F 2 N 2 O 4 : [M-H]- 434.

Example 2E46. Preparation of Compound 103: N-((lR,2R)-1-(2.3- dihydrobenzo [β] [ 1 ,41 dioxin-6-vO- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2- yl)-2-(4- (trifluoromethoxy)phenyl)acetamide

1 H NMR (400MHz, CDCl 3 ) δ 1.65 ( br, 4H), 2.48 (br, 4H), 2.69 (d, 2H), 3.40 (s, 2H), 4.08 (m, 1H), 4.17 (s, 4H), 4.80 (s, 1H), 5.84 (t, 1H), 6.55 (d, 1H), 6.66 (s, 1H), 6.70 (d, 1H), 7.10 (t, 3H); MS for C 24 H 27 F 3 N 2 O 5 : [M-H]- 481.

Example 2E47. Preparation of Compound 90: N-((lR.2R)-l-(2.3- dihvdrobenzo[βiπ ,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5- (thiophen-2-yl)isoxazole-3-carboxamide

1 H NMR (400MHz, CDCl 3 ) δ 1.82 (br, 4H), 2.73-2.81 (m, 4H), 2.89-2.93 (m, 1H), 3.02-3.07 (m, 1H), 4.23 (s, 4H), 4.41 (br, 1H), 5.07 (s, 1H), 5.30 (d, 1H), 6.74 (s, 1H), 6.83 (t, 2H), 6.90 (s, 1H), 7.12-7.14 (m, 2H), 7.47 (d, 1H), 7.52 (d, 1H); MS for C 23 H 25 N 3 O 5 S: [M-H]- 456.

Example 2E48. Preparation of Compound 92: 3-(3-chloro-4-methoxyphenyl)-N-

((lR.2R)-l-(2,3-dihvdrobenzorβiri.41dioxin-6-yl)-1-hvdro xy-3-(pyrrolidin-1- yl)propan-2-yl)propanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.77 (br, 4H), 2.38 (t, 2 H), 2.60 (br, 4H), 2.8 (m, 4H), 3.86 (s, 3H), 4.20 (br, 1H), 4.24 (s, 4H), 4.87 (s, 1H), 5.80 (d, 1H), 6.66 (d, 1H), 6.8 (m, 3H), 7.00 (d, 1H), 7.18 (s, 1H); MS for C 25 H 31 ClN 2 O 5 : [M-H]- 475.

Example 2E49. Preparation of Compound 96: N-rnR.2R)-l-C2.3- dihvdrobenzorβiπ,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2-yl)-3-(4-

(trifluoromethyl)phenyl)propanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.73 (br, 4H), 2.4 (m, 2H), 2.53 (m, 4H), 2.7 (m, 2H), 2.90-2.97 (m, 2H), 4.17 (br, 1H), 4.23 (s, 4H), 4.89 (s, 1H), 5.83 (br, 1H), 6.68 (d, 1H), 6.79 (d, 2H), 7.24 (d, 2H), 7.50 (d, 2H); MS for C 25 H 29 F 3 N 2 O 5 : [M-H]- 479.

Example 2E50. Preparation of Compound 101: 4-(benzord]thiazol-2-yQ-N- (Y 1 R.2R)- 1 -f 2.3 -dihydrobenzorβl [ 1.41dioxin-6-yl)- 1 -hvdroxy-3 -(pyrrolidin- 1 - yl)propan-2-yl)butanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.77 (br, 4H), 2.10-2.15 (m, 2H), 2.24-2.27 (m, 2H), 2.64-2.67 (m, 4H), 2.79-2.83 (m, 2H), 3.02 (t, 2H), 4.18 (s, 4H), 4.26 (br, 1H), 4.92 (d, 1H), 6.12 (br, I H), 6.75-6.81 (m, 2H), 6.86 (s, I H), 7.37 (t, 1H), 7.45 (t, 1H), 7.85 (d, 1H), 7.92 (d, 1H); MS for C 26 H 3 ,N 3 O 4 S: [M-H]- 482.

Example 2E51. Preparation of Compound 102: N-(Y 1R.2R)-1 -(2.3- dihydrobenzo[β] [ 1 ,4]dioxin-6-vP- 1 -hvdroxy-3 -(pyrrolidin- 1 -vOpropan-2-yQ-6-(2,3- dihvdrobenzo[βirL41dioxine-6-sulfonamido)hexanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.15- 1.20 (m, 2H), 1.38-1.50 (m, 4H), 1.77 (br, 4H), 2.08 (q, 2H), 2.63-2.66 (m, 4H), 2.79 (d, 2H), 2.87 (t, 2H), 4.2 (m, 9H), 4.91 (br, 1H), 5.93 (br, 1H), 6.77 (q, 2H), 6.84 (s, 1H), 6.93 (d, 1H), 7.31 (d, 1H), 7.37 (s, 1H); MS for C 29 H 39 N 3 O 8 S: [M-H]- 590.

Example 2E52. Preparation of Compound 104: N-r5-fnR,2R)-1-(2,3- dihvdroben2θ[βiπ i 41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-yl)propan-2-ylamino )-

5-oxopentvPbenzamide

1 H NMR (400MHz, CDCl 3 ) δ 1.47-1.52 (m, 2H), 1.59-1.69 (m, 2H), 1.77 (br, 4H), 2.15-2.21 (m, 2H), 2.62-2.65 (m, 4H), 2.81 (br, 2H), 3.30-3.42 (m, 2H), 4.19-4.23 (m, 5H), 4.94 (br, 1H), 5.98 (br, 1H), 6.76 (br, 1H), 6.78-6.86 (m, 3H), 7.40-7.50 (m, 3H), 7.80 (d, 2H); MS for C 27 H 35 N 3 O 5 : [M-H]- 482.

Example 2E53. Preparation of Compound 281: Nl-((l R.2R)-1-(2,3- dihydrobenzo[β][l ^jdioxin-ό-yl)- 1 -hydroxy-3-(-pyrrolidin- 1 -vOpropan-2-yl)-N5- (thiazol-2-ypglutar amide

1 H NMR (400MHz, CDCl 3 ) δ 1.74 (br, 4H), 1.97-2.03 (m, 2H), 2.20-2.26 (m, 2H), 2.40-2.45 (m, 2H), 2.64-2.68 (m, 5H), 2.88 (m 1H), 4.20 (s, 4H), 4.26-4.29 (m, 1H), 4.83 (d, 1H), 6.12 (br, 1H), 6.74-6.79 (m, 2H), 6.85 (s, 1H), 6.95 (d, 1H), 7.41 (d, 1H); MS for C 23 H 30 N 4 O 5 S: [M-H]- 475.

Example 2E54. Preparation of Compound 282: N-(πR,2R)-l-(2.3- dihvdrobenzo[β1[1,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yπpropan-2-yl)-5-(3,4- dimethoxyphenyl)-5-oxopentanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.76 (br, 4H), 1.92-2.00 (m, 2H), 2.21-2.26 (m, 2H), 2.60-2.65 (m, 4H), 2.70-2.95 (m, 4H), 3.93 (d, 6H), 4.17-4.23 (m, 5H), 4.90 (d, 1H), 5.96 (br, 1H), 6.75-6.79 (m, 2H), 6.85 (s, 1H), 6.87 (d, 1H), 7.50 (s, 1H), 7.55 (d, 1H); MS for C 28 H 36 N 2 O 7 : [M-H]- 513.

Example 2E55. Preparation of Compound 283: N-((lR.2R)-1-(2,3- dihvdrobenzo[b][1,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-y l)propan-2-yl)-5-oxo- 5-p-tolylpentanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.77 (br, 4H), 1.96-2.02 (m, 2H), 2.21-2.26 (m, 2H), 2.40 (s, 3H), 2.63-2.80 (m, 4H), 2.82-2.95 (m, 4H), 4.18-4.23 (m, 5H), 4.91 (d, 1H), 5.94 (br, 1H), 6.74-6.77 (m, 2H), 6.85 (s, 1H), 7.26 (d, 2H), 7.81 (d, 2H); MS for C 27 H 34 N 2 O 5 : [M-H]- 467.

Example 2E56. Preparation of Compound 113: N-((lR.2R)-l-(2.3- dihydrobenzo[β] [ 1 ,4]dioxin-6-v0- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-5-oxo- 5 -phenylpentanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.76 (br, 4H), 1.95-2.01 (m, 2H), 2.22-2.25 (m, 2H), 2.62-2.63 (m, 4H), 2.78-2.95 (m, 4H), 4.17-4.22 (m, 5H), 4.91 (sd, 1H), 5.99 (br, 1H), 6.77 (st, 2H), 6.85 (s, 1H), 7.44-7.58 (m, 3H), 7.92 (d, 2H); MS for C 26 H 32 N 2 O 5 : [M-H]- 453.

Example 2E57. Preparation of Compound 284: N-((lR.2R)-l-(2,3- dihvdrobenzo[β][1,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yπpropan-2-yπ-5-(4- isopropoxyphenyl)-5-oxopentanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.36 (d, 6H), 1.75 (br, 4H), 1.90-2.02 (m, 2H), 2.20-2.25 (m, 2H), 2.60-2.66 (m, 4H), 2.70-2.86 (m, 4H), 4.17 (s, 4H), 4.22 (br, 1H), 4.62-4.65 (m, 1H), 4.89 (sd, 1H), 6.07 (d, 1H), 6.77 (s, 2H), 6.85 (s, 1H), 6.87 (d, 2H), 7.86 (d, 2H); MS for C 29 H 38 N 2 O 6 : [M-H]- 51 1.

Example 2E58. Preparation of Compound 140: N-ff lR.2R)- l-f2.3- dihvdrobenzofβlfl ^idioxin-ό-yl)-1-hydroxy-S-Cpyrrolidin-1-yl)propan^-yl)-ό- ^- methoxy-3.5-dimethylphenyl * )-6-oxohexanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.61-1.63 (m, 4H), 1.77 (br, 4H), 2.16 (t, 2H), 2.32 (s, 6H), 2.61-2.67 (m, 4H), 2.74-2.89 (m, 2H), 2.91 (t, 2H), 3.75 (s, 3H), 4.21 (br, 5H), 4.90 (sd, 1H), 5.93 (br, 1H), 6.75-6.82 (m, 2H), 6.85 (sd, 1H), 7.61 (s, 2H); MS for C 30 H 40 N 2 O 6 : [M-H]- 525.

