AU2012201076A1

AU2012201076A1 - Method of treating polycystic kidney diseases with ceramide derivatives

Info

Publication number: AU2012201076A1
Application number: AU2012201076A
Authority: AU
Inventors: Seng H. Cheng; Oxana Ibraghinov-Beskrovnaya; John P. Leonard; Thomas A. Natoli; Nelson S. Yew
Original assignee: Genzyme Corp
Current assignee: Genzyme Corp
Priority date: 2007-10-05
Filing date: 2012-02-24
Publication date: 2012-03-22
Anticipated expiration: 2028-10-03
Also published as: AU2012201076B2

Abstract

(57) The invention relates to the treatment of polycystic kidney disease (PKD) using certain ceramide derivatives of the following formula: R' N(R 2R3) _X _R 4 0 (1), or a pharmaceutically acceptable salt thereof, wherein R'-R4, X and Y have the meanings indicated herein. These compounds may reduce the need for kidney dialysis or transplant in patients suffering from PKD.

Description

Regulation 3.2 AUSTRALIA PATENTS ACT, 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL Name of Applicant: GENZYME CORPORATION Actual Inventors: NATOLI, Thomas A; IBRAGHINOV-BESKROVNAYA, Oxana; LEONARD, John P; YEW, Nelson S; CHENG, Seng H Address for service in A J PARK, Level 11, 60 Marcus Clarke Street, Canberra ACT Australia: 2601, Australia Invention Title: Method of treating polycystic kidney diseases with ceramide derivatives The following statement is a full description of this invention, including the best method of perfooxning it known to us. 331336_1 - la METHOD OF TREATING POLYCYSTIC KIDNEY DISEASES WITH CERAMIDE DERIVATIVES RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 5 60/997,803, filed October 5, 2007. The entire teachings of the above applications are incorporated herein by reference. BACKGROUND OF THE INVENTION A cyst is an abnormal fluid-filled sac that can form in many parts of the 10 body, such as the kidney, liver, pancreas, spleen and heart. Polycystic disease is a disease that occurs when a large number of cysts cause damage to these organs. For example, polycystic kidney disease (PKD) is a disease characterized by the growth of numerous cysts throughout the kidneys. The PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure, 15 About half the people with the most common form of PKD progress to kidney failure and require dialysis or kidney transplantation. PKD can also cause cysts in other organs, most commonly the liver, but also the spleen, pancreas, heart and blood vessels in the brain. About 500,000 people have PKD in this country, and PKD is the fourth leading cause of kidney failure. Autosonal dominant PKD 20 (ADPKD) accounts for about 90% of all PKD cases and about 8-10% of all cases of end stage renal disease. Currently, there is no approved treatment or cure for PKD. Present medical and surgical procedures only reduce the pain resulting from expansion of renal cysts or resolve other symptoms associated with PKD such as infections or high blood pressure. None of these procedures, aside from kidney 25 transplantation, appreciably slows the progression of the disease. Thus, there is a need for agents and methods for preventing the onset of, or slowing the progression of PKD.

WO 2009/045503 PCT/US2008/011450 -2 SUMMARY OF THE INVENTION Applicants have now discovered that certain ceramide derivatives can reduce cystic growth in an animal model for polycystic kidney disease, as measured by kidney/body weight ratio and cyst volume. Based upon this discovery, a method of 5 treating polycystic kidney disease with the ceramide derivatives is disclosed herein. In one embodiment, the invention is directed to a method of treating polycystic kidney disease in a subject, comprising administering to the subject an effective amount of a.compound represented by Structural Formula (1): Y R' IN(R 2

R

3 ) HN X -R 4 10 0 (1), or a phannaccutically acceptable salt thereof. R' is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. 15 Y is -H, a hydrolyzable group, or a substituted or unsubstituted alkyl group. R2 and R3 are each independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R2 and R3 taken together with the nitrogen atom of N(R 2

R

3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring. 20 X is a covalent bond; -(CRR 6 )m-; -(CR'R 6 )n-Q-; -0-; -9-; or -NR7-; Q is -0-, -S-, -C(O)-, -C(S)-, -C(0)O-, -C(S)O-, -C(S)S-, -C(O)NR'-, -NR'-, -NRC(O)-, -NRYC(O)NRY-, -OC(O)-, -SO 3 -, -SO-, -S(O)2-, -SO 2 NR'-, or -NR8SO 2 -. When X is -(CRR 6 )m, RW is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl 25 group, -CN, -NCS, -NO 2 or a halogen.

WO 2009/045503 PCTtUS2008/011450 -3 When X is other than -(CRR 6 )m, R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group. R' and R 6 are each independently -H, -OH, -SH, a halogen, a substituted or 5 unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. Each R7 is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R7 and R 4 taken together with the nitrogen atom of NRR 4 form a 10 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. 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 polycystic kidney disease 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 polycystic 20 kidney disease. The present invention has many advantages. In particular, the present invention provides a treatment for PKD that addresses the underlying disease state, rather than simply ameliorating symptoms that are associated with PKD. Such compounds may reduce the need for kidney dialysis or transplant in patients 25 suffering from PKD. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a method of treating polycystic kidney disease (PKD) that comprises administering an effective amount of a ceramide derivative disclosed herein to a subject. As shown in Example 4, Applicants have 30 discovered that a certain ceramide derivative can reduce the growth of cyst formation and/or growth in an animal modeled PKD.

WO 2009/0455U3 PCT/U5200/011450 -4 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: 5 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)-(-lower alkyl-1,4-dihydropyridin 4-yl. In a specific embodiment, Y is -H, a hydrolyzable group, or an alkyl group. In 10 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; -(CRR 6 ).-Q-; -0-; -S-; or -NR 7 -. Q is -0-, -S-, -C(O)-, -C(S)-, -C(0)0-, -C(S)O-, -C(S)S-, -C(O)NR-, -NRs-,

-NR

8 C(O)-, -NR 8 C(O)NR-, -OC(O)-, -S03-, -SO-, -S(0)2-, -SO 2 NR8-, or 15 -NR 8 SO2-. In a specific embodiment, Q is -0-, -S-, -C(O)-, -C(S)-, -C(0)0-, -C(S)O-, -C(S)S-, -C(O)NR"-, -NR 8

C(O)NR

8 -, or -OC(O)-. In yet another specific embodiment, Q is -0- , -- , -C(O)-, -C(S)-, -NR 8 (CO)- 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 -0- or -C(O)-. 20 R' is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In a specific embodiment, R' is a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. In another specific embodiment, R' is 0 where r is 1, 2, 3 or 4, preferably 1 or 2. 25 Suitable substituents for each of the aryl and heteroary groups represented by R' include halogen, alkyl, haloalkyl, Ar', -OR 30 , -O(haloalkyl), -SR 30 , -N02. -CN, -NCS, -N(R 3 )2, -NR 31

C(O)R

30 , -NR 3 1 C(0)OR 2 , -N(R 3 )C(O)N(R3) 2 , -C(O)Ro, -C(S)R", -C(0)0R 3 0 , -OC(O)R 30 , -C(O)N(R) 2 , -S(O) 2

R

30 , -SO 2

N(R

3 1 )2, -S(O)RE, -SO3R", -NR 3

SO

2

N(R

3

)

2 , -NRS0 2 R , -V 0 -Ar', -Vr-OR 3 , -V 0 -O(haloalkyl), WU ZUUWU4 Ui UPC/U S2008/011450

-V

0

-SR

3 ", -VO-NO2 -V 0 -CN, -VeN(R 3 1

)

2 , -V 0

-NR

1

C(O)R

30 , -V,-NR 3 1 C0 2

R

2 ,

-V

0

-N(R

3 )C(O)N(R)2, -V 0 -C(O)R ', -V 0 -C(S)R, -V 0

-CO

2 R, -V 0 -OC(O)R,

-V

0

-C(O)N(R

3 1

)

2 -, -V 0

-S(O)

2

R

32 , -V 0

-SO

2

N(R')

2 , -V 0

-S(O)R

2 , -V 0 -SO3R 3 2 ,

-V

0

-NR'SO

2

N(R

3 )2, -VrNR 3 'SO2R 3 2 , -O-VOAr', -O-Vr N(R 3 )2, -S-Vo-Ar'. 5 -S-V-N(R')2, -N(R 3 )-V-Ar', -N(R 3 )-V-N(R')2, -NR' C(O)-VQ-N(R 3 ')2,

-NR

3

C(O)-V

0 -Ar', -C(O)-VN(R")2, -C(O)-V 0 -Ar', -C(S)-V 0 -N(R')2, -C(S)-Vo-Ar', -C(O)O-Vj-N(R0M)2, -C(O)O-Vo-Ar, -O-C(O)-Vr-N(R")2, -O-C(O)-V'-Ar' -C(O)N(RM)-VrN(RM)2, -C(O)N(R")-Vr1Ar', -S(O)2-V.-N(RW)2, -S(O)2-V 0 -Ar', -SO 2 N(R)-Vr-N(R 3 )2, -SO 2 N(R)-VGAr', -S(O)-V 0

-N(R

3 ')2, 10 -S(O)-V 0 -Ar', -S(O)2-O-V-N(R 3 )2, -S(O) 2 -0-V 0 -Ar', -NR 3 'S0 2 -V.,N(R")2,

-NR

3 'S0 2 -V,-Ar', -O-[CH2Jp-O-, -S-(CH2]p-S-, or -[CH2]q- . Certain specific substituents for each of the aryl and heteroary groups represented by R' include halogen, cyano, nitro, alkyl, haloalkyl, -OR 0 , -SR 3 , -N(R 1

)

2 , Ar', -V-OR 0 ,

-V

0

-N(R")

2 , -V 0 -Ar t , -O-V-Ar', -O-V-N(R) 2 , -S-V 0 -Ar', -S-V-N( 3

')

2 , 15 -N(R 3 1 )-V-Ar', -N(R 3 )-Vj-N(R 1 )2, -O-[CH2]p-O-, -S-[CH 2 ]p-S-, or -[CH2]q,. Alternatively, certain specific substituents for each of the aryl and heteroary groups represented by R' include halogen, cyano, nitro, alkyl, haloalkyl, alkylarnino, dialkylamino, aryl, aryloxy, -OH, alkoxy, -O-[CH2)p-O-, and -[CH2]q-. Alternatively, certain specific substituents for each of the aryl and heteroary groups 20 represented by R' include -OR 3 0 (e.g., -OH, -OCH 3 , -OC2H 5 ), alkyl, (e.g., C1-C6 alkyl), or -O-[CH2)p-O-. R2 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 R2 and R3 taken together with the nitrogen atom of N(R 2 R') 25 form a substituted or unsubstituted non-aromatic heterocyclic ring. In a specific embodiment, R2 and R3 taken together with the nitrogen atom of N(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, 30 -N(R 2

R

3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, preferably an unsubstituted pyrrolidinyl group.

WV 2UJIuu4uUJ PCT/US2008/011450 Suitable substituents for the aliphatic, aryl and heteroaryl groups represented by R2 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 4 ", -O(haloalkyl), -SR 4 '. -NO 2 , -CN, -N(R 4 1

)

2 , -NR 41

C(O)R

40 , -NR 4

'C(O)OR

4 2 , 5 -N(R 4

')C(O)N(R")

2 , -C(O)R 40 , -C(S)R 4 , -C(O)OR4, -OC(O)R4, -C(O)N(R 4

')

2 ,

-S(O)

2

R

42 , -SO 2

N(R

41

)

2 , -S(O)R 4 2 , -S0 3

R

4 2 , Ar 2 , V 2 -Ar2, -V 2 -0R 4 , -V2-O(haloalkyl), -V2-SR 40 , -V 2

-NO

2 , -V 2 -CN, -V 2

-N(R

4 1

)

2 , -V2-NR 4

'C(O)R

4 D, -V2-NR4'CO2R4 2 , -V 2

-N(R

4 t)C(O)N(R 4 )2, -V 2

-C(O)R

4 0 , -V 2

-C(S)R

4 , -Vr-CO 2 R4", -V2-OC(O)R 40 , -V 2

-C(O)N(R

4 ')2-, -V 2 -S(0) 2

R

4 2 , -V 2

-SO

2

N(R

4 ')2, -V 2

-S(O)R

42 , 10 -V 2

-SO

3

R

4 2 , -O-V2Ar2 and -S-V2-Ar2 Certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R2 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 4 ,

-NO

2 , -CN, -N(R 4 1)2, -C(O)R', -C(S)R 4 , -C(O)OR 4 0 , -OC(O)R*, -C(O)N(R 4 ')2, 15 Ar 2 , V 2 -Ar2, -2-OR 4 0 , -V 2 -O(haloalkyl), -V-SR 0 , -V 2

-NO

2 , -V 2 -CN, -V 2

-N(R

4 ')2,

-V

2

-C(O)R

4 ", -V 2

-C(S)R*

0 , -V 2 -C0 2

R

40 , -VrOC(O)R 4 , -O-V2-Ar 2 and -S-V 2 -Ar2. Alternatively, certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R3, and for the non-aromatic heterocyclic ring represented by N(R 2 R3) each independently include halogen, C1-Cl 0 alkyl, C1-C10 20 haloalkyl, -O(C-C10 alkyl), -O(phenyl), -O(C1-C10 haloalkyl), -S(C1-C10 alkyl), -S(phenyl), -S(C1-C10 haloalkyl), -NO 2 , -CN, -NH(C1-C1O alkyl), -N(C1-C10 alkyl)2, -NH(CI-C10 haloalkyl), -N(Cl-C10 haloalkyl)2, -NH(phenyl), -N(phenyl) 2 , -C(O)(C1-C10 alkyl), -C(O)(Cl-C10 haloalkyl), -C(O)(phenyl), -C(S)(C1-Cl0 alkyl), -C(S)(C1-C10 haloalkyl), -C(S)(phenyl), -C(O)O(C-C10 alkyl), 25 -C(O)O(C1-C10 haloalkyl), -C(O)O(phenyl), phenyl, -V 2 -phenyl, -V 2 -0-phenyl, -Vr-O(C l-C10 alkyl), -V-O(C1-C10 haloalkyl), -V2-S-phenyl, -V 2 -S(CI-C10 alkyl), -V 2 -S(C I-C10 haloalkyl), -V-NO 2 , -V 2 -CN, -V 2 -NH(Cl -C10 alkyl), -Vr-N(C I-C10 alkyl)2, -V 2 -NH(C 1-C10 haloalkyl), -V2-N(C I-C10 haloalkyl) 2 ,

-V

2 -NH(phenyl), -V-N(phenyl)2, -V 2 --C(O)(C1-C10 alkyl), -V 2 -C(O)(C1-Cl0 30 haloalkyl), -V2--C(O)(phenyl), -V 2 -C(S)(Cl-ClO alkyl), -V 2 -C(S)(Cl-Cl0 haloalkyl), -V-C(S)(phenyl), -V 2 -C(O)O(C 1-C10 alkyl), -V 2 -C(O)O(C 1-C 10 haloalkyl), -V 2 -C(O)O(phenyl), -VrOC(O)(C1-Cl0 alkyl), -VrOC(O)(C1-Cl0 WO 20091045503 PCT/US2008/011450 -7 haloalkyl), -V 2 -OC(O)(phenyl), -O-V2-phenyl and -S-V 2 -phenyl. Alternatively, certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R and for the non-aromatic heterocyclic ring represented by N(R2R 3 ) each independently include halogen, C1-C5 alkyl, Cl-CS haloalkyl, hydroxy, Cl-CS 5 alkoxy, nitro, cyano, CI-C5 alkoxycarbonyl, Cl-C5 alkylcarbonyl, Cl-CS haloalkoxy, amino, Cl-C5 alkylanino and Cl-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 10 -(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' 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, 15 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-C18 alkyl group, such as a C6, C7, CS, C9 or C10 alkyl group. In one aspect of these more specific 20 embodiment, the alkyl group, including the C6, C7, C8, C9 or C10 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, R4 is an optionally substituted phenyl 25 group or an optionally substituted alkyl group, such as C1-C10 alkyl group, or C6 C8 alkyl group. fn yet another specific embodiment, R 4 is an ary) group, a heteroaryl group, a lower arylalkyl group or a lower heteroarylalkyl group, or alterantively, R4 is an optionally substituted aryl or an optionally substituted beteroaryl group. In a more 30 specific embodiment, the aryl, the heteroaryl, the lower arylalkyl and the lower heteroaryl groups represented by R4 are selected from the group consisting of: WO 2009/045503 PCT/JUS200S/011450 -8 - (H) (C-H2)x -- CH) (CHj -(CH2X - (CH 2 ) C N -- (CH 2 )x- E,-(H) (CH2)x N - (CH-(C -H2-- J N (CH2) - (CH2) -- 2x-- - (CH2)x -- (CH2)x-- N RCH--( xI -(H 2 )x--N N N > 0 i o x -(c i). -(CHAj- . V N -(C2x W N (C 2rX(CHCH)]- z zi N NN N -(H) Z2 Z3' - (CH7-F Z Z XN wherein each of rings A-ZS is optionally and independently substituted; and each x 10 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 is an aryl group or a heteroaryl group, each indepenently optionally substituted with Ar, such as a phenyl group optionally substituted with Ar3. It is noted that, as shown above, rings A-Z5 can be attached to WSU LUUY/U4D3U3 FUT/U i2UUN/U1 J45U -9 variable "X" of Structural Formula (I) through -(CH2)x- at any ring carbon of rings A-Z5 which is not at a position bridging two aryl groups. For example, R 4 /N represented by m means that R4 is attached to variable "'X" through either ring J or ring K. 5 Suitable substituents for each of the aliphatic, the aryl and the heteroaryl groups represented by R, including the alkyl group, the arylalkyl, the heteroarylalkyl group and rings A-Z5, include halogen, alkyl, haloalkyl, Ar 3 , Ar-Ar, -OR 0 , -O(haloalkyl), -SR"', -NO2. -CN, -NCS, -N(R") 2 , -NR 1

C(O)R

50 ,

-NR

5

IC(O)OR

2 , -N(R 5

)C(O)N(R

1

)

2 , -C(O)R 0 , -C(S)R3", -C(O)OR", -OC(O)R", 10 -C(O)N(R")2, -S(O)2R 2 , -SO2N(R 5 )2, -S(O)R, -SO3Rs2, -NR 1 S0 2

N(R)

2 ,

-NRSSO

2

R

2 , -V4-Ar 3 , -V-OR", -V 4 -O(haloalkyl), -V 4

-SR'

0 , -V 4 -NO2, -V 4 -CN,

-V

4 -N(R1)2, -V 4

-NR

5

C(O)R

5 ", -V 4

-NR

1

CO

2

R

2 , -V 4

-N(R

5

')C(O)N(R

5 '), V4-C(O)R, , -V 4

-C(S)R

0 , -V 4

-CO

2 R", -V 4

-OC(O)R'

0 , -V 4

-C(O)N(R

1 ),-,

-V

4

-S(O)

2

R

2 , -V 4

-SO

2

N(R)

2 , -V 4 -S(O)R, -V 4

-SO

3 R, -V 4 -NR"SO2N(R) 2 , 15 -V 4

-NR"SO

2 Rs 2 , -O-V4-Ar, -O-Vs-N(R) 2 , -S-V 4 -Ar, -S-V 5

-N(R")

2 ,

-N(R')-V

4 -Ar, -N(R')-V 5

-N(R

5 )2, -NR' C(O)-V 4 -N(R')2, -NR" C(O)-V 4 -Ar,

-C(O)-V

4

-N(R")

2 , -C(O)-V 4 -Ar, -C(S)-V 4

-N(R

5 ')2, -C(S)-V 4 -Ar', -C(O)O-Vs-N(R")2, -C(O)O-V4-Ar3, -O-C(O)-Vs-N(R")2, -O-C(O)-V4-Ar', -C(O)N(R")-V-N(R)2, -C(O)N(R 5

)-V

4 -Ar 3 , -S(O) 2

-V

4

-N(R)

2 , -S(O) 2 -V4-Ar, 20 -SO 2 N(R')-V,-N(R)2, -SO 2

N(R

5

)-V

4 -Ar, -S(O)-V4-N(R')2, -S(O)-V4-Ar, -S(0)r-O-V5-N(R")2, -S(O)rO0-V4-Ar3 -NRMS02rV4-N(R)2, -NR'SS2rV4-Ar?,

-O-(CH

2 )-O-, -S-(CH2J.-S-, and -[CH2]- .- Certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R4, including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-ZS, 25 include halogen, CI-C10 alkyl, Cl-C10 haloalkyl, Ar, Ar9-Ar 3 , -OR 0 , -O(haloalkyl), -SR 5 0 , -N02. -CN, -N(R)2, -NRsC(O)R 0 , -C(O)R 0 , -C(O)OR 0 , -OC(O)R', -C(Q)N(R 1 )2, -V 4 -AA -V-OR' 0 , -V 4 -O(haloalkyl), -V 4

