AU2012201076B2 - Method of treating polycystic kidney diseases with ceramide derivatives - Google Patents

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

- I METII(OD (> TREATIN(i POLY(C (STIC KIDNEY DISEASES \\ ITi CR:\ILIDE DERITI\ VES RL ACTED 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 D OE THE IV\ET ION 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. Autosomal 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.

-2 It is an object of the present invention to go some way towards meeting this need and/or to provide the public with a useful choice. St \l\ARY OF TIll IN\ \ NATION 5 Applicants have now discovered that certain ceramide derivatives can reduce cystic growth in an animal model for polycystic kidney disease, as measured by kidneyibody weight ratio and cyst volume. Based upon this discovery, a method of treating polycystic kidney disease with the ceramide derivatives is disclosed herein. In one embodiment, the invention is directed to a method of treating 10 polycystic kidney disease in a subject, comprising administering to the subject an effective amount of a compound represented by Structural Formula (1): OY Ri N(R'R3) HN X R 4 0 (1), 15 or a pharnaceutically acceptable salt thereof. R is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroary I group. Y is -HI, a hydrolyzable group, or a substituted or unsubstituted alkyl group. R2 and R are each independently -I, a substituted or unsubstituted aliphatic 20 group, a substituted or unsubstituted aryl group. or a substituted or unsubstituted heteroaryl group, or R2 and R taken together with the nitrogen atom of N(R 2 R') form a substituted or unsubstituted non-aromatic heterocyclic ring. X is a covalent bond; -(CR 5 R 6 )]; -(CR R 6 )-Q-; -0-; -S-; or -NR -; Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-. -C(S)S-, -C(O)N \ , -NR 5 -, 25 -NR (0)-, -NR 5 C(O)NR -, -OC(O)-, -SO,- -SO-, -S(O)2-, -SO2NR, or -NR SO2.

-3 When X is -(CR R R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO2 or a halogen. When X is other than -(CRR)m, R 4 is a substituted or unsubstituted 5 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 unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. 10 Each R' is independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsuhstituted arvl group, or a substituted or unsuhstituted heteroaryl group, or R and R 4 taken together with the nitrogen atom of NR R 4 form a substituted or unsubstituted non-aromatic heterocyclic group. Each R 5 is independently -Il, a substituted or unsubstituted aliphatic group, a 1 5 substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. n is 1, 2, 3, 4 or 5, 6, 7, .8, 9, 10, 11, 12, 13, 14 or 15. m is 1, 2, 3, 4 or 5. Also, included in the present invention is the use of ceramnide derivatives 20 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 The present invention has many advantages. In particular, the present 25 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 suffering from PKD. DEI ILED D DESCRIPTION OF TI l IN\ENTION 30 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 -4 discovered that a certain ceramide derivative can reduce the growth of cyst formation and/or growth in an animal modeled PKD. In one embodiment, the ceramide derivative is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof. A first set of values and 5 preferred values for the variables in Structural Formula (I) is provided in the following paragraphs: Y is -H, a hydrolyzable group, or a substituted or unsubstituted alkyl group. Examples of hydrolyzable groups include -C(O)R, -C(O)OR, -C(O)NRR', C(S)R, -C(S)OR, -C(O)SR or -C(S)NRR'. Specific examples of hydrolyzable groups 10 include an acetyl, -C(= I)(C1)CH 3 and -C(=O)-( 1-lower alkyl- 4-dihydropyridin 4-yl. In a specific embodiment, Y is -IH, a hydrolyzable group, or an alkyl group. In another specific embodiment, Y is .1H, -C(O)R, -C(O)OR or -C(O)NRR. In yet another specific embodiment, Y is -H. X is a covalent bond; -(CR 5 RQ-; -O-; -S-; or -NR 7 15 Q is -0-, -5-, -C()-, -C(O)O- -C(S)-, -C(S)S-, -C(O)NR, NR-, -NRC(O)- -NR 8 C(O)NR-, -OC(0)-, -S03-, -SO-, -S(0)2- -SO)NR-, or -NRSSO20-. In a specific embodiment, Q is -0-, -5-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-. -C(S)S-, -C(O)NRK, -NRC(O)NRK, or -OC(O)-. In yet another speciLic embodiment, Q is -0- , -5-, -C(O)-, -C(S)-, -NR (CO)- or -C(O)NR. In vet 20 another specific embodiment, Q is -0-, -S-, -C(O)- or -C(S)-. In yet another specific embodiment, Q is -0- or -C(O)-. 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 0 25 another specific embodiment, R is 0 where r is 1, 2, 3 or 4, preferably I or 2. Suitable substituents for each of the aryl and heteroary groups represented by R' include halogen, alkyl, haloalkyl, Ar', -OR 3 0 , -O(haloalkyl), -SR 30 , -NO 2 , -CN -NCS, -N(R) 2 , -NR 3 IC(O)RA}, -NR 3 C(O)OR , -N(R 3 1

)C(O)N(R

1

)

2 , -C(O)R :. 30 -C(S)R 3 , -C(O)OR4, -OC(O)R30, -C(O)N(R )2, -S(O)2R 4, -SO2N(R)2, -S(O)R ,

-SO

3

R

3 , NR 3 SON(R 3 )2, -NR , SO2R, , -V '-Ar, -- OR", -V-O(haloalky1), R, -V-NO2, -Vo-C, -V-N(R')2, Vo-NR 3 C(O)R30, -Vo NR" COR1, -VoN(R)C(O)N\(R')2, -Vo,-C(O)R34, -Ve-C(S)R3 _,j -VeC R _, Vo-C(O)R0, -V-C(O)N(R ) , -Vu-S(O)2R , -V-SO'N(R,) 2

-V,-S(O)R

2 , Ve-SO 3

R

3 , 5 -V-NR SON(R 1 )2, -VoNRV S'RE, -O-V -Ar'. -O-VN(R)2, -S-V-Ar', -- N(R 31)-V-Ar (R )-VN(R ) -NEC(O)-Vo)-Ar', -C(O)-V -N(R)2,. -C(O)-VO-Ari,-()V-( 2 -O-C(O)-V-Ar', -C(O)N(R )-V,N(R3)2. -C(O)N(R3 )-Vo-Ar', -S(O)r-Vo-N(R )2, 10 -S(0) V,-Ar'. -SO2N(R 3 )-V N(R') 2 , -SO2N(R )-V,-Ar , -S(O)-V-N(R 1

)

2 , -S(O)-V-Ar', -S(O) 2 -O-V,-N(R ), -S(Oy-O-Ve-Ar', -NR SOrVe-N(R )2, -NR''SOrVo-Ar , -O-[CH-lO-, -S-[CH 2 ]p-S-, or -[CH2]-. Certain specific substituents for each of the aryl and heteroary groups represented by R include halogen, cyano, nitro, alkyl, haloalkyl, -OR 0 , -SR ', -N(R )2, Ar', -V-OR31, 15 -V-( 2 V-Ar ,-O-Ar W -O-V N( ),--V-A,!' -SVN(I2 -N )-V-AI -N(R)VN(R)2, -O-[CH2]pO-, -S-[CH 2 ]p-S-, or -[C Alternatively, certain specific substituents for each of thc aryl and heteroary groups represented by RI' include halogen, cyano, nitro, alkyl, haloalkyl, alkylamino, dialkylamino, ary, aryloxy, -OH, alkoxy, -O-[CH 2

]

0 -O-, and -[CH2]. 20 Alternatively, certain specific substituents for each of the aryl and heteroary groups represented by R include -OR (e.g., -OH, -0CH3, -OC 2 H), alkyl, (e.g., Cl-C6 alkyl), or -O-[CH2]p-O-. R and R are each independently -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group or a substituted or unsubstituted 25 heteroaryl group, or R and R taken together with the nitrogen atom of N(R 2 R) fonm a substituted or unsubstituted non-aromatic heterocycli ring. In a specific embodiment, R2 and RW taken together with the nitrogen atom of N(R2RV) form a 5 or 6-memberedl, optionally-substituted non-aromatic heterocyclic ring . In another specific embodiment, -N(R2R 3 ) is an optionally substituted pyrrolidinyl, azetidinyl, 30 piperidinyl, piperazinyl or morpholinyl group. In another specific embodiment,

-N(R

2 R3) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, preferably an unsubstituted pyrrolidinyl group.

-6 Suitable substituents for the aliphatic, aryl and heteroaryl groups represented by R2 and R 3 , nd suitable substituents for the non-aromatic heterocychc ring represented by N(R 2

R

3 ) each independently include halogen, alkyl, haloalkyl, -OR4" -O(haloalkyl), -SR 4 t 4, -NO2, -CN, -N(R 4 )2, NR 4

'C()R

4 , -NR 4

'C(O)OR

42 5 -N(R 4 ')C(0)N(R 4 ') , -C(O)R 40 , C(S)RfH, -C(O)OR, -OC(O)R 4 0 . -C()N(R 4 ' ),

-S(O)

2 R4, -SO_2N(R 4

)

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

R

4 2, Ar2, V1-Ar 2

-V

2 -OR"4. -V-O(haloalkyl), -V-SR40 -V-NO -V2-CN, -V-N(R 4 )2, -V 2 -NR'C(O)Rf" -VNR 4CO 2

R

4 , -V-N(R 4 1)C(O)N(R 41

)

2 , -V 2

-C(O)R

4 , -V 2

-C(S)R

4 0 , -V2-CO2R 4 1,

-V

2

OC(O)R

4 0, -V 2

-C(O)N(R

4 )r-, -V-S(O)2R 42 , -VrSO 2 N(R), -V-S()R 4 2. It) -V2-SO 3

R

42 . -O-V2-Ar an~d -S-V-3-Ar> Certain specific substituents for the aliphatic, aryl and heteroaryl groups represented by R 2 and R 3 , and for the non-aromatic hetcrocyclic ring represented by N(RRS) 40 each independently include halogen, alkyl, haloalkyl. -OR4, -O(haloalkyl). -SR, -NO -CN, -N(R4) 2 , -C(O)R 40 , -C(S)R4 -C(O)OR 40 , -OC(O)R4, -C(O)N(R;')2, 15 Ar 2 , VAr 2

-V.OR

4 u, -V--O(haloalkyl), -V-SRi", -V-N0 -V 2 -CN, -V2N- ) -V-C(O)R4', -V-C(S)R 4 , -V-CO2R44 -V.OC(O)Rfh, -O-V-Ar 2 and -S-VAr 2 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(R 2 R') each indepenent i t include halogen, Cl-C10 alkyl, CI-CIo 20 haloalkyl, -O(C1-C10 alkyl), -O(phenyl), -O(C1-C10 haloalkyl), -S(C-Cl10 alkyl), -S(phenyl), -S(C1-C10 haloalkyl), -NO 2 , -N1(C 1-C10 alkyl) N(C -C0 alkyl)2,. -NH(C I-C 10 haloalkyl), -N(C 1-C 10 haloalkyl) 2 , -IH(phenyl), -N(phenyl)2, -C(O)(Cl-C10 alkyl), -C(O)(C1-Cl0 haloalkyl), -C(O)(phenyl)-C(C(S)(C1-C 10 alkyl), -C(S)(C1-C 10 haloalkyl), -C(S)(phenyl), -C(O)O(C1-C10 alkyl), 25 -C(O)O(CI-Cl1 haloalkyl), -C(O)O(phenyl, phenyl, -V2-phenyl, -Vr-O-phenyl, -V-O(CI-C 10 alkyl), -V 2 -O(C 1-C10 haloalkyl). -V 2 -S-phenyl, -Vr-S(CI -C 10 alkyl), -V-S(Cl-C10 haloalkyl), -V 2 -NO -V 2 -CN, -V'-N H(C1-C10 alkyl), -V-N(Cl1-C 10 alkyl) 2 , -V 2 -NH(C 1-C10 haloalkyl), -V-N(C1-C10 haloalkyl) -V-NH(phenyl), -V-N(pheny) -V--C(O)(C 1-C10 alkyl). -VrC(O)(C1-C 10 30 haloalkyl). -V--C(O)(phenyl), -V 2 -C(S)(C 1-C10 alkyl), -V2-C(S)(CI-C10 haloalkyl), -V 2 -C(S)(phenyl), -V2-C(O)O(C1-C1 0 alkyl), -V-C(O)O(C1-C10 haloalkyl), -V 2 -C(O)O(phenyl), -V2-OC(O)(Ci-C10 alkyl), -V 2 -OC(O)(CI-C10 -7 haloalkyl), -V 2 -OC(O)(phenyl), -O-V 2 -phenyl and -S-V-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(R 2 R ) each independently include halogen, Cl-CS alkyl, Cl-C5 haloalkyl, hydroxy, Cl-C5 5 alkoxy, nitro, cyano, Cl-C5 alkoxycarbonyl, Cl-C5 alkylcarbonyl, Cl-C5 haloalkoxy, amino, Cl-CS alkylamino and Cl-C5 dialkylamino. When X is -(CR R 6 )m, R 4 is a substituted or unsubstituted aiphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -CN, -NCS, -NO2 or a halogen, or alternatively when X is other than 10 -(CR5R )m, R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group. Specifically, R4 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 is a C 6-Cl18 alkyl group, such as a C6, C7. C8, C9 or CI0 alkyl group. In one aspect of these more specific 20 embodiment, the alkyl group, including the C6, C7, C8, C9 or CIO alkyl group, is acycl ic. 4 In another specific embodiment, R is an optionally substituted aryl, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R4 In yet another specific embodiment, R4 is an optionally substituted phenyl 25 group or an optionally substituted alkyl group, such as Cl1-Cl10 alkyl group, or C6 In yet another specific embodiment, R is an aryl group, a heteroaryl group, a lower arylalkyl group or a lower heteroarylalkyl group, or alternatively, R4 is an optionally substituted aryl or an optionally substituted heteroaryl group. In a more 30 specific embodiment, the aryl, the heteroaryl, the lower arylalkyl and the lower heteroaryl groups represented by R 4 are selected from the group consisting of: -8 -- (CH 2 )x A

H

2 )x C D N s N

--

(CH

2 )x - -(CH 2 -x H2 (F H 0 //N

H(CH

2 x) SN K HN -- H 2()H 2 )H I N -- (CH2)x (CH2)xx N N - -CH .

L - N (and

N(H

2 --j

--

(CH2)xR 5N N, 0 H N -S optioal susiuedgop Alterativey, Ri Notoal -- CH T U ____ \__ 2N N (H (H) (C- ) V(CH 2

),

1

-

z LI NN N -(CH), Z2 L3 (CZ4 Z 5 N and where-in ac of rings A-Z5 is opinLindinpedtlsutiud;adah 4 10 is.1 independently 0 or I pcfcly s0 vn oepeeaby sa CH) A optionai~lly substittd group. Alentvl,0 i notoal substituted phenyl group. Alternatively, R4 is an aryl group or a heteroaryl group, each indepenently optionally substituted with Ara, such as a phenyl group optionally substituted with Ar'. It is noted that, as shown above, rings A-Z5 can he attached to 15 variable "X" of Structural Formula (I) through -(CH 2 )- at any ring carbon of rings -9 A-Z5 which is not at a position bridging two aryl groups. For example. R4

)(CH

2 )x J K represented by s means that R 4 is attached to variable "X" through either ring J or ring K. Suitable substituents for each of the aliphatic, the aryl and the heteroaryl 5 groups represented by R 4 , including the alkyl group, the arylalkyl, the heteroarylalkyl group and rings A-Z5, include halogen, alkyl. haloalkyl, Ar, Ar-Ar 3 , -OR M -O(haloalkyl), -SR, -NO 2 , -CN, -NCS, -N(R) 2 , -NR C(O)R0, NR 'C(O)OR 2-N(R )C(O)N(R),() -C(-)R ('(S)R 0 -C(()OR

M

, -OC(O)RS" -C(O)(0 ,-() 2 ,-SN( )2 -SO) -SO3R g2, -NRE4 SO2(RC)2 10 -NR'S 2 R , -VRAr, -V-OR'0, -VrO(haloalkyl), -VrSR ', -VrNO -V-CN,

-V

4 N(R)2, -V 4 NR C(O)R-, -V 4 -NR C0R7, -V 4

-N(R

5 )C(O)N(R- )2,

-V

4 C(0)RE, , -V 4 C(S)R, -V 4 CO2R, -V -OC()R , -V 4 -C(O)N(R )

-V

4 -S(O)2R, -VrSO2N(R 5 )2, -V'S(O)R 2 , -V)SO R , -V 4

NR

5 1

SO

2 N(R)2, -VrNR SO2R0( , -O-V 4 -Ar, -0-V5-N(R) -S-V 1-Ar , -S-V 5 -N(R )2 15 N(R)-V 4 -Ar, -N(R)-V-N(R"), -NR(1C(O)-V-N(R)2, -NR C(0)-V Ar', -C(O)-V4-N(R")2, -C'(0)-V ,Ar -C(S)-V-N(R") 2 , -C(S)-V 4 -rr,

-C()O)-V

5 -N(R)2, -C(O)O-V-Ar, -O-C(0)-V-N(R 5 )2, -O-C(O)-VAr 2 , -CON) -VW N( ), (O)N(R )-Ara, -S(O))2-r("2w S()-rAa

-SO

2

N(R

51 )-V- -SO 2 N(R1)-V-Ar, -S3()-V-N(R 5 )2, -S(O)-V 4 -Ar , 20 -S(O) 2

-O-V

5 -N(R" )2, -S(0) 2 -0-V-Ar 3 , -NR SO 2 -VrN(R') 2 , -NR 51

SO

2 -V-Ar 3 , -O-[CHp-O-, -S-[CH2]p-S-, and -[C1 2

]

0 - 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-Z, include halogen, CI-C10 alkyl, CI-CI0 haloalkyl, Ar 3 , Ar-Ar 3 , -OR 25 -O(haloalkyl), -SR, -NO 2 , -CN, -N(R -), -NR IC(O)R5', -C(O)R, -C(O)OR' -OC(O)R , -C(O)N(RS)2, -Vr \r, -V-OR5, -V-O(haloalkyl), -V,-SR, -V0 NO2

-V

4 CN, -V-N(R'), -V 4 -NR" C(O)R, -V-C(O)R, -VCO 2 R -V 4 -OC(O)R -V3-C(O)-N (R)2-, -- V 4

-

1 Ar, -O-V -N(-RN)2, - )S-V -S-V -(R) -N(R- )-V4-r3 -NR -V5-N(R ),-NR5 C(O)-Vr( 2 -NR;'C(O)-V4-Ar, 30 -C(O)-V\ ( 2 -C'(O)-V4-Ar , -C(O)O-VN(R)2 -C(O)O-V4-Ar, -10 -O)-C(O))-V5-N(R")2, -O-C(O)-V4-Ar', -C(O)N(R 5 )-VS-N(R 5)2, -C(O)N(R')-V4-Ar', -0-[C11]p-O- and -[CH2]q-. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryI groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl 5 group and rings A-Z5, include halogen, cyano, nitro, Cl-C0 alkyl, CI-CIO 50 3 haloalkyl, amino, Cl-C10 alkylamino, C1-Cl0 dialkylamino, -OR, -Ar -V 4 -Ar , -V-OR -. -O(Cl-C10 haloalkyl), -V 4 -O(Cl-C10 hlallkyl), -O-V 4 -Ar 3 ,

-O-[CH

2 ]p-O- and-[CIH1 2 ]q-. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the 10 alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, nitro, Cl-C 0 alkyl, C1-(10 haloalkyl, amino, Cl-C 0 alkylamino, Cl-CI1 dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, CI -10 alkoxy, -O-[CH 1 2]pO- or -[CH]q-. Alternatively certain specific substituents for each of the aliphatic group, the aryl and the heteroaryl groups represented by R4, 15 including the alkyl group, the arylalkyl group, the heteroarylalkyl group and rings A-Z5, include halogen, cyano, amino, nitro Ar 3 , Cl -C6 alkl. Cl -C6 haloalkyl, Cl C6 alkoxy, hydroxv and Cl-C6 haloalkoxy. Alternatively certain specific substituents each of the aliphatic group, the aryl and the heteroaryl groups represented by R 4 , including the alkyl group, the arylalkyl group, the heteroarylalkyl 20 group and rings A-Z5, include -OH, -OCH 3 , -OC2Hd and -O-[CH 2 ],-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 and R4 are each independently -11, -OH, -SHL a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsuhstituted lower alkylthio 25 group, or a substituted or unsubstituted lower aliphatic group. Specifically, R5 and R\ are each independently -11; -OH; a halogen; or a lower alkoxy or lower alkyl group. More specifically, Ra and R are each independently -H, -OH or a halogen. Even more specifically, R and R' are each independently -H Each of R and R independently is -, a substituted or unsubstituted 30 aliphatic group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. Alternatively, R' and R 4 taken together with the nitrogen atom of -NR R 4 form a substituted or unsubstituted non-aromatic -11 heterocyclic group. In some specific embodiments, each of R' and R independently is -H, an optionally substituted aliphatic group or an optionally substituted phenyl group. In some specific embodiments, each of R' and Ra independently is -H, an optionally substituted alkyl group or an optionally 5 substituted phenyl group. In other specific embodiments, each of R' and R independently is -H or a CI-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 RI and R independently are as described above for variable R4. Examples of suitable substituents for the non-aromatic 10 heterocyclic group represented by -NR 7

R

4 include halogen. =0, =S, =N(CI -C6 alkyl), CI-C6 alkyl, CI-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, (Cl-C6 alkoxy)carbonyl. (Cl-C6 alkyl)carbonyl, Cl-C6 haloalkoxy, amino, (CI-C6 alkyl)amino and (CI-C6 dialkyl)amino. Certain specific substituents for the non aromatic heterocyclic group represented by -NR R include halogen, Cl-(6 alkyl, 15 Cl-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 n is 1, 2, 3, 4. 5. 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Specifically, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Alternatively. n is 1,2, 3, 4, 5 or 6. Alternatively, n is 5, 6, 7, 20 8, 9 or 10. Alternatively, n is 1, 2, 3 or 4. Alternatively, n is 2 3 4 or 5. m is 1, 2. 3, 4, or 5, specifically 1, 2, 3 or 4. Each p is independently 1, 2, 3 or 4, specifically 1 or 2. Each q is independently 3, 4, 5 or 6, specifically 3 or 4. Each p' is independently 1, 2, 3 or 4, specifically I or 2. 25 Each q is independently 3, 4, 5 or 6, specifically 3 or 4. Each Vo is independently a C1-C1 0 alkylene group, specifically CI-C4 alkylene group. Each Vi is independently a C2-CIO alkylene group, specifically C2-C4 alkylene group. 30 Each V 2 is independently a Cl-C4 alkylene group. Each V 4 is independently a (l 1-(71 alkylene group, spec icaly a Cl-C4 alkylene group.