Example 2E59. Preparation of Compound 141: N-(T 1R.2R)-1 -(2.3- dihvdrobenzo[β][l λldioxin-6-yl)-l-hvdroxy-3-(pyrrolidin-1-v0propan-2-v0-6-(4 - methoxyphenvP-ό-oxohexanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.62-1.64 (m, 4H), 1.76 (br, 4H), 2.17 (t, 2H), 2.61-2.65 (m, 4H), 2.72- 2.79 (m, 2H), 2.89 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.89

(d, 1H), 6.01 (br, 1H), 6.77 (q, 2H), 6.85 (s,1H), 6.91 (d, 2H), 7.90 (d, 2H); MS for C 28 H 36 N 2 O 6 : [M-H]- 497.

Example 2E60. Preparation of Compound 155: 6-(4-tert-butylphenyl)-N-( f 1 R.2R)- l-(2,3-dihvdrobenzo[β][l ,4]dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)- 6-oxohexanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.34 (s, 9H), 1.63-1.65 (m, 4H), 1.77 (br, 4H), 2.17 (t, 2H), 2.64-2.66 (br, 4H), 2.75 (dd, 1H), 2.2.81 (dd, 1H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 2H), 6.85 (d, 1H), 7.46 (d, 2H), 7.86 (d, 2H); MS for C 3 ,H 42 N 2 O 5 : [M-H] ' 523.

Example 2E61. Preparation of Compound 156: N-((lR,2R)-1-(23- dihvdrobenzo[β]fl ,41dioxin-6-yl)-1-hvdroxy-3-(pyiτolidin-1-yl)propan-2-yl)-7 -(4- methoxyphenyl)-7-oxoheptanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.25-1.30 (m, 2H), 1.55-1.70 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.61-2.66 (m, 4H), 2.74- 2.82 (m, 2H), 2.88 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (br, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C 29 H 38 N 2 O 6 : [M-H]- 51 1.

Example 2E62. Preparation of Compound 144: N-(Cl R.2R)-1 -(2,3- dihydrobenzo[β] F 1 ,41dioxin-6-vP- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-y0-8-(4- methoxyphenyl)-8-oxooctanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.25-1.33 (m, 4H), 1.54 (m, 2H), 1.68 (t, 2H), 1.78 (br, 4H), 2.1 1 (br, 2H), 2.65 (br, 4H), 2.76-2.1 1 (m, 4H), 3.86 (s, 3H), 4.21 (br, 5H), 4.90 (br, 1H), 6.02 (d, 1H), 6.78-6.84 (m, 3H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C 30 H 40 N 2 O 6 : [M-H]- 525.

Example 2E63. Preparation of Compound 159: 7-(4-chlorophenyl )-N-((1 R.2R)-1- (2,3-dihydrobenzo[β] [ 1 ,4]dioxin-6-yl)- 1 -hvdroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-7- oxoheptanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.26-1.37 (m, 2H), 1.57 (m, 2H), 1.68 (m, 2H), 1.77 (br, 4H), 2.13 (t, 2H), 2.62-2.65 (m, 4H), 2.76-2.82 (m, 2H), 2.90 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (d, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 7.42 (d, 2H), 7.87 (d, 2H); MS for C 28 H 35 ClN 2 O 5 : [M-H]- 515.

Example 2E64. Preparation of Compound 160: 7-(4-teit-butylphenyr)-N-((lR,2R)- 1 -(2,3-dihydrobenzo[β] [ 1.4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yiy 7-oxoheptanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.27-1.34 (m, HH), 1.56-1.71 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.63-2.66 (m, 4H), 2.76-2.819 (m, 2H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (sd, 1H), 5.90 (d, 1H), 6.81 (q, 2H), 6.85 (s, 1H), 7.46 (d, 2H), 7.88 (d, 2H); MS for C 32 H 44 N 2 O 5 : [M-H]- 537.

Example 2E65. Preparation of Compound 168: N-rriR.2R)-l-r2.3- dihydrobenzofbl [ 1.41dioxin-6-yl)- 1 -hvdroxy-3-rpyrrolidin- 1 -yl)propan-2-yl)-7-(4- methoxyphenyl)-7-oxoheptanamide r2S.3S * )-2.3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 1.15- 1.19 (m, 2H), 1.40- 1.47 (m, 2H), 1.60 (m, 2H), 2.02 (br, 4H), 2.09-2.21 (m, 2H), 2.90 (t, 2H), 3.35-3.49 (m, 5H), 3.83 (s, 3H), 4.12 (br, 4H), 4.38 (s, 2H), 4.43 (m, 1H), 4.74 (sd, 1H), 6.71 (d, 1H), 6.79 (dq, 1H), 6.86 (sd, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C 29 H 38 N 2 O 6 - C 4 H 6 O 6 : [M-H]- 661 .

Example 2E66. Preparation of Compound 162: N-((lR.2R)-l-(2.3- dihydrobenzo[β][ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-rpyrrolidin- 1 -yl)propan-2-yl)-4-r4- isopropoxyphenvO-4-oxobutanamide

1 H NMR (400MHz, CDCl 3 ) δ 1.35 (d, 6H), 1.77 (br, 4H), 2.52-2.56 (m, 2H),

2.64-2.83 (m, 6H), 3.09-3.36 (m, 2H), 4.22( br, 5H), 4.63-4.66 (m, 1H), 4.89 (sd, 1H), 6.13 (d, 1H), 6.78 (s, 2H), 6.88 (t, 3H), 7.90 (d, 2H); MS for C 28 H 36 N 2 O 6 : [M- H]- 497.

Example 2E67. Preparation of Compound 176: N-(Y 1R.2R)-1 -(2,3- dihydrobenzofβl [ 1 ,4]dioxin-6-vO- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-4-oxo- 4-(4-(trifluoromethyl)phenyl)butanamide (2S,3S)-2,3-dihydroxysuccinate

1 H NMR (400MHz, CD 3 OD) δ 2.08 (br, 4H), 2.54-2.72 (m, 2H), 3.24-3.48 (m, 6H), 4.19 (s, 4H), 4.29 (m, 4H), 4.74 (sd, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 6.92 (s, 1H), 7.81 (d, 2H), 8.13 (d, 2H); MS for C 26 H 29 F 3 N 2 O 5 - C 4 H 6 O 6 : [M-H]- 657.

Example 2E68. Preparation of Compound 65: 2-(3'-chlorobiphenyl-4-yl)-N- (( 1 R.2R)- 1 -(2,3 -dihvdrobenzo[βi f 1 ,41dioxin-6-yl)- 1 -hvdroxy-3 -(pyrrolidin- 1 - yl)propan-2-yl)acetamide

I 1 H 1 NMR (400MHz, CDCl 3 ) δ 1.70 (br, 4H), 2.54 (br, 4H), 2.72-2.81 (m, 2H), 3.53 (s, 2H), 4.12-4.23 (m, 5H), 4.85 (d, 1H), 5.82 (d, 1H), 6.58 (dd, 1H), 6.70 (sd, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.32-7.34 (m, 1H), 7.38 (t, 1H), 7.46-7.49 (m, 1H), 7.52 (d, 2H), 7.59 (d, 1H); C 29 H 31 ClN 2 O 4 : [M-H]- 507.

Example 2E69. Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy- phenyl)-1-pyrrolidin-1-ylmethyl-ethyll-3-f4-methoxy-phenoxy) -propionamide

1 H NMR (CDCl 3 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H), 2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5 (br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 429

Example 2E70. Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo- pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)- 1 -pyrrolidin- 1 -ylmethyl- ethyl] amide

1 H NMR (CDCl 3 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2 (m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 483.3

Example 2E71. Preparation of Compound 285: 7-(4-Methoxy-phenyP-7-oxo- heptanoic acid [2-hvdroxy-2-(4-methoxy-phenyl)- 1 -pyrrolidin-1 -ylmethyl-ethyl]- amide

1 H NMR (CDCl 3 400 mHz, ppm); 1.25 (m, 2H), 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.75 (s, 3H), 3.9 (s, 3H), 4.2 (m, 1H), 5.0 (d, 1H), 5.9 (br. d, 1H), 6.85 (d, 2H), 6.95 (d, 2H), 7.2 (d, 2H), 7.95 (d, 2H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 483.3

Example 2E72. Preparation of Compound 262: ./V-[2-Hydroxy-2-(4-methoxy- phenyl)- 1 -pyrrolidin- 1 -ylmethyl-ethyll -3 -(4-methoxy-phenoxy)-propionamide

1H NMR (CDCl 3 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H),

2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5 (br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 429

Example 2E73. Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo- pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)- 1 -pyrrolidin- 1 -ylmethyl- ethyl] amide

1 H NMR (CDCl 3 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2 (m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 483.3

Example 2E74. Preparation of Compound 305

1 H NMR (CDCl 3 400 mHz, ppm); 1.25 (m, 14 H), 1.6 (m, 4H), 1.8 (m, 4H), 2.1 (t, 2H), 2.6 (t, 2H), 2.8 (m, 6H), 4.2 (m, 5H), 4.9 (d, 1H), 6.0 (br d, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.5 (m, 1H), 8.4 (m, 2H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 538

Example 2E75. Preparation of Compound 320: Octanoic acid [2-hydroxy-2(4- methoxy-phenyl)- 1 -Pyrrolidin 1 -ylmethyl-ethyli-amide

1 H NMR (CDCl 3 400 mHz, ppm); 0.9 (t, 3H), 1.2 (m, 8H), 1.5 (m, 2H), 1.8 (m, 4H), 2.1 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 4.95 (d, 1H), 5.9 (br d, 1H), 6.9 (2s, 2H), 7.25 (m, 2H). M/Z for C 22 H 36 N 2 O 3 [M-H] + 377.4

Example 2E76. Preparation of Cyclic Amide Analogs

(Scheme

6) Cyclic amide analogs were prepared according to Scheme 6. 2-Amino-1-

(2,3-dihydro-benzo[1,4] dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol was prepared according to the preparation of intermediate 4 of US patent 6,855,830 B2. This amine was coupled with various nitriles in potassium carbonate and glycerol, under an atmosphere of nitrogen, for example, at 1 15°C for 18 hours. Compound 323 characterized by the following structural formula was prepared by following Scheme 6. Compound 323 was purified by column chromatography using a mixture of methanol and methylene chloride.