-SR

5 0 , -V 4 -NO2,

-V

4 -CN, -V 4

-N(R

5

)

2 , -V 4 -NRslC(O)R", -V 4 -C(O)RS0, -V 4

-CO

2

R

0 , -V 4

-OC(O)R

5 ',

-V

4

-C(O)N(R')

2 -, -O-V4-Ar, -0-Vs-N(R 1

)

2 , -S-V4-Art -S-V 5

-N(R")

2 , 30 -N(R')-V4-Art -N(R 5 ' )-Vs-N(R') 2 , -NR' C(O)-V 4 -N(R")2, -NR C(O)-V 4 -Ar', WO 20091045503 PCT/US2008/011450 - 10

-C(O)-V

4

-N(R)

2 , -C(O)-V 4 Art -C(O)O-V 5

-N(R

1

)

2 , -C(O)O-V 4 -Ar. -O)-C(O))-Vr-N(R"I)2, -O-C(O)-Ar, -C(O)N(R"I)-Vs-N(R")2,

-C(O)N(R

5

)-V

4 -Ar, -O-(CH 2 J]'-O- and -[CH 2 ],.-. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups 5 represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, nitro, Cl-C10 alkyl, Cl-C 10 haloalkyl, amino, C1-C10 alkylamino, CI-C10 dialkylamino, -OR 0 , -Ar, -V 4 -Art -V-OR', -O(CI-C10 haloalkyl), -V 4 -O(CJ-C10 haloalkyl), -0-V 4 -Ar3, -O4CH 2 ]p-O- and-[CH2]q,-. Alternatively certain specific substituents for each of the 10 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, CI-C10 alkyl, CI-C10 haloalkyl, amino, C1-C10 alkylamino, Cl-C10 dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, C1-10 alkoxy, -O-[CH 2 ]p-O- or -[CH2]q-. Alternatively certain specific substituents for 15 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, Ar3, CI-C6 alkyl, C1-C6 haloalkyl, Cl C6 alkoxy, hydroxy and Cl-C6 haloalkoxy. Alternatively certain specific substituents each of the aliphatic group, the aryl and the heteroaryl groups 20 represented by R4, including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include -OH, -OCH 3 , -OC 2

H

5 and -0-[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 R6 are each independently -H, -OH, -SH, a halogen, a substituted or 25 unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. Specifically, R 5 and Rare each independently -H; -OH; a halogen; or a lower alkoxy or lower alkyl group. More specifically, R 5 and R' are each independently -H, -OH or a halogen. Even more specifically, R 5 and R' are each independently -U. 30 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, Rt 7 and R 4 taken together with the WO 2009/045503 PCT/US2008/011450 - 11 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 alipbatic group or an optionally substituted phenyl group. in some specific embodiments, each of R7 and R 8 5 independently is -H, an optionally substituted alkyl group or an optionally substituted phenyl group, In other specific embodiments, each of R and R 8 independently is -H or a Cl-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? and R8 independently are as described 10 above for variable R 4 . Examples of suitable substituents for the non-aromatic heterocyclic group represented by -NRR 4 include halogen, =0, =S, =N(Cl-C6 alkyl), Cl-C6 alkyl, Cl-C6 haloalkyl, bydroxy, CI-C6 alkoxy, nitro, cyano, (Cl-C6 alkoxy)carbonyl, (C 1-C6 alkyl)carbonyl, Cl -C6 haloalkoxy, amino, (C1 -C6 alkyl)amino and (CI-C6 dialkyl)amino. Certain specific substituents for the non 15 aromatic heterocyclic group represented by -NR7R 4 include halogen, C1 -C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (CI-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, Cl-C6 haloalkoxy, amino, (CI-C6 alkyl)amino and (C1-C6 dialkyl)amino. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Specifically, n is 1, 2, 3, 20 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 I or 2. Each q is independently 3, 4, 5 or 6, specifically 3 or 4. 25 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. is independently a Cl-C10 alkylene group, specifically C 1-C4 alkylene group. Each V I is independently a C2-C 10 alkylene group, specifically C2-C4 30 alkylene group. Each V 2 is independently a Cl -C4 alkylene group.

WV 2U9UU4NUi PCT/US2008/011450 - 12 Each V 4 is independently a Cl-C10 alkylene group, specifically a Cl -C4 alkylene group. Each V 5 is independently a C2-C 10 alkylene group, specifically a C2-C4 alkylene group. 5 Each Ar' 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' is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more 10 substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl.. C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C1-C6 haloalkyl. More specifically, Arl is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, Cl -C6 alkyl, amino, Cl 15 C6 alkylamino, C1 -C6 dialkylamino, C1 -C6 alkoxy, nitro, cyano, hydroxy, C I-C6 haloalkoxy, Cl -C6 alkoxycarbonyl, C1 -C6 alkylcarbonyl and Cl -C6 haloalkyl. Each Ar2 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, 20 hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, Cl-C6 alkylamino and CI-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, 25 nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Specifically, each Ar 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-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, 30 amino, 01-C10 alkylamino and C1-C10 dialkylamino. Even more specifically, each A? is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from WU 2009/U455U3 PCT/US2008/011450 - 13 the group consisting of halogen, Cl-C4 alkyl, CI-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 5 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 halcalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylanino, 10 dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylearbonyl. 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, C 1-C6 alkyl, amino, Cl-C6 alkylamino, Cl-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, 15 hydroxy, CI-C6 haloalkoxy, CJ-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl C6 haloalkyl; or iii) a Cl-C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-Cl dialkylamino, C-C6 alkoxy, nitro, cyano, hydroxy, C-C6 haloalkoxy, CI-C6 alkoxycarbonyl and C-C6 alkylcarbonyl. More specifically, 20 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, C 1-C6 alkyl, amino, CI-C6 alkylamino, C1-C6 dialkylamino, C-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C C6 haloalkyl; or iii) a C1-C10 alkyl group optionally substituted with one or more 25 substituents selected from the group consisting of halogen, amino, C1 -C6 alkylamino, Cl-Cl dialkylamino, C-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. Each R31 is independently R 3 ", -CO2R 0 , -So2R 0 or -C(O)R 30 ; or -N(R3)2 taken together is an optionally substituted non-aromatic heterocyclic group. In a 30 specific embodiment, each R is independently R 30 , or -N(R 3 2

)

2 is an optionally substituted non-aromatic heterocyclic group. Suitable substituents for the non aromatic heterocyclic group represented by -N(R 31

)

2 include halogen, =0, =S, WO 2009/045503 PCT/US2008/011450 -14 =N(CI-C6 alkyl), CI-C6 alkyl, Cl-C6 haloalkyl, hydroxy, CI-C6 alkoxy, nitro, cyano, (Cl-C6 alkoxy)carbonyl, (Cl-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (CI-C6 alkyl)amino and (CI-C6 dialkyl)amino. Certain specific substituents for the non-aromatic heterocyclic group represented by -N(R 3 1 )2 include halogen, Cl-C6 5 alkyl, CI-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, (Cl-C6 alkoxy)carbonyl, (Cl-C6 alkyl)carbonyl, Cl-C6 haloalkoxy, amino, (Cl-C6 alkyl)amino and (Cl-C6 dialkyl)anino. 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 10 more substituents selected from the group consisting of halogen, alkyl, amino, alkylarnino, 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, 15 haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Specifically, each R 2 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, CI-C6 alkyl, amino, C1-C6 alkylamino, CI-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1-C6 alkoxycarbonyl, 20 Cl-C6 alkylcarbonyl and C1-C6 haloalkyl; or ii) a CI-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, CI-C6 alkylamino, Cl-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl and Cl-C6 alkylcarbonyl. More specifically, each R32 is independently i) a phenyl group 25 optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl, amino, Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy and Cl-C6 haloalkyl; or ii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl-C1 30 dialkylamnino, Cl-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, CI-C6 alkoxycarbonyl and Cl-C6 alkylcarbonyl.

- 15 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, C-C6 alkyl, C-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 5 alkoxycarbonyl, C-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl-C6 alkylamino and C-C6 dialkylamino; or iii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C-C6 haloalkyl, hydroxy, C-C6 alkoxy, nitro, cyano, Cl-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 10 dialkylamino. Each R 4 ' independently is R 40 , -CO 2

R

40 , -SO 2

R

40 or -C(O)R 4 0 ; or -N(R4')2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R41 independently is R 40 , or -N(R 1 )2 is an optionally substituted non-aromatic heterocyclic group. Suitable exemplary substituents, 15 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 3 )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 20 more substituents selected from the group consisting of halogen, C1-C6 alkyl, Cl C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or ii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-C6 haloalkyl, 25 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$ 0 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, 30 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 WO 2009/045503 PCT/US2008/0UI450 - 16 halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Specifically, each R5 0 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 5 substituents selected from the group consisting of halogen, Cl -C6 alkyl, Cl -C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, CI-C6 alkylamino and C1-C6 dialkylanino; or iii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, 10 hydroxy, CI-C6 alkoxy, nitro, cyano, Cl-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Each R 5 independently is R 0 , -C0 2

R

0 , -SO 2

R

0 or -C(O)R 0 , or -N(R")2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R5 1 independently is R5 0 , or -N(R 5 1)2 is an optionally 15 substituted non-aromatic heterocyclic group. Suitable exemplary substituents, including specific exemplary substituents, for the non-aromatic heterocyclic group represented by -N(R) 2 are as described above for the non-aromatic heterocyclic group represented by -N(R) 2 . Each Rs 2 independently is i) an aryl group or a heteroaryl group, such as a 20 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, alkylanino, 25 dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Specifically, each RY 2 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, CI-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitrb, 30 cyano, Cl-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C-C6 haloalkoxy, amino, Cl C6 alkylanino and C1-C6 dialkylnamino; or ii) a Cl-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of WO 2009/045503 PCT/US2008/011450 - 17 halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C 1-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, Cl-C6 alkylamino and C1-C6 dialkylamino. R and R' are each independently i) -H; ii) a C 1-C6 aliphatic group optionally 5 substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , CI-C6 alkoxy, CI-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 , Cl-C6 alkoxy, C1-C6 haloalkoxy, Cl-C6 10 aliphatic group and C 1-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; CI-C6 haloalkoxy; C-C6 aliphatic group optionally substituted with one or more 15 substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 ,

-NH

2 , CI-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, Cl-C6 haloalkoxy, C1-C6 aliphatic group and Cl-C6 20 haloaliphatic group. In a specific embodiment, R and R' are each independently i) -H; ii) a Cl -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 25 halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C-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 ; Cl -C6 alkoxy; CI-C6 30 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 WO 2009/045503 PCTIUS2008/011450 - 18 optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , CI-C6 alkoxy, Cl-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group. In another specific embodiment, R and R' are each independently -H; a C 1-C6 aliphatic group 5 optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, hydroxy, C 1-C4 alkoxy, C 1-C4 haloalkoxy and benzyl; phenyl; or benzyl. Specific examples of each R and R' include -H, C1-C4 alkyl, phenyl and benzyl. A second set of values for the variables in Structural Formula (I) is provided 10 in the following paragraphs: Y is -H, -C(O)R, -C(O)OR or -C(O)NRR', preferably -H. R' 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' are as described in the first 15 set of values for the variables of Structural Formula (I). R2 and R 3 taken together with the nitrogen atom of N(R 2 R3) 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 20 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: 25 Y is -H, -C(O)R, -C(O)OR or -C(O)NRR', preferably -H. R' 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). 30 R 2 and R3 taken together with the nitrogen atom of N(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 WO 2009/045503 PCT/US2008/011450 -19 heterocyclic ring represented by -NR 2

R

3 are as described in the first set of values for the variables of Structural Formula (I). R5 and R6 are each independently -H, -OH, a halogen, a lower alkoxy group or a lower alkyl group. 5 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, R2, R, R and R5 independently is as described above for the 10 third set of values. X is -(CR'R) 0 -Q-; Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NRt-, -NR'-, -NR 8 C(O)-, -NReC(O)NR-, -OC(O)-, -SO 3 -, -SO-, -S(0)z-,

-SO

2 NR8-, or -NR 8

SO

2 -; and R4 is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl 15 group. Alternatively, X is -0-, -S- or -NR-; 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')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 20 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 25 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):

I~t?£UUtU~.JUJrtk A I UZUWUbf i'4aU -20 V OH R1N(R 2

R

3 ) R' N(R 2

R

3 ) HN HN j/\ R 4

(CR

5

R

6 )m R 0 01 II) R1 N(R 2

R

3 ) H (0R 5 R)r-Q-R 4 o (IV), H IH

R'N(R

2 R3) R'N(R 2 R) HN 0H

(CR

5

R

6 )n <JL'R4 0 -R 4 o MV, 0 (VI), OH

RN(R

2

R

3 )

R'N(R'R

3 ) H N HN N(R 7 R4) > -(0H 2 )m-R 4 0 (VII), 0 (Vill) WO 20091045503 PCT/US2008/011450 -21 OH Ri N(R 2

R

3 ) HN (CHz)n-o--R 4 O (IX), H H R1 N(RZR3) R

N(R

2

R

3 ) HN O H (CH2)n R4 O- R4 0 (X), 0 (XI), OH RI N(R 2

R

3 ) HN

N(R

7 R4) 5 0 (XII), WO 2009/045503 PCT/US2008/011450 -22 R1 N(R 2

R

3 ) HN > O C- (C H2)k-R * o (XIII) and H RI N(R 2

R

3 ) H N-(C[H2)k-R H o (XIV), or a pharmaceutically acceptable salt thereof. A first set of values for the variables 5 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' is an optionally substituted aryl group or an optionally substituted heteroaryl group. Examples of suitable substituents, including specific substituents, 10 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 of N(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 15 heterocyclic ring represented by -NR 2

R

3 are as described in the first set of values for the variables of Structural Formula (1). 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 20 substituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen. In one further aspect of this another specific embodiment, R4 is an optionally substituted aryl group or an WO 2009/045503 PCT/US2008/011450 - 23 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). 5 Each R4 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 10 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 R6 in Structural Formulas (III), (IV) and (V) are each 15 independently -14, -014, a halogen, a Cl-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-CS) group, an optionally substituted cyclic alkenyl (e.g., C3-CS) group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, -CN, -NCS, -NO 2 or a halogen. 20 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 R4 are as described in the first set of values for the variables of Structural Formula (1). Each R7 in Structural Formulas (VII) and (XII) is independently -H or Cl 25 C6 alkyl. For Structural Formula (IV), values and preferred values of each of Q and R' 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 -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -NR 8 (CO)-, -C(O)NR"- or -OC(O)-; and R' is 30 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-, WO 2009/045503 PCT/US2008/011450 -24 -C(S)O-, -C(S)S-, -NR 8 (CO)-, -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 -0-, -S-, C(0)-, -C(S)-, -NR 8 (CO)- or -C(O)NR 8 -; and R8 is optionally -H, an optionally substituted 5 aliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group. In yet another specific embodiment of Structural Formula (IV), Q is -0- , -S-, -C(O)-, -C(S)-, -NR'(CO)- or -C(0)NR-; and R' 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 -0- , -S-, -C(O)-, 10 -C(S)-, -NR'(CO)- or -C(O)NR-; and R 8 is optionally -H, an optionally substituted aliphatic group or an optionally substituted phenyl group; and R 8 is -H or a Cl-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 15 Formula (I). Each R1 0 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 20 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, C1 CIO alkyl, Ci-CIO haloalkyl, amino, Cl-CO0 alkylamino, CI-ClO dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, C 1-10 alkoxy, -0-[CH 2 ]p-O- or 25 -[CH2]q-. 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 30 Formulas (II)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

WO 2009/045503 PCT/US2008/011450 -25 A second set of values for the variables of Structural Formulas (11) - (XIV) is provided in the following paragraphs: Each of Y, Q, R 2 , R 3 , R 4 , R, R, R, R' and R' 0 independently is as described above for the first set of values for the variables of Structural Formulas (II) - (XIV). 5 R' is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR", -SR ', -N(R") 2 , Ar', -V 0 -OR', -V 0

-N(R

3

)

2 , -V 0 -Ar', -O-V 0 -Ar', -O-VI-N(R)2, -S-Vc-Ar', -S-Vi-N(R") 2 , -N(R 3 )-V-Ar', -N(R")-V1-N(R 3

)

2 , -O-{CH2]p-O-, S-[CH2]p-S-, or -[CH2]q-. Specifically, R1 is a phenyl group optionally substituted 10 with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, alkylamino, dialkylamino, aryl, aryloxy, -OH, alkoxy, -O-CH2],-O- and -[CH2)q-. Specifically, the "alkyl" referred to in the the alkyl, alkoxy, haloalkyl, alkylamino and dialkylamino groups of the exemplaryl substitutents independently is Cl-C6 alkyl. 15 Ar' 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, CI-C6 haloalkoxy, C1-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl. Preferably, Ar' is a phenyl group each optionally substituted with one or more 20 substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1 C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl. Each RM is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of 25 halogen, Cl-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl; or iii) a CI-C10 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, 30 cyano, hydroxy, CI-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl -C6 haloalkyl.

WO 2009/045503 PCT/[JS2008/011450 - 26 Each W is independently R 30 , or -N(R 3

)

2 is an optionally substituted non aromatic heterocyclic group. Examples of suitable substituents, including specific substituents, for the non-aromatic heterocyclic ring represented by -NR2R 3 are as described in the first set of values for the variables of Structural Formula (I). 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). A third set of values for the variables in Structural Formulas (II)-(XIV) is provided in the following paragraphs: 10 Each of Y, Q, R', R4, R, Ri, R, RtR, R' 0 , R 3 4, R' and Ar' independently is as described above for the second set of values for the variables of Structural Formulas (11) - (XIV). Each -N(R 2

R

3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected 15 from the group consisting of halogen, Cl-CS alkyl, Cl-C5 haloalkyl, hydroxyl, C1 C5 alkoxy, nitro, cyano, Cl-C5 alkoxycarbonyl, Cl-CS alkylcarbonyl or Cl-C5 haloalkoxy, amino, Cl-C5 alkylamino and Cl-C5 dialkylanino. Values and preferred values of the remainder of the variables of Structural Formulas (lI)-(XIV) are each independently as described above in the first set of 20 values for Structural Formula (1). A fourth set of values for the variables in Structural Formulas (II)-(XIV) is provided in the following paragraphs: Each of Y, Q, R', R 4 , R 5 , R 6 , R 7 , R8, R' 0 , R30, R] and Ar' independently is. as described above for the third set of values for values for the variables of 25 Structural Formulas (II) - (XIV). Each -N(R 2 i 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 30 values for Structural Formula (I). A fifth set of values for the variables in Structural Formulas (II)-(XIII) is provided in the following paragraphs: WV 2Uuy/u4DWU PCI/U S200U/011450 - 27 Each of Y, Q, R 2 , RW, R4, R 5 , R 6 , R, R 8 , R' 0 , R 30 , R 31 and Ar' independently is as described above for the fourth set of values for the variables of Structural Formulas (U) - (XIV). R' is a phenyl group optionally substituted with one or more substituents 5 selected from the group consisting of -OR (e.g., -OH, -OCH3, -OC2H 5 ), alkyl (e.g., Cl-C10 alkyl) and -O-[CH2]p-O-. Specifically, R' is 4-hydroxyphenyl or 3,4 ethylenedioxy-1-phenyl. 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 10 values for Structural Formula (I). A sixth set of values for the variables in Structural Formulas (UI)-(XIV) is provided in the following paragraphs: Each of Y, Q, R', R 2 , R RY, RB, RR,Ra, R?, R31 and Arl independently is as described above for the fifth set of values for the variables of Structural 15 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, 20 dialkylamino, -OR"', -Ar, -Ve.Art -V-OR, -O(haloalkyl), -V 4 -O(haloalkyl),

-O-V

4 -Ar', -O-[CH2]p.-O- and -[CH2]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 0 , -Ar, 4-Ar , -V-OR, -O(haloalkyl), -V-O(haloalkyl), -O-V 4 -Art -O-[CH 2 ]p-O- and 25 -{CH2]h- Each R4 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, Art -OR 5 0 , 30 -O(haloalkyl), -SR", -NO 2 . -CN, -N(R 1

)

2 , -NR 5 C(O)R, -C(O)R", -C(O)OR" 0 , -OC(O)RO, -C(O)N(R 5 ')2, -V 4 -Art -V-OR", -V 4 -O(haloalkyl), -V 4

-SR

0 , -V 4 -N0 2 . -V-CN, -V 4

-N(R

5 )2, -V-NR 51 C(O)R, -V 4

-C(O)R

5 , -V 4

-CO

2

R

0 , -V-OC(O)R 0

,

WO 2009/045503 PCT/US2008/011450 - 28 - -V4-C(O)N(R")2-, -O-V4-A?, -O-V5-N(R51)2, -S-V4-A?, -S-V5-N(R")2,

-N(R

5

')-V

4 -Ar, -N(R)-V-N(R) 2 , -NR 5

C(O)-V

4 -N(R')2, -NR 1

C(O)-V

4 -A9,

-C(O)-V

4

-N(R

5 1 )2, -C(O)-V 4 -Ar, -C(O)O-Vs-N(R 5 ')2, -C(Q)O-V4-Ar,

-O-C(O)-V-N(R')

2 , -O-C(O)-V 4 -Ar, -C(O)N(R')-VS-N(R 5 1 )2, 5 -C(O)N(R)-V 4 -Ar-, -O-[CH2]-O- and -{CHz]-. 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, -OR50, -Art -V4-Art -V-OR'4, -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar, -O-[CH 2 ]g-O 10 and -[CH2]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, -ORS, -Ar, -V4-Ar, 15 -V-OR;-O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar, -O-[CH 2 ]g-O- and -[CH21-. 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 seventh set of values for the variables in Structural Formulas (II)-(XIV) is 20 provided in the following paragraphs: Each of Y, Q, R', R2,N R R, , R , RiR, Ri' 0 ", R'", R and Ar independently is as described above for the sixth set of values for the variables of Structural Formulas (II) - (XIV). Each A? is independently a phenyl group optionally substituted with one or 25 more substituents selected from the group consisting of halogen, C1 -C6 alkyl, amino, C1-C6 alkylamino, CI-C6 dialkylnamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C -C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and Cl C6 haloalkyl. Each R5 0 is independently i) hydrogen; ii) a phenyl group optionally 30 substituted with one or more substituents selected from the group consisting of halogen, CI-C6 alkyl, amino, CL-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, Cl-C6 WO 2009/045503 PCT/US200/011450 -29 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, CI-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, C I-C6 haloalkoxy, C1 -C6 alkoxycarbonyl, Cl -C6 alkylcarbonyl 5 and Cl-C6 haloalkyl. 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 (1). An eighth set of values for the variables in Structural Formulas (II)-(XIV) is 10 provided in the following paragraphs: Each of Y, Q, R', R 2 , R, RI, R, R, RI, RI, R 30 , R", R 0 , Ar' and Ar 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. 15 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 C10 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' is an unsubstituted alkyl group (e.g., Cl-C 10 alkyl), or a phenyl group optionally 20 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, 25 alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar, -V 4 -Ar 3 , -V-OR 0 , -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar, -O-[CH 2 ]p*-O- and -[CH2],-. Specifically, the "alkyl" referred to in the the alkyl, alkoxy, haloalkyl, alkylamino and dialkylamino groups of the exemplaryl substitutents independently is Cl-C10 alkyl, or, alterantively, Cl-C6 alkyl. 30 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, Art alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy.