- 12 Each V 5 is independently a C 2 -CIO alkylene group, specifically a C2-C4 alkylene group. Each Arl is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or morc substituents selected from the group 5 consisting of halogen, alkyl, amino, alkVlamino, 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 substituents selected from the group consisting of halogen. Cl-C6 alkyl, amino, C1 C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 10 haloalkoxy, C-C6 alkoxycarbonyl, CI-C6 alkylcarbonyl and C-C6 haloalkyl. More specifically, ArI is a phenyl group optionally substitutcd 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, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl-C6 haloalkyl. 15 Each Ar 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, CI-C6 alkyl, CI-C6 haloalkyl, hydroxy, CI-C6 alkoxy, nitro, cyano, CI-C6 alkoxycarbonyl, CI-C6 alkylearbonyl, Cl-C6 haloalkoxy, amino, CI-C6 alkylamino and C l-C6 dialkylamino. 20 Each Ar 3 is independently an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxv, haloalkoxy and haloalkyl. Specifically, each Ar, is independently an aryl group or a heteroaryl group, each of which independently is 25 optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C0I alkyl, C-C10 haloalkyl, hydroxy, CI-C!0 alkoxy, nitro, cyano, Ci-C10 alkoxycarbonyl, Ci-CI alkylcarbonyl, Cl-C 10 haloalkoxy, amino, Cl-C 10 alkylamino and Cl-C I dialkylamino. Even more specifically, each Ar 3 is independently an aryl group or a heteroaryl group, each of which 30 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C-C4 alkyl, CI-C4 haloalkyl, hydroxy, C-C4 - 13 alkoxy, nitro, cyano, CI-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, CI-C4 haloalkoxy, amino, Cl -C4 alkylamino and Cl-C4 dialkylamino. Each R 4 is independntly i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more 5 substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy. nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarhonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino. alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and 10 alkylcarhonyl. Specifically, each RY 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. Cl-CO alkyl, amino, C-C6 alkylamino, Cl-CO dialkylamino, Cl -CO alkoxy, R, cyano, hydroxy, Cl-C6 haloalkoxy, C1-CO alkoxycarhonyl, Cl-C6 alkylcarbonyl and Cl 15 C6 haloalkyl; or iii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C 1-C6 alkylamino, Cl-Cl dialkylamino, Cl-CO alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl-CO alkoxycarbonyl and Cl-C6 alkylcarbonyl. More specifically, each R is independently i) hydrogen; ii) a phenyl group optionally substituted with 20 one or more substituents selected from the group consisting of halogen, Cl-CO alkyl, amino, Cl-CO alkylamino, Cl-CO dialkylamino, Cl-CO alkoxy, nitro, cyano, hydroxy, Cl-CO haoallkoxy, Cl-C6 alkoxycarbonyl, Cl-CO alkylcarbonyl and Cl Co haloalkyl; or iii) a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, CI-C6 25 alkylamino, Cl-Cl dialkylamino, Cl-C6 alkoxy, nitro, cyano. hydroxy, CI-C6 haloalkoxy, Cl-C6 alkoxycarhonyl and Cl-C6 alkylcarbonyl. Each R 3 is independently R31 -CO 2

R

3 0 , -SO 2 R34 or -C(O)R 30 ; or -N(RI)2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R 3 1 is independently R ,or -N(R ) 2 is an optionally 30 substituted non-aromatic heterocyclic group. Suitable substituents for the non aromatic heterocyclic group represented by -N(R 31 )2 include halogen, O, =S, =N(CI-CO alkyl), Cl-C6 alkyl, Cl-CO haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, -14 cyano, (CI-C6 alkoxy)carbonyl, (CI-C6 alkyl)carbonyl, Cl-C6 haloalkoxy, amno, (CI-C6 alkyl)arino and (C1-C6 dialkyl)amino. Certain specific substituents for the non-aromatic heterocyclic group represented by -N(R 3 )2 include halogen, C1-C6 alkyl, Cl -C6 haloalkyl, hydroxy, Cl -C6 alkoxy, nitro, cyano, (Cl1-C6 5 alkoxy)carbonyl, ((C1-C6 alkyl)carbonyl, Cl1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (Cl-C6 dialkyl)amino. Each R7 is independently i) an aryl group or a heteroaryl group, each of which independently is optionally substituted optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, 10 alkylamino. dialkylamino, alkoxy, nitro, cyo, , hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino. dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Specifically, each R 32 is 15 independently i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, Cl-C6 alkylamino, C1-C6 dialkylamino, CI-C6 alkoxy, nitro, cyano, hydroxy, CI-C6 haloalkoxy, C1-C6 alkoxycarbonyl, Cl -C6 alkylcarbonyl and Cl -C6 haloalky; or ii) a Cl-C 0 alkyl group optionally 20 substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, Cl -C I dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl -C6 alkoxycarbonyl and C-C6 alkylcarbonyl. More specifically, each R2 is independently i) a phenyl group optionally substituted with one or more substituents selected from the group 25 consisting of halogen, Cl -C6 alkyl, amino, C-C6 alkylamino, Cl1-C6 dialkylamino. Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy and C1-C6 haloalkyl; or ii) a C1-Cl0 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-(C6 alkylamino, Cl-CI dialkylamino, C T-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C-C6 30 alkoxycarbonyl and C1-C6 lkylcarbonyl. Each R is independently i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted - 15 with one or more substituents selected from the group consisting of halogen, Cl -C6 alky, C1-C6 haloalkyl, hydroxy,. Cl-C6 alkoxy, nitro, cyano Cl-C6 alkoxycarbonyl, Cl-CO alkylcarbonyl, C1-C6 haloalkoxy, amino, (1-C6 alkylamino and C1-C6 dialkylamino: or iii) a C 1-Cl 0 alkyl group optionally substituted with 5 one or more substituents selected from the group consisting of halogen, Cl -C6 haloalkyl, hydroxy, C1-CO alkoxy, nitro, cyano, C1 -CO alkoxycarbonyl, C I -C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Each R independently is R -CO2R 0, -SO 2

R

4 " or -C(O)R44; or -N(R4)2 10 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment, each R independently is R4, or -N(R 4

)

2 is an optionally substituted non-aromatic heterocyclic group. Suitable exemplary substituents, including specific exemplary substituents, for the non-aromatic heterocyclic group represented by -N(R )2 are as described above for the non-aromatic heterocclic 15 group represented by N(R )2 Each R 42 independently i i) a aarl 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, Cl -C6 alkyl, C1 C6 haloalkyl, hydroxy, Cl -C alkoxy, nitro. cyano. C1-C6 alkoxycarbonyl, C1-C6 20 alkylcarbonyl, C1 -CO haloalkoxy, amino, Cd-C6 alkylamino and CI -CO dialkylamino; or ii) a Cl -C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-CO haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, Cl -CO alkoxycarbonyl, Cl-CO alkylcarbonyl, C -CO haloalkoxy, amino, Cl-C6 alkylamino and Cl-C6 dialkylamino. 25 Each R" independently is i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino. alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally 30 substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino. alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonvl and haloalkyl. Specifically, each R 5 0 is - 16 independently i) hydrogen; ii) an aryl group or a heteroaryl group, such as a phenyl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen., C1-C6 alkyl, Cl-C6 haloalkyl, hydroxy. CI-C6 alkoxy, nitro, cyano, Cl-C6 alkoxycarbonyl, C-C6 5 alkylcarbonyl, C1-C6 haloalkoxy, amino, Cl-C6 alkylamino and C1-C6 diialkylamino; or iii) a Cl-C 10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, Cl-(6 alkoxy, nitro, cyano, Ci-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl, Cl-C6 haloalkoxy. amino, Cl-C6 alkylamrino and Cl-C6 dialkylamino. 10 Each RNI independently is R , -CO 2 R 0 , -SO2R 50 or -C(O)R'., or -N(R) 2 taken together is an optionally substituted non-aromatic heterocyclic group. In a specific embodiment. each R 51 independently is R5", or N(R ') is an optionally substituted non-aromatic heterocyclic group. Suitable exemplary substituents, including specific exemplary substituents, for the non-aromatic heterocyclic group 15 represented by -N(R 5 ) are as described above for the non-aromatic heterocyclic Each R 2 independently is i) an aryl group or a heteroaryl group, such as a phenyl group, each ol which independently is optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, 20 dialkylamino, alkoxy, nItro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy. haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Specifically, each RE independently is i) an aryl group 25 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, (1-C6 alkyl, C-C6 haloalkyl, hydroxy, C I-CO alkoxy, nitro, cyano, Cl-CO alkoxycarbonyl, Cl-C6 alkylcarbonyl, Cl-CO haloalkoxy, amino, Cl C6 alkylamino and C1-C6 dialkylamino; or ii) a Cl-C 10 alkyl group optionally 30 substituted with one or more substituents selected from the group consisting of halogen, C1-CO haloalkyl, hydroxy, Cl-CO alkoxy, nitro, cyano, Cl-CO - 17 alkoxycarbonyl, C-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, Cl-C6 alkylamino and C1-C6 dialkylamino. R and R' are each independently i) -H; ii) a CI-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of 5 halogen, -OH, -CN, -NCS, -NO 2 , -NI-, CI-C6 alkoxy, Cl-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 , CI-C6 alkoxy, CI-C6 haloalkoxy, CI-C6 aliphatic group and Cl-C6 haloahphatic group. Alternatively, R and R taken 10 together with the nitrogen atom of NRR' fom a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; - ; -CN; -CS-NO 2 ; -NH2; Cl-C6 alkoxy; C-C6 haloalkoxy; Cl -(6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen. -011, -CN, -NCS, NO2 15 NlH Cl -C6 alkoxy, Cl-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, -OI, -CN, -NCS, -NO 2 , -Ni- 2 , Cl-C6 alkoxy, Cl-C6 haloalkoxy, Cl-C6 aliphatic group and CI -C6 haloaliphatic group. In a specific embodiment, R and R' are each independently i) 20 -H1; ii) a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO2, -NH 2 , Cl-C6 alkoxy, Cl-C6 haloalkoxy, aryl and heteroaryl; or iii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NI2 Cl-C6 alkoxy, Cl-C6 haloalkoxy, Cl-C6 25 aliphatic group and Cl-C6 haloaliphatic group. Alternatively, R and R' taken together with the nitrogen atom of NRR' form a non-aromatic heterocVclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH; -CN; -NCSH -1 - 2 ; Cl -C6 alkoxy; C1-C6 haloalkoxy; Cl-C6 aliphatic group optionally substituted with one or more 30 substituents selected from the group consisting of halogen, -O1, -CN, -NCS, -NO 2 , -NH1, Cl-C6 alkoxy. CL-C6 haloalkoxy. aryl and heteroaryl; and a phenyl group optionally substituted with one or more substituents selected from the group - 18 consisting of halogen, -OH, -CN, -NCS, -NO_ -NH, Cl-C6 alkoxy,. Cl-C6 haloalkoxy, Cl-C6 aliphatic group and Cl-C6 haloaiphatic group. In another specilic embodiment, R and R are each independently -H; a C I-C6 aliphatic group optionally substituted with one or more substituents selected from the group 5 consisting of halogen, phenyl, hydroxy, Cl-C4 alkoxy, C-C4 haloalkoxy and benzyl; phenyl; or benzyl. Specific examples of each R and R' include -H, Cl-C4 alkyl, phenyl and benzyl. A second set of values for the variables in Structural Formula (I) is provided in the following paragraphs: 10 Y is -1H, -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 I are as described in the first set of values for the variables of Structural Formula (I). 15 R 2 and R' taken together with the nitrogen atom of N(RR ) 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 NR2R3 are as described in the firs set sof values for the variables of tructural Formula (I) 20 Values and preferred values for the remainder of the variables of Structural Fornula (I) are each independently as described above for the first set of values. A third set of values for the variables in Structural Fomula (1I) is provided in the following paragraphs: Y is -lH, -C(O)R, -C(O)OR or -C(O)NRR, preferably -H. 25 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 set of values for the variables of Structural Fornula (I). R and R 3 taken together with the nitrogen atom of N( R) fonn a 5- or 6 30 membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents, including specific substituents, for the non-aromatic - 19 heterocyclic ring represented by - itNRR are as described in the first set of values for the variables of Structural Formula (1).

R

5 and R 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 () is provided in the following paragraphs: Each of Y, R', R 2 , R, Ra and Rh independently is as described above for the 10 third set of values. X is -(CRlR)"-Q-; Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, -C(S)O-, -C(S)S-, -C(O)NR-, NR -- NR 4 C(0)-, -NR&C(O)NR- -OC(O)-, -SO, -SO-, -S(O-, -SO2NRS-, or -NRSO2-; and R 4 is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroarl 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 R)n-; 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 is a substituted or unsubstituted aryl group or a substituted or substituted heteroary I group. n is 1, 2, 3, 4, 5 or 6. Values and preferred values ot the remainder of the variables of Structural 25 Fornula (I) are each independently as described above for the first set of values. In a second embodiment, the ceramide derivative is represented by Structural ForuIVa (II) (III), (IV), (V), (VI), (VI) (VI) (IX) (X), (XI), (I (I) or

(XIV\):

Oy OH R1N(R 2 R 3 ) R1N(RFR 3 ) HN HN

//R

4 (CRR 6 )-R 4 OH

R

1

NO'P

3 HN O> - ((FIV)xQ OH OH

R

1 NRR)R1 N(R 2 R 3 ) HN 0HN ) -- (C I' ' In ' ,R 4 0 -R 4 0 (V), 0 (VI)7 O H O H R~ N(R 2

R

3 ) R(R 1 HN HN )--N(RJR 4 )

-(CH)-R

4 0 (VII), 0 (V/ill) -21 OH Rl ~ N(R 2

R

3 ) HN (C H 2 )-O 4 OH OH Rl NR2R3 RiN(R 2

R

3 ) HN 0 HN )--(C H 2 )nJ

R

4 z -4 0 NX, 0 (XI), 0OH

R

1 N(R 2

R

3 ) H N 5 0 (I) - 22 OH

R

1

N(RR

3 ) HN 0- (CH2)k-R O (XIll) and OH R' N(R2R 3 ) HN N (CH2)k-Rl 0 H O (XIV), or a phaImaceutically acceptable salt thereof. A first set of values for the variables 5 of Structural Formulas (I) - (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. RI is an optionally substituted ary 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 are as described in the first set of values for the variables of Structural Formula (I). R and R' taken together with the nitrogen atom of N(R R 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 arc as described in the first set of values for the variables of Structural Formula (I). For Structural Formula (II), in one specific embodiment, R 4 is an optionally substituted aliphatic group. In another specific embodiment, R 4 is an an optionally substituted aliphatic group, an optionally substituted aryl group, an optionally 20 substituted heteroaryl group, -CN, -NCS, NO or a halogen. In one further aspect of this another specific embodiment, R 4 is an optionally substituted aryl group or an - 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 dcscribcd in the first set of values for the variables of Structural Fonnula (I). 5 Each R 4 in Structural Fornulas (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 R4 independently is an an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted lower 10 arylalkyl group or an optionally substituted heteroarylal kyl group. Examples of suitable substituents, including specific substituents, for the aliphatic. the aryl and the heteroaryl groups represented by R4 are as described in the first set of values for the variables of Structural Formula (I). Each of R 5 and R" in Structural Formulas (III), (IV) and (V) are each 15 independently -H, -OH a halogen a CI -C6 alkoxy group or a Cl -C6 alkyl group. Each R 4 in Structural Formulas (IlI) and (VIII) independently is an optionally substituted cyclic alkyl (e.g., C3-C8) group, an optionally substituted cyclic alkenyl (e.g., C3-C8) group, an optionally substituted aryl group, or an optiona'ly substituted heteroaryl gro up, -CN, -NCS, -NO2 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 hcteroaryl groups represented by R 4 arc as described in the firs st of values for the variables of Structural Formula (I). Each Rt in Structural Fonulas (VII) and (XII) is independently -H or Cl 25 C6 alkyl. For Structural Formula (IV), values and preferred values of each of Q and Ri independently are as described above in the first st of values for Structural Fonnula (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 5 (CO)-, -C(O)NRi- 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 Fornula (IV), Q is -0-, -S-, -C(O)-, -C(S)-, -C(O)O-, - 24 -C(S)O-, -C(S)S-, -NR (CO)-. -C(O)NR- or -OC(O)-; and R8 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)-, -C(S)-, -NR(CO)- or -C(0)NR1-; and R 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(O)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(C )- or -C(O)NR 8 - and RA is optionally -Il, an optionally substituted aliphatic group or an optionally substituted phenyl group: and R 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 are as described in the first set of values for the variables of Structural 15 Formula (I). Each Rm 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 Cl-C6 alkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of with one or more substituents selected from the group consisting of halogen, cyano. nitro. Cl C 10 alkyl, Cl-C 10 haloalkyl, amino, C1-C10 alkylamino, C -C 10 dialkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy, Cl -10 alkoxy, -0-[CH21 0 -- or Each k in Structural Formulas (XIlI) 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 Fornlas (II)-(XIV) are each independently as described above in the first set of values for Structural Formula (I).

- 25 A second set of values for the variables of Structural Formulas (II) - (XIV) is provided in the following paragraphs: )2 Each of Y, Q, R , R 3 , R 4 , R 5 , R', R, R8 and R ?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 noting of halon cyano, nitro, alkyl, haloalkyl, -OR, -SR I( N(R(R )2, -V-Ar', -O-V, Ar', -O-V,-N(R- ' )2, -S--Vr)Ar', -S-V,-N(R )2, -N(RM)-Vr~Ar', -N(R 3 )-V ,N(R 3 )2, -O-[CH]p~-O-. S-[CH 2 ]p-S-, or -[CH 2 ]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, -OI, alkoxy, -O-[CH2]p-O- and -[CH 2 ]q-. Specifically, the "alkyl" referred to in the the alkyl, alkoxy. haloalkyl, alkylamiino and dialkylamino groups of the exemplaryl substitutents independently is Cl-C6 alkyl. 15 Ari is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkvl, amino, Cl C6 alkylamino, C1-C6 dialkyl amino, Cl -C6 alkoxy, nitro, cyano, hydroxy, C l-C6 haloalkoxy, Cl -C6 alkoxycarbonyl, 1 -C6 alkylcarbonyl and Cl-C6 haloalkyl. Preferably Ari is a phenyl group each optionally substituted with one or more 20 substituents selected from the group consisting of halogen, Cl-C6 alkyl, amino, C1 C6 alkylamino, C I -C6 dialkylamino Cl -C6 alkoxy, nitro, cyano, hydroxy, C1 -C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Each R 30 is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of 25 halogen, Cl -C6 alkyl, amino, Cl1-C6 alkylamino, Cl -C6 dialkylamino, Cl1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, CI-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl; or iii) a C1-Cl0 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, Cl-C6 alkylamino, Cl -C6 dialkylamino, Cl -C6 alkoxy, nitro, 30 cyano, hydroxy, CI-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl-C6 haloalkyl.