1 H NMR (CDCl 3 400 mHz, ppm); 0.95 (t, 3H), 1.35 (m, 2H), 1.6 (m, 2H), 1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (m, 5H), 5.4 (d, 1H), 6.85 (m, 3H), 7.2 (m, 2H), 7.9 (d, 2H). M/Z for C 24 H 32 N 2 O 5 [M-H] + 421.54

Example 2E77. Preparation of N-(Y1R.2R)- 1 -C2.3-dihvdrobenzo|-bl[l .41dioxin-6- yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-5 -(4-(2-methoxyethoxy * )phenyl)-5 - oxopentanamide :

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.25 (t, 3H), 1.8 (br, 4H), 1.95 (m, 2H), 2.05 (t, 3H), 2.25 (m, 2H), 3.65 (m, 4H), 2.90 (m, 4H), 3.4 (s, 4H), 3.8 (m, 2H), 4.15 (m, 9H), 4.95 (br, 1H), 5.95 (br, 1H), 6.88-6.95 (m, 5H), 7.9 (m, 2H). M/Z for C 29 H 38 N 2 O 7 [M+H] = 527.

Example 2E78. Preparation of N-((1R. 2R)-l-(4-chlorophenyl)-l-hvdroxy-3- (pyrrolidin- 1 -yPpropan-2-vl)-3-(4-methoxyphenoxy)propanamide

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.76 (br, 4H), 22.52-2.57 (sq, 2H), 2.60-2.73 (br, 4 H), 2.88-2.96 (st, 2H), 3.8 (s, 3H), 3.96-4.0 (m, 1H), 4.06-4.1 1 (1H), 4.21-4.24 (m, 1H), 5.07 (d, 1H), 6.57 (bd, 1H), 6.77-6.87 (sq, 4H), 7.20-7.27 (sd, 6H). M/Z for C 23 H 29 ClN 2 O 4 [M+H] = 433.

Example 2E79. Preparation of N-(ClR, 2R)-1-(4-chlorophenyl)-1-hvdroxy-3- (pyiτolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexa namide:

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.54-1.62 (br, 4H), 1.79 (br, 4H), 2.14 (t, 2H), 2.63-2.69 (br, 4H), 2.83-2.89 (m, 4H), 3.88 (s, 3H), 4.24 (br, 1H), 5.03 (d, 1H), 5.93 (d, 1H), 6.93 (d, 2H), 7.26-7.32 (m, 4H), 7.93 (d, 2H). M/Z for C 26 H 33 ClN 2 O 4 [M+H] = 473.

Example 2E80. Preparation of N-((1R, 2R)-I -hydroxy- l-(4-methoxy-3- methylphenyl>3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxy phenyl)-6- oxohexanamide :

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.77 (br, 4H), 1.91-2.0 (m, 2H), 2.18 (s, 3H), 2.2- 2.25 (m, 2H), 2.62-2.69 (m, 4H), 2.77-2.89 (m, 4H), 3.75 (s, 3H), 3.88 (s, 3H), 4.23 (m, 1H), 4.96 (sd, 1H), 5.93 (br, 1H), 6.75 (br, 1H), 6.94 (d, 2H), 7.1 (br, 2H), 7.88 (m, 2H). M/Z for C 28 H 38 N 2 O 5 [M+H] = 483.

Example 2E81. Preparation of N-((1R, 2R)-l -hydroxy- l-(4-methoxy-3- methylphenyl)-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-(4- (trifluoromethoxy)phenyQacetamide:

1H NMR (CDCl 3 , 400 mHz, ppm): 1.73 (br, 4H), 2.20 (s, 3H), 2.55 (br, 4H), 2.81 (st, 2H), 3.46 (s, 2H), 3.82 (s, 3H), 4.15 (m, 1H), 4.92 (sd, 1H), 5.85 (br, 1H), 672 (d, 1H), 6.95 (sd, 1H), 7.00 (br, 1H), 7.2 (m, 4H). M/Z for C 24 H 29 F 3 N 2 O 4 [M+H] = 467.

Example 2E82. Preparation of N-((1R. 2Ryi-hvdroxy-3-(pyrrolidin-1-vn-1-

(2,2,33-tetrafluoro-2,3-dihvdrobenzorbiri,41dioxin-6-yl)p ropan-2-v0octanamide:

1 H NMR (CDCl 3 , 400 mHz, ppm): 0.9 (t, 3H), 1.2 (rm, 11H), 1.5 (bm, 8H), 1.8 (br, 4H), 2.1 (m, 2H), 2.65 (m, 4 H), 2.90 (m, 2H), 4.2 (m, 1H), 5.05 (d, 1H), 5.85 (br, 1H), 7.2 (m, 3H). M/Z for C 23 H 32 F 4 N 2 O 4 [M+H] = 477.

Example 2E83. Preparation of N-((1R. 2R)-l-(2.2-difluorobenzordiπ,31dioxol-5- yP- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide:

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 5.0 (d, 1H), 5.85 (br, 1H), 6.8-6.95 (3H), 7.1-7.20 (4H). M/Z for C 23 H 23 F 5 N 2 O 5 [M+H] = 503.

Example 2E84. Preparation of N-(T 1 R, 2R)- 1 -hydroxy- 1 -(4-(2- phenoxyethoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-viy6-(4-me thoxyphenyl)-6- oxohexanamide:

1H NMR (CDCl 3 , 400 2.15 (t, 2H), 2.7 (m,

4H), 2.85 (m, 4H), 3.8 (s, 3H), 4.25 (m, 1H), 4.3 (s, 3H), 5.0 (d, 1H), 5.95 (br, 1H), 6.9 (m, 7H), 7.2 (m, 4H), 7.95 (m, 2H). M/Z for C 34 H 42 N 2 O 6 [M+H] = 575.

Example 2E85. Preparation of N-(Y 1 R, 2R)- 1 -(4-(cyclobutylmethoxy)phenyl)- 1 - hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-6-(4-methoxyphenyl)- 6-oxohexanamide

QH

1 H NMR (CDCl 3 , 400 (m, 9H), 2.05 (m, 5H), 2.75-3.0 (m, 9H), 3.8 (m, 5H), 4.3 (m, 1H), 5.0 (m, 1H), 6.2 (br, 1H), 6.9 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C 3 ]H 42 N 2 O 5 [M+H] = 523.

Example 2E86. Preparation of N-(QR. 2R)- l-(4-(4-fluorobutoxy)phenyl)-1- hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)- 6-oxohexanamide:

1H NMR (CDCl 3 , 400 10H), 2.15 (t, 2H), 2.65 (m,

4H), 2.8 (d, 2H), 2.9 (m, 5H), 2.95 (s, 3H), 4.0 (t, 2H), 4.15 (m, I H), 4.45 (t, 1H), 4.55 (t, 1H), 4.95 (br, 2H), 5.9 (br, 1H), 6.90 (m, 4H), 7.20 (m, 2H), 7.95 (m, 2H), 8.05 (br, 1H). M/Z for C 30 H 4I FN 2 O 5 [M+H] = 529.

Example 2E87. Preparation of N-((1R, 2R)-l-hvdroxy-3-(pyrrolidin-1-vn-1-(4-(3- (p-tolyloxy)propoxy)phenyl)propan-2-yl)-6-(4-methoxyphenyl)- 6-oxohexanamide:

1 H NMR (CDCl 3 , 400 2.15 (t, 2H), 2.25 (t, 2H), 2.3 (s, 3H), 2.65 (m, 4H), 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 4.15 (m, 4H), 4.25 (m, 1H), 4.95 (br, 1H), 6.85 (br, 1H), 6.8-6.95 (m, 6H), 7.05 (m, 2H), 7.2 (m, 2H), 7.95 (2H). M/Z for C 36 H 46 N 2 O 6 [M+H] = 603.

Example 2E88. Preparation of N-(QR, 2R>l-(4-butoxyphenyl>l-hvdroxy-3- (pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyiy6-oxohexana mide:

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.0 (t, 3H), 1.5 (m, 2H), 1.65 (m, 4H), 1.8 (m, 6H), 2.15 (t, 2H), 2.65 (m, 4HO, 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 3.9 (t, 2H), 4.15 (m, 1H), 4.95 (br, 1H), 5.90 (br, 1H), 6.8-6.95 (m, 4H), 7.2 (br ,2H), 7.90 (br, 2H). M/Z for C 30 H 42 N 2 O 5 [M+H] = 51 1.

Example 2E89. Preparation of N-(ClR. 2RH-C4-Chexyloxy)phenvn-1-hydroxy-3- CpyπOlidin-1-y0propan-2-yl)-5-C4-C2-methoxyethoxy)phenyl * )-5-oxopentanamide:

1H NMR (CDCl 3 , 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H), 1.7 (m, 6H), 1.95 (m, 2H), 2.20 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.45 (s, 3H), 3.75 (m, 2H), 3.90 (t, 2H), 4.15 (m, 2H), 4..25 (m, 1H), 4.95 (m, 1H), 6.0 (br, 1H), 6.8 (m, 2H), 6.9 (m, 2H), 7.2 (m, 2H), 7.90 (m, 2H). M/Z for C 33 H 48 N 2 O 6 [M+H] = 569.

Example 2E90. Preparation of N-(Cl R.2 R)-l-(4-(hexyloxy)phenvn-1-hvdroxy-3- (CS)-3 -hydroxypyrrolidin- 1 -yl)propan-2-yl)-3 -C4-methoxyphenoxy)propanamide

1H NMR (CDCl 3 , 400 (m, 2H), 1.75

(m, 3H), 2.1 (m, 1H), 2.4 (m, 1H), 2.55 (t, 2H), 2.75 (m, 3H), 2.85 (m, 1H), 3.0 (m, 1H), 3.75 (s, 3H), 3.90 (t, 2H), 4.05 (m, 2H), 4.1 (m, 1H), 4.15 (m, 1H), 5.0 (br, 1H), 6.6 (br, 1H), 6.8 (m, 6H), 7.2 (m, 2H). M/Z for C 29 H 42 N 2 O 6 [M+H] = 515.

Example 2E91. Preparation of 2-(4'-chlorobiphenyl-4-vn-N-((lR. 2R)-3-((R)-3- fluoropyrrolidin- 1 -yl)- 1 -hydroxy- 1 -(4-isopropoxyphenyl)propan-2-yl)acetamide:

1H NMR (CDCl 3 , 400 mHz, ppm): 1.15 (m, 6H), 2.10 (m, 2H), 2.4 (q, 1H), 2.5-2.75 (m, 4H), 2.95 (m, 2H), 3.55 (d, 2H), 4.15 (m, 1H), 4.45 (m, 1H), 4.85 (br, 1H), 5.10 (m, 1H), 5.9 (br, 1H), 6.75 (m, 2H), 7.05 (br, 2H), 7.20 (m, 2H), 7.4 (m, 2H), 7.5 (m, 4H). M/Z for C 30 H 34 ClFN 2 O 3 [M+H] = 528.