WO 2009/045503 PCT/US2008/011450 -30 Specifically, the optionally substituted biaryl group is an optionally substituted IA biphenyl group. Alternatively, -(CH 2 )n-R is H 2 , wherein phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar, alkyl, haloalkyl, alkoxy, 5 hydroxy and haloalkoxy. Each RO for Structural Formulas (XIII) and (XIV) is independently a Cl-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 10 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 (DX) and (X), each n is independently 1, 2, 3, 4 or 5. 15 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). 20 In a ninth set, values and preferred values of each of Y, Q, R', R2, R 4, R, R' R 7 , R8, R 30 , R, R7, R 40 , R 4 ', R42, R, R Rs 2 , Arl, At, and Ar of Structural Formulas (II)-(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) 25 (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 (II)-(XIV). Certain specific examples of ceramide derivatives that can be employed in the invention are as follows: WO 2009/045503 PCT/US2008/011450 -31 O NH (CH2)ai,-CH 3 00 (C H2).-C H 3 HO 0 (CHrir-9-CH3 HINo Oc(H2o- WU UUJYU433UJ FI/U 2UI/U1145U -32 HN (CH2h]-eA o ,and H HNo O -- NH -(CHA jA XX 5 and pharmaceutically acceptable salts thereof, wherein each ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl and alkoxy. It is to be understood that when any compound is referred to herein by name or structure, solvates, hydrates and polymorphs thereof are included. 10 The ceramide derivatives disclosed herein may contain one or more chiral center and/or double bond and, therefore, 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., 15 geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed. For example, the compound represented by Structural Formula (1) 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 (IS, 2S) stereoisomer and mixtures thereof. 20 WO 2009/045503 PCT/US200S/011450 -33 Y 1 2

N(R

2

R

5 ) HN X -R 4 0 (1). In some specific embodiments, the ceramide derivatives represented by Structural Formula (I) are (I R, 2R) stereoisomers. 5 As used herein, a racemic mixture means about 50% of one enantiomer and about 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 10 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. 15 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% optically pure. Percent optical purity 20 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 25 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 WO 2009/045503 PCT/US2008/011450 -34 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 5 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, 10 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 15 carbon atoms, typically between I and 10 carbon atoms, more typically between I 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 20 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. 25 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", 30 "lower haloalkyl", "lower arylalkyl", "lower alkylamine", "lower cycloalkylalkyl", "lower dialkyamine", "lower alkylamino", "lower dialkyamino" "lower alkylcarbonyl", "lower alkoxycarbonyl" include straight and branched saturated WO 20091045503 PCTIUS2008/011450 -35 chains containing one to six carbon atoms. In some specific embodiments, the "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", "arylalkyl", "alkylamine", "cycloalkyl", "dialkyarnine", "alkylamino", "dialkyamino" "alkylcarbonyl", "alkoxycarbonyl" and the like, independently is Cl 5 C10 alkyl, or, alterantively, Cl -C6 alkyl. The term "alkoxy" means -0-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; 10 "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, 15 Cl, Br or . 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 -[CH2]z-, wherein z is a positive 20 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-. 25 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 30 group" is substituted at any one or more substitutable ring atom. The term "C 6

.

14 aryl" as used herein means a monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, WO 2009/045503 PCT/US2008/011450 - 36 anthracenyl, 1,2-dihydronaphthyl, 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 5 "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 10 "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(Ci.

6 alkyl), O and S. Examples of monocyclic heteroaryl groups, for example, for the heteroaryl 15 groups represented by each of R', R2, R3, R4, RI, R' 0 , R, R2, R3 0 , R, R 4 , R 42 ,RS,

R

52 , Ar', Ar 2 and Ar, 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), 20 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), tetrazolyI (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3 thienyl. Examples of monocyclic six-membered nitrogen-containing heteraryl groups, 25 for example, for the heteroaryl groups represented by each of R', R, Rt R, R, R' 0 , RI, R22, R 30 , R 2 , R, R 42 , R'"),IR 2 , Ar', A? and Art include pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups, for example, for the heteroaryl groups represented by each of RI, RR, RW, R, R'", R t, R, R 30 . R',

R

4 0 , R 4 2 , R 5 0 , R 2 , Ar', Ar2 and A?, include carbazolyl, benzimidazolyl, benzothienyl, 30 benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

WO 2009/045503 PCT/US200/011450 - 37 Typically, the aryl and heteroaryl groups represented by each of R, R', R,

R

2 , W, R, R 7 , R'", R 21 , R2, R 30 , R 32 , Ra 0 , R 42 , RS 0 , Rs 2 , Ar', A? and Ar3 are C6-C14 aryl and 5-14 membered heteroaryl groups, respectively. Specific examples of the aryl and heteroaryl groups, including those represented by each of R, R', R, R2, 3, 5 R, H, R , I , R 2 , R 30 , R 2 , R 4 , R 4 2 , R 5 0 , R 52 , Ar', A2 and ArP each independently include: A Is - F N N N > N U-N X NN N N 10 n h , g r K$\N R4 R2 R\ n, moncycic ing AB ,F ,H ,N , adW hr inecrigs wherein each of rings A-ZS is optionally and independently substituted. Suitable substiruents for rings A-ZS are as described above. In a specific embodiment, the 15 aryl and heteroaryl groups, including those represented by each of R, ', ' , R , H.", k., R' 0 , , R 2 2, WO 3 , H.

3 2 , R 4

H.

2 , WO 5 , R.

5 ', Ar', A?2 and Art include rnonocyclic rings A, B, E, F, G, HI, 1, N, 0, V, and W, wherein each ring is optionally and independently substituted. The aryi and heteroarl groups, including those represented by each of R, R', 20 R1, R 2 , R, R, R, R', R 2 1 1 , R2,R 30 , R , R 0 , R 2 , Rso, RR2, Ar', Ar 2 and Ar, can be optionally substituted. In certain embodiments, the aryl and heteroaryl groups are WO 20091045503 PCT/US2008/011450 -38 each independently optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1.20 alkyl, C 2

.

2 0 alkenyl, C 2

.

20 alkynyl, amino, C1.

20 alkylamino, C.

20 dialkylamino, CI.

20 alkoxy, (Cl. io alkoxy)Ci 20 alkyl, C12o haloalkoxy, (Ci.io haloalkoxy)C.2o alkyl and C.

20 5 haloalkyl. More specific substituents for the aryl and heteroaryl groups, including tiose represented by each of R, R, R', B.

2 B., R 4 , R, R'", R 2 , R2, R 30 , R 32 , R 40 ,

R

42 , R 5 , Rs 2 , Ar2, Ar 2 and Ar, include halogen, nitro, cyano, hydroxy, C1.

10 alkyl,

C

2 .10 alkenyl, C 2

-

10 alkynyl, amino, C 1 .o alkylanino, C.

1 -.o dialkylamino, C 1

.

10 alkoxy, (C1.6 alkoxy)C..i 0 alkyl, Ci.,o haloalkoxy, (C,.. haloalkoxy)CI.

10 alkyl and C 1

.

10 10 haloalkyl. More pecific substituents include C 1 .,o 0 alkyl, -OH, C,.-o 0 alkoxy, C i.o0 haloalkyl, halogen, C- 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 15 one or more ring carbons, preferably one or two, are each replaced by a heteroatom such as N, 0, 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 20 (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), 25 thiomorpholinyl (e.g., N-tbiomorpholinyl, 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 "N" on N-morpholinyl, N-thiomorpholinyl, 30 N-pyrrolidinyl, N-piperazinyl, N-piperidinyl and the like indicates that the non aromatic heterocyclic group is attached to the remainder of the molecule at the ring nitrogen atom.

YV v~ 'ov.'fvoWV' r-. il y eUuoLUUOJ1Iq -39 The ceramide derivatives disclosed herein can be prepared by processes analogous to those established in the art, for example, in U.S. 5,849,326; U.S. 5,916,911; 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 5 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 10 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 manual, preferably a human, but can also be an animal in need of veterinary treatment, such as a companion animal (e.g., dogs, 15 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. 20 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 25 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 a polycystic kidney disease is the quantity of compound that results in a slowing in the progression of the polycystic kideny disease, a reversal of the polycystic kidney disease state, the inhibition of new 30 cyst formation (partial or complete inhibition of cystogenesis), a reduction in cyst mass, a reduction in the size and number of cysts, and/or a reduction in the severity of the symptoms associated with the polycystic kidney disease.

WO 2009/045503 PCT/US2008/011450 -40 Typically, the ceramide derivativesdisclosed herein are administered for a sufficient period of time to achieve the desired therapeutic 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, 5 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 I , 2, 3, or 4 times per day, such as, e.g.., a daily or twice-daily dosage regimen. Commercially available assays may be employed to determine optimal dose 10 ranges and/or schedules for administration. For example, assays for measuring blood glucose levels are commercially available (e.g., OneTouch*UItra, 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., 15 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 20 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. From: Mouse Rat Monkey Dog Human (20g) (150 g) (3.5 kg) (8 kg) (60 kg) To: Mouse 1 1/2 1/4 1/6 1/12 To: Rat 2 1 1/2 1/4 1/7 To: Monkey 4 2 1 3/5 1/3 To: Dog 6 4 3/5 1 1/2 To: Human 12 7 3 2 1 WO 2009/045503 PCT/US2008/011450 -41 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 5 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 PKD. 10 In another embodiment, the method of the invention is a co-therapy with other therapeutically active drug(s). The disclosed ceramide derivatives are co administered either simultaneously as a single dosage form or consecutively as separate dosage forms with other agents that ease the symptoms and/or complications associated with PKD. The associated symptoms with PKD include pain, headaches, 15 urinary tract infections and high blood pressure. Examples of the agents that can be co-administered with thecompounds of the invention include, but are not limited to, 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 20 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, chloramphemicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofloxacin, streptomycin, rifamycin, 25 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 30 benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, rarnipril and trandolapril.

WO 20091045503 PCT/US2008/011450 -42 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 S butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5h 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 10 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, 15 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 20 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 25 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. 30 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 WO 2009/045503 PCT/USZOOS/011450 - 43 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 5 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, 18t ed. 10 (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 15 Example 1. Synthesis of Ceramide Derivatives General Methods for the Preparation of Amide Analogs Example 1A. Synthetic Route 1 20 -OH HQ NR + HOO NN=2C=N N N, 0RCH2C! ' A R' (Scheme 1) 25 Method 1 A mixture of Compound A (1 mmol), such as (1R, 2R)-2-amino-1-(2,3 dihydrobenzo[p][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, an acid (Compound B, 1.2 mmol), DCC (dicyclohexylcarbodiimide, 1.2 mnol) and HOBT WU At~yUa/UDUJ FUTIJ5N2UU3/Ull45U -44 (1-hydroxy benzotriazole, 1.2 mmol) was dissolved in CH2C1 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 5 (CH 2 Cl 2 IMeOH/NH 4 0H). Method 2 A mixture of Compound A (1 mmol), such as (1R, 2R)-2-amino-1-(2,3 dihydrobenzo[p3 (1,4]dioxin-6-yl)-3-(pyrrolidin- 1 -yl)propan- I -ol, an acid 10 (Compound B, 1.2 mmol) and DCC (dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CHC1 3 (5 ml). The mixture was placed in the microwave reactor (T = 120 *C, time = 1min) and it was then filtered and purified by column chromatography using, for example, a mixture of (CH 2 Cl 2 /MeOHINH 4 OH). 15 Method 3 A mixture of Compound A (1 mnmol), such as (1R, 2R)-2-amino-1-(2,3 dihydrobenzo[p](1,4jdioxin-6-yl)-3-(pyrralidin-1-yl)propan-1-ol, an acid chloride of Compound B, 1.2 mmol) and K 2 C0 3 (2 mmol) was suspended in THF (5 ml). The mixture was stirred at room temperature and monitored by TLC for completion. 20 After completion, the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH 2 Cl 2 /MeOH/NH40H). Example 1B. Synthetic Route 2 HQr 0 NH 2 j R4 25A D p 25 (Scheme 2) Compound A, such as (IR, 2R)-2-amino-1-(2,3-dihydro-benzo[l,4] dioxin 6-yl)-3-pyrrolidin-1-yI-propan-1-ol, was coupled with a variety of N- WO 2009/045503 PCT/US2008/03E450 -45 hydroxysuccinamide esters (Compound D prepared according to the method below) in methylene chloride under an atmosphere of nitrogen, for example, for 18 to 24 hours depending on the ester used. 5 Preparation of N-hydroxysuccinamide esters + 4 IN H -N=c=N - §9 NO R4 -o (Scheme 3) 10 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 'H NMR and the crude material was then used in the preparation of amide analogs without further 15 purification. Example 1C. Preparsion of Compound A of Schemes 1 and 2 (1R, 2R)-2-amino-1-(2,3-dihydro-benzo[1,4] dioxin-6-yl)-3-pyrrolidin-1-yl propan- 1-ol was prepared by according to the preparation of intermediate 4 of U.S. 20 5,855,830, the entire teachings of which are incorporated herein by reference. A general synthetic route for prepating Compound A with various -NR 2

R

3 is depicted in Scheme 4 below.

WO 2009/045503 PCT/US2008/011450 -46 HO OHEOC I OH HO N TBDMSO NrO NHCbz HNN HCbZ DMF NHChz CM.1 TBDMSO O lecide TBM AvOH E V EIJI H QH HO N 0EVI HycOtysi6 s M 9" R2 QH gvu1 (Scheme 4) Preparation of ElI: (R) -benzyl 3,8,8,9, 9-pentamethyl-4 oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate 5 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 TBDMSiCI (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 10 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). 'H NMR (400 MHz, CDC 3 ) 6= 0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 15 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 214), 5.7 (d, 1H), 7.2-7.4 (in, 5H).

WO 2009/045503 PCT/US200S/011450 -47 Preparation pf EI: (Rbenzyl 3-(tert-butyldimethylsilvloxy)- -(2,3 dihydrobenzo[fljl,4ldioxin-6-yl)-l-oxopronan-2-vlcarbamate. (2,3-dihydrobenzo[s][1,4]dioxin-6-yl)magnesium bromide (26 g, 78 mmol) dissolved in 40 mL of THF (tetrahydrofuran) under a nitrogen atmosphere was 5 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 TH4F (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 10 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). 1H NMR (400 MHz, CDC 3 ) 5= 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). 15 Preparation of EV: benzyl (IR. 2R)-3-(tert-butyldimethylsilyloxy1-(I2,3 dihydrobenzo[l][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbanate. (R)-benzyl 3-(tert-butyldimethylsilyloxy)- 1 -(2,3 dihydrobenzo(p](1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (3.1g, 6.6 mmol) 20 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 25 by column chromatography using 2.5%EtOAc-2%acetone-methylene chloride. The desired diastereomer was obtained in 80% yield (2.5 g ). 'H NMR (400 MHz, CDCl 3 ) &= 0 (d, 6H), 0.9 (s, 9H), 3.5 (broad s, 1H), 3.7-3.9 (m, 2$), 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, 511). 30 Preparation of EV: benzyl (1R, 2R)-1-(2,3-dihydrobenzofpl[1,4ldioxin-6-vl)-1,3 dihydroxypropan-2-vlcarbamate.

WO 2009/045503 PCT/US2008/011450 -48 Benzyl (IR,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3 dihydrobenzo[][1,4]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 5 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,) 8= 3.4-3.8 (m, 4H), 4.1 (broad s, 4H), 4.8 (s, 1 H), 4.9 (broad s, 2H), 5.7 (broad s, iH), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H). 10 General procedure for preparation of EVI and EVII Benzyl (1R, 2R)-1-(2,3-dihydrobenzofp)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 15 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 20 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. 25 Examples ofE VII compounds i) ( R. 2R)-2-amino- I -(2,3-dihydrobenzofl1,4]dioxin-6.yl)-3 moi-pholinopropan-1-ol.

WO 2009/045503 PCT/US2008/011450 - 49 OH 'H NMR (400 MHz, CDCl 3 ) 8= 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, 3H4); MS for CisH2N 2 04 5 m/z 294.8 [M+H]. ii) (IR. 2R)-2-amin-I-(2,3-dihydrobenzo[p1 ,4]dioxin-6-yl)-3-(piperidin 1- vlihropan-1-ol. OH 10 'H NMR (400 MHz, CDC 3 ) &= 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, 11), 6.7-6.9 (m, 3H). 15 Example lD. Preparation of Substituted Phenoxy Propionic Acids for Compound B in Scheme 1 Example IDI: Preparation of 3.(4-methoxyphenoxy)propionic acid. 20 i) 3-(4-nethoxyphenoxy)propionitrile (1). 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 nL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 nL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a 25 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 VT I. zUUYnU4a1U., ruI/ u U3U/UI14143 -50 acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether)10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 1 as white crystals (Yield: 89.48 %). 'H NMR (450 MHz, CDCIs): 3= 2.72 (t, 2 H; CH2CN); 5 = 3.83 (s, 3 H; OCH 3 ); 3= 4.05 (t, 2H; OCH2); 6= 6.70 (m, 4H; 5 Ar-H); 13 C NMR (112.5 MJz, CDCl 3 ): d= 18.843 (CH 2 CN); 55.902 (OCH 3 ); 63.699 (OCH2); 114.947 (CHOCCH); 116.183 (CH 2 OCCH); 117.716 (CN); 151,983 (CH 3 0C); 154.775 (CH2OC). ii) 3-(4-methoxyphenoxy)propionic acid (2). 10 A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile (1)) 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 H20. 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 15 the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 2. 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 20 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 2 as a white solid (Yield: 86.04 %). 'H NMR (450 MHz, CDC 3 ); 6= 2.78 (t, 2H; CH 2 COOH); 3.70 (s, 3H; OCH3); 4.18 (t, 2H; OCH 2 ); 6.78 (m, 4 H; Ar H); "C NMR (112.5 MHz, CDC 3 ): 3= 34.703 (CH2COOH); 55.925 (OCH 3 ); 25 64.088 (OCH 2 ); 114.855 (CH 3 0CCH); 115.984 (CH 2 OCCH); 152.723 (CH 3 OC); 154.302 (CH 2 0C); 177.386 (COOH). Example ID2: Preparation of 3-(4-(3-oxobutyl)phenoxv)propanoic acid 30

HO

WO 2009/045503 PCT/US2008/011450 -51 Step 1: a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B (400 g), 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 5 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 HCI (37%, 5 mL) and placed in the microwave reactor (T= 110 *C, 5 min). The mixture was poured onto iced water (20 g), filtered, and the solid was washed with 10 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). 'H NMR (CDCb, 400 mHz, ppm); 2.2 (s, 314). 2.7 (t, 2H), 2.85 (m, 4H), 4.25 (t, 2H), 6.8 (d, 2H), 7.1 (d, 2H). 15 Example 1D3: Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid 0 HO Step 1: a mixture of 4-(2-methoxy ethyl) phenol (1.