- 26 Each R is independently RU, 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 -NR 2 R3 are as described in the first set of values for the variables of Structural Formula (1). 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 (1). A third set of values for the variables in Structural Eourmulas (1l)-(XIV) is provided in the following paragraphs: 10 Each ofY, Q, R', R 4 , R, R 6 , R', R R' 0 " R " R 3 ' and Ar independently is as described above for the second set of values for the variables o Structural Fornulas (1) -I (NIV). Each N(R 2 R3) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected 15 from the group consisting of halogen, CI-CS alkyl, Cl -C haloalkyl, hydroxyl Cl C5 alkoxy, nitro, cyano, Cl-C alkoxycarbon yl, Cl-C5 alkylcarbonyl or CI-C5 haloalkoxy, amino, Cl-CS alkylamino and CI-C5 dialkvlamino. Values and preferred values of the remainder of the variables of Structural Formulas (II)-(XIV) are each independently as described above in the firs set of 20 values for Structural Fonmula (I). A fourth set of values for the variables in Structural Formulas (ll)-(XIV) is provided in the following paragraphs: Fach of Y, Q, R , R4, R, R4, R, R , R ., R 3, R and Arl independently is as described above for the third set of values for values for the variables of 25 Structural Fomulas (II) - (XIV). Each -N(RR ) is an unsubstituted pyrrolidinyl, a/et id inyl, piperidinyl, pi pera/inyl or morpholinyl group. Values and preferred values of the remainder of the variables of Structural Fornulas (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 (1)-( 111) is provided in the following paragraphs: - 27 Each of Y, Q, R2 R 3 , R 4 , R 5 , R 6 , R7, R8, R 1 0 ., R 30 , R 3 and Ar' independently is as described above for the fourth set of values for the variables of Structural Formulas (II) - (XIV). R1 is a phenyl group optionally substituted with one or more substituents 5 selected from the group consisting of -OR3 0 (eg., -OH, -OCH 3 , -OC 2

H

5 ), alkyl (e.g., Cl-CI0 alkyl) and -O-[CH 2 ]pO-. Specifically, Rl 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 (II)-.(XIV) is provided in the following paragraphs: Each of Y, Q PP, R, R R, R , R, R1, R , R34 R 3 and Ar independently is as described above for the fith set of values for the variables of Structural 15 Formulas (1) - (XIV). Each R 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, -ORv4, -ArT, -V-Ar', -V-OR 5 , -O(haloalkyl), -VO(haloalkyl),

-O-V

4 -Ar , -O-[CH2]p-O- and -[CH 2 ]-; 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, -Ar, -V-Ar 3 , -V-OR 0 , -O(haloalkyl). -V-O(haloalkyI), -O-V-Ar', -O-[CH 2 ]'-O- and 25 -0 m . Each R4 for Structural Fornnulas (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, Ara, -OR-J, 30 -O(haloalkyl), -SR 0 , -NO2, -CN, -N (R)2, -NRE C(O)R30, -C(O)R 5 0 , -C(O)OR ,

-OC(O)RS

1 , -C(O)N(R 5 )2, -VIAr', -V-OR-', -VO 4 -(haloalkyl), -VrSR 5 0 , -V-NO2,

-V

4 -CN, -V 4

-N(R

5 ')2, -V 4 -NR 5 C(O)R 5 0, -V 4 -C(O)R 5 0, -V-CO2R4, -V-OC(O)R 5

,

-28 -rC(O)N(R")2-, -O-V,-Ar', -V NR)2, -S-VrIra -S-Vr-N(R)2 -N(R )-V 4 rr, -N(R )-V 5 -N(R')2 -NR' C(O)-V-N(R')2, -NR C(O)-V-Ar 3 , -C(O)-V 5N(R'), -C(O)-V 4 -Ar 3 , -C(O)O-V 5 -- N(R5) 2 , -C(O)O-V 4 -Ar', -- ()NR-O-C( O-CO)Vera -CONR)V-N(R")2, 5 -C(O)NRS')-V 4 -Ar, -O-[CH2pO- and -[CH2]q-. Specifically, R 4 is an optionally substituted aryl or an optionally substituted heteroaryl group, each optionally substituted with one or more subsihtuents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR5(, -Ar 3 , -V-A4, -V-OR; 0 , -O(haloal kyl) -V 4 -O(haloalkyl), -O-V 4 -Ar 3 . -O-[CH 2 ]p-O 10) and W Cbl~q. Each R for Structural Formulas (III) and (VIII) independently is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, amino, alkylamino, dialkylamino, -OR 4, -Ar 3 , -V 4 -Ar 3 , 15 -V-OR", -O(haloalkyl), -Va-O(haloalkyl), -O-V-Ar., -O-[CH 2 ]p-O- and -[CH2]- 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 Fomulas (Il)-(XIV) is 2)0 provided in the following paragraphs: Each of Y, Q, R', R 2 , R , R 4 , R5, R', R', R', R ", R, R and Ar' independently is as described above for the sixth set of values for the variables of Structural Fonnulas (II) - (XIV). Each Ar 3 is independently a phenyl group optionally substituted with one or 25 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, CI-C6 haloalkoxy, CI-C6 alkoxycarbonyl, C-C6 alkylcarbonyl and Cl C6 haloalkyl. Fach R 0 is independently i) hydrogen; ii) a phenyl group optionally 30 substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl, amino, Ci-C6 alkylamino, CI-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, CI-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, CI-C6 - 29 alkylcarbonyl and Cl-C6 haloalkyl: or iii) an CI-CIO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl -C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl 5 and C -C 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 (I). An eighth set of values for the variables in Structural Fornulas (IlH-(XIV) is 10 provided in the following paragraphs: Each of Y, Q, R', R , R, R 3 , R, s. R R 3 0. R, R5 , Ar' and Ar 3 independently is as described above for the seventh set of values for the variables of Structural Formulas (II) (XIV). Each -N(RR ) is independently N-pyrrolidinyl or N-morpholinyl. 15 R4 for Structural Formula (II) is an aliphatic group. Specifically, R' is a C6 C18 alkyl group or a C6-C8 alkyl group (e.g., C6, C7, C8, C9 or C10 alkyl group). Each R4 for Structural Fonulas (IX) and (X) is independently an alkyl group, or an optionally substituted phenyl group. Specifically, each R4 is an unsubstituted alkyl group (e.g., Cl-C10 alkyl), or a phenyl group optionally 20 substituted with one or more substituents selected from the group consisting of-OH, -0C11 3 and OC2H 5 . Fach \ for Structural Fomulas (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", -Ar, -V 4 -Ar 3 , -V-OR 5 0 , -O(haloalkyl), -V 4 -O(haloalkyl), -O-V 4 -Ar 3 , -O-[CH2-O- and -[CHL 2 q Specifically, the "alkyl referred to in the the alkyl, alkoxy, haloalkyl, alkylamino and dialkylamino groups of the exemplaryl substitutents independently is Cl-Cl0 alkyl, or, alterantively, Cl-C6 alkyl. 30 R 4 for Structural Formula (Ill) or (VIII) 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.

30 Specifically, the optionally substituted biaryl group is an optionally substituted A biphenyl group. Alternatively, -(CH 2 ),-RS is H2 , 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 RW for Structural Formulas (XIII) and (XIV) is independently a C-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 a as described 1 0 in the first set of values for R4 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 RS for Structural Formulas (XIII) and (XIV). For Structural Formulas (III) and (VIII). m is 1, 2 or 3. For Structural Formulas (IX) and (X), each n is independently 1, 2, 3, 4 or 5. 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 , R4, R3, R 6 , RI, R7 0 , R1 , R , R 4 , R, ".R . R, R", RI, Ar, Ar 2 , and Ar 3 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: 30 - 31 OH 0H No NH 0 0== ~C ,CH,. OH ND NH HO 0 (GHh CH 3 OH N0 0 - 32 OH N0 O N HN A 0 and OH ON xx 5 and pharma~ceutically acceptal sAltsA thereof,% wherein each ring A is optionally subitiiutedl with one orn more substituents selcte d fro m the grou consstin of haognalylan akoy It is to be understood that when any compournd is, referred tolherein by name orhUUC struture sovaes\hdrates And polymrpIhs thereof'1 areicuded. 10 Thei ceramide derivative disclosed herinm miay cotinoe or more chiral center and/or double bnd and, thereforeex\ist as, strosoes;uch as doublle bonid ioes(e.gemti iomers),l enlantiolmrs or \I)I diaseemr.We ch ceramde drivatves predicted or naImd herinI without iniaigthe steeohemstyit is to be unlderstoodta seemeial pure forms (e.g,., 15 geometricall pure, enantimericall pure, or diastereomerically pure) anld s'tereoisomerlic ixtures are eCncomssed For ex'ample, th1compound rereseted by Stuctural Forula (1) below has chiral cents 1 and 2. Accordingly, the ceramide derivaive depicd by Stuctua Formula (I) include the (1R,2R), (1R, 2S), (1S, 2R) or(IS, 2S) steiomer andmixtures the f. 20 -33 oY R 2 N(R 2 R HN X-R4 0 ( . In some specific embodiments, the ceramide derivatives represented by Structural Formula (I) arc (1 R, 2R) stercoisomers. 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 steroisomers 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 di astereomeri cally- 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%, 900%, 99%0 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 999% 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 acidss. Suitable pharmaceutically acceptable acid addition salts include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, 34 gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, suceinic, p- toluenesulfonic, and tartaric acids). The ceramide derivatives that include one or more acidic groups, such as carboxylic acids, can fKom pharamceuticallv acceptable salts with pharmaceutically acceptable base(s). 5 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 ten "halo" as used herein means halogen and includes chlioro, fluoro, bromo and iodo. 10 An aliphaticc group" is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation. e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between 1 and 20 carbon atoms, typically between I and 10 carbon atoms, more typically between 1 15 and 6 atoms. When cyclic, an aliphatic group typically contains between 3 and 10 carbon atoms, more typically between about 3 and 7 carbon atoms. A "substituted aliphatic group" is substituted at any one or more "substitutable carbon atom". A "substitutable carbon atom" in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms. One or more hydrogen atoms can be 20 optionally replaced with a suitable substituent group. A "haloaliphatic group" is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group. The term alkyll" used alone or as part of a larger moiety, such as "alkoxy", 25 "haloalkyl", "arylalky1", "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 terns "lower alkoxy". "lower haloalkyl", "lower arylalkyl", "lower alkylamine", "lower cycloalkylalkyl", 30 "lower dialkyamine", "lower alkylamino", "lower dialkyamino" "lower alkylcarbonyl", "lower alkoxycarbonyl" include straight and branched saturated chains containing one to six carbon atoms. In some specific embodiments, the -35 "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, independently is Cl C10 alkyl, or, alternatively, CI-C6 alkyl. 5 The tern "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; "dialkylamine" means amine substituted with two alkyl groups; "alkylearbonyl" 10 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 ease may be, substituted with one or more halogen atoms. The ten "halogen" means F, Cl. Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F. 15 The term "aeyl 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 -[CH2j, wherein z is a positive integer, preferably from one to eight, more preferably from one to four. 20 An 'alkenylene group" is an alkylene in which at least a pair of adjacent methyl genes are replaced with -CH= CI. An "alkynylene group" is an alkylene in which at least a pair of adjacent methylenes are replaced with -C C-. The term "aryl group" used alone or as part of a larger moiety as in 25 "arylalkyl", "arylalkoxy", or "aryloxyalkyl", means carbocyclic aromatic rings. The tern "carbocyclic aromatic group" may be used interchangeably with the terns "aryl", "aryl ring" "earboeyelie aromatic ring", "aryl group" and "earboeyelie aromatic group". An aryl group typically has 6-14 ring atoms. A "substituted aryl group" is substituted A any one or more substitutable ring atom. The ten "C.14 30 arVl" as used herein means a monocyclic, bicyclic or trieyclic earboeyelie ring system containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, - 36 anthracenyl. 1.2-dihydronaphthy l, 2,34-tetrahydronaphthyl, fluorenyL, indanyl, indenvl and the like. The term "heteroaryl". "heteroaryl ring", "heteroaryl group" and "heteroaromatic group", used alone or as part ofa larger moiety as in 5 "heteroarylalkyl" or "heteroarylalkoxy", refers to aromatic ring groups having five to fourteen ring atoms selected front carbon and at least one (typically I - 4, more typically I 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 rns. 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 alkyl), ) and S. Examples of monocyclic heteroaryl groups, for example, for the heteroaryl 15 groups represented by each of R', R 2 , R 3 , R 4 , R', R 0 , R 2 , R, R3, R , R4 , R , R,Ar i, Ar 2 and Ar include furanyl (eg, 2-furanyl, 3-furanyl), imidazolyl (e.g., AN 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), tetrazolyl (etg etrazolyl) 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', R2, R , R, R, R"

R

2 1 , R', R", R, R , R", R 0, R, Ar, Ar2 and Ar, include pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups, for example, for the heteroaryl groups represented by each ofA R, R , , IR, R i, R , R ,Ra", R7,

R

4 R , R', Arl, Ar2 and Ar include carbazolyl, benzimidazolvl, benzothienyl, 30 benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

- 37 Typically, the aryl and heteroaryl groups represented by each of R, R', R'. RR, R , R R , R ,R 2

,R

3 ,R , R 4 R , R, Ar', Ar and Ar 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, It R', RIR R 5 R 4 , R"0 RA, RA R4R R 4 , R 4 2 , R R, Ar Ar and Ar each independently include: A B ___C D Es,-\ N N NN N NN N s N G -- -1 1 N K I 0N N N 0N 10 Q-. S N N N NN N and wherein each of rings A-Z5 is optionally and independently substituted. Suitable substituents for rings A-Z5 are as described above. In a specific embodiment, the 15 aryl and heteroaryl groups, including those represented by each of R, RI, RI, R, R

R

4 , R 7 , R"', R, ,J 2

R

3 , R , R0, R 4 2 , R 4, R, Ar', Ar 2 and Ar, include monocyclic rings A. B, . F. G, H, I, N, 0 V, and WN, wherein each ring is optional and independently substituted. The aryl and heteroaryl groups, including those represented by each of R. R'. 20 R', R, R, R4, Ri, Rt R',, RR', R4 R 42 , RM4, R 2 , Ar', Ar 2 and Ar 3 , can be optionally substituted. in certain embodiments, the aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected - 38 from the group consisting of halogen, nitro, cyano, hydroxy, C,2, alkyl. C2- 2 0 alkenyl, C 2

-

0 alkynyl, amino, C 1 12 0 alkylarnino, C 20 dialkylamino, C2 alkoxy. (CC Jo alkoxy)C 1 2 0 alkyl, Cs20 haloalkoxy, (C 1 i haloalkoxy)C.20 alkyl and C 1 20 haloalkyl. More specific substituents for the aryl and heteroaryl groups, including those represented by each of R. R', R P R, R , R , R , R, R, R", R", R , R4

R

4 2, RQ,R ,Ar', Ar 2 and Ar , include halogen, nitro, cyano, hydroxy. Ciio alkyl, Ca akenyl, C2- 1alkynyl, amino, C io alkylamino, C 10 diaaminomino, C0 alkoxy, (C alkoxy)C-:: alkyl, C 1 -o haloalkoxy, (C 1 ), haloalkoxy)C 11 0 alkyl and C 0 haloalkyl. More pecific substituents include C 0 alkyl, -OH, C 1 o alkoxy, C-o 0 10 haloalkyl, halogen, Co haloalkox y,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 t welve members, preferably five to seven, i which one or more ring carbons, preferably one or two, are each replaced by a heteroatom 15 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 groupth at latone niroe rng atom. Examples of non-aromatic heterocyclic groups include (tetrahydrofuranyl (e.g, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), [1.31 20 dioxalanyl [ 1,3]-dithiolanyl, [1,3]-dioxanyl, tetrahydrothienyl (eg, 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 (eg., Nmorpholinyl, 2-morpholinyl, 3-morpholinyl), thiomorpholinyl (e.g., N-thiomorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl), 25 pyrrolidinyl (e.g., N-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) piperazinyl (e.g., N piperazinyl. 2-piperazinyl), piperidinyl (e.g., N-piperidinyl), 2-piperidinyl, 3 piperidi nyl. 4-piperidinyl), thiazolidinyl (e.g., 4-thiazolidinyl), diazolonyl and N substituted diazolonyl. The designation "AN on N-morpholinyl, A-thiomorpholinyl, N-pyrrolidinyl, N-piperazinyl, N-piperidinyl and the like indicates that the non 30 aromatic heterocyclic group is attached to the remainder of the molecule at the ring nitrogen atom.

-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. 7148,251; U.S. 6,855,830; U.S. 6,835,831; and U.S. Provisional Application No. 60/3 W370, filed May 31, 2007, the entire teachings of 5 which are incorporated herein by re ference. It is noted that the definitions of ternms provided herein prevail over those of the references incorporated herein by reference. I he ceramide deri ati es 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, transdenally, rectally, sublingually, intravenously, buccally or via inhalation. Typically, the compounds are administered orally or intravenously. As used herein a "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, such as a companion animal (e.g., dogs, 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 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 processing. 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 for action (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.

- 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 1, 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 dlose 10 ranges and/or schedules for administration. For example, assays for measuring blood glucose levels are commercially available (e.g.. OneTouch" Ultra", 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 e al OCbes. Res. 11 (1 ):75 (2003); Rubino et al., Ann. Surg 240(2):89 (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 incorporated herein by reference) and Table A below for equivalent surface area dosage factors. Iroml: 1 Muse Rat lonkey Dog I uLman (2g) (150 g) 1 (35 kg) (8 kg) (60 kg) IKfo: Mouse 1 1/2 1/4 1 /6 1/12 To: Rat 1 1/2 1/4 1 /7 To: Monkey 4 2 1 3/5 '3 To: Dog 6 4 To: Human 12 7 3 2 1 -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 ommencing 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 administcrcd either simultaneously as a single dosage forn 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 the compounds of the invention include, but are not limited to, over-the counter pain medications, antibiotics, antimicrobials, thiazide diuretics, angiotensn-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, crythromycin, chloramphemicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofioxacin, 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 trichilormethiazide. Examples of angiotensin-converting enzyme inhibitors include 30 benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril quinapril ramipril and trandolapril.

- 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 recipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and 5 butyl parabens, can also be included. More complete listings of suitable recipients can be found in the Handbook of Pharmaceutical Excipients (5" Ed., Pharmaceutical Press (2005)). The carriers, diluents and/or recipients 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 fonn and can be prepared by any suitable method known to the skilled artisan. In general, the pharmaceutical compositions are prepared by unifTrmly and natly bringing into association the compounds disclosed herein with the carriers, diluents and/or recipients 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, igum or l ne. A syrup formulation will generally consist o a suspension or solution ot 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 fonn 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 for 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 ol a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums. cellulose, 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 - 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 phannaceutical 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 pharmaceutical compositions of the invention can be fonrulated for injection, or for transdermal or trnasmucosal administration. Illustrative of various modes of administration methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18" ed. 10 (1990). the disclosure of which is incorporated herein by reference. The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which include the tenn "comprising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or 15 claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner. The invention is illustrated by the following examples which are not intended to he limiting in any way. 20 EX\M PLHF TIO>N Fample 1. Synthesis of Ceramide Deri atives: General Methods for the Preparation of Amde Analogs 25 Example IA. Synthetic Route 1 - 44 O N-OH HQ

NH

2 0O A B ( Scheme l1) 5 \Method 1 A mixture of Compound A (1 mmol), such as (1 R 2R)-2-amino-1I-(2,3 dihydrobenzofjp][[,4]dioxin-6-yl)-3-(pyrrolidin-1I-yl )propan- 1-ol, an acid (Compound B, 1 .2 mmol), DCC (dicyclohexylcarbodiimide, 1 .2 mmol) and HOBT (1 -hydroxy benzotriazole, I.2 mmol) was dissolved in CH2LCl2 (5 ml). The mixture 10 was stirred at room temperature and monitored by TLC (thin liquid chromatography) for completion. After completion the mixture was filitered and purified by column chromatography using, for example, a mixture of

(CH

2 C2/MeOH/NH 4 0H). 15 method 2 A mixture of Compound A (1 mmol), such as (IR, 2R)-2-amino-1-(2,3 dihydrobenzo P][1,4]dioxin-6-yl)-3-(pyrrolidin- I -yl )propan-I -ol, an acid (Compound B, 1.2 mmol) and DCC (dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CiC13 (5 ml). The mixture was placed in the microwave reactor (T 20 120 *C, time Imi) and it was then filtered and purified by column chromatography using, for example, a mixture of (H2Cl2/MeOH/NH 4 0H). 15 Method 3 A mixture of Compound A (I mmol), such as (1 R, 2R)-2-amino- 1-(2,3 25 dihydrobenzo[p]1[1 ,4]dioxin-6-yl)-3 -(pyrrolidin- 1-yl)propan- 1-ol, an acid chloride of Compound B, 1.2 mmol) and K2CO 3 (2 mmol) was suspended in THF (5 ml). The mixture was stirred at room temperature and monitored by TLC for completion. After completion, the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH2Cl2/MeOH N) 4 01).