Example 2E92. Preparation of N-((1R, 2R)-l-hydroxy-3-((S)-3-hydroxypyrrolidin- l-vO-1-(4-isopropoxyphenyl)propan-2-vO-3-(4-methoxyphenoxy)p ropan amide:

1 H NMR (CDCl 3 , 400 mHz, ppm): 1.35 (d, 6H), 1.7 (m, 1H), 2.1(m, 1H), 2.45 (m, 1H), 2.55 (t, 2H), 2.7-2.9 (m, 4H), 3.0 (m, 1H), 3.8 (s, 3H), 4.05 (m, 1H), 4.15 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.5 (m, 1H), 4.95 (d, 1H), 6.55 (br, 1H), 6.75-6.85 (m, 6H), 7.2 (m, 2H). M/Z for C 26 H 36 N 2 O 6 [M+H] = 473.

Example 2E93. Preparation of N-(αR,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy- 3 -(YR)- 3 -hydroxypyrrolidin- 1 -yl)propan-2-yl)-5 -(4-methoxyphenyl)-5 - oxopentanamide

1 H NMR (400 MHz, CDCl 3 ) 5=1.7-2.2 (m, 12 H), 2.4 (dd, 1H), 2.65-2.9 (m, 6H), 3.0(dd, 1H), 3.90 (s, 3H), 3.91(dd, 2H), 4.1-4.22 (m, 1H), 4.3-4.4 (m,1H), 4.4(dd, 1H), 4.6 (dd, 1H), 4.91 (d, 1H), 6.19(d, 1H), 6.83(d, 2H), 6.92 (d, 2H), 7.22(d, 2 H), 7.9 (d, 2H); MS for C 29 H 39 FN 2 O 6 m/z 531 [M+H].

Example 2E94. Preparation of N-(T 1 R.2R)- 1 -(4-(4-fluorobutoxy)phenyl)- 1 - hydroxy-3-((Ry3-hvdroxypyiTolidin-1-yl)propan-2-yl)-8-methox yoctanamide

1 H NMR (400 MHz, CDCl 3 ) 6=1.2-1.34 (m, 6H), 1.45-1.6 (m, 4H), 1.7-1.8(m, 1H), 1.86-1.95 (m, 4H), 2.0-2.2 (m, 4), 2.4-2.5 (m, 2H), 2.7-2.8 (m, 4H), 2.98 (dd, 1H), 3.3 (s, 3H), 3.53 (dd, 1H), 4.0 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4 (m, 1H), 4.5 (dd, 1H), 4.58 (dd,1H), 4.9(d, 1H), 5.9 (d, 1H), 6.85 (d, 2H), 7.22 (d, 2H) ; MS for C 26 H 43 FN 2 O 5 m/z 483 [M+H]

Example 2E95. Preparation of N-((lR,2R)-l -(4-(4-fluorobutoxy)phenvn-1- hydroxy-3-((Ry3-hvdroxypyrrolidin-1-yl)propan-2-v0-4-(4- methoxyphenoxy)butanamide

1 H NMR (400 MHz, CDCl 3 ) δ=l .6-2.2 (m, 9H), 2.3-2.5 (m, 4H), 2.6-2.8 (m, 5), 2.9 (dd, 1H), 3.7 (s, 3H), 3.85 (dd, 2H), 3.95 (dd, 2H), 4.2-4.3 (m, 2H), 4.5 (dd, 1H), 4.6 (dd, 1H), 4.9 (d, 1H), 6.0 (d, 1H), 6.7-7 (m, 6H), 7.1-7.2 (d, 2H); MS for C 28 H 39 FN 2 O 6 m/z 519[M+H].

Example 2E96. Preparation of N-(Y 1 R.2R)- 1 -f4-(4-fluorobutoxy)phenvn- 1 - hvdroxy-3-((R)-3-hvdroxypyrrolidin-1-v0propan-2-yl)-3-(4- methoxyphenoxy * )propanamide

1 H NMR (400 MHz, CDCl 3 ) δ=1.6-1.7 (m, 1H), 1.8-2 (m, 4H), 2.1-2.2 (m, 1), 2.4- 2.5(m, 1H), 2.6(t, 2H), 2.7-2.85 (m, 4H), 3.0 (dd, 1H), 3.7 (s, 3H), 4.0 (t, 2H), 4.1- 4.3 (m, 4H), 4.5 (dd, 1H), 4.6 (dd, 1H) 4.98 (d, 1H), 6.6 (d, 1H), 6.7-6.9 (m, 6H), 7.1-7.22 (d, 2H); MS for C 27 H 37 FN 2 O 6 m/z 505[M+H].

Example 2E97. Preparation of N-((1 R.2R)-1 -(4-(4-fluorobutoxy)phenyl)- 1-hvdroxy-

3-((R)-3-hydroxypyrrolidin-1-yl ' )propan-2-yl)-7-(4-methoxyphenyl)-7- oxoheptanamide

1 H NMR (400 MHz, CDCl 3 ) δ=l.l-1.4( m, 3H), 1.5-2.0( m, 12H), 2.1-2.2 (dd, 4H), 2.4-2.90(m, 10H), 3.0(dd, 1H), 3.75 (s, 3H), 3.9 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4.5 (m, 2H), 4.57 (dd, 1H), 4.9 (d, I H), 5.9 (d, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H), 7.9 (d, 2H); MS for C 31 H 43 FN 2 O 6 m/z 559[M+H].

Example 2E98. Preparation of N-((lR.2R)-l-(4-(4-fluorobutoxy)phenvn-1- hvdroxy-3 -((R)-3 -hvdroxypyrrolidin- 1 -yl)propan-2-y 0-6-(4-methoχyphenyl)-6- oxohexanamide

1 H NMR (400 MHz, CD 3 OD) 5=1.4-1.6 (m, 4H), 1.6-1.8 (m, 5H), 2.0-2.2 (m, 1H), 2.2-2.3(m, 2H),2.4-2.6 (m, 3H), 2.7-3.0 (m, 5H), 3.8 (s, 3H), 3.9 (dd, 1H), 4.1-4.25 (m, 1H), 4.3-4.38(m, 1H), 4.4 (dd, 1H), 4.5 (dd, I H), 6.8 (d, 2H), 7.1(d, 2H), 7.2(d, 2H), 8 (d, 2H); MS for C 30 H 41 FN 2 O 6 m/z 545[M+H]

Example 2E99. Preparation of N-((lS,2R)-1-(5-chlorothiophen-2-yl)-1-hvdroxy-3- (pyrrolidin- 1 -yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

1H NMR (400 MHz, CDCl 3 ) δ=1.7 (broad s, 4H), 2.5-2.7 (m, 7H), 2.8 (dd, 1H), 2.94 (dd, 1H), 3.77 (s, 3H) 4.1-4.2(m, 2H), 4.3-4.35( m, 1H), 5.18 (d, 1H), 6.55 (d, 1H), 6.66 (d, 1H), 6.67 (d, 1H), 6.7-6.9 (m, 4H);MS for C 21 H 27 ClN 2 O 4 S m/z 439[M+H].

Example 2E100. Preparation of N-((1S.2R)-1 -hydroxy- l-(3-methyrthiophen-2-yl> 3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanam ide 2,2,2- trifluoroacetate

1 H NMR (400 MHz, CD 3 OD) δ= 1.8-2.2 (m, 4H), 2.24 (s, 3H) 2.5-2.8(m, 2H), 3.0- 3.2 (m, 2H), 3.5 (dd, 2H), 3.7 (s, 3H), 3.6-3.8 (m, 2H), 4.0-4.2(m, 2H), 4.5 (dd, 1H), 5.2 (s, 1H), 6.8 (d, I H), 6.84 (broad s, 4H), 7.2 (d, 1H);MS for C 22 H 30 N 2 O 4 S m/z 419[M+H].

Example 2E101. Preparation of Compound 257: N-((1R, 2R)-1-(2,3- dihvdrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-morpholinoprop an-2-yl)-3-(4- methoxyphenoxy)propanamide

1 H NMR (400 MHz, CDCl 3 ) δ= 2.4-2.6 (m, 7H), 2.7 (dd, 1H), 3.5-3.7 (m, 4H), 3.8 (s, 3H), 4-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, I H), 4.9 (d, 1H), 6.5 (d, 1H), 6.7-6.9 (m, 7H); MS for C 25 H 32 N 2 O 7 m/z 473.1 [M+H].

Example 2El 02. Preparation of Compound 261: N-((1R. 2R)- 1 -(2.3- dihvdrobenzo[βiri.41dioxin-6-yl)-1-hvdroxy-3-(piperidin-1-y l)propan-2-yl)-3-(4- methoxyphenoxy^propanamide

1 H NMR (400 MHz, CDCl 3 ) δ= 1.4 (br, 2H), 1.6 (br, 4H), 2.2-2.8 (m, 6H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (s, 1H), 6.4 (d, 1H), 6.7-6.9 (m, 7H); MS for C 25 H 34 N 2 O 6 m/z 471.1 [M+H].

Example 2Bl . Preparation of Compound 6: l-benzyl-3-(dR,2R)-l-(2,3- dihydrobenzo [βl f 1 ,41dioxin-6-yl)- 1 -hydroxy-S-Cpyrrolidin- 1 -yl)propan-2-yl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.6 (m, 5H), 2.6-2.7 (dd, 1H), 4.0 (m, 1H), 4.2 (s, 4H), 4.3 (m, 2H), 4.8 (d, 1H), 4.86 (d, 1H), 5.0 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5 H); MS for C 23 H 29 N 3 O 4 m/z 412.2 [M+H]

Example 2B2. Preparation of Compound 17: 1-((1R. 2R)-1-(2,3- dihydrobenzo[βl| ' L41dioxin-6-yπ-1-hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3- (4- fluorobenzyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (m, 1H), 4.0-4.1 (m, 2H), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, 1H), 6.6-7.1 (m, 7H); MS for C 23 H 28 FN 3 O 4 m/z 430.2 [M+H].