5 47g, 10.3 mmol), 20 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 25 (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)/HCI (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 30 methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification by column chromatography using a mixture of hexane/ethyl acetate.

WO 2009/045503 PCT/US2008/011450 - 52 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 E101, 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 5 using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). 'H NMR (CDC1 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 1 D4: Preparation of 3 -(4-(3-methylbutanoylphenoxy)propanoic acid 10 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 15 (5.0 g, 27.7 mmol, 92.5%). Step 2: aluminum chloride (1.1 g, 8.34 nmol) 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 CF1 2 Cl 2 (9 nL) and the reaction mixture was stirred overnight. The mixture was evaporated and the residue was 20 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 nmol) in 2 25 mL of HCI (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 X10 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%). 30 Example E. Preparation of Amide Analogs WO 2009/045503 PCT/US2008/011450 -53 Example El. Preparation of Hemi-Hydrate of Compound 163 N-[2-Hydroxy-2 (2,3-dihydrobenzopl1J,41dioxin-6-vl)- 1 -pvrrolidin- 1 -ylmethyl-ethyl-3-(4 methoxy-phenoxy)-propionamide N-OH

CH

2 C6 OH

-

N=C=N . Co2H 5- -- -1 + N 2) ONH

NH

2 03 ' H -- CH '- C

H

2 0 OH (Scheme 1 A) Compound 163 was prepared by following Scheme 1A above. 3-(4 methoxyphenoxy)propanoic acid (see Example 1D1, 34.47g, 169imol, 96% purity 10 by HPLC), DCC (34.78g, 169 mmol) and N-hydroxysuccinimide (19.33, 169mmol) were combined as dry powders and methylene chloride (500mL) 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 step 5 amine (50g, 15 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 Buchner funnel to remove DCC urea. The solid urea was washed with 500mL of methylene chloride. The organic layers were combined, placed in a separatory funnel, and treated with 500mL of 1.OM NaOH. The layers 20 were separated, and the cloudy organic layer was recharged into a separatory funnel and treated with a 6% HCl solution (adjusted to pH=0.03-0.34, 100mL 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 200mL of solution). The organic layer was WO 2009/045503 PCT/US2008/011450 -54 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 (500mL) with heating and transferred to a 1 L round bottom flask equipped with a mechanical stirrer and heating mantel. The solution was heated to 50*C and 5 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 10 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 Bichner finnel. Any remaining solid in the flask was washed onto the funnel using ice-cold isopropyl alcohol (100mL). 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 15 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 scanning calroimetery) showed a melting point of 134.89 0 C. A total of 69.3g of white solid was collected (65.7% overall yield). 1H NMR (400 MHz, CDCl 3 ) 6- 1.8 (M, 4H), 2.4-2.6 (m, 4H), 2.6 (m, 20 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, 7 H), 7.8 (d, 1H); MS for C 29

H

4 oN 2 0 13 m/z 457.3 [M+HJ for main peak (free-base). Example 1E2. Preparation of Compound 247: N-( (R. 2R)-1-hydroxy-1-(4 25 methoxvhenvl)-3-(pyrrolidin- 1 -vllpropan-2-vl)-3-(p-tolvloxy)propanamide.

WO 2009/045503 PCT/US2008/011450 - 55 Q OH NH O OO Compound 247 was prepared in a similar manner as described above, following Scheme 1 using (iR, 2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1 5 yl)propan-1-ol as the amine. 'H NMR (CDC 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, IH), 6.5 (br, 1H), 6.8 (m, 4H), 7.1 (d, 2H), 7.2 (d, 2H). M/Z for C 2 4 H32N 2

O

4 [M-H]"= 413. (1R, 2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as 10 the amine was prepared by the procedures described below: C)

H

2 NV'. HO ..._ O) A mixture of benzyl (1R, 2R)- 1 -hydroxy- I -(4-inethoxyphenyl)-3 (pyrrolidin-1-yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5 %, 21 mg) 15 in EtOH (1 mL)/HCI (1 M, 50 pL) 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).

WO 2009/045503 PCT/US2008/011450 - 56 gxample 1E3. Preparation of Compound 251: N-((1R. 2R)-1-hydroxy-1-(4 methoxyphenyl-3-pyrrolidin-1-yl)propan-2-yl)-2-(4 (trifluoromethvl)phenvl)acetamide. SOH N 0 NH X FL F F 5 Compound 251 was prepared in a similar manner as described above, following Scheme 1 using (1R, 2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1 yl)propan-1-ol as the amine (see Example lE1). 'H NMR (CDC 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 10 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, 21), 7.2 (d, 2H), 7.55 (d, 214). MIZ for C2 3 H27F 3

N

2 0 3 (M-1]- = 437. Example 1E4. Preaparation of Comnound 5: N-((1R, 2R)-1-(2,3 dihydrobenzoFpl[1,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin- I -ylpropan-2 15 yl)benzoblthiophene-2-carboxamide Compound 5 was prepared in a similar manner as described above, following Scheme 1. NOH O N H 4, 20 WO 2009/045503 PCT/US2008/011450 - 57 'H NMR (CDC 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.45 (m, IH), 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, 21). M/Z for C 2 4H2 6

N

2 0 4 S [M-H]- = 439. 5 Example IE5. Preparation of Compound 11: N-((R, 2R)-1-(2,3 dihvdrobenzo[11,4jdioxin-6-vl)-1-hydroxy-3-(pvrrolidin-1-yl)propan-2-yl)-2 (phenylthio)acetanide Compound 11 was prepared in a similar manner as described above, 10 following Scheme 1. N OH 6 'H NMR (CDC1 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (br, 2H), 15 3.6 (q, 2H), 4.1.5 (m, 1H), 4.2 (s, 4H), 5.9 (sd, 1 H), 6.7 (m, 2H), 6.8 (s, 1H), 7.2 (m, 7H). MIZ for C 23

H

28

N

2 0 4 S [M-H]-= 429. Example 1E6. Preparation of Compound 12: N-((IR. 2R)-1-(2,3 dihydrobenzo[p1,.4ldioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-vl)phropan-2 20 yl)biphenyl-4-carboxamide Compound 12 was prepared in a similar manner as described above, following Scheme 1.

YVLP AUUavI-no.'-7-J r- A/ IUUUO/U1143U - 58 NQOH 'H NMR (CDC1 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 21), 4.25 (s, 4H), 4.4 (br, IH), 5.05 (sd, 1H), 6.6 (sd, IH), 6.85 (m, 2H), 6.95 (s, 1H), 5 7.45 (m, 3H), 7.6 (m, 4H), 7.75 (in, 2H). M/Z for C2sH 3 oN 2

O

4 (M-H]'= 459. Example 1E7. Preparation of Compound 19: N-((IR, 2R)-1-(23 dihydrobenzo[lf 1.4ldioxin-6-vl)-1-hydroxy-3-fpyrrolidin-1 -yl)propan-2 vl)benzo~b|thiophene-5-carboxamide 10 Compound 19 was prepared in a similar manner as described above, following Scheme 1. o ] 0NQH 15 'H NMR (d 6 -dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (m, IH), 4.15 (s, 4H), 4.25 (m, IH), 4.75 (sd, IH), 5.6 (br, I H), 6.7 (m, 3H), 7.5 (sd, 1iH), 7.7 (sd, IH), 7.8 (sd, IH), 7.85 (sd, 1H), 8.0 (sd, 1H), 8.2 (s, 1H). M/Z for C 24 12 6

N

2 0 4 S (M-H]- = 439. 20 Example IE8. Preparation of Compound 23: 2-(biphenyl-4-yl)-N-((1R, 2R)-1-(2,3 dihydrobenzolil[1.4ldioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yllpropan-2 yl)acetanide WO 2009/045503 PCTIUS200S/011450 -59 Compound 23 was prepared in a similar manner as described above, following Scheme 1. N OH 5 'H NMR (CDC 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (d, 2H), 3.55 (s, 2H), 4.2 (m, 511), 4.85 (sd, 1H), 5.95 (br, 1 H), 6.6 (m, 1H), 6.75 (m, 2H), 7.2 (sd, 211), 7.4 (m, 1H), 7.5 (st, 2H), 7.6 (m, 4H). M/Z for C 29

H

32

N

2 0 4 [M-H]-= 473 10 Example 1E9. Preparation of Compound 24: N-( 1R, 2R)-1-(2,3 dihydrobenzo[Bl [1 4ldioxin-6-vl)- 1 -hydroxy-3 -(vyrrolidin- 1 -vlinropan-2-vlI-2-(4 phenoxyphenyl)acetamide Compound 24 was prepared in a similar manner as described above, 15 following Scheme 1. NQH

O-

0 9 yNH 0 6 'H NMR (CDC 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2f), 20 3.45 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1M), 5.9 (br, 1H), 6.6 (m, 1H), 6.7 (s, 1H), 6.8 (in, 1H), 7.15 (m, 7H), 7.4 (m, 2H). M/Z for C 2 9

H

3 2

N

2 0 5 [M-H] = 489.

WO 2009/045503 PCT/US2008/01450 -60 Example ElO. Preparation of Compound 25: (S)-N-((IR, 2R)-1-(2,3 dihydrobenzo[plf 1,4ldioxin-6-yI)-1-hydroxy-3-(prolidin-1-vl)proan-2-yl)-2 hydroxy-3-phenylpropanamide 5 Compound 25 was prepared in a similar manner as described above, following Scheme 1. Q OH & NH 10 'H NMR (CDC 3 , 400 mHz, ppm); 1,8 (br, 4H), 2.65 (br, 7H), 3.1 (dd, 211), 4,2 (m, 6M), 4.8 (sd, 1H), 6.6 (m, 11-H), 6.8 (m, 3H), 7.3 (m, 5H). M/Z for

C

2 4HoN2,Q (M-H- = 427. Example 1E 11. Preparation of Compound 27: N-((I R, 2R)-1-(2,3 15 dihydrobenzo[0][1,41dioxin-6-yl)-I-hydroxy-3-(pyrrolidin-1-yl)propan-2-yI-3 phenoxypronanamide Compound 27 was prepared in a similar manner as described above, following Scheme 1. QH 20 WO 2009/045503 PCT/US2008/011450 -61 'H NMR (CDC13,400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 61-), 2.9 (m, 2H), 4.2 (m, 7$), 4.95 (sd, 11), 6.45 (m, IH), 6.75 (s, IH), 6.85 (m, 3H), 6.95 (t, 1H), 7.2 (m, 3H). M/Z for C 24 H30N 2 0s [M-H]^= 427. 5 Example 1E12. Preparation of Compound 31: N-((IR, 2R)-1-(2 dihydrobenzo[31[,4jdioxin-6-yI)-1-hydroxv-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo 2-phenylacetamide Compound 31 was prepared in a similar manner as described above, following Scheme 1. 10 Q QH 'H NMR (CDCl, 400 mHz, ppm); 1.8 (br, 4H), 2.8 (br, 4H), 3.0 (m, 2H), 4.2 (s, 41H), 4.3 (m, IH), 5.05 (sd, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.35 (m, 1EH), 7.45 (t, 15 2H), 7.6 (t, 1H) 8.2 (d, 2H). M/Z for C2H 2 6

N

2 0 5 [M-HT = 411. Example lE13. Preparation of Compound 32: N-((IR, 2R)-1-(23 dihvdrobenzo1pl3[1 4jdioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3 (phenylthio)propanamide 20 Compound 32 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 62 0 NH 8 H NMR (CDC 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, S 1H), 7.3 (m, 3H). M/Z for Cz4HoN 2 0 4 S [M-H] = 443. Example 1E14. Preparation ofConmpound 35: N-((] R, 2R)-1-(2,3 dihydrobenzo[) [1,4]dioxin-6-y)--1-hydroxy-3-(pyrrolidin-1-yl)propan-2-vl)-2-o tolylacetamide 10 Compound 35 was prepared in a similar manner as described above, following Scheme 1. QOH 15 'H NMR (CDC 3 , 400 mHz, ppm); 1.7 (br, 411), 2.1 (s, 311), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (s, 2H), 4.1 (m, I H), 4.25 (s, 4H), 4.8 (sd, 1H), 5.75 (br, I H), 6.5 (d, 1H), 6.65 (s, 1H), 6.75 (d, IH), 7.1 (d, 1H), 7.2 (m, 311). M/Z for C 24

H

3 3

N

2 0 4 [M-H]~= 411. 20 Example IE15. Preparation of Compound 36: N-((1R, 2R)-1-(2,3 dihydrobenzo[bl1 ,4ldioxin-6-yI)-1-hydroxy-3-(pvrrolidin-1-v)propan-2-yl)-2-m tolylacetamide WO 2009/045503 PCT/US2008/011450 -63 Compound 36 was prepared in a similar manner as described above, following Scheme 1. QOH 0 Q N H 0 5 'H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 31H), 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, 11), 6.55 (d, 1H), 6.75 (m, 2H), 6.9 (d, 2H), 7.1 (sd, 1H), 7.2 (m, 11-). v/Z for 10 C 24

H

30

N

2 0 4 (M-H'= 411. Example 1E16. Preparation of Compound 39: 2-(benzylthio)-N-((lR. 2R)-1-(2,3 dihvdrobenzof~l I 1,4ldioxin-6-vl)- 1 -hydroxy-3-(Pvrrolidin- 1 -vl)provan-2 yl)acetamide 15 Compound 39 was prepared in a similar manner as described above, following Scheme 1. COH

NH

WO 2009/045503 PCT/US2008/011450 - 64 1H NMR (CDC1 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, IH), 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 2 4H3N20 4 S [M-H]- = 443. 5 Example 1E17. Preparation of Cempound 47: N-i(R, 2R)-1-(2.3 dihydrobenzof13 ,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yI)-2-(4 (pyridin-3-yl)phenyl)acetamide Compound 47 was prepared in a similar manner as described above, following Scheme 1. 10 SOH NH0 N 'H NMR (CDC 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 15 (m, 2H), 7.25 (d, 3H), 7.4 (m, 11-), 7.6 (sd, 2H), 7.9 (sd, 1H), 8.6 (sd, I H), 8.85 (s, 1H). M/Z for C2sH31N3O4 (M-H]= 474. ExampIe 1E18. Preparation of Compound 48: 2-(4'-chlorobphenyl-4-yl)-N-((1 R, 2R )-I-(2,3-dihydrobenzo[l(1,41di9xin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)pronan 20 2-yIacetamide Compound 48 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 65 QOH CI H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 211), 4.15 (m, 1 H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, IH), 6.75 5 (m, 2H), 7.2 (d, 2), 7.4 (m, 2H), 7.55 (sd, 4H). M/Z for C 29

H

31 C1N 2 0 4 [M-H]"= 508. Example 1E19. reparation of Compound 51: N-((R,. 2R)-1.(2,3 dihydrobenzofL ,41dioxin-6yl)-1-hydroxy-3--(pyrrolidin-1-yllpropan-2-y1)-2-(3 10 (trifluoromethvl)phenvl)acetamide Compound 51 was prepared in a similar manner as described above, following Scheme 1. Q QH 0ONHI 0 F F F 15 'H NMR (CDC13, 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, 1I), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.55 (sd, IH). M/Z for C 24

H

2 7

F

3 N20 4 [M-H] 465. 20 WO 2009/045503 PCT/US2008/011450 - 66 Example 1E20. Preparation of Compound 53: N-((1R. 2R)-1-(2.3 dihydrobenzoBl [1 ,4ldioxin-6-yl)-1 -hydroxy-3-(pyrrolidin-1 -yI)prqpan-2-yl)-2-(3 fluorophenyl)acetamide Compound 53 was prepared in a similar manner as described above, 5 following Scheme 1. 00 F 'H NMR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 10 3.50 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, IH), 5.8 (br, IH), 6.6 (d, IH), 6.75 (m, 1 H), 6.8 (d, IH), 6.85 (d, 1H), 6.9 (d, 1 H), 7.0 (t, 1H), 7.3 (sq, 1H). M/Z for C23H27FN204 [M-HJ~= 415. Example 1E21. Preparation of Compound 54: N-((1R, 2R)-1-(2,3 15 dihydrobenzo[pl[1.41dioxin-6-yl).1-hydroxy-3-(pvrrolidin-1-yl)propan-2-vl)-3-(3 methoxyphenoxy)propanamide Compound 54 was prepared in a similar manner as described above, following Scheme 1. O OH 2ONH 09 20

%

WO 20091045503 PCT/US2008/011450 - 67 'H NMR (CDC 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, 1H). M/Z for C 2 sH32N 2

O

6 [M-H] - 457. 5 Example 1E22. Preparation of Compound 55: 3-(2.5-dichlorophenoxy)-N-((R 2R)-I-(2,3-dihydrobenzoFjjT1,4ldioxin-6-yl)-1-hvdroxy-3-(pvrrolidin-1-yl)propan 2-vl)ropanamide Compound 55 was prepared in a similar manner as described above, following Scheme 1. 10 N QH CI OQ '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, 1 H), 6.75 (s, 2H), 6.8 (s, 1H), 6.9 15 (m, 2H), 7.25 (m, 1H). MIZ for C 24

H

28 C1 2

N

2 0 5 [M-H]~= 496. Example 1E23. Preparation of Comipound 57: 3-(4-chlorophenoxy)-N-((IR, 2R)-1 (2,3-dibydrobenzof3l[1 .4ldioxin-6-yl)- I -hydroxy-3 -(pyrrlidin- -yl)propan-2 yl)propanamide 20 Compound 57 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 68 N QH Cl 'H NMR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H). 2.65 (br, 614), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, iH), 6.3 (br, 1H), 6.8 (m, 5H), 7.2 (m, 2H), MIZ for 5 C 2 4 H29ClN 2 0s [M-H]- = 461. Example 1E24. Preparation of Compound 58: N-((1R, 2R)-1-(2,3 dihydrobenzoF1 [1,41dioxin-6-yl)-1-hydroxy-3-(vyrrolidin-1-yl)propan-2-yl)-3-(4 fluorophenoxy)propanamide 10 Compound 58 was prepared in a similar manner as described above, following Scheme 1. NOH SNH 'H NMR (CDC 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 15 4.2 (m, 7H), 4.95 (sd, 1H), 6.4 (br, IH), 6.8 (in, 5H), 7.0 (m, 2H). M/Z for

C

24

H

29

FN

2 0 5 [M-HJ- = 445. Example 1E25. Preparation of Compound 59: N-((1R, 2R)-1-(2,3 dihydrobenzo [1[1,41dioxin-6-yI)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p 20 tolyioxyrpananmide Compound 59 was prepared in a similar manner as described above, following Scheme 1, flU h-U'YIU4Dev3 P~U/UI2UUl/U11450U - 69 N O 'H NMR (CDCl, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 31H), 2.65 (br, 6H), 5 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 2 sH32N 2

O

5 [M-H]-= 441. Example 1E26. Preparation of Compound 60: N-((1R, 2R)-1-(2.3 10 dihydrobenzoL 1 1.4jdioxin-6-yl)-1 -hydroxy-3-(pyrrolidin- I -vl)nropan-2-yli-3 -(2 fluorophenoxv)propanamide Compound 60 was prepared in a similar manner as described above, following Scheme 1. N QH 0JNH 0 15 F 'H NMR (CDC1 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 21-), 4.2 (m, 7H), 4.95 (sd, 111), 6.35 (br, 111), 6.7 (s, 2H), 6.85 (s, 1l), 6.95 (m, 21-1), 7.05 (m, 2H). MZ for C 24

H

29

FN

2 0 5 (M-H]J= 445. 20 Example 1E27. Preparation of Compound 61: N-((I R, 2R)-1-(2.3 dihydrobenzo[$|[1,4]dioxin-6-yl)-1-hydroxv-3-(pyrrolidin-I-yl)propan-2-yl)-3-(4 methoxyphenoxvlropanamide WO 2009/045503 PCT/US2008/011450 - 70 Compound 61 was prepared in a similar manner as described above, following Scheme 1. NQ H 00 50 'H NMR (CDCl3, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.2 (br, 5H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.8 (m, 7H). M/Z for C2sH32N2O6 [M-H]"= 457. 10 Example 1E28. Preparation of Compound 188: N-((1R, 2R)-1-(2,3 dihydrobenzofb) (1,4dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1 -vhlpropan-2-vl)-3-(4 ethylphenoxypropanamide (2R, 3R)-2,3-dihvdroxysuccinate Compound 188 was prepared in a similar manner as described above, 15 following Scheme 1. NH- H OH 0 20 '1H NMR (D2O, 400 mHz, ppm); 0.93 (t, 3$), 1.75 (br, 2H), 1.86 (br, 2H), 2.35 (q, 2-), 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, 1 H), 6.6 (m, 51), 7.0 (d, 2H). MIZ for C 26 .%4N 2 0 5 C4JHO 6

[M

H]"= 454.