- 45 Example l B. Snithetic Route 2 0 0~Nb HQ OH HQ 0 NR 2 3 0 NR;D 1 0 + X HN 0

NH

2 0RO A D 5 (Scheme 2) Compound A, such as (IR, 2R)-2-amino-l-(2,3-dihydro-benzo[1,4] dioxin 6-yl)-3-pyrrolidin- 1 -yl-propan-1-ol, was coupled with a variety of N hydroxysuccinamide esters (Compound D prepared according to the method below) 10 in methylene chloride under an atmosphere of nitrogen, for example, for 1 8 to 24 hours depending on the ester used. IPrepartionf~l of' In)"\ sucmamide esters 0 0 Nc=N 00 0 HO NOH N- 0 15 0 (Scheme 3) variouss mono- and di-keto acids were coupled with N-hydroxysuccimide in the presence of N, N'- dicyc lohexylcarbodiimide in ethyl acetate under an 20 atmosphere of nitrogen for 1 8 hours. The products were filtered to remove the dicclohexyILurea. 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 purification. 25 Example 1C. Preparation of Compound A of Schemes 1 and 2 - 46 (1R, 2R)-2-amino-I-(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. 5.855,830, the entire teachings of which are incorporated herein by reference. A general synthetic route for preparing Compound A with various -NR 2 R is depicted 5 in Scheme 4 below. O 0 0 HO OH HO N TBDMSO / OMe ImiaOoee NHCbz HN.. NHCbz DMF NHiCbz OH O 1T30SO0 ____ TBDMS 4OO -700 C-~ b AcOH 0 0 OH OH N O 1,0l 0 O NHCbz O EV 0 NN n n (Scheme 4) Preparation of EII: (R) -benzyl 3,8,8,9,9-pentamethyl-4 10 oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate Imidazole (1.8 g 26.5 mmol) was added to a solution of (R)-benzyl 3 hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiC (tert butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at 15 room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chiroride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers werc washed with brine and concentrated. The crude product was purified by colun - 47 chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). H NMR (400 MHz, CDCl3) 6 0 (s, 611),) 0.9 (s, 91-1), 3.2 (s, 31), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, IH), 5.1 (q, 211), 5.7 (d, 1H), 7.2-7.4 (m, 5H). 5 Preratn of 3111 (1F I -cnv 3 I( I:tbtlietysll ) 1 -(2_3 dihydrobenzo f5 1 4Adioxin6-v I- Inoxoropan-2-Icarbamate. (2,3-dihydrobenzo [] [1,4]dioxin-6-y)manesiunm bromide (26 g, 78 mmol) dissolved in 40 mL of TIHF (tetrahydrofuran) under a nitrogen atmosphere was cooled down to -70 C and (R)-benzyl 3,8.89,9-pentamethyl -4 oxo-2,7-dioxa-3-aza 10 8-siladecan-5-ylearbamate (12.3 g, 31 mmol) dissolved in TIIF (13 ml) were added dropwise. The reaction mixture was allowed to wanm up to -15 OC and left to react for 12 hrs followed by stirring at room temperature for 2 hrs. After cooling the reaction mixture to -40 C it was quenched using aqueous ammonium chloride and the aqueous layer was extracted with EtOAc dried over magnesium sulfate and 15 concentrated. The crude product was purified by column chromatography using 25% EtOAc-hexanes to give pure product (13 g, 88% yield). Hl1 NMR (400) M1iz, CDCl 3 ) = 0 (d, 6H), 0.9 (s, 911), 4.0-4.2 (m, 2H), 4.4 (, 21H), 4.5 (s, 21H), 5.2 (s 2H), 5.4 (in 1 I1). h.1 (d 11 H), 7 (d, 11 H), 7.4-7.7 (m, 7H). 20 liPr rain of ELV be l R. W2-3 tctbtliehliy y -I - 2.3 dihy'drobenzo[fi 1.4hdioxin-6-vil -- hydroxypropan-2-vlcarbamate. (R)-benzyl 3-(tert-butyldimethylsilyloxy)- 1-(2,3 dihydrobenzo[$ [I,4]dioxin-6-yl)- -oxopropan-2-ylcarbamate (3.1g, 6.6 nmol) were dissolved in THF (25 ml) and cooled down to -70 *C under nitrogen 25 atmosphere. L Selectride (13.2 ml of EM solution in THF, 1 3mmol) was added dropwise while keeping the temperature at -70

T

C. After I hour, the reaction was quenched with a IM aqueous solution of potassium tartrate (13 ml) and extracted with EtOAc. The organic layer was evaporated down and the product was purified by column chromatography using 2.5%EtOAc-2%acetone-methylene chloride. The 30 desired diastereomer was obtained in 80% yield (2.5 g). 'H NM R (400 Hz, CDCl 3 ) 6= 0 (d, 6H), 0.9 (s, 91). 3.5 (broad s, IH), 3.7-3.9 (m, 2H), 4.2 (s, 4H), 4.9 (broad s, IH), 5.0 (d, 2H), 5.4 (d, 111), 6.8 (s, 2H), 6.9 (s, 11), 7.2-7.4 (n, 5H).

-48 Preparation of EV: benzyl R 2R -l - 2.3 dihydrobenzof If 1,t4 dioxin-6-vl)-1,3 Benzyl (I R2R)-3-(tert-butyldimcthylsi1yloxy)-(1-2,3 5 dihydrobenzo[p][1,4]dioxin-6-yl)-l -hydroxypropan-2-ylcarbamate (0.5g) was dissolved in a 4 ml mixture of Acetic acid/TIIF water (3/1/1) and left to stir over night. The crude was evaporated down and the product aieotropically dried with EtOAc (10 ml). The crude product was purified by column chromatography using 50% oEtOAc-hexane. The pure product was obtained in 74% yield (0.28 g). H 10 NMR (400 MHz, CDC 3 ) 6= 3.4-3.8 (m, 411), 4.1 (broad s. 4H), 4.8 (s, 11). 4.9 (broad s, 211), 5.7 (broad s, 1H), 6.8 (s, 211), 6.9 (s. 1H), 7.2-7.4 (n, 5H). General procedure for preparation of E\'I and E\VIl Ben/I 1( R. 2R)- -(2.3-dihv droben/o|[ I 4dioxin-6-yl)- 1.3 1 5 (ihydroxypropan-2-ylcarbamate was dissolved in excess pyridine, cooled to -15 'C and one equivalent of methanosulfonyl chloride was added to the mixture. Mixture was stirred about half an hour, and ten equivalents of the amine were added. The reaction mixture was allowed to warm up to room temperature and then heated at 50 "C overnight. The crude was ev aporated down and the product was purified by 20 column chromatography using a mixture of methanol/methylene chloride ammonium hydroxide. The pure compound EVI was then dc-protected by hydrolysis in the microwave, using aqueous NaOHl (40%in weight)/methanol solution as solvent and heating the mixture to 150 "C for about 15 minutes to give the free ammes of the type LVI. The final product was purified by silica-gel column 25 chromatography using a mixture of methanol methylene chloride ammonium Lam i/es ofE /l o'nio wn/s 30 i) I R, 2R -2-amino-1- (2,3-dih drobenzo0[I jlldioxin-6- y -3 IIor holinop opaI 1 -ol - 49 OH N--'' 0 N 0 H 2 HII NMR (400 MHz, CDCl 3 ) S= 2.3 (dd, 211). 2.4 (dd, 211), 2.5-2.6 211). 3.2 (m. 1H), 3.6-3.7 (i, 4), 4.2 (s, 411) 4.4 (d, 1H), 6.5-6.9 (im, 31); NS for C I- O 5 miZ 294.8 [{MH ni) (1 R 9 R)-2-anmo-l-2 -dhhydtohen/offj[1,4]dioxm->- 1)-3-(pipelidm 1_- ylpro an-1ol. OH * 0 10 N H 2 H NMR (400 MHz, CDCl3) 6= 1.4 (broad s, 2H), 1.7 (in. 411), 2.2-2.6 (in. 61) 3. 2 (m, I H), 4.2 (s, 4H), 4.5 (s, I H). 6.7-6.9 (m, 3H). 15 Example ID. Preparation of Substituted Phenoxv Propionic Acids for Compound B in Scheme 1 Example 1 Dl: Preparation of -(4-methon yphenonv)pro pionic acid. 20 ij 3- 4-methox phenoxv propiontnle (1). A 740 g (5.96 mol, 1 eq.) sample of4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 inL, 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 - 50 acrylonitrile. The crude material was recrystallized from TBMIE (tert-butyl methyl ether)l10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of I as white crystals (Yield: 89.48 %). 'H NMR (450 MHz. CDC 3 ): 6 2.72 (t, 2 H; CIHN); 6 = 3.83 (s, 3 H; OCH 3 ); 6 = 4.05 (t, 211; OCH2); 6 6.70 (m, 4H; 5 Ar-H); 3C NMR (112.5 MHz, CDC1 3 ): d= 18.843 (CH2CN); 55.902 (OCH3); 63.699 (C1-); 114.947 (C1301CC1); 116.183 (CH2 OCCH); 117.716 (CN); 151 .983 (ClHOC); 154.775 (CH20). ii) 3- 4-methovphnxr ionc cd2 10 A 945 g (5.34 mol, 1 eq.) sample oft (3-(4-methoxyphenoxy)propionitrile (1)) was charged to a 22 L round bottom flask equipped with an overhead stirrer under N. To the stirred solids, 4 L of concentrated 1-1H1 was slowly added, followed by 2 L of H 2O. The reaction mixture was heated to 10()0 C for 3.5 h, at which point the reaction was complete by -IPLC 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- Lof 6 wt. % sodium carbonate (such that pH1 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 hack into the 22 L 20 flask. The p1 of the aqueous layer was carefully adjusted to 4.0, hy slow addition of6 M HOI. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 2 as a white solid (Yield: 86.04 %). I NR (450 MHz, CDl 3 ); M = 2.78 (t, 2H; CH 2 COOH); 3.70 (s 311: OCH ); 4.18 (1. 2H; OCH2); 6.78 (in. 4 H: Ar H); '"C NMR (112.5 MHz. CDCl 3 ): 6 = 34.703 (I2COOH); 55.925 (OC-13): 25 64.088 (0(11); 114.855 (CH30CCH); 115.984 (CH 2 OCCH); 152.723 (CH30C); 1 -4.302 (C 100); 177.386 (0011). E xample I D2: Preparation of 3(4-( 3-oxobuty i)phenoxyx)propanoic acid 30 00 H0

HO

- 51 Step 1: a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B (400 pL), acrylonitrile (4 mL) and MeOH (0.8 mL) was heated at 70 C for 20 hours. The mixture was cooled to room temperature and the solvent was removed to dryness. 3-(4-(3-oxobutyl)phenoxy)propanenitrile was obtained as a white solid 5 g) after purification by column chromatography using ethyl acetate hexane. Step 2: 3 -(4-(3-oxobutyl)phenoxy)propanenitrile (0.478g~ ) was suspended in HMCI (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 water (2 X 5 mL). After column chromatography purification using a mixture of 1(0 methylene chloride/methanol. 3-(4-(3-oxobutyl)phenoxy)propanoic acid was obtained as a white solid (0.3 g). H NMIR (CDCl 3 , 400 mHz, ppm); 2.2 (s 3H), 2.7 (t, 2) 2.85 (m, 4), 4.25 (t, 21) 6.8 (d, 2H), 7 1 (d, 211). Example I D3: Premration of-(4-(2-methoxyethyl)phenox ~ropanoic acid 15 0 \ H O Step 1: a mixture of 4-(2-methoxy ethyl) phenol (1.547g, 10.3 mmol), propiolic acid tert-butyl ester (1 3 6 7 g, 10.8 mmol) and N-methyl morpholine (1.18 20 mL, 10.8 mmol) in CH2C 2(15 mE) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO 2 (90 g) and purified hy column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/ (Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g). 25 Step2: ( E)! ( tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (057 g) was suspended in a mixture of TH (5 mL)/HiC (2 M, 5 mL) and placed in the microwave reactor (T 100 C, 15 sec). TIE was removed by rotary evaporation and the mixture was extracted with CH2Cl (10 mL). (E)/(Z)-3-(4-(2 methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification 30 by column chromatography using a mixture of hexane/ethyl acetate. Step 3: (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5 %, degussa type E 101, 40 mg) was added.

- 52 The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). 'H NMR (CDCl 3 , 400 mHz, ppm); 285 S(t, 411), 3.35 (s, 311), 3.55 (t, 211) 4.25 (t, 211), 685 (d, 211), 7.1 (d, 2H). Exam ipc 1D4: Preparation of 3-(4-3methylbutanovlphenoxy5propanoic acid Step 1: 3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MCOH (12 mL) and I-1S0 4 (18 NI, 3 drops) wvas added. The mixture was place in the 10 microwave reactor (T: 140 'C, t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaGH (2N, 20 mL). The organic phase was dried over N gSO4, filtered, and evaporated to give methyl 3 -phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%). Step 2: aluminum chloride (1.1 g, 8.34 mmol) was added to a cold solution 15 (0 "C) solution of methyl 3-phenoxypropanoate (1.0 g, 5.56 mmol) and tert butylacetyl chloride (1.25 mL, 8.34 mmol) in CIHlI 2 (9 mE) and the reaction mixture wvas stirred overnight. The mixture was evaporated and the residue was diluted with EtOAc (30 mL) and then washed with water (2 X 20 mL). The organic phase was removed and purified with silica chromatography using of a gradient 20 hexanes/EtOAc (I 00:0 0:100) to give methyl 3-phenoxypropanoate (600 mg, 2.27 mmol, 40%). Step 3: a solution of methyl 3-phenoxypropanoate (200 mg, 0.76 mmol) in 2 mL of HCl (37%) was placed in a microwave reactor (T: 120 0 C, t: 5 min). The mixture wvas poured into iced vater (2g) and washed with EtOlH (3 X10 mL). The 25 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-methylHutanoyl)phenoxy)propanoic acid (120 mg, 0.48 mmol, 63%). Example E. Preparation of Anide Analogs 30 - 53 Examprle IE. Preparation of IHemiI Iydrate of CompouInd 163 N-[2lHydrox 2 VIVO h~iy&obnzo/J"Ljd 41doxin-6-1 1I -pyrrIlidin-l7 In Imcth I I-ethyfl-3 - I II t I n y-pIII Io w,)-p Iop ion Ia IIIi (I 1) N OH CH 2 C 0 OH 00 CO2H N OH O HO 0 H 0'' 2) H20 2

NH

2 0 OH HN 0 0 HO 2 C CO 2 H o- O 0 H, OH 5 (Scheme I A) Compound 163 was prepared by following Scheme 1A above. 3-(4 methoxyphenoxy)propanoic acid (see Example 1D1, 34.47g, I19mmol, 96 purity 10 by HPLC), DCC (3 4 .78g, 169 mmol) and N-hydroxysuccinimide (19.33, 169mmol) were combined as dry powders and methylene chloride (500mL) was added. The Mc~oin mechanicall stirredihci suspension was mehncll\tre oernight, ambient temperature, under a nitrogen atmosphere. HPLC analysis showed complete conversion of the acid to the N IS ester (N-lhdroxy succinyl ester). To the mixture w as added step 5 amine (50g, 15 169mmol) and stirring continued for 2.5 hours. iPLC showed conversion to the product and loss of both the NHS ester and step 5 amine. The reaction mixture was vacuum filtered on a Bichner funnel to remove DCC urea. The solid urea was \ashed with 500mL of methylene chloride. The organic layers wvere combined. placed in a separatory funnel, and treated with 500mL of 1.OM NaOlH. The layers 20 were separated. and the cloudy organic layer was recharged into a separatory funnel and treated with a 60 HICl solution (adjusted to p11 0.03-0.34, 10(JmL of solution). Two clear layers formed. The resultant biphasic solution w as 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 25 separated from the aqueous layer, dried over sodium sulfate and evaporated to yield -54 83.6g of yellow oil (theoretical yield: 77.03g). The oil was dissolved in isopropyl alcohol (500mL) with heating and transferred to a 1L round bottom flask equipped with a mechanical stirrer and heating mantel. The solution was heated to 50'C and the mechanical stirrer was set to a rate of 53-64 rpm. Tartaric acid (25.33g, 5 1 68mmol) was dissolved in deionized water (50mL) and added to the stirred solution at 50C. Once the solution turned from milky white to clear, seed crystals were added to the mixture and crystallization immediately began (temperature jumped to 56*C). After 20 minutes, the mixture was set to cool to a temperature of 35'C (cooling took 1.15 hours). H eating was removed and the solution was allowed 10 to stir for 12 hours. The resulting thick slurry vas filtered on a Bichner funnel. Any remaining solid in the flask was washed onto the funnel using ice- cold isopropyl alcohol (1 00mL). The material was transferred to a drying tray and heated to 48 0 C under vacuum for 3 days (after two days the material weighed 76g and after three days it weighed 69.3g). The solid was analyzed by LC and shown to be 98.1% pure 15 (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 I 34.89"C. A total of 6 9

.

3 g of white solid was collected (65.7% overall yield). N: R (400 MHz, CDCl 3 ) S= 1.8 (NI, 411), 2.4-2.6 (in, 4H11), 2.6 (i, IH), 2.85 (in, 2H), 3.0 (n. 1H), 3.65 (s, 3H), 3.8 (im, 2H). 3.86 (2, 2H), 4.18 (br s, 20 5H), 4.6 (s, 1H), 6.6-6.8(m, 7 H), 7.8 (d, I H); MS for C2 9

H

4 :N2O 1 m/z 457.3 [1- I] for main peak (free-base). Example 1E 2 Prep ration of Comound 247: 'N((1 R, 2R I -hy droxv- 1 -(4 methoxypheny)-3-(pyrrol idin-1-vljpropan-2-vl)3-tolloxypropanamide. 25 - 55 N OH 0 NH 00 Compound 247 was prepared in a similar manner as described above, following Scheme 1 using (1 R. 2R)- 2 -amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1 5 yl)propan-1I-ol as the amnine. 1H NR (CDCl 3 , 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s. 311). 2.65 (br, 6H), 2.85 (in, 21), 3.75 (s, 311) 4.1 (i 2H), 4.25 (in, 1 H), 5.05 (sd, 1 H), 6.5 (br, 1H), 6.8 (in. 4H), 7.1 (d. 211), 7.2 (d. 2H). 1/Z for C2 4

H

32 N2O 4 [M-H1 = 413. (1 R, 2R)-2-amino- 1-(4-methoxyphenyl)-3-(pyrrolidin- 1-yl)propan- 1-ol as 10 the amine was prepared by the procedures described below: N

H

2 N Iih HO O A mixture of benzyl (1 R, 2R)- -hydroxy-1 -(4-metoxyphenyl)-3 (pyrrolidin- I -yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5 %, 21 mg) 15 in EtOH (1 mL)/HICl (1 M, 50 puL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was filtered over elite and the solvent was removed to dryness. The product was obtained i as a colorless oil (63.5 m. 85 "o yield1). 20 111afluo I e. pharataio of e C mpouei d 251: I e. 2R)i-d-hedrox- (4- - 56 N OH 0 NH 0 F F F Compound 251 was prepared in a similar manner as described above, following Scheme 1 using (1 R, 2R )-2-amino- 1-(4-methoxyphenyl)-3-(pyrrolidin-1I 5 yl)propan-1-ol as the amine (see Example 1E1). 'H NMR (CDCI 3 , 400 miiz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.5 (s, 2-), 3.8 (s, 3H), 4.2 (in, 1H), 5.05 (sd. 1 H), 5.8 (d, I H), 6.8 (d, 2H), 7.1 (d. 2H). 7.2 (d, 21H) 7.55 (d, 211). M for C23H-7F3NO 3 [M-H]~- 437. 10 Exa le 114 [eajrttIol of , Compond5: 1-~ R, 2 I\')-j2 Ih IdrobenIzol I )' 1 ' I~d ox n- - 1 hvd(Ix'll -jprii I -v\ 1)pr n ylLbenzo b thIo hene- 2-carboxamide Compound 5 was prepared in a similar manner as described above, following Scheme 1. 15 N OH ONH S H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br. 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (, 411), 4.45 (in, I H), 5.05 (sd, 1H), 6.6 (br, 1 H), 6.85 (s, 2H), 6.95 (s, IH), 7.4 20 (in, 2H), 7.7 (s, 1 H), 7.85 (in, 2H). I/ for C24! I N2O 4 S [I-I ] = 439.