Example 2B3. Preparation of Compound 40: l-(4-bromobenzyl)-3-((lR. 2R)-l -(2.3- dihydrobenzo [β] [ 1 ,41 dioxin-6-yl )- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2- vOurea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.8 (m, 6H), 4.0 (m, 1H), 4.1-4.2 (m, 2H) 4.2 (s, 4H), 4.8 (d, 1H), 5.3 (d, 1H), 5.6-5.8 (br, 1H), 6.8-7.0 (m, 3H), 7.0 (d, 2H), 7.4 (d, 2H); MS for C 23 H 28 BrN 3 O 4 m/z 490 [M], 491 [M+H], 492 [M+2].

Example 2B4. Preparation of Compound 41: 1-((1R. 2R)-H2.3- dihydrobenzo[β] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-(4- methoxybenzyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3.9 (m, 1H), 4.1 (d, 2H), 4.2 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.5-5.7 (br, 1H), 6.6-6.8 (m, 5H), 7.1 (d, 2H); MS for C 24 H 31 N 3 O 5 m/z 442.2 [M+H]

Example 2B5. Preparation of Compound 80: U(IR, 2R)-I -(2.3- dihydrobenzo [β] [ 1 ,41 dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-3 -(3 - methoxybenzyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.6 (m, 6H), 3.8 (s, 3H), 4.0 (m, 1H), 4.1-4.2 (s, 6H), 4.8 (d, 1H), 5.1 (d, 1H), 5.2-5.4 (br, 1H), 6.6-6.8 (m, 6H), 7.2 (dd, 1H); MS for C 24 H 31 N 3 O 5 m/z 442.2 [M+H]

Exampl 2B6. Preparation of Compound 42: 1-(TlR, 2R)-1-(2.3- dihydrobenzo [β] [1,4] dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-3 -(4- methylbenzyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.6 (s, 4H), 2.3 (s, 3H), 2.4-2.6 (m, 6H), 4.0 (m, 1H), 4.2 (d, 2H), 4.21 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.4-5.6 (br, 1H), 6.7-7.1 (m, 7H); MS (for C 24 H 3 ,N 3 O 4 m/z 426.2 [M+H].

Exampl 2B7. Preparation of Compound 43: l-(4-chlorobenzyl)-3-((lR. 2R)-1-(2,3- dihydrobenzorβl Tl ,41dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.5-2.7 (m, 6H), 4.0 (m, 1H), 4.2 (s, 6H), 4.8 (d, 1H), 5.2 (d, 1H), 5.4-5.5 (br, 1H), 6.7-6.9 (m, 3H), 7.1 (d, 2H), 7.3 (d, 2H); MS for C 23 H 28 N 3 ClO 4 m/z 446 [M+H], 447.5 [M+2].

Example 2B8. Preparation of Compound 10: 1-((1R, 2R)-1-(Z3- dihydrobenzofβl F 1 ,41dioxin-6-yQ- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-((S)- l-phenylethyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.4 (d, 3H), 1.6 (s, 4H), 2.2-2.5 (m, 4H), 2.5 (dd, 1H), 2.6 (dd, 1H), 3.9 (m, I H), 4.2 (s, 4H), 4.5 (m, 1H), 4.8 (d, 1H), 5.0 (d, 1H), 5.1-5.3 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C 24 H 3 ,N 3 O 4 m/z 426.2 [M+H].

Example 2B9. Preparation of Compound 286: 1-((1R, 2R)-1-(2.3- dihydrobenzorβir 1 ,4IdJOXJn-O-Vl)- l-hvdroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((R)- 1 -(R-phenylethyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.3 (d, 3H), 1.7 (s, 4H), 2.2-2.6 (m, 6H), 3.9 (m, 1H), 4.2 (s, 4H), 4.6-4.7 (m, 2H), 5.3 (d, 1H), 5.6-5.7 (br, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 7.2-7.4 (m, 5H); MS for C 24 H 3 ,N 3 O 4 m/z 426.0 [M+H].

Example 2B10. Preparation of Compound 69: 1-(YlR. 2R)-l-(2.3- dihydrobenzo[β][ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3- (naphthalen-2-yl)urea

1H NMR (400 MHz, CDCl 3 ) δ= 1.6 (s, 4H), 2.4-2.8 (m, 6H), 4.1 (s, 5H), 4.8

(s, 1H), 6.0 (d, 1H), 6.7 (s, 2H), 6.9 (s, 1H), 7.1-7.8 (m, 7H); MS for C 26 H 29 N 3 O 4 m/z 448.1 [M+H].

Example 2Bl 1. Preparation of Compound 288: 1-(TlR. 2R)-1-(2.3- dihydrobenzo| ' βl| ' L41dioxin-6-yl)-1-hvdroxy-3-(pyiτolidin-1-yl ' )propan-2-yl)-3- (naphthalen- 1 -vDurea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.6 (s, 4H), 2.4 (s, 4H), 2.6 (d, 2H), 4.1 (m, 1H), 4.2 (s, 4H), 4.8 (d, 1H), 5.4 (d, 1H), 6.5 (d, 1H), 6.6 (d, 1H), 6.7 (s, 1H), 7.2-7.6 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.0 (d, 1H); MS for C 26 H 29 N 3 O 4 m/z 448.1 [M+H].

Example 2B12. Preparation of Compound 71: 1-((1R, 2R)-I -(2.3- dihydrobenzof β] [ 1 ,41dioxin-6-yl)-l -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-((S)-

1 -(naphthalen- 1 -yl)ethyl)urea

1H NMR (400 MHz, CDCl 3 ) δ= 1.4 (s, 4H), 1.5 (d, 3H), 2.3 (s, 4H), 2.4 (dd,

1H), 2.6 (dd, 1H), 3.9 (br, 1H), 4.2 (s, 4H), 4.7 (s, 1H), 5.0 (d, 1H), 5.3 (br, 1H), 5.5 (br, 1H), 6.6 (m, 3H), 7.4-7.6 (m, 4H), 7.7 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H); MS for C 28 H 33 N 3 O 4 m/z 476.2 [M+H].

Example 2B13. Preparation of Compound 70: l-(biphenyl-4-vn-3-((lR. 2R)-l-(2,3- dihydrobenzorβi [ 1 ,41dioxin-6-vO- 1 -hvdroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.6-2.8 (m, 6H), 4.1 (br, 1H), 4.2 (s, 4H), 4.9 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 9H); for C 28 H 3 I N 3 O 4 m/z 474.1 [M+H].

Example 2B14. Preparation of Compound 81: 1-((1R. 2R)-l-(2,3- dihydrobenzo [β] [ 1 ,4-|dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 - yl)propan-2-yl )-3 -(4-

(trifluoromethyl)phenyl)urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.3 (d, 2H), 7.5 (d, 2H); MS for C 23 H 26 F 3 N 3 O 4 m/z 465.97 [M+H].

Example 2B15. Preparation of Compound 68: 1-((1R. 2R)-l -(2.3- dihydrobenzo [β] [ 1 ,41dioxin-6-yl )- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2-yl)-3 -(3 - (trifluoromethyQphenvDurea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.5-2.9 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 4H); MS for C 23 H 26 F 3 N 3 O 4 m/z 466.0 [M+H].

Example 2B16. Preparation of Compound 82: 1-((1R, 2R)-1-C2.3- dihvdroben2θ[β][l ,41dioxin-6-yπ-1-hydroxy-3-(pyrrolidin-1-yl ' )propan-2-yl)-3-(4-

(-trifluoromethoxy)phenyl)urea

1H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H),

4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.0 (d, 2H), 7.2 (d, 2H); MS for C 23 H 26 F 3 N 3 O 5 m/z 481.5 [M], 482.5 [M+H].

Exampl 2B17. Preparation of Compound 133: MdR, 2R)-l-f2.3- dihydrobenzo[β1[1,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yl ' )propan-2-yl * )-3-(4- (2-methylthiazol-4-yl)phenv0urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.4-2.7 (m, 6H), 2.7 (s, 3H), 4.1 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2 (s, 1H), 7.3 (d, 2H), 7.7 (d, 2H); MS for C 26 H 30 N 4 O 4 S m/z 494.9 [M+H].

Example 2B18. Preparation of Compound 7: H(IR, 2R)-1-C23- dihydrobenzofβifl, 4IdJQxJn-O-Vl)-l -hydroxy-S^pyrrolidin-1-yl)propan-σ-yl)-S- dodecylurea

1H NMR (400 MHz, CDCl 3 ) δ= 0.9 (t, 3H), 1.3 (br, 18H), 1.4 (m, 2H), 1.8

(s, 4H), 2.5-2.7 (m, 6H), 3.1 (q, 2H), 4.0 (m, 1H), 4.3 (s, 4H), 4.4 (br, 1H), 4.76 (d, 1H), 4.8 (d, 1H), 6.7-6.8 (dd, 2H), 6.9 (s, 1H); MS for C 28 H 47 N 3 O 4 m/z 489.7 [M+H], 490.9 [M+2].

Example 2B19. Preparation of Compound 287: 1-((1R. 2R)-I -(2,3- dihvdrobenzo[β][1,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin-1- yl)propan-2-yl)-3-(2- (thiophen-2-y0ethv0urea

1 H NMR (400 MHz, CDCl 3 ) δ= 1.7 (s, 4H), 2.5-2.7 (m, 6H), 3.0 (t, 2H), 3.8 (q, 2H), 4.0 (m, 1H), 4.2 (s, 4H), 4.8 (d, 2H), 4.9 (d, 1H), 6.7-6.8 (m, 3H), 6.9 (d, 1H), 6.9 (dd-1H), 7.1 (d, 1H); MS for C 22 H 29 N 3 O4S m/z 432.1 [M+H].

Example 2B20. Preparation of l-(πR,2R)-1-(4-(4-fluorobutoxy)phenvn-1-hydroxy- 3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyben zyl)urea 2,2,2- trifluoroacetate

1H NMR (400 MHz, CD 3 OD) δ= 1.8-2.2 (m, 6H), 3.2-3.3 (dd, 2H), 3.4-3.7 (m, 3H), 3.8 (s, 3H), 3.82-4.1 (m, 4H), 4.3 (dd, 2H), 4.4 (dd, 1H), 4.5 (dd, 2H), 4.8 (dd, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7 (m, 2H), 7.3 (d, 2H); MS for C 26 H 36 FN 3 O 5 m/z 491 [M+H].