WO 2009/045503 PCT/US2008/011450 -71 Example 1E29. Preparation of Compound 189; N-((IR. 2R)-1-(2,3 dihvdrobenzo(b)(1.4dioxin-6-yl)-1-hydroxy-3-(pvrrolidin-1-yl)propan-2-yl)-3-(4 5 propionylphenoxy)propanamide (2R 3R)-2.3-dihydroxysuccinate Compound 189 was prepared in a similar manner as described above, following Scheme 1. NH QH 0 NH7 a O OH OH OH 0 0 10 'H NMR (D 2 0, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.8 (q, 211), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 61), 4.3 15 (br, 3H), 4.6 (br, 11H), 6.5 (d, I H), 6.5 (d, 2H), 6.7 (d, 2H), 7.7 (d, 2H). M/Z for C27H 34

N

2 0 6

C

4

H

6 0 6 (M-HJ = 483. Example 1E30. Preparation of Compound 193: N-((1R, 2R)-1-(2,3 dihydrobenzobl[1.4Idioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-vl)-3-(4 20 (3-oxobutyl)phenoxy)propanamide (2R, 3R)-2,3-dihydroxysuccinate Compound 193 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 72 H OH 0 OH0 OHO 0 1H NMR (D 2 0, 400 mHz, ppm); 1.75 (br, 2H4), 1,86 (br, 2H), 1.94 (s, 3H), 2.45 (br, 2H), 2.6 (m, 4H), 2.9 (br, 2H), 3.25 (m, 214), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 5 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for CUH 3 6 N20 -C4PH0o [M H]= 497. Example 1E31. Preparation of Compound 202: N-((R, R)-1-(2.3 dihydrobenzo[@Jfl [14idioxin-6-yl)-1-hydroxy-3-(pvrrolidin-1-vl)pronan-2-yl)-3-(4 10 (2-methoxyethyl)phenoxy)propanamide (2R, R)-2,3-dihydroxysuccinate Compound 202 was prepared in a similar manner as described above, following Scheme 1. NH QH -I OH OHOH OHO0 15 'H NMR (D 2 O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 211), 2.62 (t, 2H), 2.9 (br, 2H), 3.1 (s, 314), 3.25 (m, 2H), 3.4 (br, 4H), 3.9 (br, 6H), 4.3 (br, 31), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C 2 7

H

3 aN 2 06-C 4

H

6

O

6

[N-I

= 485. 20 WO 2009/045503 PCT/US2008/011450 - 73 Example 1132. Preparation of Compound 63: N-(1R, 2R)-1-(2,3 dihydrobenzorrlf 1,4ldioxin-6-yl)-1 -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-2-(3' methoxybiphenyl-4-yJ)acetamide Compound 63 was prepared in a similar manner as described above, 5 following Scheme 1. N H N O O0 H I 'OHO ON 'H NMR (CDCI, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.75 (m, 2H), 10 3.5 (br, 21), 3.9 (sd, 3H), 4.2 (m, 5H), 4.95 (sd, IH), 5.9 (br, 1H), 6.5-7.6 (m, 11H). M/Z for C 30

H

34

N

2 05 [M-H]= 503. Example 1E33. Preparation of Compound 127: N-((1R, 2R)-1-(2,3 dihvdrobenzofbl[1.4ldioxin-6-vl)-1-hydroxy-3-(pyrrolidin-1-vlipropan-2-yl)-4-(4 15 ethoxyphenyl)-4-oxobutanamide Compound 127 was prepared in a similar manner as described above, following Scheme 1. 0QH 0 20 WO 2009/045503 PCT/US200S/011450 - 74 H 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 (in, 2H), 4.25 (m, 5H), 4.95 (sd, IH), 6.05 (br, IH), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C 2 7

H

34

N

2 0 6 (M-H]-= 483. 5 Example 1E34. Preparation of Compound 154: N-((1R, 2R)-1-(2,3 dihydrobenzoh[[I,4]dioxin-6-yl}.I-hydroxy-3-(pvrrolidin- -vl)propan-2-yl).4-(4 methoxyphenyl)-4-oxobutananide Compound 154 was prepared in a similar manner as described above, following Scheme 1. 10 N QH 0 'H NMR (CDC 3 , 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, IH), 3.45 (s;3H), 3.9 (s, 3 H), 4.2 (m, 5H), 4.95 (sd, 1H), 6.05 (br, IH), 6.9 (m, 5H), 7.95 (d, 211). M/Z for C 26

H

32

N

2 0 6 [M-H] = 469. 15 Example 1E35. Preparation of Compound 181: N-((1R, 2R)-1-(2,3 dihydrobenzo bl[1,4]dioxin-6-yl)-i-hydroxy-3-(pyrrolidin-1-yllpropan-2-vl)-6-(4 isopropoxyphenyl)-6-oxohexanamide Compound 181 was prepared in a similar manner as described above, 20 following Scheme 1.

WO 2009/045503 PCT/US200/011450 - 75 QH CN 0 H 0 'H NMR (CDC1 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, lH), 6.05 (br, 1H), 6.9 (m, 5H), 5 7.95 (d, 2H). M/Z for C3 0 H4 0

N

2 0 6 [M-H) - 525. Example 1E36. Preparation of Compound 191: N-((IR. 2R)-1-(2.3 dihydrobenzorBll1,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-y)-5-(4 methoxvvhenyl)-5-oxopentanamide (2R,3R)-2,3-dihydroxysuccinate 10 Compound 191 was prepared in a similar manner as described above, following Scheme 1. NH+ OH O N H 0 OH O ,.0 15 'H NMR (D20, 400 mHz, ppm); 1.40 (br, lH), 1.53 (br, 11H), 1.75 (br, 2H), 1.91 (br, 2H), 1.98 (m, 1M), 2.15 (m, 1H) 2.45 (m, 2H), 2.95 (m, 2H), 3.35 (dd, 2H), WO 20091045503 PCT/US2008/011450 -76 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, 21), 7.63 (d, 2H). M/Z for C 27

H

3 4

N

2 0 6

C

4

H

6 0 6 [M-H] 483 Example 1 E37. Preparation of Compound 265: N-((]R, 2R)-1 5 (benzo[ r [1.31dioxol-5-yD- 1-hydroxy-3-(pyrrolidin-1-y)propan-2-yI)-5-(4 isorropoxyvhenyl)-5-oxopentanamide (2,. 3S)-2,3-dihvdroxysuccinate Compound 265 was prepared in a similar manner as described above, following Scheme 1. NH+H O IYOH 10 0 H .H NMR (400MHz, CD 3 0D) 8 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, 2), 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, 21-1), 6.66 (d, 11H), 6.82-6.95 (m, 4H), 7.84 15 (d, 2H); MS for C 2 sH 36

N

2 0 6

-C

4 H 606: [M-H] 645. Example 1E38. Preparation of Compound 267: N-((IR, 2R)-1 (benzoi[1.31dioxol-5-vl)-1-hydroxy-3-(pyrrolidin-I -yI)proPan-2-yl)-6-(4 metboxyphenyl)-6-oxohexanamide (2S, 3S)-2,3-dihydroxysuccinate 20 Compound 267 was prepared in a similar manner as described above, following Scheme 1. NH H N O OH 0 OH WO 2009/045503 PCT/US2008/011450 - 77 'H NMR (400MHz, CD 3 0D) S 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, 21-1), 4.43 (d, 1H), 4.76 (br, IH), 5.81 (s, 2H), 6.68 (d, IH), 6.81 (d, 1), 6.88 (s, iH), 6.96 (d, 2H), 7.92 (d, 2H); MS for

C

27 H3 4

N

2 0 6 gC4H 606: (M-HJ 633. 5 Example 1E39. Preparation of Compound 268: N-((1R, 2R)-1 (benzo[1[l,3ldioxol-5-yll-1-hydroxy-3-(pyrrolidin-1-ylpropan,-2-yl)-7-(4 isopropoxyphenyl)-7-oxoheptanamide (2S, 3S)-2,3-dihydroxysuccinate Compound 268 was prepared in a similar manner as described above, 10 following Scheme 1. N O 0 "OH- OH 'H NMR (400MHz, CD 3 OD) 6 1.15-1.18 (m, 2H), 1.30 (d, 6H), 1.40-1.45 15 (m, 2H), 1.57-1.65 (m, 211), 2.03 (br, 4H), 2.12-2.17 (m, 2H), 2.88 (t, 2H), 3.33-3.48 (m, 5H), 4.38 (s, 211), 4.42 (d, 1H), 4.67 (m, lH), 4.78 (d, 1H), 5.83 (d, 2H), 6.71 (d, 1H), 6.82 (d, 1ff), 6.89 (s, 114), 6.92 (d, 2H), 7.90 (d, 2H); MS for C 3 oH4oN20-C 4 H 606: [M-H) 675. 20 Example 1E40. Preparation of Compound 197: N-((lR, 2R)-1-(2,3 dihydrobenzoffilf 1,41dioxin-6-yl)-1-hydroxy-3-(Pyrrolidin-1-yl)propan-2-yl)-4-(4 methoxyvhenoxy)butanamide (2S, 3S)-2,3-dihydroxysuccinate Compound 197 was prepared in a similar manner as described above, following Scheme 1. 25 WO 2009/045503 PCT/US2008/011450 - 78 NHIH N' 0 P NHT OH tO 0 OH H NMR (400MHz, CD 3 0D) S 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), 4.11 (br, 4H), 4.37 (s, 2H), 4.41 5 (d, 1H), 4.72 (d, 1H), 6.69-6.86 (m, 7H); MS for C 26

H

34

N

2 O)CC4H 606: (M-H]f 621. Example 1E41. Preparation of Comnound 187: N-((1R. 2R)-l-(2.3 dihydrobenzoBl1.4ldioxin-6-vl)-1-hydroxy-3-(pvrrolidin-1-vlpropan-2-vfl-3-(4 (3-methylbutanoyl)lphenoxv)propanamide (2S, 3S)-2,3-dihvdroxvsuccinate 10 Compound 187 was prepared in a similar manner as described above, following Scheme 1. NH kNpO )"-OOOH O OH 'H NMR (400MHz, CD 3 0D) S 0.95 (d, 6H), 2.00 (br, 4H), 2.17 (m, 2H), 15 2.66 (t, 2H), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40 (s, 21), 4,45 (d, IH), 4.73 (sd, 1H), 6.67 (d, 1I), 6.79 (d, 1H), 6.86 (s, 11), 6.93 (d, 2H), 7.91 (d, 2H); MS for C 29

H

3 sN 2 0 6 C4H 606: [M-H]- 661. Example 1E42. Preparation of Compound 83: 2-(4-chlorophenoxy).N-((lR,2R)-1 20 (2.3-dihydrobenzofBlE14]_dioxin-6-yl)-1-hydroxy-3-(pyrrolidin--y1-)propan-2 yl)acetamide Compound 83 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 79 OyrNH 0~ ci 'H NMR (400MHz, CDCl 3 ) 8 1.76 (br, 4H), 2.63 (br, 4H), 2.78 (dd, IH), 5 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, IH), 7.24 (s, 1H); MS for C 23

H

27

CN

2 0 5 : (M-H]- 447. Example 1E43. Preparation of Compound 87: 2-(3,4-dichlorophenoxy)-N-((lR,2R) 1-(2.3-dihydrobenzo[fl]1,4]dioxin-6-yl)-1 -hydroxy-3-(pyrrolidin-1-yl)propan-2 10 vl)acetamide Compound 87 was prepared in a similar manner as described above, following Scheme 1. N H N

O

1 H 15 CI 'H NMR (400MHz, CDCh3) 8 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd, IH), 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 C2H 2 6 Cl 2

N

2 Os: [M-H] 482. 20 TVW Uavv;'IV v.YU.Y r%.1/U L4UU/U l143U - 80 Example 1E44. Preparation of Coimpound 86: N-(iR,L2R)-l-(2,3 dihydrobenzofblri.41dioxin-6.yl)-1-hydroxy-3-(pvrrolidin-1-yl)propan-2-yl)-2-(3 phenoxVphenyl)acetamide Compound 86 was prepared in a similar manner as described above, 5 following Scheme 1. N H 'H NMR (400MHz, CDC 3 ) 8 1.72 (br, 41), 2.57 (br, 4H), 2.75-2.80 (m, 10 2H), 3.45 (s. 2H), 4.11-4.13 (m, 111), 4.23 (s, 4H), 4.84 (d, 1M), 5.86 (d, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.74 (d, 111), 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 0 5 : (M-H]- 489. Example 1E45. Preparation of Compound 280: 2-(3,4-difluorophenyl)-N-((IR,2R) 15 1-(2.,3-dihydrobenzo1 [1.41dioxin-6-yl-1-hydroxy-3-(pyrrolidin-1-vl)propan-2 yI)acetamide Compound 280 was prepared in a similar manner as described above, following Scheme 1. H N FHo F 20 20( WO 20091045503 PCT/US2008/011450 - 81 - 'H NMR (400MHz, CDCI,) 8 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, TH), 5.88 (d, 1H), 6.65 (d, IH), 6.79 (d, iH), 6.95 (m, 1), 6.95 (t, iH), 7.13 (q, IHi); MS for C23H 26

F

2

N

2

O

4 : [M-H]- 434. 5 Example 1E46. Preparation of Compound 103: N-((R,2R)-1 -(2,3 dihvdrobenzoFp1[1,4 dioxin-6-yl)- 1-hydroxy-3-(pyrrolidin-1-yl propan-2-yl)-2-(4 (trifluoromethoxv)phenvl)acetamide Compound 103 was prepared in a similar manner as described above, following Scheme 1. 10 Q H NY OO% F 'H NMR (400MHz, CDC1 3 ) 8 1.65 ( br, 4H), 2.48 (br, 4H), 2.69 (d, 2H), 3.40 (s, 2H), 4.08 (m, iH), 4.17 (s, 4H), 4.80 (s, iH), 5.84 (t, 1H), 6.55 (d, 1H), 6.66 15 (s, 1H), 6.70 (d, IH), 7.10 (t, 3H); MS for C 24

H

27

F

3

N

2 0 5 : (M-H}- 481. Example 1E47. Preparation of Compound 90: N-((IR,2R)-1 -(23 dihydrobenzo f [1,4ldioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-y)-5 (thiophen-2-yl)isoxazole-3-carboxamide 20 Compound 90 was prepared in a similar manner as described above, following Scheme 1. N H N' N WO 2009/045503 PCT/US2008/011450 - 82 'H NMR (400MHz, CDCl 3 ) 6 1.82 (br, 4H), 2.73-2.81 (m, 4H), 2.89-2.93 (m, 1 H), 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, 5 1H); MS for C23H 25

N

3 0 5 S: [M-H]" 456. Example IE48. Preparation of Compound 92: 3-(3-chloro-4-methoxyphenyl)-N ((1R,2R)-1 -(2,3-dihydrobenzoll1,4ldioxin-6-yl)-1-hydroxy-3-(pvrrolidin-1 yl)propan-2-vlo)roPanamide 10 - Compound 92 was prepared in a similar manner as described above, following Scheme 1. N H O I 15 'H NMR (400MHz, CDC 3 ) S 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 2 sH 31 ClN 2 0 5 : [M-H]^ 475. Example 1E49. Preparation of Compound 96: N-((R,2R)-1-(2.3 20 dihydrobenzofp)(1.4)dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1 -yl)propan.2-yi)-3-(4 (trifluoromethyl)phenvl)propanamide Compound 96 was prepared in a similar manner as described above, following Scheme 1. 25 WO 2009/045503 PCT/US2008/011450 - 83 / 7 F F HF Nr 'H NMR (400MHz, CDCl 3 ) & 1;73 (br, 4H), 2.4 (m, 2M), 2.53 (m, 4H), 2.7 (ni, 2W-), 2.90-2.97 (m, 2H), 4.17 (br, 1H), 4.23 (s, 4H), 4.89 (s, 1H), 5.83 (br, 1H), 5 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 0s: [M-H] 479. Example 1 E50. Preparation of Compound 101: 4-(benzo[d]thiazol-2-yl)-N ((1R,2R-1-(2,3-dihydrobenzopl[1.41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin- I 10 yl)propan-2-yl)butanamide Compound 101 was prepared in a similar manner as described above, following Scheme 1. 0 NH : 15 'H NMR (400MHz, CDC 3 ) 5 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, iH), 6.12 (br, 1H), 6.75-6.81 (m, 2H), 6.86 (s, 1H), 7.37 (t, 1H), 7.45 20 (t, 1H), 7.85 (d, IH), 7.92 (d, 1H); MS for C 26

H

31

N

3 0 4 S: (M-]- 482.

WO 2009/045503 PCT/US2008/011450 - 84 Example IES1. Preparation of Compound 102: N-((I R,2R)-1-(2,3 dihydrobenzo[lrl .4ldioxin-6-vl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-vl)-6-(2,3 dihydrobenzol]r1,4ldioxine-6-sulfonamido)hexanamide Compound 102 was prepared in a similar manner as described above, 5 following Scheme 1. 2 HN) o HO -NH 'H NMR (400MHz, CDC 3 ) 8 1.15-1.20 (in, 2H), 1.38-1.50 (m, 4H), 1.77 10 (br, 4H), 2.08 (q, 2H), 2.63-2.66 (m, 4H), 2.79 (d, 21H), 2,87 (t, 2H), 4.2 (m, 9H), 4.91 (br, 1H), 5.93 (br, 1H), 6.77 (q, 21H), 6.84 (s, 1H), 6.93 (d, IH), 7.31 (d, 1H), 7.37 (s, 1H); MS for C 29

H

39

N

3 0 9 S: [M-H]' 590. Example 1E52. Preparation of Compound 104: N-(5-((1R,2R)-1-(2,3 15 dihydrobenzojp[i1,4]dioxin-6-yl)-I -hydroxy-3 -(pyrrolidin- I -yl)propan-2-ylanino) 5-oxopentyl)benzamide Compound 104 was prepared in a similar manner as described above, following Scheme 1.