- 57 Examnple IFS. Preparation of Compound 11; N-((R, 2R )-1-(2, 2heny'ltiolacetamide 5 Compound 11 was prepared in a similar manner as described above, following Scheme 1. N OH 0ONH 0~ S 6 10 1 N1R (CDCl, 400 mHi., ppm); 1.7 (br, 4H), 2.5 (hr, 4H), 2.8 (br, 2H), 3.6 (q, 2H), 4.1.5 (n, 11), 4.2 (s, 411), 5.9 (sd, 1H), 6.7 (in, 2-1), 6.8 (s, 1H), 7.2 (m, 711). M/Z for C2 3 HsN2O 4 S [M-H]~ =429. Example 1E6 Preparation of Compound 12: N-((1R2R)-1(2,3 1 5 dihydIrobenzo[ 1[L,41di oxin-6-y)-1 -hydroxy- 3 -(pyrrolidin-1I-yl )propan-2 Compound 12 w as prepared in a similar manner as described above, following Scheme 1 N OH ON x 20 H NMR (CDCl 3 , 400 mliz, ppm); 1.8 (br. 41), 2.7 (br, 4H), 3.0 (in. 2H), 4.25 (s, 4H). 4.4 (br, IH). 5.05 (sd, I H), 6.6 (sd, 11 ), 6.85 (in, 2H). 6.95 (s, 1H). 7.45 (in, 31H), 7.6 (in, 4H), 7.75 (in, 2H). M / for C28H;)N 2 0 4 [M-H = 459.

-58 ExaImplec i1E7. Prepatration or( Copnd1: N-(( R. R--23 dlh\drbe I, 3 t) 1, .4/o ldoi-vl-I -hdo- .pvrol Id In I -i)pnopanI -, 5 Compound 19 was prepared in a similar manner as described above, following Scheme 1. N OH ONH S 10 H NMR (d6-dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (in, IlH), 4.15 (s, 411) 4.25 (i, U H), 4.75 (sd, 111), 5.6 (br, I H), 6.7 (i, 31), 7.5 (sd, 1 H). 7.7 (sd, 111), 7.8 (sd, 1 H), 7.85 (sd, 1 1), 8.0 (sd, 1H), 8.2 (s. If H). M / for ( I I \ ( [M-l- 439. 15 Ex ample 1E8. Preparation of Compound 23: 2-(biphenvl-4-yD-N-(IR 2R)1{2 Compound 23 \was prepared in a similar manner as described above, following Scheme I. 20 N OH ON 0 - - 59 H NMR (CDCl 3 . 400 mHz, ppm); 1.7 (br. 4H), 2.5 (br, 4H), 2.8 (d, 2H), 3.55 (s, 21), 4.2 (m, 511), 4.85 (sd, IH), 5.95 (br, I H), 6.6 (m, 1 H), 6.75 (m, 2H), 7.2 (sd, 2H), 7.4 (m, I H), 7.5 (st, 2H), 7.6 (m, 4H). N1I %for c O ( 4 [M-H]~ 473 5 Example 1E9. Preparation of Compound\24-N R, 2-14 2.3 dihydrobenzofl3[I,4]dioxin-6-yl) 1-hydroxy-3-(p rrolidin- 1-ypropan-2-yl -2 (4 phenox v phenx 1)aeumide Compound 24 was prepared in a similar manner as described above, 10 following Scheme 1. N OH 0 O NH 0& H NMR (CDCI 3 , 400 mHz, ppm); 1.8 (br, 411), 2.6 (br, 4H), 2.8 (sd, 2H), 15 3.45 (s, 2H), 4.15 (m, I H), 4.25 (s,411), 4.85 (sd, 11 ), 5.9 (br, 1H), 6.6 (n. 1H), 6.7 (s, 1H), 6.8 (m, I H), 7.15 (m, 711), 7.4 (im, 2H). lz for (>I1 NOi M-H] 489. Exampe 1E,10. Preparation of Compiound 25: S-N-((1R 2R)-1-(2,3 20 hudron-3phenvlpropanamide compoundd 25 uas prepared in a similar manner as described ahove, following Scheme 1.

- 60 N OH O0 O NH 10 H NMR (CDCI, 400 mH z, ppm); 1.8 (br, 4H)1. 265 (br, 7H), 3.1 (dd, 2H), 4.2 (in, 6H), 4.8 (sd, I 1H) 6.6 (in, I H). 6.8 (in, 3H), 7.3 (in, 5H). M/Z for 5 C24H 3 oN20 [M-H]~ 427. 1 example 11-11. Preparation olfompound 27: N-( iR. 2R)-l-(2.3 10 Compound 27 w as prepared in a similar manner as describe ed above. following Scheme 1 N OH 0 N 15 'H NMR (CDC 3 l, 400 mHz. ppm); 1.8 (br, 41), 2.7 (br, 6H), 2.9 (in, 2H), 4.2 (in. 7H), 4.95 (sd, I I), 6.45 (m, 11H), 6.75 (s, 1 H), 6.85 (in, 3H). 6.95 (t, 1H), 7.2 (in, 3H). M/Z for C2 4 H30N20 [M-H]~= 427. Example 1E12. Preparation of Compound 31: N-((1R,2R)-1-(2_3 20 dihydrobenzofl[1.ldioxin-6-vl)-1-hydroxy-3-(pyrrolidin-l1yl)propan-2-vl)-2-oxo- -61 Compound 31 was prepared in a simibir manner as described above, following Scheme 1. N OH O0 O N 5 H NMR (CDCls, 400 mHz, ppm); 1.8 (br. 4H). 2.8 (br, 4H), 3.0 (m, 2H), 4.2 (s, 4H). 4.3 (m, 1 H), 5.05 (sd, 111), 6.8 (s, 2H), 6.9 (s, I H), 7.35 (m, 1H), 7.45 (t, 11), 7.6 (t, IIH) 8.2 (d, 211). MI for C 2 3 H N20 [MI -H] = 411. 10 ample I H 3. Preparatin of (ompound 32: -,( R. 2R)-1- 2,3 dihydrobenzo $i iox in-6-vl )1 hydroxy-3-(pyrrolidin- 1 1) ro an-2-yll-3 Compound 32 was prepared in a similar manner as described above, following Scheme 1. 15 N OH >0 O N S H NMR (CDC 3 , 400 mI z, ppm); 1.8 (br, 4H), 2.4 (1 H), 2.7 (br, 4H), 2.8 (m. 2H), 3.1 (in, 2H), 4.2 (in, 511) 4.9 (sd, IH), 5.95 (br, 1H), 6.8 (m, 3H), 7.2 (m, 20 1 H), 7.3 (m, 3H). M/Z for C2 4

H

3 N2O 4 S [M-H]~ = 443. Example 1E14. Preparation of Compound 35: N-(GR. 2R).l-(2,3 dihydrobenzof61[1,.4]dioxin:6-yl )-1-hydroxy-3 -pyrrolidin- 1-vl)propan-2-vl)-2-o tolvlacetamide - 62 Compound 35 was prepared in a similar manner as described above, following Scheme 1. N OH 0 NH 5 H1 NMR (CDC1 3 , 400 mHz, ppm); 1.7 (br 4H), 2.1 (s, 3H), 2.5 (br, 411), 2.75 (m, 2H) 3.5 (s. 2H), 4.1 (in, 1H), 4.25 (s, 4-1), 4.8 (sd. IIH), 5.75 (br, 11H), 6.5 (d. I H), 6.65 (s, IH). 6.75 (d, I H), 7.1 (d, IH), 7.2 (n, 3H). M/Z for C 24 H N 2 0 4 (\l-lII 411. 10 Example 1 El 5. Preparation of Compi oun 6 -IR R--23 dihydrobeazo b]]1,4]dioxin-6-vl -1-hy'droxy-3-pyrrolidin-lI vi propan-2-y) -2-mn tolylacetamide Compound 36 was prepared in a similar manner as described above, 15 following Scheme 1. N OH 0 NH 20 'H NMR (CDC 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 31H), 2.5 (br, 4H), 2.75 (m, 211), 3.45 (s,. 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, IH).

- 63 6.55 (d, I H). 6.75 (m. 2H), 6.9 (d, 211). 7.1 (sd, I H), 7.2 (m, 1 H). M/Z for C2 4

H

30

N

2

O

4 [M-H] 411. Example 1 E16. Preparation of Compound 39: 2-(benzylthio)-N~ ((1R, 2R)-1-(2,3 5 dihy'drobenzof3[L,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin:1:llpropan:2 vl acetamide Compound 39 was prepared in a similar manner as described above. following Sheme i1. N QH 0 0 NH NH s0 S 10 H1 NMR (CDC, 400 mHz, ppm); 1.8 (br, 4H-1), 2.7 (br, 4H), 2.9 (m, 2H), 3.0 (m, 2H), 3.3 (d, 1H), 3.55 (d. 11H), 4.2 (in, 5H), 5.05 (sd, lH), 6.85 (s, 2H), 6.9 (s, IH), 7.1 (sd, 2H), 7.3 (m, 3H). M/Z for C2 4 HN20 4 S [M-H]~ = 443. 15 Example 1E17. Preparation of Compound 47: N(( IR 2Rll-(2 3-. dihydrobenzo fp][1 4]dioxin-6-vl)-1-hydroxy-3 -(pyrrolidin-1I-vl )pro an-2-vl) -2 (4 riodi3 m-y lphcnvl jacetamide Compound 47 was prepared in a similar manner as described above, 20 following Scheme 1.

- 64 N OH 0 0 NH0 N 'H NMR (CDCI 3 , 400 mHz. ppm); 1.7 (br, 4H), 2.6 (br, 4H), 2.8 (sd. 2H), 3.55 (s 211), 4.15 (m, 1 H), 4.2 (s, 4H), 4.8.5 (sd, I H), 5.85 (br, 1 H), 6.6 (d, 1iH), 6.75 5 (in, 2H), 7.25 (d, 3H), 7.4 (m, 1 H), 7.6 (sd, 211), 7.9 (sd, 1 H), 8.6 (sd, I H), 8.85 (s, 1 H). M/Z for C 2

,H

3

N

3 0 4 [M-H] = 474. Example IFE18. Preparation of Con pound 48: -(4'-chlorobi phenvl-4-v IN( IL) 10 2-Alaetarnide Compound 48 was prepared in a similar manner as described above., following Scheme I N OH 0 CI 15 H NMR (CDCla, 400 mHz, ppm): 1.75 (br. 4H), 2.55 (br, 4H), .8 (sd, 2H), 3.55 (s 211), 4.15 (m, 1H), 4.2 (s, 411) 4.85 (sd. 1 H), 5.8 (br, 11H), 6.6 (d, 111), 6.75 (m, 2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.55 (sd, 4H). M/Z for C 9 H CN20 4 [M-H] = 508. 20 -65 Examle 1E19. Preparation of Compound 51: i((1R ,2R)- (2,3 (tIil 1 tII\ydrben hjCll 4 d ixin 2 ll-I~ yrx- I i( Irldn C 9pqa~j-~ Compound 51 was prepared in a similar manner as described above, 5 following Scheme 1. N QH 0 0 NH0 F F F H NMR (CDC 3 , 400 mIIz, ppm); 1.7 (hr. 411), 2.55 (br, 4H), 2.8 (sd, 2H), 10 3.55 (s, 21), 4.15 (m, 1 H). 4.25 (s, 4H), 4.85 (sd, 1 H) 5.8 (br, 1 ), 6.6 (di 1 H), 6.75 (i, 2H), 7.35 (d, I H) 7.45 (in, 21), 7 55 (sd, H). M/Z for CHH2F 3 N2O 4 [M-H] 465. ExamJlc 11120. Preparato of Cmpound 53:N{1 R R-I-23 15 dihy4drohenzopl 40ldioxin-6-y ! -hydroxy 3-(pyrroidin- I -vipropan2v)- 2 fluorophegyljacetamnide Compound 53 was prepared in a similar manner as lescrihed ahxe, following Scheme 1. SQH 0 NH 7 200 20 F H INMR (CDCl, 400 m l, ppm): 1.7 (br, 411), 2.55 (br. 4H), 2.8 (sd, 211), 3.50 (, 211), 4.15 (n, H) 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d. 1H), 6.75 - 66 (m, ill), 6.8 (d, I ), 6.85 (d, 1 H). 6.9 (d, 1 H), 7.0 (t, 1 H), 7.3 (sq I H). M/Z for C2 3

H

9

FN

2

O

4 [M-H]~= 415. Example 1E21. Preparation of Compound 54: N-(( R, 2R)- 1-(2,3 5 dihydrobenzo[p[[ldioxin-6:vl hdroxv-3-(rrolidin-1-yl propa9n-2-vY3-(3 methoxyphenoxy)propanamide Compound 54 was prepared in a similar manner as described above, following Scheme 1. N QH 0 NHKI 10 Os H NMR (CDC 3 , 400 mHz, ppn); 1.7 (br, 4H), 2.65 (br, 6H), 2.85 (m, 2H), 3.80 (s, 3H), 4.2 (m, 711). 4.95 (sd, 1MH), 6.45 (n, 4H), 6.75 (s, 2H), 6.85 (s, 1H), 7.2 (t,1. H) /.\l kr l I I[ Al-II 457. 15 Example 1 E22. Preparation of Compound 55: 3(2. 5-di chlorophenoxv)-N-(( 1R. 2-yl)jpropallanide Compound 55 was prepared in a similar manner as described above, 20 following Scheme 1.

- 67 N QH O0 CNH -CI H NMR (CDCl 3 , 400 mHz, ppm); 1.8 (br, 4H). 2.65 (br, 611), 2.8 (m, 2H). 4.1 (m, 111) 4.25 (m, 61 1), 4.95 (sd, 111), 6.3 (br, 1H), 6.75 (s, 2H), 6.8 (s, 1H) 6.9 5 (m, 2H), 7.25 (m, 11). MiZ for C2 4 H28Cl2N20 5 [MH] = 496. Exa mple I1I3' 3 Prepartio of"(IP Compoud 57: 0I(4-chloopbenox4-W I R2---P) (2,3-dihydrobenzo[Q1[l4ldioxin-6-vl)-1I-hydroxy'-3-(pyrrolidin 1 -vlipropan-2 y1)popaamide 10 Compound 57 was prepared in a similar manner as described above, following Scheme 1. N OH OH Cl 15 1 NMR (CDCl 3 . 400 mHz. ppm); 1.75 (br, 4H). 2.65 (hr 6H), 2.8 (i, 2H), 4.2 (m1, 71H), 4.95 (sd, 11), 6.3 (br, 1 H), 6.8 (m, 5H), 7.2 (m, 2H). M/Z for

C

24

H

2 ClN20 [M-H]~ = 461. Example 1E24. Preparation of Compound 58: N-(R. 2R)-1-(2,3 20 dihydrobenzof ldioxin6-y )- I -hdroxy-3 -(pvrrolidin- -vi)propan-2-vl)-3-(4 Compound 58 was prepared in a similar manner as described above, following Scheme 1.

- 68 N OH o NH a,:-) F H NMR (CDC 3 , 400 mHz, ppm); 1.75 (br. 4H), 2.65 (br, 6H), 2.8 (in, 2H), 4.2 (m, 711), 4.95 (sd, 1 H), 6.4 (br, I H). 6.8 (m, 5H), 7.0 (m, 2H). M/Z for 5 C2IIFN20 [M-1]~= 445. Example 1E25. Preparation of Compound 59: N{(1R§2R)-42,3: dihydrobenzo p][l4ldioxin-6-vl)-1hydroxy-3-(pyrolidin-1 -vi propan:2-yl)-3-(p 10 Compound 59 was prepared in a similar manner as described above, following Scheme 1. N OH 15 'H NMR (CDC1 3 , 400 mHz, ppm); 1.75 (br, 4H). 2.3 (s., 3H), 2.65 (br, 6H), 218 (n, 211), 4.2 (m, 7H), 4.95 (sd, 111). 6.45 (br, 1H), 6.75 (m, 4H), 6.85 (s, 111), 7.1 (m, 2H). M /Z [or C2 5 H3 2 N20 [M-H]~= 441. 20 Example 1E26 Preparation of Compound 60: N'((R, 2R)-1-(2,3 didrbnofl1 4doi--l-I-hdov3( pvrldin 1 1v)1)1a-2 -3 Compound 60 was prepared in a similar manner as described above, following Scheme 1.

- 69 N QH 0"0 0 NHK0 H[ NMR (CDCl 3 , 400 mlz, ppm); 1.75 (br. 4H), 2.65 (br, 6H), 2.75 (m, 5 2H), 4.2 (m, 7H), 4.95 (sd, 11H), 6.35 (br, 11H), 6.7 (s, 2H), 6.85 (s, 1 H), 6.95 (m, 2H), 7.05 (m, 2H). M/Z for C 24 H2 9 FN20 [M-H] = 445. Ixm1 1 Ili. cPr~ Waaino Corn oun md 61 VWft R., 110- 1-2 dihydrobenzo$1L4]dioxin-6:yl)I hydroxy -3(pyrrolidin-1-yl propan-2-vl)-3-(4 10 Compound 61 was prepared in a similar manner as described above, following Scheme I. N OH 0 NH 0 0 15 H NMJR (CDC1, 400 mHz, ppm); 1.75 (br, 411), 2.65 (br, 6H), 2.75 (m, 2H), 3.8 (, 311), 4.1 (i, 21H), 4.2) (br, 5H) 4.95 (sd, I H), 6.45 (br, 1 H). 6.8 (m, 7H). /Z for C2 H N20, [M-H]= 457. 20 Example 1E28 Preparation of Compound 188: N-((1R. 2R}-1-(2,3 dihydrobenzofbl 4dioxin-6-vl)- I -hydroxy-3-( pyrrolidin- 1 -vl)propan-2vl )-3- 4- - 70 Compound 188 was prepared in a similar manner as described above, following Scheme 1. NH+ QH O NH O 0 OH OH 0 -O OH O 5 'H NMR (D20, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br. 2H), 2.35 (q, 2-), 2.4 (br, 2-), 2.9 (hr. 2H), 3.25 (in, 2H), 3.4 (br, 211), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H). 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C2 6 11, 4

N

2 0 5 C4H O( [M 10 H]~ = 454. Example 11E29. Pre paration of Com pound 189RN-(RI\2R)l-232 djiiydrobenzofblJj A4diox in-6-y1)-il-hydroxy-3-(pyrrolidinil-yl~propan-2-y1)-3-(4 15 propion Iphenoxv )proanamide (2R. 3R) -23-diin drox succinaLe Compound 189 was prepared in a similar manner as described ahove. following Scheme 1. NH+ OH 0 ON H O 0 OH O !OH 0 OH O 20 - 71 H11 NMR (D 2 O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br. 2H), 1.86 (br, 2H), 2.45 (br, 211), 2.8 (q 21), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 211) 3.9 (br, 6H), 4.3 (br, 311), 4.6 (br, 1H), 6.5 (d, 1H), 6.5 (d, 2H), 6.7 (d, 2H), 7.7 (d, 2H). M/Z for C27H- 4

N

2 0 6

C

4 H606 [M-H]- = 483. Ex mll lI IE0 P-rprtion of( ompound 193: - 1R R 0-142,3 dihydrobenzofb][l,4ldioxin-6-vl)-1-hy'droxy-3 -(pyrrolidin- 1-yll)propan-2-yl )-3- 4 (3-oxobuty1l)phenoxy)propanamide (2R 3 R)-2,3 -dihydroxysuccinate Compound 193 was prepared in a similar manner as described above, 10 following Scheme 1. H* OH 0 NH 0 O OH O OH O OH 0 H NMR (D20, 400 mHz, ppm): 1.75 (br 2H), 1.86 (br, 2H), 1.94 (s, 3H), 2.45 (br, 211), 2.6 (im. 4H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 211), 3.9 (br 6H), 4.3 15 (br. 31), 4.6 (br, 11), 6.6 (n, 51), 7.0 (d, 2H). M/Z for C211N 2 O(, C 4 HO [M H] = 497. Exan~ 1L3. Prearaton(o Compund 202:_-1 _ _ 20 (-methoxvethyl )phenox )propanamide (2R, R -23 -dihydroxysuccinate Compound 202 was prepared in a similar manner as described above, following Scheme 1.