Example 2B21. Preparation of l-f4-chlorobenzyl)-3-(TlR,2R)-1-(4-(4- fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hvdroxypyrrolidin-1- yl)propan-2-vπurea

1 H NMR (400 MHz, CDCl 3 ) δ=l .6-1.8(m, 3H), 1.8-2 (m, 5H), 2-2.2 (m, 2H), 2.2- 2.3 (m, 2H), 2.8-2.4 (m, 5H), 2.9 (m, 1H), 3.9-4.0 (m, 3), 4.1-4.4 (m, 3H),4.5 (t, 1H), 4.6-4.7 (m, 1H), 4.75 (d, 1H),6.8 (d, 2H), 7.1 (d, 2H), 7.15-7.3 (m, 4H); MS for C 25 H 33 ClFN 3 O 4 m/z 494[M+H].

Example 3: GM3 Elisa Assay

B 16-FO cells from ATCC (American Tissue Culture Collection) were grown in DMEM media (ATCC) with 10% Fetal Bovine Serum (Hyclone) and

Pen/Step/Glutamine (Biowhittaker). 4000 cells per well were plated on collagen coated plates (BD) and allowed to attach for 6 hours in an incubator (37 degrees, 5% CO2). After 6 hours the compounds and controls were added to the wells, the plates mixed and returned to the incubator for 2 days. Day of assay the cells were fixed for 20 minutes with 1% formaldehyde and then washed with Tris Buffered Saline (TBS) 3 times, 150 μl of TBS was left in the wells and 50 μl of goat serum (Invitrogen) was added, the plates mixed and incubated for 1 hour at room temperature. The plates were flicked and the cells incubated with the monoclonal Antibody to GM3 (NeuAc) (Cosmo) for 45 minutes as room temperature. The plates were then washed 3 times with TBS, leaving 150 μl of TBS in the wells and Peroxidase AffinPure F (ab') 2 frag Gt Anti-mouse IgM, μ Chain Specific (Jackson Immno Research) was added in 50 μl, the plates mixed and incubated for 45 minutes at room temperature. The plates were washed 3 times with TBS, flicked and blotted and 100 μl of Quantablu (Pierce) was added to the wells and incubated for 1 hour then read on a Fluorometer at Ex 325 and Em 420. The data was then analyzed using standard programs.

The results of the GM3 Elisa assay are summarized in Tables 1 and 2. In Tables 1 and 2, IC50 values are indicated as "A," "B," C," "D," and "E" for those of less than or equal to 0.1 μm; those of greater than 0.1 μm, and less than or equal to 1 μm; those of greater than 1 μm, and less than or equal to 3 μm; those of greater than 3 μm, and less than or equal to 10 μm; those of greater than 10 μm, respectively. As shown in Tables 1, 2 and 3, numerous compounds of the invention were shown to be inhibitors of GM3.

Table 2. IC 50 Values from GM3 Elisa Assay

Table 3: IC 50 Values

Example 4: Treatment of Jurkat T Cells with Compound C9 (iV-((lR,2R)-1-(2,3- dihvdrobenzo[Z>l[1,41dioxin-6-yl)-1-hvdroxy-3-(pyrrolidin -1-yl)propan-2- yl)nonanamide * 1/2 2,3-dihydroxysuecinate)

(Compound C9)

Culture of Jurkat T cells:

Jurkat cells (Clone E6-1) was purchased from American Tissue Culture Co. (ATCC) and propagated in cell culture media (Gibco RPMI- 1640 cell media containing 25 mM Hepes, 1 mM sodium pyruvate, 10% fetal calf serum (FCS) and Ix penicilin/streptomycin) in a humidified cell culture incubator under 5% CO 2 at 37 °C. Typically, cells were seeded at 2x10 5 cells/ml and subcultured when cells reach density at 2-3x10 6 cells/ml.

Treatment of Jurkat T cells with Compound C9:

Freshly propagated Jurkat cells were transferred into two T-75 flasks with 20 ml of fresh Jurkat cell culture media at cell density of approximately 1x10 6 cell/ml. 7.04μl of beta -mercaptoethanol from stock (0.142 M dissolved in H 2 O) were added to each flask, to a final concentration of 50 μM. 20 μl of Compound C9 from stock (250 μM dissolved in sterile water) were added to one flask to a final concentration of 250 nM. After gentle mixing, the cells were incubated at 37°C under 5% CO 2 in a cell incubator. An aliquot of 20 μl Compound C9 were supplemented every 24 hours for a total of 3 days without changing the media.

Activation of Jurkat Cells:

C9 treated or non-treated Jurkat (~2xlO 7 ) were stimulated with anti- CD3/CD28 conjugated Dynabeads (Dynal Corp). The beads were prewashed with Phosphate Buffered Saline (PBS) containing 5% bovine serum albumin before adding to the cell cultures. Cells were activated for 1 , 5 and 15 minutes at a bead to cell ratio of 1 : 1 in a humidified cell culture incubator at 37 °C. An aliquot of cells were taken out without Dyanbeads treatment as time 0. At each time point after activation, an aliquot of approximately 5x10 6 cells were removed and placed in a pre-chilled Falcon tube. T cell activation was stopped at each time point by adding three volumes of ice-cold PBS to the Falcon tubes. The tubes were kept on the ice water slurry until all time points were completed. Cells were pelleted by brief centrifugation at 4 °C for 5 min at 1,500 rpm. Cell pellet were resuspended in 1 ml of ice cold PBS, transferred to pre-chilled microcentrufudge tubes, and repelleted in a microcentrifuger for 3 min at 1,500 rpm in cold room. Cell pellets were quickly frozen on dry ice after removing all supernatant and stored at -80 °C until analysis.

SDS-PAGE and Western Blot analysis for proximal TCR signaling molecules:

Frozen or freshly harvested cell pellets (from approximately 5x10 6 cells) were lysed by adding 200 μl of the cell lysis buffer (50 mM Tris pH 7.5, 150 mM NaCl, 1% Triton X-100, 0.25% sodium dodecyl sulfate (SDS), 1 mM ethylenediamine tetraacetic acid (EDTA), 1 mM NaF, 5 mM sodium orthovanadate

(Na 3 VO 4 ), preheated on the heating block to 1 OO °C) and mixing, the samples should become viscous. The samples were further heated on a heating block for 5 minutes at 100 °C and sonicated briefly to break up the DNA until the samples are no longer viscous (approximately 5 seconds). Protein content of each sample was measured with Micro BCA protein assay kit (from Pierce). 25-50 μg of protein from each sample were mixed with 4 x SDS sample buffer and heated for 5 minutes. Samples were loaded onto 10% Tris-HCL polyacrylamide gel, along with pre-stained protein molecular weight standards. Proteins were transferred onto nitrocellulose membrane for Western Blot with different antibodies against different TCR proximal proteins according to standard protocol. The following antibodies were used. Anti-LAT antibody (# Sc-7948); Anti-Lck (#Sc-13) were purchased from Santa Cruz Biotechnology Inc. Anti-phospho-LAT (# 07-278); Anti-Zap-70 (# 05-253) and Anti-phospho-Src (#05-857) were obtained from Upstate Biotechnology (now Millipore). Anti-phospho-Zap-70 (#z-0151) was from Sigma Alderich. Anti- GAPDH (#ab9485-200) was from Abeam. Horseradish Peroxidase labeled anti- rabbit and anti-mouse secondary antibodies (#31462, #31432) were purchased from Pierce.

Analysis of GMl and CD3 on cell surface of Jurkat T cells with or without C9 treatment by flow cytometry

Jurkat T cells, either mock-treated or treated with C9 for 3 days were monitored for GMl level by CTB staining and representative proximal signaling molecule by CD3 staining respectively. For CTB staining, cells were pelleted by centrifugation and washed once with Ca2+ free PBS. For each cell sample, cells were resuspended in 0.5 ml of CTB-binding buffer (PBS + 0.5% BSA (sigma # A- 8412)) by flicking and divided into two tubes, one for CTB-Alexafluor488 stainining and one for FITC -hamster IgG as control. CTB or IgG control was added to a final concentration of 10 microgram/ml and the cells were incubated for 30 minutes on ice in the dark. After labeling, the cells were pelleted and washed once with CTB binding buffer, fixed in 2% formaldehyde for 10 minutes, rewashed with CTB binding buffer and analyzed by flow cytometry on a BD FACScalibur apparatus. For CD3 staining, cells were pelleted and washed with wash buffer (PBS

+ 1% BSA) twice and resuspended in staining buffer (PBS + 5% normal mouse serum). Cells were stained either with biotinylated anti-CD3 antibody or biotinylated IgG isotype control at a final concentration of 5 microgram/ml for 30 minutes on ice, then washed three times with wash buffer and incubated with PE-streptoavidin (2 microgram/ml) for 30 minutes in the dark. After washing 5 times with wash buffer, the cells were fixed in wash buffer plus 1% paraformaldehyde for 10 minutes and rewashed 2 times with wash buffer and analyzed by flow cytometry on a BD FACScalibur apparatus.

Monitoring of early Ca2+ response in Jurkat T cells with or without C9 treatment

Cells were allowed to grow to 1 x 10 6 cells/mL in a T- 150 flask (avoid excessive pipetting and no media changes after the last passage) and then transferred (~2 x 10 7 cells) to 50 ml falcon tube. lOμl of Fura-2-AM were added to a final concentration of 5μM (from 10 mM stock in DMSO) to the tube and incubated for 30 min to load the Fura-2A. Cells were collected by centrifugation at 1000 RPM for 5 mins. With dim light, remove all media and resuspend cells in 2 mis of Ca+ Assay Buffer (140.0 mM NaCl, 5.0 mM KCl, 0.7 mM CaCl 2, 0.7 mM Mg2Cl 2 , 20.0 mM HEPES, 10.0 mM glucose, 0.1% BSA, pH 7.4). Protect from light, allow cells to equilibrate for ~10 min before using them in Ca+ assay. Transfer 400 μl of labeled cells to fluorometer cuvette, add 4μl of 0.5 M CaCl 2 to cuvette to a final concentration of 5 mM, record baseline with Fura-2-AM program. After establishing baseline, anti-CD3/CD28 beads or control agonist (thapsigargin or H 2 O 2 as positive controls) were added with immediate mixing, continuing monitoring of Ca2+ was recorded for at least another 500 seconds.

IL-2 production by human primary T cells with or without C9 treatment

Isolated human primary T cells were seeded at IxIO 5 cells/well in wells of a round- bottom 96-well plate. Cells in triplicates were pretreated or mock treated with C9 for 3 days as described for the Jurkat cells, after which they were activated with anti- CD3/CD28 antibody Dynal beads as for the Jurkat T cells at a bead to cell ratio of 1 : 1. Cells were cultured overnight at 37 0 C in a tissue culture incubator, culture

supernants were collected the next day after removing cells by centrifugation. IL-2 level in each culture supernatant was assayed with an IL-2 Elisa kit from Invitrogen according to manufacturer's protocol.