WO 2009/045503 PCT/US2008/011450 - 85 00 HN50 'H NMR (400MHz, CDC 3 ) 8 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), 5 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 CzH35NaOs: [M-H]' 482. Example 1E53. Preparation of Compound 281: N1-((lR,2R)-1-(2,3 dihydrobenzoFBl[1.4Idioxin-6-vl)-1-hydroxy-3-f'uvrrolidin-1 -vIl)vrouan-2-yl)-N5 10 (thiazol-2-yl)glutaramide Compound 281 was prepared in a similar manner as described above, following Scheme 1. N H H N -, N N 0O <0 15 'H NMR (400MHz, CDC1 3 ) 5 1.74 (br, 4H), 1.97-2.03 (m, 2H), 2.20-2.26 (m, 2H), 2.40-2.45 (in, 2H), 2.64-2.68 (in, 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 2 3H 30

N

4 0 5 S: [M-H]^ 475. 20 WO 2009/045503 PCT/US2008/011450 - 86 Example 1E54. Preparation of Compound 282: N-((1R,2R)-I-(2,3 dihvdrobenzo[11,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-I-yI)propan-2-yl)-5-(3,4 dimethoxyphenyl)-5-oxopentanamide Compound 282 was prepared in a similar manner as described above, 5 following Scheme 1, OH *~0 'H NMR (400MHz, CDCl 3 ) 8 1.76 (br, 4H), 1.92-2.00 (m, 2H), 2.21-2.26 10 (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, 1IH), 6.75-6.79 (m, 2H), 6.85 (s, 1H4), 6.87 (d, 1H), 7.50 (s, IH), 7.55 (d, IH); MS for C 2

H

36

N

2 0 7 : [M-H]" 513. Example 13 55. Preparation of Compound 283: N-((I1R,2R)-1-(2,3 15 dihydrobenzo bl[1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-y)-5-oxo 5-p-tolylpentananide Compound 283 was prepared in a similar manner as described above, following Scheme 1.

rL" L/U2UU5/U1i4.5U - 87 NOH 00 0 NH 0 'H NMR (400MHz, CDCI 3 ) 5 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 5 (d, 1H), 5.94 (br, 1H), 6.74-6.77 (m, 2H), 6.85 (s, 1H), 7.26 (d, 211), 7.81 (d, 2H); MS for C 27

H

34

N

2 0 5 : [M-HJ- 467. Example 1E56. Preparation of Compound 113: N-(( R,2R)-1-(2,3 dihydrobenzo[Blfl,4Ldioxin-6-yl)-I-hydroxy-3-(pyrolidin-I1-vl)propan-2-vl)-5-oxo 10 5-phenylpentanamide Compound 113 was prepared in a similar manner as described above, following Scheme 1. NH N r 110o 0 15 'H NMR (400MHz, CDCl 3 ) S 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, 11H), 7.44-7.58 (m, 3H), 7.92 (d, 2H); MS for

C

26

H

32

N

2 0 5 : [M-H]^ 453. 20 WO 2009/045503 PCTUS200/011450 -88 Example 1E57. Preparation of Compound 284: N-((1R,2R)-1-(2,3 dihydrobenzofl .1.,4ldioxin-6yl- 1 -hydroxy-3-(pyrrolidin- I -ylpropan-2-yl)-5-.(4 isopropoxyphenyl)-5-oxpentanamide Compound 284 was prepared in a similar manner as described above, 5 following Scheme 1. N 'H NMR (400MHz, CDCl3) 6 1.36 (d, 6H), 1.75 (br, 4H), 1.90-2.02 (m, 10 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, I H), 6.87 (d, 2H), 7.86 (d, 2H); MS for C 29

H

3

N

2

O

6 : (M-H]" 511. Example E58. Preparation of Compound 140: N-((iR,2R)-1-(2.3 15 dihydrobenzof l14ldioxin-6-yl)-1-hydroxy-3-(orolidin-l-yI)pro an-2-yl)-6-(4 methoxy-3,5-dimethylphenyl)-6-oxohexananide Compound 140 was prepared in a similar manner as described above, following Scheme 1. ""OH 0 20 'H NMR (400MHz, CDC1 3 ) 8 1.61-1.63 (m, 4H), 1.77 (br, 4H), 2.16 (t, 211), 2.32 (s, 6M), 2.61-2.67 (m, 4H), 2.74-2.89 (m, 21H), 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

4

GN

2 0 6 : [M-H]^ 525. 25 WO 2009/045503 PCT/US2008/011450 - 89 Example 1E59. Preparation of Compound 141: N-((lR,2R)-l-(2,3 dihydrobenzo(fJ( 1.4)dioxin-6-yl)-1 -hydroxy-3-(vyrrolidin-I -yl)propan-2-yl)-6-(4 methoxyphenyl)-6-oxohexanamide Compound 141 was prepared in a similar manner as described above, 5 following Scheme 1. H 'H NMR (400MHz, CDCl 3 ) 8 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 10 (d, 1H), 6.01 (br, 111), 6.77 (q, 2H), 6.85 (s,1H), 6.91 (d, 2H), 7.90 (d, 2H); MS for q 28 H3 6

N

2 06: [M-1] 497. Example 1,E60. Preparation of Compound 155: 6-(4-tert-butvlphenyl)-N-((1R,2R)-+ 1-(2,3-dihydrobenzoELl14]Adioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)p1ropan-2-yl 15 6-oxohexanamide Compound 155 was prepared in a similar manner as described above, following Scheme 1. QH N 200 20 'H NMR (400MHz, CDCI3) 8 1.34 (s, 9$), 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, 1-), 2.91 (t, 2H), 4.20 (br, SH), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 2H), 6.85 (d, 1H), 7.46 (d, 211), 7.86 (d, 2H); MS for C 31 H42N 2

O

5 : [M-H]f 523.

WO 2009/045503 PCT/0S2008/011450 -90 Example I E61. Preparation of Compound 156: N-((IR,2R)-1-(2,3 dihydrobenzo[BI I .4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-I-yl)vropan-2-vl)-7-(4 methoxyphenyl)-7-oxoheptanamide 5 Compound 156 was prepared in a similar manner as described above, following Scheme 1. N 'too 'H NMR (400MHz, CDCl,) 8 1.25-1.30 (m. 2H), 1.55-1.70 (m, 4H), 1.77 10 (br, 4H), 2.13 (t, 2H), 2.61-2.66 (in, 4H), 2.74- 2.82 (m, 2H), 2.88 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.90 (d, IH), 5.93 (br, IH), 6.78 (q, 2H), 6.85 (s, I H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C29-1SN206: [M-H] 511. Example 1E62. Preparation of Compound 144: N-((1R.2R)-1-(2.3 15 dihydrobenzo[ )C1.41dioxin-6-yI)- 1 -hydroxy-3-(pyrrolidin- 1 -yl)ropan-2-vl)-8-(4 methoxyphenyl)-8-oxooctanamide Compound 144 was prepared in a similar manner as described above, following Scheme 1. 20 'H NMR (400MHz, CDCb3) 6 1.25-1.33 (m, 4H), 1.54 (m, 21-1), 1.68 (t, 21-1), 1.78 (br, 4H), 2.11 (br, 2H), 2.65 (br, 4H), 2.76-2.11 (m, 4H), 3.86 (s, 3H), 4.21 (br, 5H), 4.90 (br, 1H), 6.02 (d, 14), 6.78-6.84 (m, 3H), 6.91 (d, 2H), 7.92 (d, 2H); MS 25 for C 3 oH14oN2O 6 : [M-H)- 525.

WO 2009/045503 PCT/US2008/011450 -91 Example 1E63. Preparation of Compound 159: 7-(4-chlorophenyl)-N-((lR,2R)-I (2,3-dihydrobenzorpl (1,4]dioxin-6-yl)- 1 -hydroxy-3-(pyrrolidin- 1 -vllpropan-2-yl)-7 oxoheptanamide 5 Compound 159 was prepared in a similar manner as described above, following Scheme 1. 'H NMR (400MHz, CDCl 3 ) 3 1.26-1.37 (m, 2H), 1.57 (m, 2H), 1.68 (in, 10 2H), 1.77 (br, 4H), 2.13 (t, 2H), 2.62-2.65 (m, 4H), 2.76-2.82 (m, 21), 2.90 (t, 2H), 4.20 (br, 5H), 4.90 (d, 11H), 5.93 (d, 111), 6.78 (q, 2H), 6.85 (s, 1H), 7.42 (d, 2H), 7.87 (d, 2H); MS for C 2 sH 3 s C1N 2 0s: [M-H]- 515. Example IE64. Preparation ofiComjpound 160: 7-(4-tert-butylphenyl)-N-((1R,2R) 15 1-(2.3-dihydrobenzopl[1, 4ldioxin-6-y)-I -hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl) 7-oxoheptanamide Compound 160 was prepared in a similar manner as described above, following Scheme 1. NH N Y . 20 'H NMR (400MHz, CDCl 3 ) 5 1.27-1.34 (n, I 1H), 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, 2$), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (sd, 1H), 5.90 (d, 1H), 6.81 (q, 2), 6.85 (s, 111), 7.46 (d, 2H), 7.88 (d, 2H); MS for C 32

HN

2 0s: [M-H]" 537.

WJ LUU'JU433U.3 FUT/ U2U0/01145U -92 Example 1E65. Preparation of Compound 168: N-((IR,2R)-1-(2.3 dihvdrobenzorbl [ 1,41dioxin-6-yl)- 1 -hydroxy-3-(pvrrolidin- I -yl)propan-2-vl)-7-(4 methoxyphenyl)-7-oxoheptanamide (2S,3S)-2,3-dihydroxysuccinate 5 Compound 168 was prepared in a similar manner as described above, following Scheme 1. NH+ H O OH 'H NMR (400MHz, CD 3 OD) 8 1.15-1.19 (m, 2H), 1.40-1.47 (m, 2H), 1.60 10 (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, 3-), 4.12 (br, 4H), 4.38 (s, 2H), 4.43 (m, 1H), 4.74 (sd, 1 H), 6.71 (d, 1H), 6.79 (dq, 1H), 6.86 (sd, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C 29 H1,NZ0 6

C

4 H 606: (M-HJ 661. 15 Example 1E66. Preparation of Compound 162: N-((1R,2R)-1-(2,3 dihydrobenzorflf 1.4ldioxin-6-vl)-1-hydroxy-3-(pyrrolidin-1-vl)propan-2-yl)-4-(4 isopropoxyphenyl)-4-oxobutanamide Compound 162 was prepared in a similar manner as described above, following Scheme 1. 20 H

N

NOR H NMR (400MHz, CDC] 3 ) 5 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, 1M), 4.89 (sd, WO 2009/045503 PCT/TS2008/011450 - 93 1H), 6.13 (d, IH), 6.78 (s, 2H), 6.88 (t, 3H), 7.90 (d, 2H); MS for C 28

H

36

N

2 0 6 : (M H]- 497. Example IE67. Preparation of Compound 176: N-((] R.2R)-1-(2,3 5 dihydrobenzofil[1,4]dioxin-6-yl)-I-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-oxo 4-(4-(trifluoramethyl)phenyl)butanamide (2,S,3S)-2,3-,dihydroxysuccinate Compound 176 was prepared in a similar manner as described above, following Scheme 1. N F .. F, 0 OH 10 'H NMR (400MHz, CD 3 0D) 8 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, 1fH), 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 0 5 - C 4 H 606: [M-H] 657. 15 Example 1E68. Preparation of Compound 65 (Genz-528152-1): 2-(3' chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzop131f,4ldioxin-6-vl)-1 hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl)acetarnide Compound 65 was prepared in a similar manner as described above, 20 following Scheme 1. QHy

CI

WV 20UU0U455U5 PCTUS2008/011450 -94 'H NMR (400MHz, CDCl 3 ) 6 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, I), 7.19 (d, IH), 7.32-7.34 (m, IH), 7.38 (t, 1H), 7.46-7.49 (m, 1H), 7.52 (d, 2H), 7.59 (d, 1H); C 29

H

3 1 C1N 2 0 4 : (M-H]^ 507. 5 Example I E69. Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy phenvl)-1-pyrrolidin-1-ylmethyl-ethyll-3-(4-methoxy-phenoxy)-propionamide Compound 262 was prepared in a similar manner as described above, following Scheme 2. 10 OH 0 '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, I), 6.8 (m, 411), 7.25 (m, 4H). M/Z for C 24 H32N 2 0 5 [M-H]* 429 15 Example 1E70. Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo pentanoic acid (2-hydroxy-244-methoxv-phenyl)- 1 -pyrrolidin- I -ylmethyl ethyl) amide Compound 270 was prepared in a similar manner as described above, 20 following Scheme 2.

WO 2009/045503 PCT/US2008/011450 - 95 OH NN O 0 OJI 'R NMR (CDC 3 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 21H), 2.2 (m, 2H), 2.6 (m, 4M), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 5 1H), 5.95 (br. d, IH), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C 2 4H 32

N

2 0 5 (M-H]' 483.3 Example 1E71. Preparation of ompound 285: 7-(4-Methoxy-phenvl)-7-oxo heptanoic acid 2-hydroxy2-.(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyll 10 amide Compound 285 was prepared in a similar manner as described above, following Scheme 2. OH N 0 0 e 15 'H NMR (CDC 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, 211), 7.95 (d, 2H). M/Z for C 24 H32N 2 0 5 [M-H]* 483.3 WO 2009/045503 PCT/US2008/011450 -96 Example I E72. Preparation of Compound 262: N-r2-Hlydroxy-2-(4-methoxy phenyl)--pyrrolidin-1-vimethyl-ethyll-3-(4-methoxy-phenoxy-propionaide Compound 262 was prepared in a similar manner as described above, 5 following Scheme 2. N N OH 00 'H NMR (CDCl 3 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H), 10 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 2 4 H3 2

N

2 0 5 (M-14"' 429 Example 1E73. Preparation of Cormound 270: 5-(4-Isopropoxy-phenyl)-5-oxo pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)- 1 -pyrrolid in- -vimethyl 15 ethyll aide Compound 270 was prepared in a similar manner as described above, following Scheme 2.

WO 2009/045503 PCT/JS2008/011450 - 97 OH N OI 0 o '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, IH), 5.0 (d, 5 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). M/Z for C2 4 H3N20s [M-H]* 483.3 Example 11E74. Preparation of Compound 305 Compound 305 characterized by the following structural formula was 10 prepared in a similar manner as described above, following Scheme 2. OH Q0 N NH 0 WU 2UU'/U4::u.3 FCI/US2008/011450 - 98 'H NMR (CIC1 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 2 4

H

32

N

2 05 [M-H]* 538 5 Example 1E75. Preparation of Compound 320: Octanoic acid [2-hydroxy-2(4 methoxy-phenyl)-l-Pyrrolidinl-ylmethyl-ethyll-amide Compound 320 characterized by the following structural formula was prepared in a similar manner as described above, following Scheme 2. OH 0 0 10 'H NMR (CDCl 3 400 mHz, ppm); 0.9 (t, 31H), 1.2 (m, SH), 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, I H), 6.9 (2s, 2H), 7.25 (m, 211). MIZ for C22H 3 6N 2

O

3 [M-H]* 377.4 15 Example 1E76. Preparation of Cyclic Amide Analogs

K

2 00 3 , OH glycerol, + R' CN 1150C 00 R (Scheme 6) 20 Cyclic amide analogs were prepared according to Scheme 6. 2-Amino-1 (2,3-dihydro-benzo[1,4) dioxin-6-yl)-3-pyrrolidin-1-yI-propan-1-ol was prepared WO 2009/045503 PCT/US2008/011450 - 99 according to the preparation of intermediate 4 of US patent 6,855,830 82. This amine was coupled with various nitriles in potassium carbonate and glycerol, under an atmosphere of nitrogen, for example, at I15C for 18 hours. Compound 323 characterized by the following structural formula was prepared by following Scheme 5 6. Compound 323 was purified by column chromatography using a mixture of methanol and methylene chloride. 0'>) 0 N 0 10 'H NMR (CDCl 3 400 mHz, ppm); 0.95 (t, 3H), 1.35 (m, 211), 1.6 (in, 2H), 1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (m, 5H), 5.4 (d, lH), 6.85 (m, 3H), 7.2 (m, 2H), 7.9 (d, 2H). M/Z for C24H32N 2 Os [M-H] 421.54 Example 2. Synthesis of Ceramide Derivatives: Preparation of Carbamate 15 Analogs Example 2A1. Preparation of (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3 carboxylate WO 2009/045503 PCT/US2008/011450 - 100.

N I o o NO Steps 1-2: preparation of (R)-benzyl 4-(nethoxy(methyl)carbamoyl)-2,2 dimethyloxazolidine-3-carboxylate: N,0-dimethylhydroxylamine hydrochloride (45 5 g, 0.46 mmol, 1.5 eq) and N-methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly toa cold (-15 *C ) suspension of d-CBz serine (73.0 g, 0.305 mol) in

CH

2 Cl 2 (560 nL) 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 10 by rotary evaporation and the mixture was partitioned between HC1 (1 M, 300 mL)and EtOAc (500 mL).The organic layer was separated and washed with 1C (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 15 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 20 from both steps) after purification by column chromatography using a mixture of hexane/EtOAc/acetone. 'H NMR (CDC 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 (i, 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, I H), 7.4 (m, 25 8 H).

WO 2009/045503 PCT/US2008/011450 - 101' Step 3: preparation of (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3 carboxylate: 0 H 0 N O . 5 ~ A solution of LiALH4 (1 M, 20 nL, 20 nmol) 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 10 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 (Si02, using a mixture of 15 hexane/EtOAc). 'H NMR (CDC 3 , 400 mHz, ppm); 1.7 (m, 6 H), 4.15 (m, 2H), 4.4 (m,I 1H), 5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 114). Example 2A2. Preparation of (R)-benzyl 4-((R)-hydroxv(4-methoxyphenvl)methyl) 2,2-dimethyloxazolidine-3-carboxylate 20 0 -0 N0 Cry\4 O

H

WO 2009/045503 PCT/US2008/011450 - 102 1,2-dibromoethane (0.2 mL) was added slowly to a hot (65 *C) solution of magnesium turnings (0.91 g, 37 mrnmol) in THF (14 m), 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 5 grignard solution was added dropwise to a suspension of CuI (6.8 g, 36 mmol) in a mixture of Me 2 S (20 mL)/tIHF (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 J(3.20 g, 12.6 10 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 NH4Cl (sat. 100 mL) and extracted with EtOAc (50 mL). The solvent was removed to dryness and the mixture was purified by column chromatography (SiO2, using a mixture of hexane/EtOAc/acetone)and the product was obtained as a 15 colorless oil (1.697 g, 36 % yield). Example 2A3. Preparation of benzvl (1R 2R)-1,3-dihydroxy-1-(4 methoxyphenvl)propan-2-ylcarbamate 0 206 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 WO 2009/045503 PCT/US2008/011450 - 103 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 CHzCI 2 /EtOAc) the product was obtained as a white solid (1.26 g, 84 % 5 yield). 10 Example 2A4. Synthesis of Compound 289: benzvl (1R 2R)-1-hydroxy-1-(4 methoxvhenvl)-3-(vrrolidin-1-vllpropan-2-ylcarbamate CN OH HNyQ 15 Mesityl chloride (0.28 mL, 3.6 rnmol) was added slowly to a cold (-10 "C) solution of benzyl (1 R, 2R)- 1,3 -dihydroxy- 1-(4-methoxyphenyl)propan-2 ylcarbamate (1.97 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 20 dryness. After purification by column chromatography (SiO 2 , using a mixture of

CH

2 Cl 2 , MeOH, NH40H), the product was obtained as a clear oil (0.8 16 g, 66 % yield). Example 3: Synthesis of Ceramide Derivatives: General Procedures for the 25 Synthesis of Urea Analogs WO 2009/045503 PCT/US2008/011450 - 104 OH QH + 0==N-R 4

-"

N H 2 NH H, 0 = NH OI NH R4 (Scheme 5) (IR, 2R)-2-amino-(2,3-dihydrobenzo [p][,4[dioxin-6-yl)-3-(pyrrolidin-1-yl) 5 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), was dissolved in methylene chloride and activated 5 A molecular sieves were added to the solution, followed by addition of the particular isocyanate (R 4 NO). Reaction times varied depending on the isocyanate substitution from one to twelve hours. 10 Compounds 6, 7, 10, 17, 40, 41, 42, 43, 68, 69, 70, 71, 80, 51, 82, 133, 257, 261, 286 and 287, shown in Examples 3A1 - 3A21 below, were prepared following reaction Scheme 5. The compounds were purified by column chromatography. Example 3AL. Preparation of Compound 6: 1-benzyl-3-((R,2R)-1-(2,3 15 dihydrobenzofalF,41dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yJlpropan-2-yl)urea N CC "OH 0 'H NMR (400 MHz, CDCl 3 ) 8= 1.7 (s, 4H), 2.4-2.6 (m, 5H), 2.6-2.7 (dd, 20 1H), 4.0 (m, IH), 4.2 (s, 4H), 4.3 (m, 2$), 4.8 (d, IH), 4.86 (d, IH), 5.0 (br, IlH), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5 H); MS for C 23 H2 9 N30 4 m/z 412.2 [M+HJ WO 2009/045503 PCT/US200/011450 - 105 5 Example 3A2. Preparation of Compound 17: 1-((1R, 2R)-1-(2,3 dihydrobenzoj B[1 ,4ldioxin-6-yl)-1 -hydroxy-3-(pvrrolidin- 1 -yll)ropan-2-yl)-3-(4 fluorobenzyl)urea N H HN 10 'H NMR (400 MHz, CDC13) S= 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (m, lIH), 4.0-4.1 (m, 2H), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, iH), 6.6-7.1 (m, 7H); MS for

C

23 H2 8

FN

3 0 4 n/z 430.2 [M+H]. Example 3A3. Preparation of Compound 40: 1-(4-bromobenzyl)-3-((R, 2R)-1-(2,3 15 dihydlrobenz[$][),4|dioxin-6-yl)- -hydroxy-3-(pyrrolidin-1-yl)prropan-2-vl)urea N H N 0 Br HN OO 'H NMR (400 MHz, CDC1 3 ) S= 1.7 (s, 4H), 2.4-2.8 (m, 6H), 4.0 (m, I H), 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, 20 3H), 7.0 (d, 2H), 7.4 (d, 2H); MS for C23HUBrN 3 0 4 m/z 490 [M], 491 [M+H], 492 [M+2].