- 72 NH*OH 0 OH - OH _0 HOH OO H O 'I NMR (D 2 0, 400 mHz. ppm); 1.75 (hr, 2H), 1.86 (hr, 2H), 2.45 (br, 2H), 2.62(t1 2H), 29 (br, 2H), 3.1 (s 311), 3.25 (m, 21), 3.4 (hr, 411), 3.9 (hr, 61), 4.3 5 (hr 3H), 4.6 (hr1 1) 6.6 (n 5H) 7.0 (d 2H). M/Z for C271 6

N

2 O, C 4 1HO , [M-H] 10 (Compound 63 was prepared in asmilar manner as deserihed abho e, following Scheme I. N H N O ObH 15 H1 N IR (CDCl 3 , 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2 75 (m, 2H), 3.5 (br 211), 3.9 (sd,. 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 5.9 (br, 1H), 6.5-7.6 (m, I H). M/Z for C3H 34 N20 5 [M-H] = 503. 20 Example 1133. Preparation of Compound 127: N-(( R. 2R)-l(2,3 dihydrohenzo 1,41dioxin-6-vl )- 1-hydroxy-3: (pyrrolidin-1: vl)propan-2-y1)-4-{4 ethoxvphenyn)-4-oxobutanaide - 73 Compound 127 was prepared in a similar manner as described above, following Scheme 1. N OH ON1 0 NH 0 0 5 H NMR (CDCli, 400 mHz, ppm); 1.4 (t, 3H), 1.8 (br, 4H), 2.7 (br 6H), 3.2 (m. 21), 4.05 (q, 2H), 4.2 (m, 2H), 4.25 (i, 51), 4.95 (sd, IH) 6.05 (br, 1 H), 6.9 (m 5H), 7.95 (d. 2H). M/Z for C27H 34 N2 0N [-H] =483. 10 E ea f o54:_N(I_ incth~yphn '1 4-oxbutaninid Compound 154 wasi prepared in a sillar manner as described above, ouing Sceme 1. 15 N OH OON 0 0 N 00 H \\4R (CDC)(1 3 , 400mIi-, ppm);1 .8 (hr.411), 2.7 (br,-I).3.2 (i, IH), 3.5(.3139(,3 H1).4.2 (m, 511).4.95 (sd, 111), 6.05 (br, 111), 6.9 (in,51-1), 7.95 (d, 211). MtI/Z for i-1 3 N [M-H]- 469.

- 74 Exanple 1E35. Preparation of Compound 181- N-((1R, 2R)-1-2,3 1dpdoenzoAll Q[1 .4doxn6-l)-1-hdOxy-34yr din- i )jpropan --v Q--( Compound 181 was prepared n a similar manner as described above, 5 ollow Ing Sceme 1. OH

-

0'

N

1 . 0 N 0 0 H NM 11 (CDC , 400 mHz, ppm); 1.4 (d, 61), 1.8 (br, 8H), 2.15 (br, 2H), 10 2.8 (br, 10 H) 4.25 (m, 5H), 4.65 (m, I H), 4.95 (sd. 1 H). 6.05 (br, I H), 6.9 (ni, 5H), 7.95 (d, 2H). M/Z for CoHON2Or [M-H] = 525. Exm le 1]-6. Preparmion o Com pound 191: N-( R 2R -1-(2. 15 Compound 191 was prepared in a similar manner as described above, hollowing Seheme 1.

- 75 NH+ H O OH OHO OH0 5 H NMR (D20, 400 mHz, ppm); 1.40 (br, 1H), 1.53 (br, 1H), 1.75 (br, 2H), 1.91 (br, 21) 1.98 (m, 1 H), 2.15 (m,i 1H) 2.45 (m, 21-1), .95 (im 211), 3.35 (dd, 2H), 3.4 (m, 2H), 3.68 (br, 5H), 3.77 (br, 2H) 4.3 (br, 31). 4.68 (br, 111), 6.47 (d, I H), 6.65 (d, 2H1), 6.85 (d, 2H), 7.63 (d, 2H). M/Z for C i (\ n Ic 4 H0, |1-1 483 10 Example IF'17._ Preparation of Compounid 265: V1(IR.2 P- (benzo[S 1,3]dioxol-5-yl) -hydroxy-3-(pvrrolidin- 1 vi propan-2-vl )-5:(4 isopropoxvpheny1lh5-oxopentanamide (2S, 3S -2,3dihydroxysuccinate Compound 265 was prepared in a similar manner as described above, following Scheme 1. 15 NH -0 OH 0 OH H NMR (400MHz, CD 3 0D) 6 1.30 (sd, 6H). 1.70-1 .85 (m, 2H), 2.04 (br, 4H), 2.09-2.26 (m. 2H), 2.64-2.82 (m, 2H), 3.31-3.48 (n, 5H), 4.37 (s, 1), 4.43 (br, 20 IH), 4.68 (m, I H), 4.71 (sd. 1H), 5.76 (s, 2H), 6.66 (d. 114), 6.82-6.95 (m, 4H), 7.84 (d, 2H); MS for C2 8

H;

6 N20s-C 4 H 606: [M-H]~ 645.

- 76 Example 1E38. Preparation of Compound 267: N-f(1R. 2R)-1 Compound 267 was prepared in a similar manner as described above, 5 following Scheme 1. NH H \_0 _ OH 0 OH H NMR (400MHz, CD 3 0D) 6 1.49 (hr. 4H), 2.03 (br 4H), 2.89 (t., 2), 10 3.33-3.46 (m, 6H), 3.84 (s, 311), 4.37 (s 211), 4.43 (d, 1H), 4.76 (br, 1H). 5.81 (s, 2H). 6.68 (d, 11H), 6.81 (d, 111), 6.88 (s, IH), 6.96 (d, 2H). 7.92 (d, 2H); MS for

C(H

4 N206- C4H 606: [M-H] 633. Exampleaanf Compound 268: N-(R.2R)-l 1 5 tbenlzo[I (I 1 1 :dixl5y%1 ) 1 -hydro \3 1- t )roIdHIn- I )proi -yj )-@ isoprpoxvphenyl)-7-oxohejptanamnide (2S 3S)-2.3 -dihydroxysuccinate Compound 268 w\ as prepared in a simil mnner as described above. following Scheme 1. NH O 0 0 O OH OHO -- O OH O OH 20 H NMR (400MHz, CD 3 OD) 6 1.15-1.18 (in. 2H) 1.30 (d, 6H), 1.40-1.45 (, 211), 1.57-1.65 (m, 2H), 2.03 (br, 4H), 2.12-2.17 (in, 2H), 2.88 (t, 2H), 3.33-3.48 - 77 (m, 5H), 4.38 (s, 2H), 4.42 (d. 1H), 4.67 (m, 1H), 4.78 (d. 1 H), 5.83 (d, 2H). 6.71 (d, I H), 6.82 (d, I H). 6.89 (s, 1H), 6.92 (d, 2H). 7.90 (d, 2H); MS for C;IH 4 jN0-' C4H 606: [MHf-I 675. 5 RExamle~ 1EF40._ Prario If Comond 197: ,N-( IR R 1- 1-(2,13 Compound 197 was prepared in a simlar manner as described above, follow ing Scheme 1 10 NH H N '"0 O H O 'POHOH O O OH II NMR (400M 1)z CDOD) 6 1.78-1.91 (m, 2H), 2.00 (br, 4H), 232 (t, 21), 3.33-3.47 (m, 6H), 3.69 (s, 3H), 3.72 (t, 21h), 4.11 (br, 4H), 4.37 (s, 2H), 4.41 15 (d, 111). 4.72 (d, 1 1), 6.69-6.86 (I, 7H); MS for CH 34 N20 (C 4 H 606: [M H]~ 621. Example 1E41. Preparation of Compound 187: ((1 R. 2R)-- -2.3 dihydrobenzo[6hi il 4dioxin-6:vl)- 1-hydroxy-3-(pyrrolidin- I y1)propan-2-yl)-3-(4 (3-methylbutanovl phenoxv propianamide (2S, 3S )-2,3 -dihydroxvsuccinate 20 Compound 187 was prepared in a similar manner as described above, 1ollou ing Scheme 1. NH+H NO HR 0 OH - 78 H NMR (400MHz, CDOD) 6 0.95 (d, 6H), 2.00 (br., 4H), 2.17 (n, 2H), 2.66 (t, 211), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40 (s. 2H), 4.45 (d, 11). 4.73 (sd,. 1H), 6.67 (d, 1H), 6.79 (d. 1H), 6.86 (s, 1H), 6.93 (d, 211), 7.91 (d, 211): MS for C , I 9 0( C 4 H 606: [M-H] 661. 5 Exam 1ple -1 k42. )1 i P iprt IoI of Com poun td 83 71-14-cl Iorophenoxv)-NI( I i, R.2R (2 3dihy'drobenzo[6][1l 4dioxin-6-yl)-1 -hydroxy-3 (pywrrolidin- 1-yl )propan-2 yI acetamtide Compound 83 was prepared in a similar manner as described above. 10 following Scheme 1. N QH 0 O NH 0 CI H NMR (400MHz, CDCI 3 ) 6 1.76 (br, 4H), 2.63 (br, 4H). 2.78 (dd, I H), 15 2.9 (dd. 1H), 4.24 (s, 4H), 4.27 (br, IH), 4.36 (q, 21-1), 4.94 (d, 111). 6.71 (d, 1 H), 6.77-6.82 (m, 4H), 6.86 (d, 1H), 7.)4 (s, I): \1S for 7 (CI1(N 5 ( : [ M-H]~ 447. Example SFE43. Preparation of Comp ound 87- 2-(3A4-dichlorophenoxy)-N-((1lR,2R 1-(2.3dihydrobenzo[Bl .lfdioxin-6-ylk-lI hydroxy-3 -(pyrrolidin- 1-ylipropan-2 20 Iacetamide Compound 87 was prepared in a similar manner as described abov e following Scheme I.

- 79 N H N "OHO O CI O CI H NM R (400MHz, CDC1 3 ) 6 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd. IH), 2.92 (dd, 1H), 4.25 (br, s. 5H), 4.35 (q, 211), 4.95 (d, IH), 6.71-6.84 (in, 5H), 7.01 5 (d, 11H), 7.34 (d. 11H); MS for C23H1C1N20: [M-H]~ 482. Example 1 E44. Preparation of Compound 86: N-(t 1R,2 R)-1-(2,3 dihydrobenzo bl1 l4ldioxin-6-vl)-1 hydroxy-3-(pyrrolidm--in:y)propan:2yv)- 2 -13 Ii i~ I)Ihen1y1Kl Iaetamd 10 Compound 86 was prepared in a similar manner as described above, follow ing Scheme 1. N H H IN 0 OO 0 15 11 MR (400M 1Hz CDCl 3 ) 6 1.72 (hr, 4H), 2.57 (br, 4H), 2.75-2.80 (i, 2H), 3.45 (s, 2H), 4.11-4.13 (i. I H), 4.23 (s, 411), 4.84 (d, 1 H), 5.86 (d, 111), 6.55 (dd, 1H), 6.71 (d, 11H), 6.74 (d, IH), 6.80 (br, 1H), 6.85 (dd. 1H), 6.92 (dd, 1H), 6.98 (d, I H), 7.14 (t. 1H), 7.28-7.36 (m,. 211); MS fr C 2 9

H

32

N

2 0 5 : [M-H]~ 489. 20 Exam 1c I E45. Pre ration of CoIpound 28: 2(3 4-difluoropheny)-N(( I R,2R) 1 -(2,3-dihydrobenzolf 1,4[ldioxin-6-yl )- hydroxy-3 -(pyrrolidin-lI vl)propan-2 '1 acetamlide - 80 Compound 280 was prepared in a similar manner as described above, following Scheme I. N H F N & F HO 5 H NM R (400MH z, CDC1 3 ) 6 1.80 (br, 411, 2.68 (hr, 411). 2.84 (d, 2H). 3.45 (s, 2H), 4.17 (in, IH), 4.25 (s. 4H), 4.88 (d, 1H), 5.88 (d, 1 H). 6.65 (d, IH), 6.79 (d, 1 H), 6.95 (in, I H). 6.95 (t, 1I ), 7.13 (q 111): NS for I P1, I C N 4 1-1 I f 434. 10 Example 1 E46. Preparation of Coip ound 103: N-((IR 2R)- 1 (2.3 dihvdrobenzo 3p1[lidioxin-6-y)l-hydrox v-3 r{pvrrolidin-l-yl propan-2-vl) -2-(4 (n fi rluoromethoxy)pheny1jacetaunide Compound 103 was prepared in a similar manner as described above, fo~llowing Scheme I. 15 N H N FF OH OF 0 iH NMR (400MHz, CDCI 3 ) 1.65 ( r. 4H), 2.48 (br, 4H), 2.69 (d, 211) 3.40 (s, 21-1), 4.08 (in, IH), 4.17 (s,. 411), 4.80 (s, 1 1), 5.84 (t, IH), 6.55 (d. IH), 6.66 20 (s, 1 H), 6.70 (d, I H), 7.10 (t, 3H); MS for C 2 4 I 7 FN 05: [M-H]- 481. Example 1E47. Preparation of Compound 90: N-((1R,2R)-l-(23 dihyvdrobenzo [Pi3][1.4dioxin-6-vl )-1I-hydroxy-3 -(pvrrolidin- 1-yl)propan-2-yl )-5- -81 Compound 90 was prepared in a similar manner as described above, following Scheme 1. S N 0 N "OH 0 5 H NMR (400MHz, CDCl 3 ) 6 1 .82 (br, 4H), 2.73-2.81 (in, 4H), 2.89-2.93 (in, 1H), 3.02-3.07 (m, 1H), 4.23 (s, 4H), 4.41 (br, 1H), 5.07 (s, IH), 5.30 (d, 1-I). 6.74 (s, 1H), 6.83 (t, 2H), 6.90 (s. 1 H), 7.12-7.14 (im, 211), 7.47 (d, I H) 7.52 (d, IH); MS for C23H2 5

N

3 0 5 S: [M-H]~ 456. 10 Example 1E48I Preparation of Compound 92:3-(3-chloro-4-methoxypenyl)-N Compound 92 was prepared in a similar manner as descri bed above, 15 following Scheme . NHO I NMR (400I Hz, CDCl 3 ) 6 1.77 (br, 411), 2.38 (t, 2 H), 2.60 (br, 4H)., 20 2.8 (i, 4H), 3.86 (s, 3H), 4.20 (br, lH), 4.24 (s. 4H), 4.87 (s. 111), 5.80 (d, IH), 6.66 (d. 1 H), 6.8 (m, 3H), 7.00 (d, 1H), 7.18 (s, I H); MS for C 2 -H 1 ClN20<: [M-H]~ 475. xampl 1 Il49 Prpara ttino omon 96: -( 1 R.2R-I(23 dihydrobenzof51[l 4dioxin-6-vl)-1-hydroxy-3-(pyrrolidin-lyl)propan-2-yl)-3-(4 25 (tri fiuoromethyl )phenyl )propanamide - 82 Compound 6 w as prepared in a similar manner as described abo e, following Scheme 1. F F N "HO N F 0 0, 5 0 H NMR (400MHz, CDC1 3 ) 6 1.73 (br, 4H), 2.4 (in, 2H), 2.53 (in, 4H), 2.7 (n 2H), 2.90-2.97 (m, 2H), 4.17 (br, IH), 4.23 (s, , 114.89 (s,. 1 H), 5.83 (br, 1 H), 6.68 (d, 1 H), 6.79 (d. 2H), 7 24 (d, 2H), 7.50 (d, 2H); MS for C 2

IH)F

3 N20 5 : [M-H] 10 479. Ex mple 1 E0S Pre ration of Com pound 101 4-(benzold]thiazol2-I -N ({ R,2R1(12.3di hydrobenzo[Qj141dioxin-6-yl)--hydiroxy- 3-(pyrrTolidin- 1 15 (Compound 101 Ns prepared in a similar manner as described above. Iollouing Scheme 1. N HO 0 NH /S Il - N 20 H NMR (400MHz, ('DC 3 ) 6 1 .77 (br, 4H), .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 (, 211), 4.18 (s, 4H), 4.26 (br, 83 1H). 4.92 (d, IH), 6.12 (br, IH), 6.75-6.81 (m,. 211), 6.86 (s. 1H), 7.37 (t, 11H), 7.45 (t, IH), 7.85 (d, iH), 7.92 (d, 111): MS for CJH 1

N

3 0 4 S: [M-H] 482. Example lE51. Preparation of Compound 102: N((1R2R)(2,3 5 dpmd( dihydrobenzofp) 1.41dioxine-6 sulfonamido)hexanamide Compound 102 was prcparcd in a similar manner as described above, following Scheme 1. N b HO ' to - 'NH 10 0 1 11 /M 00MHz, CDCl3) 6 1.15-1.20 (m, H), 1.38-1.50 (in. 41), 1.77 (br. 411), 2.08 (q 211), 63-2.66 (m, 4H), 279 (d, 2H), 2.87 (t, 2H). 4.2 (m, 911), 4.91 (hr, IH), 5.93 (br, 111), 6.77 (q, 2H) 684 (s, 1H), 6.93 (d, 1H), 7.31 (d, 1H), 15 7.37 (s, I H) MS for C 29

H

39

N

3 0 8 S: [M-H]~ 590. Examl Ic TE2 Prepgirain)i of Compound_1104- N-('7(_R, I~) 93 dihydrobenzofD I1 4 dioxin-6-vl)-I hydroxv-3-(pyrrolidin- v-l propan:2:vlamino) 5-oxopenty'Ibenzainide 20 Compound 104 was prepared in a similar manner as described above, following Scheme 1.