Results:

As shown in FIG. 1, significant reduction in the GMl level was observed in the Jurkat T cells treated with Compound C9 ("+ C9" in the figure), compared with that of the mock treated T cells 3 days after treatment. In addition, no substantial change in the CD3, a component of the TCR signaling complex (FIG. 2) was observed, suggesting that the reduction of GMl level (and possibly other glycosphingolipids as well) did not significantly change the overall protein levels of the TCR complex. Similar findings were observed in Ramos B cells and U937 monocytes, there were clear reductions on GMl levels but the CD79 and CD32 expression did not change after 3 days of Compound C9 treatment (data not shown). Compound C9 treatment also resulted in changes of the early TCR signaling process upon activation. Substantial reductions of phosphorylation of various proximal signaling molecules, Lck, Zap-70, Lat were observed in the Jurkat T cells treated with Compound C9 after activation by anti-CD3/CD28 dynal beads (FIG. 3). The reduction in phosphorylation of Lck was most appearant at the early time point (1 minute) after activation. It appeared that as the signaling relays on, the reduction of phosphorylation also extended to late time points. For Zap-70, the reduction in phosphorylation could be observed at 5 minte time point, and for Lat, reduction in phosphorylation could be observed throughout the entire 15 minutes monitoring period (FIG. 3). Also, reduction in phosphorylation of Lyn was observed in Ramos B cells and U937 monocyte/macrophage cells after BCR or FcγR receptor activation (data not shown).

FIGs. 4 and 5 show changes in early Ca 2+ response in the tested Jurkat T cells and late IL-2 production in purified primary human T cells, respectively with or without Compound C9 treatment. As shown in FIG. 4, Compound C9 dampened early Ca 2+ response in Jurkat T cells. In the primary human T cells treated with Compound C9, significant reduction in IL-2 production after anti-CD3/CD28

activation was observed as shown in FIG. 5, which might indicate dampening of later T cell functions.

In summary, C9 compound treatment of Jurkat T cells, B cells and monocytes reduced GMl levels in vitro. The reduction of phorsphorylation of proximal protein signaling molecules, such as Lck, Zap-70 and Lat, the attenuation of early Ca 2+ response, and the reduction of later T cell functions suggested that the C9 compound treatment abated T cell response and function toward activation. The reduction of phosphorylation of protein kinase Lyn indicated that the C9 compound treatment may also altered B cell or monocyte/macrophage response and functions.

Example 5: Treatment of Compound C9 (iV-(qR,2R)-1-(2,3- dihvdrobenzo[61H,41dioxin-6-yl)-1-hydroxy-3-fpyrrolidin-1-yl )propan-2- yl)nonanamide » 1/2 2,3-dihydroxysueeinate) showed several beneficial effects for treating lupus in murine model

The effects of Compound C9 in vivo were assessed in a murine model of lupus, the NZB/W Fl mouse model. Fl hybrids of NZB/B1NJ and NZW/LacJ (NZB/W Fl /J) at 13-15 weeks of age were purchased from Jackson Lab. Animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (U.S. Department of Health and Human Services, N1H Publication no. 86-23).

Animals were divided into 3 groups (n=10) according to treatments. Animals in the first group received daily oral gavage of sterile water as vehicle control; animals in the second group were administered with 75 mg/kg of Compound C9 either with a once daily (QD) or a twice daily (BID) oral gavage. A positive control group of mice were dosed with 50 mg/kg of cyclophosphamide (CYC) through weekly intraperitoneal injection. Every three weeks, blood samples were collected by eye bleeding to monitor anti-dsDNA antibody titer, and 24-hour urine samples were collected by metabolic cage for monitoring of proteinuria. Throughout the study, once an animal began to show increased level of proteinuria, the animal was closely monitored for signs of severe morbidity and sacrificed for tissue collection. Both kidneys were collected and cut in half longitudinally, two halves of the kidneys

of each animal were fixed in 10% neutral buffer fixative (formaldehyde), one half was frozen in OCT compound on dry ice/isopropanol bath, and one half was quickly frozen on dry ice and store at -8O°C. Spleens were collected and weighed for measurement of spleenmegaly. All animals were sacrificed at week 49 after about 5 months of treatment with tissues collected as described above.

Methods of anti-dsDNA and proteinuria detection:

Anti-dsDNA Titer ELISA: For the detection of anti-dsDNA autoantibodies (autoAbs) from plasma, 96- well high-binding ELISA plates (VWR, West Chester, PA) were coated with 0.01% protamine sulfate solution (Sigma-Aldrich, St. Louis, MO) for 1.5 hours at room temperature. The plates were then washed 4 times with dH 2 O and coated with dsDNA (Jackson Immunoresearch, Bar Harbor, ME) at a concentration of 1 μg/mL in 0.1 M NaHCO 3 (Pierce, Rockford, IL) Plates were incubated for a minimum of 16 hours at 4°C. The coating solution was then flicked out of the plates, and the plates were blocked with 2.5% BSA (Sigma-Aldrich) for 1 hour at 37°C. Plates were then washed 4 times with PBS-T ween20 wash buffer (PerkinElmer Life Sciences, Inc., Boston, MA). Two-fold serial dilutions of plasma samples, beginning at 1 : 100, were prepared in 0.1 %BSA/PBS-Tween20 dilution buffer in the ELISA plate. Pooled plasma from MRL/lpr and NZB/NZWF1 mice with previously measured high anti-dsDNA titers was used as a positive control, and pooled normal mouse serum (Sigma-Aldrich) was used as a negative control for the assay. Test samples and controls were incubated at 37°C for 1 hour. After plates were washed 8 times with PBS-Tween20 wash buffer, bound IgG anti-dsDNA was detected with an HRP- labeled goat anti-mouse IgG (Fc) antibody (Pierce) which was diluted 1 : 50,000 in 0.5% BSA dilution buffer and incubated at 37°C for 1 hour. The plates were then washed 8 times with PBS-Tween20 wash buffer. An OPD substrate (Sigma- Aldrich) was then added to the plates and allowed to incubate at room temperature in the dark for 30 minutes. The enzymatic reaction between the OPD substrate and the HRP bound in the well was stopped using 4.5M H 2 SO 4 (J.T.Baker, Phillipsburg, NJ). The plates were read on a VMax ELISA Plate Reader (Molecular Devices,

Sunnyvale, CA) at a wavelength of 490 nm with a reference wavelength of 650 nm. The anti-dsDNA antibody titer was defined as the reciprocal of the dilution of plasma yielding an O. D. reading of greater than or equal to . 0.100.

MicroPro tein-PR Kit (Quantitation of total urine protein):

The Micro-PR kit (Sigma-Aldrich, St. Louis, MO) was utilized for the measurement of total urine protein. The Microprotein-PR reagent was allowed to warm to 37°C for 30 minutes. 20 μL of the 100 mg/dL standard control (Sigma- Aldrich) and blank control dH 2 O were added to 1 mL of reagent. 5 μL normal mouse control urine or test urine were added to 1 mL of reagent. This was a 1 :4 dilution of the sample and generally was taken into account when doing the final calculations. Satndard, control and test samples were then incubated at 37°C. Following a 10 minute incubation, 100 μL of each sample, in duplicate, were transferred to an ELISA plate (VWR, West Chester, PA) and read on a VMax ELISA Plate Reader (Molecular Devices, Sunnyvale, CA) at a wavelength of 600 nm. The following calculation was used to determine the protein concentrations of the standard, normal mouse urine control and test samples: e

Severe proteinuria was defined as a total urine protein level of greater than or equal to 400 mg/dL.

Urine Albumin Measurement:

Levels of albumin in the urine were assessed with a quantitative ELISA assay (Albuwell-M, Exocell Inc.) as well as a semi-quantitative "Albustix" method (Roche Diagnostics).

Albustix Urine Albumin Measurement:

10 μL of urine was deposited on an indicator filter paper that changes color according to the amount of albumin present in the urine and was compared to a color

chart on the packaging. The albustix measurement was graded on a semiquantitative scale (O=negative, l=trace, 2=30+ mg/dL, 3=100+ mg/dL, 4=300+ mg/dL, 5=2000+ mg/dL).

Albuwell ELISA:

The Albuwell-M ELISA kit (Exocell) was used to quantitate albumin in mouse urine. Diluted samples and standards and rabbit anti-murine albumin antibody were added to pre-coated wells containing murine albumin and allowed to incubate for 30 minutes at room temperature. During this time, the antibody was bound to the albumin immobilized to the plate (stationary phase) or with albumin present in the urine sample or standard (fluid phase). The plates were then washed 10 times with dH 2 O. An HRP-conjugated anti-rabbit antibody was then added to the assay plate and allowed to incubate for 30 minutes at room temperature. This antibody would bind only to the stationary phase. Following the incubation period, the plates were washed as previously described, and a color developer (TMB) was added to the plate and allowed to incubate for 10 minutes at room temperature. The chromogenic reaction was stopped with HCl and read on a VMax ELISA Plate Reader (Molecular Devices) at a wavelength of 450 nm. The color intensity (optical density reading) was inversely proportional to the amount of albumin in the fluid phase.

Assessment of kidney pathology:

Two longitudinal sections of kidney were examined for each mouse. Sections were cut at a thickness of approximately 3 micrometers and stained with hematoxylin and eosin.

Slide evaluation was performed by a board-certified veterinary pathologist blinded to group designation. Tissues were scored on a scale of 0-6 for glomeruli score or 0-4 based for proteincast on the following characteristics shown in Tables 1 and 2:

Table 2: Protein casts

Assessment of T cell infiltration in the kidney

Kidney tissues in OCT compound were frozen sectioned at 5 micrometers in thickness and placed on coverslides. Tissue sections were fixed in acetone for 10 minutes and air dried, washed once with 1% bovine serum albumin (BSA) in phosphate buffer saline (PBS) for 2 minutes then washed in plain PBS once. Tissue sections were blocked with 2-3 drops/slide of DAKO protein block (X0909 from DAKO) and incubated for 10 minutes. Remove protein block from slides and add rat anti-mouse CD4 (#553043, BD Pharmingen) at 1 : 125 dilution, or rat anti-mouse CD8a (#01040D, BD Pharmingen) at 1 :200 dilution, or rat isotype IgG 23 control (#1 1020D, BD Pharmingen) at 1 :200, each in DAKO antibody diluent (S3022 from DAKO), incubate for 1 hour. Remove antibody solutions and wash slides 3 times for 2 minutes each with plain PBS at RT. Add 150ul of goat anti-rat alexafluor488,

secondary antibody at 1 :500 dilution (#A 11006, Molecular Probes) and let incubate in the humidified chamber covered with aluminum foil for 30 minutes. Wash slides three times for two minutes each in plain PBS at RT, cover top of wash containers with aluminum foil during washing steps to prevent quenching of fluorescence by light. Remove PBS remove slides and cover the tissue section with 50μl of

Vectashield Mounting Media. Slides were examined under a fluorescent microscope.