WO 2009/045503 PCT/US2008/011450 - 106 Example 3A4. Preparation of Compound 41: 1-((R. 2R)--(2,3 dihydrobenzo[lfl,4jdioxin-6-yl)-I -hydroxy-3-(pyrrolidin- 1 -yl)propan-2-yl)-3-(4 5 methoxybenzyllurea N H ON 0 0O :0 HN . OH 'H NMR (400 MHz, CDC1 3 ) 8- 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3,9 (m, IH), 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 10 (m, SH), 7.1 (d, 2H); MS for C 24 H3 1

N

3 0 5 m/z 442.2 [M+H] Example 3A5. Preparation of Compound 80: 1-((1R, 2R)-1-(2,3 dihydrobenzorl1l,41dioxin-6-vl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yI)-3-(3 methoxybenzyl)urea Q HO N O OH 15 0 'H NMR (400 MHz, CDCl 3 ) 8= 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

3 1 N30 5 m/z 442.2 [M+H] 20 WO 2009/045503 PCT/US2008/011450 -107 Exampl 3A6. Preparation of Compound 42: 1-((1R, 2R)-1-(2,3 dihydrobenzofll,41dioxin-6-yl)-1-hydrox-3-(pyrrolidin-1-yl)pronan-2-yl)-3-(4 methylbenzyl)urea N H O .. N O HN 5 IO 'H NMR (400 MHz, CDCl 3 ) 8- 1.6 (s, 4H), 2.3 (s, 3H), 2.4-2.6 (m, 6H), 4.0 (I, 1H), 4.2 (d, 2H), 4.21 (s, 4H), 4.7 (d, 1H), 5.2 (d, IH), 5.4-5.6 (br, IH), 6.7-7.1 (m, 7H); MS (for CuH3jN304 m/z 426.2 [M+H] 10 Example 3A7. Preparation of Compound 43: 1-(4-chlorobenzyl)-3-((1R. 2R)-1-(2,3 dihvdrobenzof1 ,4ldioxin-6-yl)-l-hydroxy-3-(pyrrolidin-L-yl)propan-2-llurea N H 15 OH 15 'H NMR (400 MHz, CDC 3 ) 8= 1.7 (s, 4H), 2.5-2.7 (m, 611), 4.0 (m, I H), 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 C23H2SN3CO4 m/z 446 (M+HJ, 447.5 [M+2]. 20 Example 3A8. Preparation of Compound 10: 1-((1R, 2R)-I-(2,3 dihydrobenzor]f[1,4)dioxin-6-y)-1-hydroxy-3-(pvrrolidin-,1-yl)propan-2-yI)-3-((S) I -phenylethyl urea VWUt IJU'JU43YU3 a. I/ULUUWUI143UJ - 108 N H CO -HN OH 'H NMR (400 MHz, CDCI) 8= 1.4 (d, 3H), 1.6 (s, 4H), 2.2-2.5 (m, 4H), 2.5 5 (dd, 1H4), 2.6 (dd, 1H), 3.9 (m, 1Hl), 4.2 (s, 4H), 4.5 (m, 1H), 4.8 (d, 1f), 5.0 (d, 1H), 5.1-5.3 (br, 1I), 6.6-6.9 (m, 31-), 7.2-7.4 (m, 5H); MS for C24H 3

N

3 04 m/z 426.2 (M+H]. Example 3A9. Preparation of Compound 286: l-((R, R)-1-(2,3 10 dihydrobenzo[pl(1,4Ldioxin-6-l-hydroxy-3-(pyrrolidin-1..yl)propan-2-yl)-3-((R) 1-phenylethvl)urea H N 0 15 'H NMR (400 MHz, CDC 3 ) 8= 1.3 (d, 3H), 1.7 (s, 4H), 2.2-2.6 (m, 6H), 3.9 (m, 1IH), 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 C24H3N30 4 m/z 426.0 (M+H]. Example 3A10. Preparation of Compound 69: 1-((R. 2R)-1-(2,3 20 dihydrobenzofBlfl.4]dioxin-6-yl)-1-hydroxy-3-(pvrrolidin- I -vInropan-2-y)-3 (naphthalen-2-yl)urea WO 2009/045503 PCT/US2008/011450 -109 H N 0 'H NMR (400 MHz, CDC1 3 ) 8= 1.6 (s, 4H), 2.4-2.8 (m, 6H), 4.1 (s, 5$), 4.8 5 (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

2 9

N

3 04 m/z 448.1 [M+H). Example 3A I1. Preparation of Compound 288: 1-((1R. 2R)-1-(2,3 dibydrobenzo l[ l.41dioxin-6-vl)-1-hydroxy-3-(pvrrolidin-1-vilpropan-2-vl)-3 10 (naphthalen- 1 -vl)urea NH H N O O -s,,HN 'H NMR (400 MHz, CDC1 3 ) 8= 1.6 (s, 4H), 2.4 (s, 4H), 2.6 (d, 2H), 4.1 (m, 15 1H), 4.2 (s, 4H), 4.8 (d, IH), 5.4 (d, 1H), 6.5 (d, 1H), 6.6 (d, IH), 6.7 (s, IH), 7.2-7.6 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.0 (d, IH); MS for C 2 6H 29

N

3 0 4 m/z 448.1 [M+H]. Example 3A12. Preparation of Compound 71: I-((1R. 2R)-1-(2,3 dihydrobenzo|fff I |,4]dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- I -ylpropan-2-yl)-3-((S) 20 1 -(naphthalen- 1 -vl)ethyl)urea WO 2009/045503 PCT/US2008/011450 -110 N H N 0 HN O"H 'H NMR (400 MHz, CDCla) 8= 1.4 (s, 4H), 1.5 (d, 3H), 2.3 (s, 4H), 2.4 (dd, I1), 2.6 (dd, 1H), 3.9 (br, IH), 4.2 (s, 4H), 4.7 (s, IH), 5.0 (d, IH), 5.3 (br, 1H), 5.5 5 (br, 1H), 6.6 (m, 3H), 7.4-7.6 (m, 4W), 7.7 (d, 1H), 7.8 (d, IH), 8.1 (d, iH); MS for CnH33N3O4 m/z 476.2 [M+H]. Example 3A13. Preparation of Comound 70: -l.(biphenyl-4-yl)-3-((IR, 2R)-1-(2,3 dihydrobenzorplL,41dioxin-6-yI .1-hydroxy-34pyrrolidin-1-yllpropan-2-yllurea N H N N 10 C 8 3 N0 nz441 c >O 'H NMR (400 MHz, CDCI,) 8= 1.7 (s, 4H), 2.6-2.8 (m, 6H), 4.1 (br, IH), 4.2 (s, 4H), 4.9 (br, IH), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 11H), 7.2-7.6 (m, 9H); for C2HjN304 m/z 474.1 [M+H. 15 Example 3A14. Preparation of Compound 81: 1-((1R. 2R)-1-(2.3 dihvdrobenzo(B1.4dioxin-6-yl-1-hydroxy-3-(prrolidin-1-yl)propan-2-yl)-3-(4 (trifluoromethyl)phenyl)urea WO 20091045503 PCT/JS2008/011450 -111 N H -N O . HN f~i OH F F 'H NMR (400 MHz, CDC1 3 ) 8= 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, 5 2H); MS for C23H2 6

F

3

N

3

O

4 m/z 465.97 [M+HJ. Example 3A15,. Preparation of Compound 68: 1-((1R, 2R)-1-(2,3 dihydrobenzoF lf l.41dioxin-6-yfl-I -hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3 (tifluoromethyl)phenyl)urea 10 H N 0 N O F HN "'bH F 'H NMR (400 MHz, CDCl 3 ) S= 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 15 for C23H 26

F

3

N

2 0 4 m/z 466.0 [M+H]. Example 3A16. Preparation of Compound 82: 1-(f IR, 2R)-1-(2,3 dihydrobenzofBl F 1.41dioxin-6-yl)- 1 -hydroxy-3-(nvrrolidin- 1 -ylpropan-2-yl)-3 -(4 (trifluoromethoxy)phenyl)urea 20 WO 2009/045503 PCT/US2008/011450 - 112 N H N

-.

, HN F 'H NMR (400 MHz, CDCl 3 ) 8= 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), 7.9 (d, 2H), 7.2 (d, 5 2H); MS for C 23

H

2 6

F

3 N305 m/z 481.5 [MJ, 482.5 (M+H]. Example 3A17. Preparation of Compound 133: 1-((]R, 2)-1-(2,3 dihydrobenzopl[1.4ldioxin-6-yl)-1-hydroxy-3-(pvrrolidin-1-yI)propan-2-yl)-3-(4 (2-methylthiazol-4-yl)phenyl)urea N H N 0 0 H N 10 r 'H NMR (400 MHz, CDC1 3 ) 8= 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, IH), 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 0 4 S m/z 494.9 [M+H]. '5 Example 3A18. Preparation of Compound 7: 1-((1R, 2R)-I-(2,3 dihydrobenzo[pll,4]dioxin-6-yI)-1 -hydroxy-3-(pvrrolidin-1 -vl)propan-2-yl)-3 dodecylurea WO 2009/045503 PCT/US2008/011450 - 113 N H 0 'H NMR (400 MHz, CDC1 3 ) 8= 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, 5 1H), 4.8 (d, 1H), 6.7-6.8 (dd, 2H), 6.9 (s, 1H); MS for C2814N304 m/z 489.7 [M+H], 490.9 [M+2]. Example 3A19. Preparation of Compound 287: 1-((IR. 2R)-1-(2,3 dihydrobenzof 1[1,4ldioxin-6-yl)-I -hydroxy-3-(pyrrolidin-1 -yl)propan-2-yl)-3-(2 10 thiophen-2-y)ethyl)urea N H C> ..FHN~= 'H NMR (400 MHz, CDCl 3 ) 8= 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, 31H), 6.9 (d, 15 1H), 6.9 (dd-IH), 7.1 (d, 1H); MS for C22H29N304S m/z 432.1 (M+H]. Example 3A20. Preparation of Compound 257: N-((IR, 2R)-1-(2,3 dihvdrobenzo[B[l.4]dioxin-6-yl)-1-hydroxy-3-morpholinopropan-2-yl)-3-(4 methoxyphenoxy)propanamide 20 WO 2009/045503 PCT/US2008/011450 -114 0 N H N 0 "OH 'H NMR (400 MHz, CDC1 3 ) 8= 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, 1H), 4.9 (d, 1H), 6.5 (d, IH), 6.7-6.9 (m, 7H); MS for C 2 SH32N 2 0 7 in/z 473.1 [M+H]. 5 Example 3A21. Preparation of Compound 261: N-((1R, 2R)-1-(2.3 dihydrobenzoBlr 1.41dioxin-6-yl)-1-hydroxy-3-(piperidin-1-yl)Trovan-2-vl)-3-(4 rnethoxyphcnoxy)propanamide H N 0 cO H N 10 'H NMR (400 MHz, CDC 3 ) 6= 1.4 (br, 2H), 1.6 (br, 4H), 2.2-2.8 (m, 611), 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, i1H, 6.7-6.9 (m, 7H); MS for C 2 5 H3 4

N

2 0 6 m/z 471.1 (M+HJ. 15 Example 4: Compound A ()-((1R,2R)-1-(2,3-dihvdrobenzobl[1,41dioxin-6-yl) 1-hydroxy-3-(pyrrolidin-1-VI)propan-2-yl)nonaanmide) Effectively Inhibited PKD in a Mouse Model WO 2009/045503 PCT/US2008/011450 -115 N H NH 0 Design: jck mice was administered Compound A ad libitum in feed (0.225% Compound A mixed with a standard diet chow in powdered format) from 26-64 5 days of age. Controljck mice were fed a control powdered diet from 26-64 days of age. At 63 days of age, animals were transferred to metabolic cages for 24 hour urine collection. At 64 days of age, animals were sacrificed by CO 2 administration. Blood was collected by heart puncture for serum isolation. Kidneys were isolated and bisected; half of each kidney was fixed in 4% paraformaldehyde in PBS 10 overnight for paraffin embedding and H&E staining. Results: Results are summarized in table I and discussed below. Table 1. Summary of results, 0.225% Compound A in feed, 26-64 days of age No of Dose Cystic volume animals Gender (mglkg) Body weight (g) KIBW ratio (%) (%BW) BUN (mg/dL) 9 M Vehicle 22.03± 1.58 7.55*& 1.65 2.86 1.04 90.11 t 10.02 9 M Treated 18.43 ± 1.82* 4.46 t 0.46* 0.88* 0.23* 39.25 ± 10.70* 10 F Vehicle 19.20±t 1,80 4,94 * 0.73 1.22+0.41 50.50 ± 14.32 10 F Treated 15.93 ± 1.65* 3.57 * 0.58* 0.58 ± 0.29* 34.67 ± 9.41* *, p<0.05% compared to control (2-tailed t-test) 15 Kidney and body weight Total body weight and kidney weight were determined at sacrifice. A statistically significant decrease in total body weight was noted (p-value <0.05, two- WO 2009/045503 PCT/US2008/011450 -116 tailed t-test). A significant difference in kidney weight/body weight ratio was also observed (p-value <0.05, two-tailed t-test) for the treated animals, suggesting efficacy of the drug. 5 Cyst volume: Cyst volume was measured by quantitating the percentage of cystic area in histological sections of kidneys from the treated and control animals, multiplied by the kidney/body weight ratio. A significant decrease in cyst volume was observed (p-value <0.05, two-tailed t-test) for the the treated animals. 10 Kidney function: Blood urea nitrogen (BUN) levels were determined in serum samples derived from animals at sacrifice. BUN levels were elevated in the untreated controls, while the treated animals demonstrated a significant reduction of BUN levels (p-value 15 <0.05, two-tailed t-test). Conclusion: Administration of Compound A in feed at 0.225% resulted in a statistically significant reduction of cystic disease, as measured by kidney/body weight ratio and 20 cyst volume. This was accompanied by improved renal function in treated animals relative to controls. These improvements were observed in both males and females. Therefore, these results demonstrate that glucosylceramide synthase inhibition is an effective strategy to treat polycystic kidney disease. 25 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.

Claims

1. A method of treating polycystic kidney disease in a subject, comprising administering to the subject an effective amount of a compound represented 5 by the following structural formula: Y R' N(R 2 R 3 ) HN X-R 4 0 or a pharmaceutically acceptab6 salt thereof, wherein: 10 R' 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; R2 and R3 are each independently -H, a substituted or unsubstituted 15 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 of N(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring; X is a covalent bond; -(CR 5 R'),-; -(CR 5 R 6 )-Q-; -0-; -S-; or -Nt-; 20 Q is -O-, -S-, -C(O)-, -C(S)-, -C(0)0-, -C(S)O-, -C(S)S-, -C(O)NR-, -NR-, -NR 8 C(O)-, -NR'C(O)NR'-, -OC(O)-, -SO 3 -, -SO-, -8(0)2-, -SO 2 NR 8 -, or -NR 8 SO 2 -; WO 2009/045503 PCT/US200S/011450 - 118 When X is -(CRR')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 -(CRR 6 )m, R 4 is a substituted or unsubstituted 5 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 10 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 of NR 4 form a substituted or unsubstituted non-aromatic heterocyclic 15 group; each R 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; and 20 m is 1, 2, 3, 4 or 5.

2. The method of Claim 1, wherein R' 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, 25 Ar', -OR 30 , -O(haloalkyl), -SR4, -NO 2 , -CN, -NCS, -N(R) 2 , -NRIIC(O)R30, -NR? C(0)OR2, -N(RI)C(O)N(RII)2, -C(O)RII, -C(S)R30 -C(O)OR3, -OC(O)R' 0 , -C(O)N(R 3 ) 2 , -S(O) 2 R 30 , -SO 2 N(R) 2 , -S(O)R 2 , -SQ3R2, -NRSO 2 N(R) 2 , -NRSO 2 W 2 , -Vo-Ar, -V-OR 30 , -V 0 -O(haloalkyl), -V 0 -SR 0 , -V-NO 2 -V-CN, -Vc-N(R) 2 , 30 -V 0 -NR 31 C(O)R 30 , -V 0 -NR 3 C0 2 R 2 , -V 0 -N(R 3 )C(O)N(R 3 t) 2 , -V 0 -C(O)R 30 , -VO-C(S)R 3 0 , -V-COz 3 ", -V 0 -OC(O)R4, -V 0 -C(O)N(R')2-, -V 0 -S(O)2R 2 , -V.-SO 2 N(R 1 )2, -Vo-S(O)R, -Vr-SOR 3 2 , -V-NR 3 'SO 2 N(R") 2 , WO 2009/045503 PCT/US2008/011450 -119 -V 0 -NR 31 SOzR 2 , -O-Vo-Ar', -O-VI-N(R) 2 , -S-V 0 -Ar', -S-V-N(R 3 )2, -N(R')-V 0 -Ar', -N(R')-VI-N(R')2, -NR 3 C(O)-V 0 -N(R?')2, -NR' C(O)-V 0 -Ar', -C(O)-V-N(R')2, -C(O)-V 0 -Ar', -C(S)-V 0 -N(R')2, -C(S)-VO-Ar', -C(O)O-V-N(R) 2 , -C(O)O-V-Ar', -O-C(O).V-N(R)Z, 5 -O-C(O)-V 0 -Ar', -C(O)N(R)-V-N(R) 2 , -C(O)N(R 3 )-V 0 -Ar' -S(0) 2 -VO-N(R )2, -S(O)2-V,-Ar, -SO 2 N(R 3 )-V 1 -N(R 3 )2, -SO 2 N(R')-V-Ar', -S(Q)-V-N(R)2, -S(O)-V 0 -Ar', -S(0) 2 -0-V-N(R)2, -S(O)2-O-VO-Ar', -NRS0 2 -V-N(R) 2 , -NR 3 S 2 -V.-Ar', -0-(CH 2 ]-O-, S-[CH 2 ]p-S- and -[CH 2 ]q-; 10 each V. is independently a Cl-C10 alkylene group; each VI is independently a C2-C 10 alkylene group; Ar' 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, 15 dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and each R3 0 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which 20 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 25 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 30 each Rt1 is independently R'", -CO2R3 0 , -SO 2 R 30 or -C(O)R 3 0 ; or -N(R 3 ') 2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting V M X rU bU72UU/U11450 - 120 of halogen, =0, =S, =N(CI-C6 alkyl), CI-C6 alkyl, CI-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1 -C6 haloalkoxy, amino, (Cl -C6 alkyl)amino and (CI -C6 dialkyl)amino; and 5 each R 2 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, 10 hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and baloalkyl; 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, 15 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: 20 Y is -H, -C(O)R, -C(O)OR or -C(O)NRR'; and R and R' are each independently -H; a Cl -C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NH 2 , Cl-C6 alkoxy, CJ-C6 haloalkoxy, aryl and heteroaryl; or an aryl group or a 25 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, Cl -C6 aliphatic group and Cl -C6 haloaliphatic group; or R and R' taken together with the nitrogen atom of NRR' form 30 a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; WO 2009/045503 PCTIUS2008/011450 - 121 -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, Cl-C6 haloalkoxy, aryl and 5 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 , Cl-C6 alkoxy,-CI-C6 haloalkoxy, C1-C6 aliphatic group and CI-C6 haloaliphatic group. 10

4. 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 , 15 -NR 41 C(O)R 40 , -NR 4 'C(O)OR 42 , -N(R 4 )C(O)N(R) 2 , -C(O)R 4 0 , -O(S)R 40 , -C(O)O'4, -OC(O)R 40 , -C(O)N(R 4 ')2, -S(O) 2 R 4 , -SO2N(R 4 1 )2, -S(O)R 42 , -S0 3 R 42 , Art, V 2 -Ar 2 , -V 2 -OR 4 0 , -V 2 -O(haloalkyl), -V2-SR 40 , -V 2 -NO2. -V 2 -CN, -V 2 -N(R4')2, -V 2 -NR 4 'C(O)R 4 0 , -V2-NR 4 'CO 2 R 4 2 , -V 2 -N(R 4 ')C(O)N(R 41 )2, 20 -V 2 -C(O)R 40 , -V 2 -C(S)R 4 0 , -V 2 -CO 2 R 40 , -V 2 -OC(O)R 40 , -V 2 -C(O)N(R 4 1 ) 2 -, -V 2 -S(O) 2 R 4 2 , -V2-SO2N(R 4 ')2, -V 2 -S(O)R 4 2 , -V 2 -SO 3 R' 2 , -O-V 2 -Ar 2 and -S-V2-Ar 2 ; each V 2 is independently a CI-C4 alkylene group; Ar2 is an aryl group or a heteroaryl group, each of which 25 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, CI-C6 alkyl, amino, C -C6 alkylamino, C1-C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, CI-C6 haloalkoxy, C-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C1-C6 haloalkyl; and 30 each R 4 is independently i) hydrogen; WO 2009/045503 PCT/US2008/011450 -122 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, CJ-C6 alkyl, amino, CI-C6 alkylamino, 5 Cl -C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, CI-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group 10 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; and each R 4 ' is independently R 40 , -CO 2 R 40 , -S 2 R 40 or -C(O)R4; 15 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, CI-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, C-C6 20 alkoxycarbonyl, C-C6 alkylcarbonyl, CI-C6 haloalkoxy, amino, C1 C6 alkylamino and C-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 25 more substituents selected from the group consisting of halogen, C-C6 alkyl, amino, C1-C6 alkylamino, CI-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, C 1-C6 haloalkoxy, C-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or 30 ii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C-C6 alkylamino, CI - WO 20091045503 PCT/US2008/011450 - 123 C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, CJ-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C1-C6 haloalkyl.