- 84 N OH 0 N H ; 0 HN 0 1 NMR (400MHz, CDCl 3 ) 6 1.47-1.52 (m, 2I), 1.59-1.69 (m, 2H), 1.77 (hr, 411), 2.15-221 (mn, 211), 2.62-2.65 (m, 4H), 2.81 (br, 2H), 3.30-342 (m, 211), 5 4.19-4.23 (T, 5H) 4.94 (br, 11H), 5.98 (br, IH), 6.76 (br. 111), 6.78-6.86 (i, 3H), 7.40-7.50 (i, 3H), 7.80 (d, 2H); MS for CH;5N 3 0 5 : [M-H] 482. Example 1E53 Preparation of Compound 281: NI-((1R,2R)-1-(2,3 dihydrobenzo[[ 1.4]dioxin-6-y)- i-hyd)roxy-3-(pyrrolidin1 y)propan-2-v )-\5 10 a Compound 281 was prepared in a similar manner as described ahove, following Scheme I. N H H N N N ~ O S 0 D O 15 H NM (40M/z CDCl3) (5.7 (br, 4H1), 1.97-2.03 (mn, 2H), 2.20-2.26 (mn, 2H), 2.40-2.45 (m, 2H1), 2.64-2.68 (mn, 5H1), 2.88 (mn 1H), 4.20 (s, 4H), 4.26-4.29 (mn, 1H), 4.83 (d, 1 H), 6.12 (br, 1H), 6.714-6.79 (mn, 2H), 6.85 (s, 1 H), 6.95 (d, I H), 7.41 (d, 1H); MIS for C-)21 H3\ 0N40S: [M-H ]- 475. 20 - 85 Example I E54.Preparation of Compond 282: N-(( I RR)-12L3 Compound 282 was prepared in a i r manner as described above, 5 following Scheme 1. N QH O0 00 O ,~0 H NMR (400NM/. CDCI 3 ) 6 1.76 (br, 4H) L92-2.00 (m, 2H), 2.21-2_26 10 (m, 2H), 2.60-2.65 (, 4H11) 2.70-2.95 (, 41), 3.93 (d, 6H), 4.17-4.23 (i, 511), 4.90 (d, 1 H), 5.96 (br, 1 ), 6.75-6.79 (m, 2H), 6.85 (s, 1 H), 6.87 (d, 1 H). 7.50 (s, lH), 7.55 (d. 11H); MS for C 2 bH 6 N2 0: [IM-H] 513. Example lE55. Preparation of compound 283: N-((1R2R -1-( 23 1 5 1i(1drobeniLb11L 1, 4 doxn--1j 1 -b" d rox{pro idill-I-jyljplopan2 v 5 o Compound 283 was prepared in a similar mnner as described abov e, flow~ing Scemeie 1. N OH 20 0 0 20 - 86 1H NMR (400MHz, CDCl 3 ) 6 1.77 (br, 4H). 1.96-2.02 (m. 211), 2.21-2.26 (m, 2H), 2.40 (s. 3H). 2.63-2.80 (m, 4H), 2.82-2.95 (m, 4H), 4.18-4.23 (m, 5H), 4.91 (d. 1H). 5.94 (br, 11 H), 6.74-6.77 (m, 2H). 6.85 (s, 111), 7.26 (d, 2H) 7.81 (d, 2H); 5 MS for C2 7

H

34 N20s: [MI1~ 467. Example 1E56. Preparation of Compoud 113: N- I((R2R)-1-(2.3 dih 'd,-1[oJ~ 1.4]I do\xIn1-6- IL1 -11h 'drox-3-1c1-r1 id I I- I-yihpl opa n---5-xo 10 Compound 113 was prepared in a similar manner as described above, tolloing Scheme 1. N H N '1/0o0 0 0 15 HI NMRP (4(0M1 1. CfDCl 3 )6 1.76 (br, 41-), 1.95-2.01 (m,. 21-1), 2.22-2,25 (I, -2 .6-2_63 (m-in l. 4H) 78-2.95 (i,41.41-.2(in, 5fl),4.91 Isd 111) 5.99, (hr. 11M) 6.77 (st, 211), 6.85 (s, 111), 7.44-7.58 (in, 311), 7.92 (d, 211); NM SIfo c) H ;T\ n ,\ f-H11 453. 20 1Examjple, 1[ 57. Preparaiti of Compound 284: N-( IR2 1-)3 Compound 284 was L prepared in a similari manner! as- des,: lribd above , followinit Schemem 1. 25 - 87 ) N O 0f H NMR (400MHz, CDCl 3 ) 6 1.36 (d, 611), 1.75 (br, 4H), 1.90-2.02 (m, 2H), 2.20-2.25 (m, 2H), 2.60-2.66 (m 4H), 2.70-2.86 (m, 4H), 4.17 (s, 411), 4.22 (br, 5 1H), 4.62-4.65 (in, 1 H), 4.89 (sd, 1H), 6.07 (d, I H), 6.77 (s, 2H), 6.85 (s, I H), 6.87 (d, 2H), 7.86 (d, 2H-); MS for C 29

H-]N

2 01 : [M-H]~ 511. Exam 1E5 I 8. Prep ration of Compound 140; N-( 1R,2R)12- , -(3 dihydirobenzo Il l4ldioxin-6:- -I-hydov3 proldnylpoan2y -4 1 0 methoxy-3-dlhth bpenvli ____u_ uid ('ompound 140 was prepared in a similar mamner as described above, follouwing Scheme 1. N H 15 H NMR (400M1z, CDCl,) 6 1.61-1.63 (i, 41), 1.77 (br, 41), 2.16 (t 211), 2.32 (s, 6H), 2.61-2.67 (, 411). 2.74-2. 89 (m, 2H) 2.91 (t, 2H), 3.75 (s, 3H) 4.21 (br. 5H), 4.90 (sd, 111), 5.93 (br, 1H), 6.75-6.82 (m, 2H), 6.85 (sd, IH), 7.61 (s, 2H); MS for C30H1eN 2 0,: [M-H1 ]525. 20 Example 1E59. Preparation of Compound 141 N-(( iR.2R)-( 3 dihydrobemolf 1 ,4ldioxin-vl-lhydroxy-3-(pvrrolidin- I -yl)prop an-2-vl-6-4 methoxy phenyl )-6-oxohexanainale Compound 141 was prepared in a similar manner as described above, following Scheme 1. 25 - 88 N, H 0, 0 H NMR (400MHz, CDC1 3 ) 6 1.62-1.64 (in, 4H), 1.76 (br, 4H), 2.17 (t, 2H), 2.61-2.65 (m, 4H), 2.72- 2.79 (m, 2H), 2.89 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H) 4.89 (d, 1 H), 6.01 (br, I H), 6.77 (q, 2H). 6.85 (s. 1 H), 6.91 (d, 2H), 7.90 (d, 2H); MS for 5 C 2 8H1 ,N 0: [M-H]~ 497. IIample 11 60. Preparation ( Con pou id 155: 64-tert-bu ilphcnyl -N-(I R2R ) 1- 2 .3-dihi)drohn/o l[ I. 4|dioxin-6- )-l -h idroxy-3-(i rrolidin- - 1)ro aii-2-l 6-oxohexanaunide 10 compound 155 was prepared in i similar irnaiincr as described above., following Scheme I. H 0 15 11 NMR (400MHz, CDCl3) 6 1.34 (s, 9H), 1.63-1.65 (in. 4H). 1.77 (br, 4H), 2.17 (, 2H), 2.64-2.66 (hr, 4H11) 275 (dd, 11), 2.2.81 (dd, 111), 2.91 (t,2H1), 4.20 (br, 5Ih), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 211), 6.85 (d, 11H), 7.46 (d, 211), 7.86 (d. -1- IS for Cl H \N_0<: [M-11 523. 20 Example 1E61. Preparation of Compound 156: N-1 R,2R: -2,3 dihydrobenzo[ 131f 1 ,4dioxin-6-vl)- 1-hydroxy-3-(pyrrolidin- I-yl )propan-"-yl )-7-(4 Compound 156 was prepared in a similar manner as described above, following Scheme 1. 25 - 89 NH N ' 0 /OHO 0 O H NMR (400MHz, CDC1 3 ) 6 1.25-1.30 (m, 2H). 1.55-1.70 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.61-2.66 (m, 4H), 2.74- 2.82 (m 2H)7 2.88 (t, 2H), 3.86 (s. 3H), 4.20 (hr. 5H) 4.90 (d. I H), 5.93 (br, 1 H), 6.78 (q. 2H), 6.85 (s, IH), 6.91 (d, 5 211), 7.92 (d. 2h); MS for C2 IHsN20: [M-H] 511. IIxamiple II ,2. Pri arion ofi Compun 144.: N \-ftIR.2R) --(23 dk ihx droh Cnzo/jj AidioUin-60-" 1 -1\ hdr ox (1 '-3trlkidi-1 Ipon--l8-4 10 Compound 144 was prepared in a similar manner as described above, following Scheme 1. N 0 HO 15 1H NMR (400MHz, CDCl3) 6 1.25-1.33 (, 411), 1.54 (i. 2H), 1.68 (t, 2H), 1.78 (hr, 41) 2.11 (br, 21H), 2.65 (br, 4H), 2.76-2.11 (i. 4H), 3.86 (s. 31), 4.21 (br, 51H), 4.90 (hr, 11), 6.02 (d, 1H), 6.78-6.84 (m, 3H-1), 6.91 (d, 2H) 7.92 (d, 2H-1): MS for C 3

H

4 0

N

2 0b: [M-H1] 525. 20 Example 1E63. Preparation of Compound 1591 7-(4-chloropheny1 )-N-( (1R,2R (2,3-dihydrobenzo[pFlifIh41dioxin-6-yl)- 1-hydroxy-3-(pyrrolidin- I -y)propan-2-yl )-7 Compound 159 was prepared in a similar manner as described above, following Scheme 1. 25 - 90 ""0 0 0 'IH NMR (400M\1/.lz, CDCI 3 ) 6 1.26-1.37 (in, 2H), 1.57 (m, 2H), 1.68 (m, 2H), 1.77 (br. 4H), 2.13 (t 211), 2.62-2.65 (m, 4H), 2.76-2.82 (n, 21H), 2.90 (t, 2H), 4.20 (br 5H), 4.90 (d, 111), 5.93 (d, 1H), 6.78 (q, 2H), 6.85 (s, IH), 7.42 (d, 2H), 5 7.87 (d. 211): NMS for (C l CIN 2 0 5 : [NI-11| 515. Ixample I 64. PreparaTon of o mound 160: 7-(4-tert-hutl lpheny-N-( 1R.2R) I-(2 3-ih drohen/or[ / 4]dioxmi-6- I)-I -hvdrol)\-3-(p vrolidIHn-1 -v1l)prpan-?-I -l 7-oxoheptalaiade 10 Compound 160 was prepared in a similar manner as described above. followim Scheme 1. NH N 0 0 H NMR (400M IHz CDCI) 6 1.27-1.34 (m, 1 lMH), 1.56-1.71 (in 411) 1.77 15 (br, 4H), 2.13 (t, 2H), 2.63-2.66 (n, 41), 2.76-2.819 (m, 2H), 2.91 (t, 21), 4.20 (br, 5H), 4.90 (sd, 11), 5.90 (d, IH), 6.81 (q, 21H), 6.85 (s, IH). 7.46 (d, 2H), 7.88 (d, 21l) MS for( I (k 4 N20< [\ 1-H] 537. 1mple 1E 65. Preparaton o)f Compoun~d 168: N~(RRI~hl J3. 20 dUITM DI mnethoxyphenyl)-7-oxoheptanamnide (2 S.3S)-2,3 -dihydroxysuccinate compoundd 168 was prepared in a similar manner as described above, following Scheme 1.

-91 NH N NH O7H 0 OH 'H NMR (400M1-Iz, CD 3 OD) 6 1.15-1.19 (in, 21), 1.40-1.47 (m. 21), 1.60 (in, 2H), 2.02 (br, 4H), 2.09-2.21 (in, 2H), 2.90 (t, 2H), 3.35-3.49 (m, 5H), 3.83 (s. 5 3H), 4.12 (br, 4H), 4.38 (s, 2-1), 4.43 (in. 1H) 4.74 (sd, 1HT), 6.71 (d, IH), 6.79 (dq. 111), 6.86 (sd. 1 ). )>96 (d. 211). 7.92 (d, 211); \S f or C - \ ( 11 6(>: |\-Il 661 Examllple 1 [66.- Prepatio oQmpound 162: \-fIL9- j1-7 10 d rr4-(4 Compound 162 was prepared in a similar manner as described above, following Scheme 1. IN H N 15 H NMI (400MHz CDC 3 ) 6 1.35 (d, 611), 1.77 (br, 4H), 2.52-2.56 (in, 21H), 2.64-2.83 (m, 6H), 3.09-3.36 (m, 21T), 4.22( br, 5H), 4.63-4.66 (m, 1H), 4.89 (sd. I H), 6.13 (d, 1 1), 6.78 (, 2H), 6.88 (t, 31). 7.90 (d. 21): MS for C2H:N 2 0 6 : [M 20 H]1497. example 1E67. Preparaition of Corn ound 176: _N-C(1R-2R)-1-42_,3 dihydrobenzof f3][1l.4dioxin-6-yl})-1 -hydroxv-3 -( pyrrolidin-:1-vil)propan-2-yl )-4-oxo 4-(4-( trifluoromethylphenvl butanamide (2S,3 S)-23 3-dihydroxvsuccinate - 92 Compound 176 w 'a: prepared in a similar manner as described above, following Scheme 1. NHH -_0Y F

-

O H 0 5 H NMR (400MHz CD3OD) 6 2.08 (br. 4H), 2.54-2.72 (m, 2H), 3.24-3.48 (m, 6H1). 4.19 (s, 4H), 4.29 (in, 4H), 4.74 (sd, 1 H), 6.76 (d, IH). 6.86 (d, I H), 6.92 (s, 1 H), 7.81 (d. 2H), 8.13 (d. 211): MS for ( I I (>N (C) I JO(6: [M-H] 657. 10 Example 1E68. Preparation of Co11pound 65 (Wenz-528152-1) chIorobi phenyl4-yl) N-( , ( I2R>-1 -(2 ,3-dihydrobenzo [1 ] dioxin-6-yI)- 1 Compound 65 was prepared in a similar manner as described above, following Scheme 1. 15 NHy 0 NH O CI H1 N IR (400MHz, CDC 3 ) 6 1.70 (br, 4H), 2.54 (br, 4H), 2.72-2.81 (in, 2H), 3.53 (s, 2H), 4.12-4.23 (m, 5H), 4.85 (d, 111), 5.82 (d, 1H), 6.58 (dd, 111), 6.70 20 (sd, 1 H), 6.73 (d, 1H). 7.19 (d, 1 H), 7.32-7.34 (m, 1H), 7.38 (t, 1 H), 7.46-7.49 (in, IH), 7.52 (d, 2H), 7.59 (d, 1H); C2 31 C1N2O4: [M-H]~ 507.

- 93 Iample I . 0jreParation ofpCorpounL 262: A2- 2-h\ydroxy 2-Iethoxy phenl)U-I -pyrjiIlin1-yjlethIl-ethj- 1 - -ellv-p)eny)-pro ionamide ( compound 262 was prepared in a similar manner as described aboe. following Scheme 2. 5 OH N C NH' a0 (0 O I NMR (CDCI\ 400 mHz, ppm); 1.75 (. 411), 2.55 (I 2H), 2.65 (I 4H), 2.85 (m, 2H). 3.8 (s 6H), 4.1 (in, 2H). 4.25 (in. IH), 5.0 (d, 1H), 6.5 (br. d, 1H1), 6.8 (m, 411), 7.25 (in, 4H). M 7 for C24H32N20s [M-H]* 429 10 Wxape I E70. Preprtin oA opund 270 5-4-Isopropox-pen'j--o pntanoic acid [2-h drox 2-4-methox phen I yl)- I -pyilidin-1 yn Imethyl ethylJ unide compoundd 270 was prepared in a similar manner as described above, 15 following Scheme 2. _OH NO 0 0

O

- 94 'H NMR (CDCl 3 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (in, 2H), 2.2 (in, 2H). 2.6 (m, 4H), 2.8 (m. 4H), 3.75 (s, 3H). 4.25 (in, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, IH). 6.85 (m, 4H), 7.25 (in, 2H), 7.9 (m,2-1). M/Z for C 4 H 32N205 [M-H] 483.3 5 Example 11E71. Preparation of Compound 285: 74-Methoxy-phenyl)-7-oxo heptanoic acid 1 2 -hydroxy-2-(4-methoxv-phenyl)-1-pyrrolidin:1-ylmethyl-ethyl] amnide Compound 285 was prepared in a similar manner as <describetd above. 10 following Seheme 2. OH N . OO 0 -u 00 H NMR (CDCl 3 400 mHz. ppm); 1.25 (in, 2H), 1.6 (in, 41-1) 1.8 (in, 4H), 2.15 (i, 2H), 2.65 (in, 4H), 2.85 (i, 411). 3.75 (s. 3H), 3.9 (s. 3H), 4.2 (m, 1 H). 5.0 15 (d, 1 H), 5.9 (br. d. I H) 6.85 (d 2H), 6.95 (d, 2H)7 7.2 (d, 21-1), 7.95 (d, 2H). M/Z for C2 4 12N 2 0 5 [M-H] 483.3 20 Compound1 262 was prepared in a similar manner as descrihed above, following Scheme 2.

- 95 OH

N

0 ~~0 iH NMR (CDCl 3 400 mHz, ppm); 1.75 (m, 4H), 2.55 (in, 2H), 2.65 (in, 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. IH), 6.8 5 (m, 4H), 7.25 (in, 4H). M/Z for C 2

.

1

H

32

N

2 0 [M-H]4 429 Examp e 173 re aralion of Compound 270: 5-(4-sopropoxy-henyl)'-5oxo pentanoic acid J2-hydroxy-2-(4-imethoxy~-phenyl)-l1pyrrolidin- 1 -vmethyl pihyl ainide 10 Compound 270 was prepared in a similar manner as described above. following Scheme 2. OH N 0 O 0 ~~ 15 'H NMR (CDCl 3 400 mHz, ppm); 1.4 (d. 611), 1.8 (m. 4H), 2.0 (m, 2H), 2.2 (in, 2H), 2.6 (in, 4H), 2.8 (in. 4H), 3.75 (s, 311). 4.25 (in, 1 H), 4.65 (in, 1H), 5.0 (d, 1H), 5.95 (br. d. 1H). 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m,2H). MIZ for C24H32N205 \M-HI 483.3 -96 Example 1E74. Preparation of Compound 305 Compound 305 characterized by the following structural formula was prepared in a similar manner as described above, following Scheme 2. 5 OH NH 0 N i N IR (CDClh 400 mHz, ppm); 1 .25 (m, 14 H), 1.6 (in, 4H), 1.8 (m, 4H). 2.1 (t, 2H), 2.6 (t, 2H), 2. 8 (in, 6H), 4.2 (in, 5H). 4.9 (d, I HI, 6.0 (hr d, I H), 6.8 (in, 10 311). 7.2 (in, 1 H), 7.5 (in. 1 H), 8.4 (m, 2H). M/Z for C24H 3 2N20s [NI-H] 538 Example I1E75. Preparation of Compound 320: Octanoic acid [2hydroxy-2(4 Compound 320 characterized by the following structural formula was 15 prepared in a similar manner as described above, following Scheme 2.

- 97 OH N 0 H NMR (CDC 3 400 mHz, ppm); 0.9 (t, 3Hl), 1.2 (m, 8H), 1.5 (m, 2H), 1.8 (m, 4H), 2.1 (t, 2H), 2.65 (in, 411) 2.8 (d, 21), 3.8 (s, 31), 4.2 (m, I H), 4.95 (d, 1 H) 5 5.9 (br d, 1H), 6.9 (2s, 2H), 7.25 (m, 211). M/Z for C22HN2O3 [MH-1-f 377.4 Kni mle1I.7. irie ration o( che Amide Analos

K

2 C0 3 , O OH glycerol0 NN 1150C

NH

2 N 0 R (Scheme 10 6) Cyclic amide analogs were prepared according to Scheme 6. 2-Amino-1 (2,3-dihydro-benzo[1I,4] dioxin-6-yl)-3-pyrrolidin- 1-yl-propan-1I-ol was prepared 15 according to the preparation of intermediate 4 of US patent 6,855,830 B. This amine was coupled with various ntriles in potassium carbonate and glycerol, und r an atmosphere of nitrogen, fr example, at 115"C for 18 hours. Compound 323 characterized by the following structural formula was prepared by following Scheme 6. Compound 323 was purified hy column chromatography using a mixture of 20 methanol and methylene chloride.