Assessment of GMl levels on peripheral T cells and B cells Peripheral blood from mice were collected by eye bleeding into EDTA tubes and stored at room temperature (RT). 50 ul of whole blood were aliquoted into each tube and mixed with 50μl mouse block (RPMI 1640 w/10% normal mouse serum (Sigma # M5905)/0.05% NaN 3 sterile filtered) for 30 minutes at RT. 1 microliter of each CTB-Alexafluor488 , anti-CD4-APC (#553051, BD Pharmingen) and anti- CD19-PE (#553786, BD Pharmingen) antibodies were added to each sample and incubated for 20 minutes at RT, after which 2 ml of Ix FACS lysing solution (BD #349202, BD Pharmingen) were added to each sample for 15 minutes at RT. Samples were centrifuged at 1200 rpm for 5 minutes, after removing supernatants, cell pellets were resuspended in 200 ul of MFF (1% methanol-free formaldehyde (Polysciences #04018- 1 ) in PBS) and analyzed by flow cytometry with a

FACScalibur with 4-color setting. Quantum FITC MESF standard beads (#826A) were purchased from Bangs Lab to normalize the fluorescent intensity of CTB- Alexafluor for GMl levels according to manufacture's instruction. Percent of CD4 positive T cells and CDl 9 positive B cells were gated and calculated as percent of total cells. Average GMl levels on gated CD4 T cells and CD 19 B cells were used for comparison.

Purification of T cell and B cells from mouse spleens

Animals in vehicle and C9 treated groups were subgrouped into subgroups of animals with proteinuria or without proteinuria. Splenocytes from 3 spleens of each subgroup were pooled for T cell and B cell isolation. However, due to only one animal in the C9 treated group developed proteinuria at the sacrifice time; we did not include this subgroup in our analysis. Typically, mice were sacrificed and

perflised with PBS, splenocytes from each spleen were released into ~3 ml of RPMI- 1640 + 2% heat inactivated fetal bovine serum (RPMI- 1640 + 2% HIFBS), pooled and filtered through 60-micrometer tissue strainer. Cells were pelleted by centrifugation at 300 g for 8 minutes and resuspended in red blood cell lysis buffer per spleen, followed immediately by adding 20 ml of RPMI- 1640 + 2% HIFBS media. Cells were again pelleted by centrifugation and resuspended in 2 ml of buffer 1 (PBS + 0.1% HIFBS + 2 mM EDTA, pH 7.4) and kept on ice until purification. T cells and B cells from pooled splenocytes were isolated with Dynal ® Mouse T Cell Negative Isolation Kit (#114-13D, Invitrogen) and Dynal ® Mouse B Cell Negative Isolation Kit (# 1 14-2 ID, Invitrogen) respectively following manufacturer's suggested protocol. Typically, the isolated T cells and B cells are >90% in purity.

T cell activation ex vivo and mornitoring of IL-2 production

5x10 5 purified T-cells are seeded into wells of a 96-well round bottom plate, in two sets of triplicate for each subgroup. The cells are suspended in 200 μl of RPMI- 1640 media (containing 2 g/L bicarbonate, 2.2g/L-glucose, 25 mM Hepes with 1 mM sodium pyruvate, 10 % HIFCS, Ix penicilin/streptomycin), beta- mercapitol ethanol at 1 micromolar is add fresh for each experiment. T-cells that came from animals treated with C9 were incubated with 250 nM of C9 during the assay. One set of triplicate cells (per group) are stimulated with anti-mouse -

CD3/CD28 Dynabeads (Invitrogen) at 1 :1 cell/beads ratio. The other set of triplicate cells (per group) only get buffer 1. The 96-well plate is incubated overnight at 37°C, in a tissue culture incubator. The next day (+18 hours) the supernatants were collected by centrifugation and quick frozen in liquid N 2 and placed into a -8O°C freezer to be analyzed for IL-2 or other cytokines by either a Biosource mouse IL2 kit or a Lincoplex mouse cytokine/chemokine kit.

Glycosphingolipid analysis of kidney tissues and purified T cells and B cells by mass-spectrometry

Pieces of kidney tissues weighing approximately 25mg were cut and placed into 2OmL glass vials, then enough organic solution to have 2.5mg of tissue per milliliter of solution (i.e. 25mg in 1OmL) was added proportionally. The tissues were then homogenized, sonicated, and clarified by centrifugation. An aliquot of the supernatant of each sample was then transferred to an autosampler vial containing dried internal standards.

Cell samples (1x10 7 cells) were removed from a -80°C freezer and allowed to thaw. An internal standard cocktail was added to microcentrifuge tubes and dried under nitrogen gas. Cells were added to a tube and vortexed to help incorporate the internal standards into the cell solution. Organic solution was then used to precipitate proteins from the cell sample, and the resulting solution was sonicated. The tubes were centrifuged and an aliquot of the supernatant was then transferred to an autosampler vial prior to analysis.

LC/MS/MS: Samples were analyzed on a system consisting of an HTC PAL autosampler, Agilent 1200 HPLC, and API-4000 mass spectrometer. During analysis, samples were stored at 9°C in the autosampler cool stack. The HPLC was run in isocratic mode with normal-phase silica column, and MS/MS was performed in MRM mode.

Results:

FIG. 6 shows cumulative proteinuria of a typical study in NZB/W Fl mice: a group treated with vehicle only (daily oral gavage of sterile water; filled square); a group treated with Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of

Compound C9 BID; filled circle), and a group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide; filled triangle). Treatments were started at 24 weeks of age (arrow) when Fl mice developed noticeable increase in anti-dsDNA titers, yet most of the animals had not developed proteinuria-early onset of disease. As shown in the FIG.6 and FIG. 7, treatment with Compound C9 showed a decrease in the incidences of animals developed severe proteinuria (FIG. 6) with a concomitant increase of animal survival (FIG. 7).

Average total proteinuria and average aluminuria levels observed in three groups of NZB/W Fl mice over time are summarized in FIGs. 8 and 9, respectively: a first group treated with vehicle only (daily oral gavage of sterile water, filled square); a second group treated with Compound C9 (daily oral gavage of 2 x 37.5 mg/kg of Compound C9, filled circle); and a third group treated with cyclophosphamide as a positive control (weekly intraperitoneal injection of 50 mg/kg of cyclophosphamide, filled triangle). As shown in FIG. 8 and FIG.9, treatment with Compound C9 substantially reduced average of proteinuria and albuminuria, respectively. Assessment of kidney pathology of the tested NZB/W Fl mice is summarized in FIGs. 10 and 11 (glomerular scores in FIG. 10 and protein cast scores in FIG. 1 1). As indicated in the figures, treatment with Compound C9 substantially attenuated kidney pathology of glomerular scores and protein cast scores (see FIGs. 10 and 11), except in those three animals that somehow did not respond to Compound C9 treatment. Compound C9 treatment also significant decreased splenomegaly as observed in the vehicle treated animals, to similar level of cyclophosphamide treated group (see FIG. 12).

FIG. 13 is a graph showing the contents of anti-dsDNA titer over time observed in the tested NZB/W Fl mice. As indicated in the figure, there were no substantial changes in the content of anti-dsDNA titer in the mice treated with

Compound C9, compared with those of the control treated with sterile water only. Consistent with this finding, immune complex deposition also did not change significantly between the Compound C9 treated animals and vehicle treated animals (data not shown). This also suggests that the benefits or action of Compound C9 in the kidney should be downstream of the immune complex deposition.

FIG.14 shows that infiltration of inflammatory lymphocytes (shown here with CD4 and CD8 T cells) were significantly reduced in kidneys of animals treated with Compound C9, this is consistent with the proteinuria results that animals which showed no CD4 and CD8 infiltrations in their kidney did not develop proteinuria. FIG. 15 shows the ceramide, GLl, GL3, GM3 and GMl levels observed in purified B cells and purified T cells from the spleens of the tested NZB/W Fl mice at the end of a typical study. As shown in these figures, Compound C9 treatment

prevented the development of disease and also the increase in certain GSLs, especially GL3, GM3 and GMl in purified B cell and T cells from the spleens, as compared to animals that developed disease in the vehicle treatment group. This suggests that there is a good correlation between lupus disease (nephritis/proteinuria) and increase in glycosphingolipids on T cells and B cells.

These glycosphingolipid were also analyzed in kidney tissues from individual animals of the same study. The levels of ceramide, GLl, GM3 and GMl were less consistent as were observed in T cell or B cells, however, GL3 levels were consistently higher in animals that developed disease in the vehicle treated group (see FIG. 16), and Compound C9 treatment prevented the increase of this particular glycosphingolipid.

FIG. 17 shows IL-2 production levels from T cells isolated from the spleens of the tested NZB/W Fl mice ex vivo after overnight activation by anti-mouse CD3/CD28 antibodies coupled to Dynal beads. Similar to what was observed in the in vitro data discussed in Example 4 above, the C9 compound treatment dampened IL-2 production from the T cells ex vivo.

In summary, treatment of NZB/W Fl lupus mice with Compound C9 provided several benefits, including increased animal survival, reduced proteinuria and albuminuria, prevented T cell infiltration in the kidney, alleviated kidney pathology as indicated by glomerular and protein cast scores, decreased spleen size in mice with normal proteinuria, reduced GSLs in T cells and B cells from the spleen as well as in kidneys, and desensitized T cell activation. In addition, based on the observations of no effect on anti-dsDNA titers in the mice treated with Compound C9 and minimal reduction of immune complex deposition occurred in the kidney glomeruli, although not being bound to a particular theory, the benefits of Compound C9 may arise from reducing Fcγ receptor signaling in immune effector cells in the kidney, such as on macrophages or neutrophils, thereby reducing immune mediated pathology in the animal models of lupus.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in

the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.




 
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