5 5. The method of Claim 4, wherein R5 and R 6 are each independently -H; -OH; a halogen; or a C 1-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 R4, R 7 and R 8 10 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar, AP-AA, -OR", -O(haloalkyl), -SR 5 ", -NO2. -CN, -NCS, -N(R) 2 , -NR" C(O)R 0 , -NR 51 C(O)OR 2 , -N(R)C(O)N(R 1 ) 2 , -C(O)R 0 , -C(S)R 0 , -C(O)OR0, -OC(O)R 50 , -C(O)N(R')2, -S(O) 2 R, 15 -SO 2 N(R)2, -S(O)R2, -S0 3 R 2 , -NR 5 'SO2N(R 5 5 2 , -NR 51 S0 2 Rs 2 , -V-Ar, -V-OR 0 , -V 4 -O(haloalkyl), -V 4 -SR 50 , -V4-NO2. -V 4 -CN, -V 4 -N(R 51 )2, -V 4 -NR 1 C(O)R"", -V-NR 'CO 2 , -V 4 -N(R 51 )C(O)N(R) 2 , -V 4 -C(O)R 50 , , -V 4 -C(S)R, -V 4 CO 2 R 0 , -V 4 -OC(O)R 0 , -V 4 -C(O)N(R 5 ')2r, -V 4 -S(0) 2 R' 2 , -V 4 -SO 2 N(R 5 )2, 20 -V 4 -S(O)R 2 , -V 4 -SO 3 R 2 , -V 4 -NR 1 SO 2 N(R) 2 , -V 4 -NRSO 2 R, -N-Ve), -O-VS-N(R)2, -S-V- R , -S-Vs'N(R)2, -N(RO)-V 4 -A , -N(R)-V5-N(R)2, -NR C(O)-V 4 -N(R)2, -NR" C(O)-VedA, -C(O)-V4-N(Ra')2, -C(O)-VedA, -C(S)-V4-N(R5')2, -C(S) -e, -C(O)O-Vs-N(R")2, 25 -C(O)O-V 4 -A , -O-C(O)-VS-N(R) 2 , -O-C(O)-V 4 -Ar, -C(O)N(R 5 ')-Vs-N(R 5 ')2, -C(O)N(R')-V 4 -Ar3, -S(O) 2 -V 4 -N(R' )2, -S(O)2-V4-Ar, -SO 2 N(R')-Vs-N(R')2, -SO 2 N(R)-V4-Ar, -S(O)-V 4 -N(R 5 ) 2 , -S(0)-V 4 -Ar, -S(O)z-O-Vs-N(R) 2 , -S(O)rO-V4-Ar, -NR 5 ISOrVeN(R 5 ')2, -NRS0 2 -V,-Ar, 30 -O-[CH 2 ]p.-O-, -S-[CH2)S-, and -[CH2]q-; each V 4 is independently a Cl-C 10 alkylene group; WO 2009/045503 PCT/US2008/011450 -124 each V 5 is independently a C2-C10 alkylene group; each Ar3 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, 5 alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and baloalkyl; and each R 50 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which 10 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitrq, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 15 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 20 each R 5 ' is independently R"!, -CO 2 R 0 , -SO 2 R 50 or -C(O)R5"; or -N(R 1 ) 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, 25 C-C6 haloalkyl, hydroxy, Cl -C6 alkoxy, nitro, cyano, Cl -C6 alkoxycarbonyl, CI-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl C6 alkylamino and Cl -C6 dialkylamino; and each R5 2 is independently: i) an aryl group or a heteroaryl group, each of which 30 independently is optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, v t...1/U4UU5U/U1143U - 125 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 5 halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and - the non-aromatic heterocyclic group represented by -N(RR 7 ) is optionally substituted with one or more substituents selected from 10 the group consisting of halogen, -0, =S, =N(CT-C6 alkyl), CI-C6 alkyl, C1-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, (CI-C6 alkoxy)carbonyl, (C1 -C6 alkyl)carbonyl, C1 -C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (CJ-C6 dialkyl)amino; each p' is 1, 2, 3 or 4; and 15 each q' is 3, 4, S or 6.

8. The method of Claim 7, wherein the compound is represented by the following structural formula: Y R 1 N(R 2 R 3 ) HN /-F 20 0 or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted aliphatic group.

9. The method of Claim 8, wherein: WO 2009/045503 PCT/US2008/011450 -126 R is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR 3 0 , -SR"', -N(R 3 ) 2 , Ar', -V 0 -OR 0 , -V 0 -N(R) 2 , -V 0 -Ar', -O-V 0 -Ar t , -O-V-N(R 1 ) 2 , -S-V 0 -Ar', -S-Vr-N(R 3 )2, 5 -N(R 3 )-Vo-Ar', -N(R 3 )-V-N(R) 2 , -O-[CH 2 ],O-, -S-[CH 2 ]-S-, and -[CH2]q- ; Ar' is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C-C6 alkyl, amino, C1-C6 alkylamino, C-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, 10 hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and C-C6 haloalkyl; and each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more 15 substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl-C6 alkylamino, C1-C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1 C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or 20 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C 1-C6 alkylamino, C1-C6 dialkylamino, C C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1 -C6 alkylcarbonyl and C1-C6 haloalkyl; 25 and each R 3 ' is independently R 3 , 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), C-C6 alkyl, C I-C6 haloalkyl, hydroxy, C-C6 alkoxy, nitro, cyano, C1-C6 30 alkoxycarbonyl, C-C6 alkylcarbonyl, C-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. WO 2009/045503 PCT/US2008/01 1450 -127

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, Cl-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, Cl -C5 5 alkoxycarbonyl, Cl -C5 alkylcarbonyl or Cl -C5 haloalkoxy, amino, Cl -C5 alkylamino and Cl-C5 dialkylamino,

11. 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-C10 alkyl, C1-C10 haloalkyl, Ar, A?-Art -OR 0 , 10 -O(haloalkyl), -SR 0 , -NQ 2 , -CN, -N(R) 2 , -NR 1 C(O)R 0 , -C(O)R 0 , -C(Q)QR", -OC(O)R 0 , -C(O)N(R 5 ) 2 , -V 4 -Ar, -V-OR 0 , -V 4 -O(haloalkyl), -V 4 -SR 5 , -V 4 -NO 2 , -V 4 -CN, -V 4 -N(R')2, -VrNR'C(O)R 5 0 , -VrC(O)R 0 , -V 4 -CO 2 R 0 , -V 4 -OC(O)RP 0 , -V 4 -C(O)N(R) 2 -, -O-V 4 -Ar, -O-V 5 -N(R 5 1 ) 2 , -S-V 4 -Art -S-V 5 -N(R 5 1) 2 , -N(R 5 ')-V 4 -Ar, -N(R )-VS-N(R)2, 15 -NR" C(O)-V 4 -N(R)2, -NR'C(O)-V4-Ar, -C(O)-V 4 -N(R)2, -C(O)-V 4 -Ar , -C(O)O-V 5 -N(R 5 ) 2 , -C(O)O-V 4 -Ar 3 , -O-C(O)-V 5 -N(RC)2 -O-C(O)-V 4 -Art -C(O)N(R 51 )-V 5 -N(R 5 ) 2 , -C(O)N(R 5 )-V 4 -Ar, -Q-[CH 2 ]p-O- and -[CH2]q-. 20

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' is optionally substituted with one 25 or more substituents selected from the group consisting of -OR 30 , alkyl, and -O-[CH2]p-O-.

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 WO 2009/045503 PCT/US2008/011450 - 128 consisting of halogen, cyano, nitro, haloalkyl, amino, alkylanino, dialkylamino, -OR 50 , -A?, -V4-Ar, -V-OR 5 0 , -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar, -O-(CH2]J-O- and -[CH2]-.

16. The method of Claim 15, wherein: 5 A? 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, CI-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, C-C6 haloalkoxy, CJ-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl-C6 haloalkyl; and 10 each R5( is independently i) hydrogen; ii) 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, Cl-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, 15 hydroxy, Cl -C6 haloalkoxy, C I-C6 alkoxycarbonyl, Cl -C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an Cl-C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, CI-C6 alkylamino, Cl-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, 20 hydroxy, Cl-C6 haloalkoxy, CI-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and Cl-C6 haloalkyl.

17. The method of Claim 16, wherein RW is an aliphatic group. 25

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' is 4-hydroxyphenyl or 3,4 ethylenedioxy- 1 -phenyl. 30

20. The method of Claim 19, wherein R is a C6 - C18 alkyl group. WO 2009/045503 PCT/US2008/011450 -129

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

22. The method of Claim 7, wherein: 5 X is -(CR 5 R6)"Q-; Q is -0-, -S-, -C(O)-, -C(S)-, -C(0)O-, -C(S)O-, -C(S)S-, -C(O)NR'-, -NR'-, -NR'C(O)-, -NR"C(O)NRS-, -OC(O)-, -SOr-, -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 10 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 -(CRR 6 )m-; and R 4 is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or 15 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. 20

23. The method of Claim 22, wherein the compound is represented by a structural formula selected from the group consisting of: WO 2009/045503 PCT/US2008/011450 -130 OH OH R' N(R 2 R 3 ) R' N(R 2 R 3 ) HN HN R' W(CR 5 R)m-R 4 0 ,0 H R' N(R2R 3 ) HN (CR 5 R)n-Q- R 4 H H R N(R 2 R 3 ) Ri N(R 2 R 3 ) HN H (CRSR)n R4 O- R 4 0 , 0 OH Ri N(R 2 R 3 ) HN N(R 7 R 4 ) and 0 5 or a pharmaceutically acceptable salt thereof, wherein R 7 is -H or Cl -C6 alkyl.

24. The method of Claim 23, wherein: Y - Mv v v.r-'Y'V u-- I/U 'UUI U14 U - 131 R' is a phenyl group optionally substituted with one or niore substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, -OR 30 , -SR 3 0 , -N(R 3 1 ) 2 , Ar', -V-OR 3 ", -V 0 -N(R) 2 , -V,,-Ar', -O-Vo,-Ar', -O-Vi-N(R')2, -S-Vo-Ar', -S-VI-N(R31)2, 5 -N(R 3 )-Vo-Ar, -N(R)-V-N(R 31 ) 2 , -O-fCH 2 ]r.O-. -S-[CH2]p-S-, and -[CH2]q-; Arl is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, Cl -C6 alkyl, amino, CI-C6 alkylamino, Cl-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, 10 hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R0 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more 15 substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, Cl-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and CI-C6 haloalkyl; or 20 iii) an CI-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C I-C6 alkylamino, Cl -C6 dialkylamino, Cl C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and CI-C6 haloalkyl; 25 and each R 3 ' is independently R", or -N(R 3 1 ) 2 is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, -0, =S, =N(Cl-C6 alkyl), Cl-C6 alkyl, CI-C6 haloalkyl, hydroxy, CI-C6 alkoxy, nitro, cyano, CI-C6 30 alkoxycarbonyl, CI-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Yv~~~r vuuutaaU1/UZ .UU5/UJA4:)U - 132

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, Cl-C5 alkyl, Cl-C5 haloalkyl, hydroxyl, Cl-C5 alkoxy, nitro, cyano, Cl-C5 5 alkoxycarbonyl, Cl-C5 alkylcarbonyl or Cl-C5 haloalkoxy, amino, Cl-CS alkylanino and Cl-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 R4, R 7 and R8 independently is optionally substituted with one or more substituents selected from the 10 group consisting of halogen, C1-C10 alkyl, CI-C10 haloalkyl, Ar, Ar?-Ar3 -OR", -O(haloalkyl), -SRO, -NO2 -CN, -N(R) 2 , -NR 1 C(O)R 50 , -C(O)R 5 0 , -C(0)OR 0 , -OC(O)R 0 , -C(O)N(R 5 1 )2, -VeAr, -V-OR 5 0 , -V 4 -O(haloalkyl), -V-SR", -V 4 -NO 2 , -V 4 -CN, -V 4 -N(R')2, -VNR 5 C(O)R 5 0 , NV-C(O)R, -V-CO 2 R 0 , -V 4 -OC(O)R, -V-C(O)N(R") 2 -, -O-V 4 -Ar 3 , -O-V 5 -N(R 5 ) 2 , 15 -S-V-Ar 3 , -S-Vs-N(R 5 ) 2 , -N(R 5 )-V 4 -Art -N(R)-VS-N(R) 2 , -NR 51 C(O)-V 4 -N(R)2, -NRl C(O)-V 4 -Ar, -C(O)-V 4 -N(R) 2 , -C(O)-V 4 -Ar, -C(O)O-V 5 -N(R 1 )2, -C(O)O-V-Ar, -O-C(Q)-Vs-N(R 5 )2, -O-C(O)-V-Ar 3 , -C(O)N(R)-V 5 -N(R) 2 , -C(O)N(RS)-V 4 -Art -Q-[CH2j]-O- and -[CH2]q'-. 20

27. The method of Claim 26, wherein the compound is represented by the following structural formula: OH RI N(R 2 R 3 ) HN (CH2)m R4 0 WO 2009/045503 PCT/US2008/011450 - 133 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. 5

29. The method of Claim 28, wherein: the phenyl group represented by R' is optionally substituted with one or more substituents selected from the group consisting of-OR 3 0 , alkyl, and -O-[CH2]rO. 10

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, halgalkyl, amino, alkylamino, dialkylamino, -OR 50 , -Ar, -V 4 -Ar, -V-OR 0 , 15 -O(haloalkyl), -V 4 -Q(haloalkyl), -O-V 4 -Ar 3 , -O-[CH 2 ,)-O- and -[CH2Jq-.

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, CI-C6 alkyl, 20 amino, C1-C6 alkylarnino, CI-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, Cl -C6 haloalkoxy, C1 -C6 alkoxycarbonyl, Cl -C6 alkylcarbonyl and Cl-CO haloalkyl; and each R' is independently i) hydrogen; 25 ii) 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, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and Cl-C6 haloalkyl; or 30 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, WO 2009/045503 PCT/US2008/011450 -134 Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl -C6 haloalkyl. 5

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. 10

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, alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy.

35. The method of Claim 34, wherein the optionally substituted biaryl group is an optionally substituted biphenyl group. 15. IA N 0 .0

36. The method of Claim 33, wherein -(CH 2 )m-R 4 is H 2 , and wherein phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar3, alkyl, haloalkyl, alkoxy, hydroxy and haloalkoxy. 20

37. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of: *rK v UUJ/ U.U. rE .a IUUUOviI*;U -135 H R1 N(R 2 R 3 ) HN / -(CHz)n-O-R4 o and H R1 N(RZR3) HN 0 (CH 2 )n R4 or a pharmaceutically acceptable salt thereof. 5

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

39. The method of Claim 38, wherein: the phenyl group represented by R1 is optionally substituted with one or more substituents selected from the group consisting of-OR 0 , alkyl, and 10 -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 15 group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR", -Ar, -V4-Ar -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar 3 , -O-[CH 2 ],--O- and -[CH2]-; or WO 2009/045503 PCT/US2008/011450 - 136 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", -Ar, -V 4 -Ar, -V-OR'", -O(haloalkyl), -V 4 -O(haloalkyl), -O-V4-Art 5 -O-[CH2]p.-O- and -[CH2]q-.

41. The method of Claim 40, wherein: Ar3 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, 10 amino, Cl-C6 alkylamino, Cl-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, CI-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C 1-C6 haloalkyl; and each R 5 " is independently i) hydrogen; 15 ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-C6 alkyl, amino, CI-C6 alkylamino, Cl-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and CI-C6 haloalkyl; or 20 iii) an C 1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, CI-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C 1-C6 alkoxycarbonyl, C 1-C6 alkylcarbonyl and Cl-C6 haloalkyl. 25

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

43. The method of Claim 42, wherein R 4 is an optionally substituted alkyl group, 30 or an optionally substituted phenyl group. WO 2009/045503 PCT/US2008/011450 -137

44. The method of Claim 43, wherein R' 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 5 phenyl group optionally substituted with one or more substituents selected from the group consisting of -OH, -003 and -0C 2 H 5 .

46. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of: H OH RI N(R 2 R 3 ) R1 N(R 2 R 3 ) H HN . O- R 4 N(R 7 R 4 ) 10 0 and 0 or a pharmaceutically acceptable salt thereof.

47. The method of Claim 46, wherein R4 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 15 selected from the -group consisting of halogen, alkyl, haloalkyl, Ar, -OR 0 , -O(haloalkyl), -SR' 0 , -NO 2 , -CN, -N(R)2, -NR 1 C(O)R 0 , -C(O)R 0 , -C(O)OR' 0 , -OC(O)R 0 , -C(O)N(R 5 1 ) 2 , .V4-Ar, -V-OR 0 , -V-O(haloalkyl), -V-SR 0 , V 4 -N0 2 . -V 4 -CN, -V 4 -N(R 1 ) 2 , -V 4 -NR 5 C(O)R 0 , -V 4 -C(O)R 0 , -V-CO 2 R 0 , -VeOC(O)R 5 ", -V 4 -C(O)N(R) 2 -, -0-V,-Ar, -0-Vs-N(R' )2 20 -S-V 4 -Ar, -S-Vs-N(R)2, -N(R')-V4-Ar, -N(R')-VS-N(R1)2, -NR'C(O) V 4 -N(R)z, -NR 5 1 C(O)-V 4 ,-Ar -C(O)-V,-N(R) 2 , -C(O)-V 4 -Ar, -C(O)0-VS-N(Rs')2, -C(O)O.VrAr, -0-C(O)-V-N(R 5 1 )2, -O-'C(O)-V4rAr 3 , -C(O)N(R)-V 5 -N(R 5 )2, -C(O)N(R")-V 4 -A , -0-[CH2J-0- and -[CH2]q-. WO 2009/045503 PCT/US2008/011450 - 138

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' is optionally substituted with one 5 or more substituents selected from the group consisting of -OR 30 , alkyl, and -O-[CH2]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 10 or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylarnino, -OR 0 , -Ar3, -V4-Ar, -V-OR 50 , -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar3, -O-[CH 2 ]p-O- and -[CH2]- 15

51. The method of Claim 26, wherein the compound is represented by a structural formula selected from the group consisting of: H RI N(R 2 R 3 ) HN /)-o-(CH2)k-'Ro 0 and H RI N(R 2 R 3 ) HN N-(CH 2 )-R' H 0 20 or a pharmaceutically acceptable salt thereof, wherein: WO 2009/045503 PCT/US2008/011450 -139 k is 1, 2, 3, 4, 5 or 6; and R'" is i) -H, or ii) an aryl group or a heteroaryl group, each independently 5 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 10 consisting of with one or more substituents selected from the group consisting of halogen, cyano, nitro, Cl-C10 alkyl, C1-C10 haloalkyl, amino, Cl-C1O alkylamino, Ci-ClO dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, C1-10 alkoxy, -0-{CH 2 ]p-O- or -[CH2]q 15

52. The method of Qlaim 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' is optionally substituted with one 20 or more substituents selected from the group consisting of -OR 3 0 , alkyl, and -O-[CH42]p-0-.

54. The method of Claim 53, wherein R1 0 is a Cl-C6 alkyl group; an optionally substituted phenyl group; or an optionally substituted, monocyclic or bicyclic 25 heteroaryl group.

55. The method of Claim 26, wherein the compound is represented by the following structural formula: " "-'"" -4...7/U0UUO/U11KLU -140 OH R1 N(R 2 R 3 ) HN 0, 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. 5

57. The method of Claim 56, wherein: the phenyl group represented by R' is optionally substituted with one or more substituents selected from the group consisting of -OR 0 , alkyl, and -O-[CH2],-O-. 10

58. The method of Claim 57, wherein each of the aryl and the heteroaryl groups represented by R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR", -Ar, -V4-Ar 3 , -V-OR, -O(haloalkyl), -V4-O(haloalkyl), -O-V 4 -Ar, -O-(CH)p-O- and 15 -[CH 2 ]q*-

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, CI-C6 alkyl, 20 amino, Cl -C6 alkylamino, Cl -C6 dialkylarnino, C1 -C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl; and each R is independently i) hydrogen; - 141 ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, CI -C6 alkylarnino, Cl -C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 5 alkylcarbonyl and CI-C6 haloalkyl; or iii) an Cl-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, CJ-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 10 alkylcarbonyl and Cl-C6 haloalkyl.

60. The method of Claim 59, wherein -N(R 2 R') is N-pyrrolidinyl or N morpholinyl. 15

61. The method of Claim 60, wherein R' 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: 20 OH O N H N O O= (CFH2)G-8-CH3 WO 2009/045503 PCT/US2008/011450 -142 O N N7H 0 00 (CH2)sa--CHa 0 (CH 2 )-a-C 4 H 3 HOH NH No H (H 0=< (CF12)v.. 0 CH 3 0HC 2 1 .- WO 2009/045503 PCT/US2008/011450 - 143 H 0 A/ (C H2)1-e 0 ,or H 0 H N N o o NH-(CH 2 )1.6 A or apharmaceutically acceptable salt there, wherein each ring A 5 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 polycystic kidney disease is an autosomal dominant polycystic kidney disease.

64. The method of Claim 1, wherein the compound is represented by the 10 following structural formula: H 00 D[ -N H No (CH 2 ) 6 . -CH 3 or a pharmaceutically acceptable salt thereof.