- 98 0a 0 0 N H NM1R (CDC 3 400 mHz, ppm); 0.95 (1 311) 1.35 (m. 211), 1.6 (m, 2H), 1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (in, 5H), 5.4 (d, 1 H), 6.85 (m, 3H), 7.2 5 (in, 2H), 7.9 (d, 2H). M/Z fr C2 4

H

3 2N 2 0 [M-H] 421.54 [Eample 2. Synthesis of Ceramide Derivatives: Preparation of Carhamate 10 xapl 21. Pre (ratim of1-ezv -~ -22 -d I m"01loxazo(lid I I -3 10 N O N 0 0 Steps 1-2: preparation of (R)-benzyl 4-(methoxy(mIthyl )carbamoyl)-2 15 dimethyloxazolidine-3-carboxylate: N,0-dimethylhydroxylaimine hydrochloride (45 g, 0.46 minol, 1.5 eq) and N-methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly to a cold (-15 TC ) suspension Eof d-CB/ serine (73.0g, 0.305 mol) in

CH

2 Cl 2 (560 mL) keeping the temperature below -5 C. The mixture was cooled back to ~ -15 OC and EDCI (62 g, 0.323 mol, 1.05 eq) was added. The mixture was -99 stirred for 5 hours keeping the temperature below 5 0 C. The solvent was removed by rotary evaporation and the mixture was partitioned between HCI (1 M. 300 mL)and EtOAc (500 mL).The organic layer was separated and washed with HCIl (I M, 2X 100 mL) and then sat. NaHCO 3 (2 X 150 mL). The mixture was dried over 5 MgSO 4 , filtered and then the solvent was removed by rotary evaporation. (R) benzyl 3-hydroxy- I -(methoxy(methyl )amino)- 1 -oxopropan-2-ylcarbamate was re dissolved in a mixture of acetone (375 mL) and 2,2-dimethoxy propane (375 mL) and boron trifluoride ethereate (3 mL,) was added. The mixture was stirred at room temperature for 5 hours and then triethyl amine (3 mL) was added. The solvent was 10 removed to dryness and (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2 dimethyloxazolidine-3-carboxylate was obtained as a white solid (73.0 g, 74 % yield from both steps) after purification by colun chromatography using a mixture of hexane/ EtOAc/acetone. H IN4MR (CDC 3 , 400 mHz, ppm); 1.5 (s, 2 H), 1.6 (s, 3H), 1.7 (s, 2H), 1.75 15 (s, 3H), 3.14 (s, 3 H), 3.24 (2 H), 3.4(3 H), 3.76 (s, 2 H), 4.0 (m, 1.7 H), 4.16 (in, I H). 4.2 (m, 1.7), 4.78 (m, 1 H). 4.88 (m, 0.6 H), 5.06 (q, 2 H), 5.18 (q, 1 H), 7.4 (m, 8 H). Stp3: preparation of (R)-benzvl 4-formvyl-2, --dimethyloxazolidine-3 carbox ylat: 20 0 H 0 A solution of LiALI4 (1 M, 20 mL, 20 inmol) as added dropwise to a cold (-15 25 "C) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2 ,-dimethyloxazolidine 3-carboxylate (12.2 g,37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0 C. A saturated solution of KiSO 4 (100 mL) -100 was added slowly to the mixture and it w -as warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl 2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92 % yield) after purification by column chromatography (SiO 2 , using a mixture of 5 hexane/EtOAc). H NMR (CDC 3 . 400 mHz, ppm); 1.7 (m. 6 H), 4.15 (in, 2H), 4.4 (in1 H), 5.15, (s, IH), 5.2 (n, 111), 7.3 (m, 51H), 9.6 (in, I H). xample A2. Preparation of (R)-hen/yl 4-ttR)-hvdroxy(t4-metho xyphenyl methyl l 220hmethvloxa/olihne3earhox late 10 0 OH 0 1, 2 -dibromoethane (0.2 ml) was added slowly to a hot (65 "(C) solution of 15 magnesium turnings (0.91 g, 37 mmol) in THF (14 ml), followed by the dropwise addition of a solution of 4-bromo anisole (4 mL, 32 minol) in T HF (14 mL). The mixture was refluxed for 2 hours and then cooled to room temperature. The grignard solution was added dropwise to a suspension of Cul (6.8 g, 36 mmol) in a mixture of Me 2 S (20 mL)/THF (100 mL) at -78 C. The mixture was warmed 20 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 1(3.20 g, 126 mm1ol) in TIF (15 mL) was added dropwise. The mixture was stirred at low temperature overnight (15 h, T max = 10 0 C). The reaction mixture was quenched 25 with NH 4 Cl (sat. 100 mL) and extracted with EtOAc (50 mL). The solvent was removed to dryness and the mixture was purified by column chromatography (SiO 2 , using a mixture of hexane/EtOAc/acetone)and the product was obtained as a colorless oil (1.697 g, 36 % yield).

- 101 Example ?,\3. Preparati of wnzvl (ITT. 2R )- 12 -dihdroxy- 1 (4 mecthoxv phenyl I)propamn--Lcabmt 0 HO OH H O O H 0 5 A mixture of benzyl 4-(hydroxy-(4-methoxyphenyl)methyl)- 22 dimethyloxazolidine-3-carboxylate (1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOHI (20 mL) was stirred at room temperature for 2 days. The mixture was 10 centrifuge and the solid was washed with McOH (2 X 40 mL). The solvent was removed to dryness and after purification by column chromatography (SiO 2 using a mixture of CH 2 Cl 2 EtOAc) the product was obtained as a white solid (1.26 g, 84 0 y ield). 15 xamIc 0A4. S\nthesis of Comud 289: beuzyl IH. 2Q- Ih dRoxv-1- 4 methox plenylIJP -3 rrldidim n- 1 l)rpn2cal baniat 20 - 102 0 N OH HN O 0 NMsityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (-10 "C) solution of benzyl (IR, 2R)-1 I,3-dihvdroxy-1-(4-methoxyphenyl)propan-2 5 ylcarbamate (1.07 g, 3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min and then pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. The mixture was heated to 45 C for 6 hours and then the solvent was removed to dryness. After purification by column chromatography (SiO 2 , using a mixture of CH2C(2, MeOH, NH 4 0H), the product was obtained as a clear oil (0.816g, 66 % 10 yield). Example 3: Synthesis of CeraIide Derivatives: Gcneral Procedures for the Synthesis of Urea Analogs OH OH + O==N

NH

2 NH NH 15 (Scheme 5) (1R, 2R)-2-amino-(2,3-dihydrobenzo [p][1,4[dioxin-6-yl)-3-(pyrrolidin-1-yl) propan-l-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 20 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 - 103 times varied depending on the isocyanate substion from one to twelve hours. Compounds 6, 7, 10, 17, 40, 41, 42, 43, 68, 69, 70, 71, 80, 81, 82, 133, 257, 261, 286 and 287, shown in Examples 3AI - 3A21 below, were prepared following reaction Scheme 5. The compounds were purified by column chromatography. 5 Exam _le 3A 1. Ore artinofCmpond 6: 1 W/Onz1-3-1 112 R)-l1-(23 dih ~ ~ ~ ~ ~ I drb-z b3 RAI doi-yjlhdrx-Airodidin - 1-v Qropan-2-vl u)rea N H H N yN" OH 10 'H NMR (400 MIHlz CDC 3 ) 1= 1.7 (s, 41-1) 2.4-.6 (n, 511), 2.6-2.7 (dd, 111), 4.0 (i. 11H) 4.2 (s 4H), 4.3 (m. 211), 4.8 (d, I H), 4.86(d, 1H), 5.0 (br, 1 H), 6.6-69 (m, 3H), 7.2-7.4 (m, 5 H); MS for C 23 H2I 9 N30 4 i/z 412 2 [M-H] 15 20 Example 3A O of coMu 17: 1- R 21011 (2A3 LuorobenzylIurea -104 N H NJ , 0 F O .)HN OOH 0 11 NMTR (400 MHz, CDCl 3 ) 6= 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (in, 1H), 4.0-4.1 (in 211), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, 1H), 6.6-7.1 (m, 7H); MS for

C

2 3 1 2F\ 04 n/z 430.2 [M+H]. 5 x\anmple 3:\3. Preparation of (Cornpound 40: 1-(4-hrornohen/z -3-( i R, 2R)-1-(2 3 ihdrohen/o[LfjlL 4]<hoxul-6-v l-1I-h) dro x -3-( pyrrolidin- l -yljprojpan-2-vl)urea N H N 0 Br ( 0 .,,HN "OH 0:1 10 1H NMR (400 MHz, CDC1 3 ) 6= 1.7 (s, 4H), 2.4-2 (rn. 6H), 4.0 (n, 1 H), 4.1-4.2 (m, 21H) 4.2 (s, 4H), 4.8 (d, I H), 5.3 (d - H), 5.6-5.8 (br, 1 H), 6.8-7.0 (m. 3H), 7.0 (d. 2H) 7.4 (d, 211); MS for C 2 3

H

2 irN0 4 rn/i 490 (M], 491 [M H], 492 15 metho2benD rea 20 - 105 N H O N 0O0 COOHN OH 0 H1 NMR (400 M-li, CDCl 3 ) = 1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3.9 (in I H), 4.1 (d, 211), 4.2 (s, 411), 4.7 (d, I 1H), 5.2 (d, 11H). 5.5-5.7 (br, 1 H), 6.6-6.8 (m, 5H), 7.1 (d, 2H); MS for C 24

H-;N

3 0 m/z 442.2 [MIH] 5 Example 3A5. Preparation of Compound 80: 1-(1 R, 2R)- (2_3 dihydrobenio[l I Aldioxin-6-yl)-1 -hydrox -3-(pyrrolidin 1-y p rop an-2-y-3-3: nethoxvbenil'1urea N 0 H O H 10 IH NMR (400 MH z, CDCl 3 ) = 1.7 (s, 4H), 2.4-2.6 (i 6H), 3.8 (s, 3H), 4.0 (m, 1H), 4.1-4.2 (s, 6H), 4.8 (d, 1H), 5.1 (d, I 1H) 52-5.4 (br, 1 H), 6.6-6.8 (m, 6H), 7.2 (dd, 11I); MS for C2H1-N 3 0s m/i 442.2 [M+H] 15 Exam I 3A6. Preparatio of Compound 42: 1-(( R 2R)-1-(2,3 dihydrobenzoft6j{1Al4dioxin-6-yl -hydroxy-3 -(pvrrolidin-l-yl)propan- 2 -vl)-3-(4 rnethvlbenzyl urea -106 N H N 0 O0, HN OH 'H NM (400 M111. (DO1 3 :0 1.6 (s,411),) 3 (s 311),.2 4-2.6 (i.611). 4.0 ( -, 1 ) .2 (d. 2H), 4.21 1(s 411), 4.7 (d, I H), 5.2 (d, 1-) 5.4A-5.6 (hr. I1-H), 6.7-7. 1 5 (m,. 7H): MS (for C2.H 31 N ) 0m r/, 426.2 [1MIT] djj~~1rbcnz LUl .4dioin-6yjI -h- 'drxy-3 I I prohdil- I p-opmn2v1o N H N 0 aCI 10 0Ox 1H NMR (400 HUT/ CDC ),-) 1.7 (s, 411). 2.5-2-.7 (ii. 6O1), 4.0 (mn. 111), 4.2 (s. 611), 4.8 (d, I H), 5.2 (d, IlH), 5.4 -5.5 (hr. 114). 6.7-6.9) (i.3), 7, 1 (d, 21-), 7.3 (d, 2H), MS for C, 1HN1 O 4 rn/iz 446 tM H ]. 447.5 [M421 15 Exipi kA8 Pre cra ti ot~ orn() pounid 10: 1-(1IR, 2 R) -1-f- 32 I Ihv1 oenzo 3IA I w,1ox1-0-v -1h(1 'doxv3 roii-1-i)rpn2 3(~ - 107 N H ON 0 (0 *.,HN OH 00 ]I NVR (400 N1I1/. ( D() I .4 (d. 3HI). 1.6 (s, 41), 2.2-2.5 (m. 4H), 2.5 (dd, 1 H), 2.6 (dd, 1 1H), 4.2 (s, 4H) 4.5 (m, 1H), 4.8 (d,. 1 H), 5.0 (d, 1H), 5 5.1-5.3 (br, IH), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C2 4

H

3

N

3

O

4 m/z 426.2 \Ml-H]. 10 1 phenylethyl )urea N H N y0 (O., HN OH H NMR (400 MHz, CDC13) = 1.3(d, 31H), 1.7 (s, 41), 2.2-2.6 (m. 6H), 3.9 15 (m. 1H), 4.2 (s, 4H), 4.6-4.7 (m, 2H), 5.3 (d, 1 H), 5.6-5.7 (br, I H), 6.6 (d, 1 H), 6.7 (d, 1H), 6.8 (s, IH), 7.2-7.4 (m, 511); MS for C2 4

H

3 1

N

3 0 4 m/z 426.0 [M+H]. Example 3A10. Preparalion of Compound 69: 1-((1R- 2R)1-(2,3 dihydrobenzo[11 .4idioxin-6-yI)- 1 -1hydroxy-3-(pyrrolidin- I-vl)propan-2-yl)-3 20 (naphthalen-2'urea -108 N H N 0 O .,,HN OH 1H NMRl (400 MII/, CDI) 6= 1.6 (s,411), 2.4-2'.8 (in 61-), 4.1(s 51 .8 5 -1i 4X.1 I{M+H]. Exarnni23'A 11. Pireara tik~ol ofnornpoond 288: 1-W( iR. R1(2 dijldroenzo~jJ l ,, dii-0 y1 ~voxv"\(prro di 1 i- 1, -oa~~D3 10( N H N --- 0 CO *.,HN OH 11H), 4.2 (s, 41 1), 4.8 (d, I H ). 5.4 (d, 1 H), 6.5 (d, 11-1). 6.6 Id 11), 6.7 (s, 1 H), 7.2-7.6 15 (mn, 3 H), 7.7 (d, 1 H), 7. 8 (d. I H), 8.0 (d., F 1 -) I for CmH.NO 4 448.1 1Mill1 - 109 N H N y0 (0 .,,HN OH 0 'H NMR (400 MHz . CDC 3 ) 6= 1.4 (s, 4H), 1.5 (d 3H) 2.3 (s, 4H), 2.4 (dd, I H), 2.6 (dd. I H). 3.9 (hr. I H). 4.2 (s. 411), 4.7 (s, 1 H), 5.0 (d, I H), 5.3 (br, I H), 5.5 5 (br I H), 6.6 (m, 3H). 7.4-7.6 (i, 411), 7.7 (d, 1H), 7.8 (d, I H), 8.1 (d, 1 H); MS for C 11 hN:0 4 m/z 476.2 [MH]. Example 3A13. Preparation of Compound 70: 1±(biphenyk-4-vl)-3-0 AR, 2R -1(2,3 dihydrobenzofp]{l4]dioxin-6yl)-ehydroxy-3-(pyrrolidi n-l-yijpropanr-y-urea N N 0 O HN OH 100 'H NMR (400 MHz, CDC1 3 ) = 1.7 (s,. 4H), 2.6-2.8 (m, 6H), 4.1 (br. 1H), 4.2 (s, 4H) 4.9 (hr, 1H), 5.9 (d, 1H), 6.8 (s, 211). 6.9 (s, 1H), 7.2-7.6 (mn, 9H); for C, I 1

N'

3 0 4 mx 474.1 L 11]. 15 Example 3A14. Preparation ofCompound 81:1-((R, 2R) 1-(2,3 l ruonomet\h n1 4iolOilrea -110 N H N 0 O .HN OHF 0 F HI NMR (400 MHz, C~D;l) S= 1.7 (s. 4H), 24-2.7 (im, 6H) 4.0 (br, H), 4.2 (s, 4H), 4.8 (br, 1 H), 5.9 (hr, 11H), 6.8 (s, 2H), 6.9 (s, I H), 7.3 (d, 211) 7.5 (d, 5 211); MS for C2 3 H 1F N04 1 m/z 465.97 [MH1. trilluorometphqw W enPjre 10 N H N 0 y ~FF ( 0 *.,HNF OHF 1 NMR (400 MHz, CDC13) = 1.7 (s, 4H), 2.5-2.9 (m, 6H), 4.0 (br, 1H), 4.2 (s 4H). 4.8 (br. I H), 5.9 (br. I H), 6.8 (s, 2H), 6.9 (s, 1H) 7.2-7.6 (n, 411); MS 15 for C2 3 H2F NV04 m/z 466.0 [M+ H]. Example 3A16 Preparation of Compound 82: 1-((R. 2R)-1-(23 dihydrobenzo[f I ,4ldioxin-6-vl)- 1-hydroxy-3-(pyrrolidinr1I-vl )propan-2-yl )-3-(4 20) N H N 0 OH FI OH 0 FF H NN[R (400 Ml z, CDC1 3 ) 6= 1 2 (s. 41), 2.4-22 (n, 61-), 4.()(br, 1H), 4 2 (s, 41H), --I. (br. I H), 5.9 (br, I H), 6.8 (s, 211). 6. 9 (s, I H). '7.0 (d, 211), 7.2 (d, 5 2H); NIS for C-I HmF 3 N;O05 rn'/z 481.5 jjNI, 482.5 [M+ H]. IE\ajpi A1 7. Prcpara tio o Cmpun 133- 1 -((l1 R. 2) -1 -(-L3 dihydobeuo {U1 AidhoiHl- h-\yih- I -hydri k 3t\\ o idindM- I )lproa-2y _-4 N H N 0., ~ O 0H )all N 0 10 S 1'H \1 NMR(00 M11z CDC 3 -il.7ls41)- 2.4-1 7 (m.6-)27 s3) 4.1 (bri-1, .2 4 H- ).8 (bri IHl). 5.9) (d. Ill),.8 s 211)_ 6. (. ), 7.20(s. 111), 7.3 (di 21-). 7.7 (d, 2H); NI S for C' , HI ,N 10 4 S mz494.9 [MI-HI. 15 1ExamI t I c _"A1I8. Prpato of Compound 7- 1 -(IR.2R)-L-f2,3 dh jlld(roblcnz f jdkJ 1 ] .4d i-0-y h- 1 -hdox- \4 diroi I I lI-v ro hmn21-3 -112 N H N 0 (0 OH 0 1-1 iR 400 I I, CDI 3 ) 0.9(t,311), 1 .3 (br, 1811), 1.4 (i 2H), 1 .8 (s, 41). 2.5-217 (wn 61) 3.1 - (q. 2H)740 (in, I1H), 4.3 (s, 4H), 4.4 (br, I1-1), 4.76 (d, 5 111), 4.8 (d, I 4) 6.7-6.8 (dd, 21), 6.9 (s. I H); MS for C2 8 sH4-N 3 04 in'z 489.7 [M\1I111.490.9N [ )I2. (11 ll IArpb1*nko Ij4dII-6-vlI) -1(1 -hdo\\ 1 (d3 rrl(Id-1 -vi ropan2--- 2 I0 111 Uopjlcen-2-v1 cmv! ureat IC~ N H N 0 "O0H S (0 IH NMR (400 MHz, CDI ) 6:) 1. 7 (s, 411) 2.5 -2.7 (in, 6 H) 3.0(1,3.8 (q. 21-). 4.0 (III, 111), 4.2 (s, 411),. . d,2). 4.9 (d. 1H). 6.7-6.8 (11, 311), 6.9) (d, 15 114, 6.9 (dd-1 Hi), 7.1 (d, 11H); MSP for- C- I llNVO4S 12. 4 1 [M--H]. 20 - 113 (0) N H (0 .,H N '11 ~ \11/ NMR(40 Mz, ) 5rz 24-)_6 (ii, 7H) 2.7 (dd, IH). 3.5-3.7 (i. 41-). 3.8 (,. 3--1 ), 4-42. (m.2 2H). 4.2 (s,. 4H). 4.2-4.3 (ill. IH). 4.9 (d, IH). 6.5 (d, IH), 6.7-6.9) (in. 7H); MPS for ('-,IN~O I it\ /( 473.1 [Miii]. 5 N H OH 100 H NMIR (400 Mli., CDCI,) &= 1.4 (br, fl), 1.6 (br. 4H),) '."-28 (i, 6H), 3.8 (.311), 41.0-4.2 (in 211). 4.2 (s,411), 4.2-4.3 (i,. 1I), 4.9 (s. 11-1), 6.4 (d, 1H-), 6.7-6.9 (m,. 71H);, MS for_ C 2 5

-

3 4N 2 )06 in/i 47 1.1 [M\-I-,I]. 15 l-hyrox-3-pyroliin-vl~ropn-2yI~onaanide)Effectivel Inhibited PKD inl a Mouse M. odel - 114 N OH 0 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 paraflin embedding and IH 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 (mg/kg) Body weight (g) K/BW ratio (%) (%BW) BUN (mg/dL) 9 M Vehicle 22.031.58 7.55 1.65 2.86± 1,04 90.11 1002 9 M Treated 18.43 1 182*1 446 0.46* 088 ±023* 39 25 1070* 10 Vehicle 19.20 1,80 4-94±073 220S41 50 1432 10 F Treated 15.93 1 ,65* 3.57 0.58* 0.58 0.29* 34.67 9.41* p<005% compared to control (2-tailed t-test) 15 Kidney and body weights 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 tailed t-test). A significant difference in kidney weight/body weight ratio was also - 115 observed (p-value <0.05, two-tailed t-test) for the treated animals, suggest ing efficacy of the drug. Cvst volume: 5 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 ( N) levels w ere determined in serum samples deriv ed from animals at sacrifice. BUN levels were elevated in the untreated controls, while the treated animals demonstrated a significant reduction of IBUN levels (p-value <0.05, two-tailed t-test). 15 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 cyst volume. This was accompanied by improved renal function in treated animals 20 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. While this invention has been particularly shown and described with 25 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 friom the scope of the invention encompassed by the appended claims. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the 30 purpose of providing a context tor discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in - 116 any jurisdiction, are prior art or form part of the common general knowledge in the art. In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That 5 subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Claims (24)

1. 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, Ar, -OR 0 , -O(haloalkyl), -SR 0 , -NO 2 -CN, -N CS, -N(R 3 )2, -NR 3 ' C(O)R 3 , INR 3 1 C(O)ORc, -N(R ')C(O)N(RM)2, -C(O)R 0' -C(S)R3, -C(O)OR 30 , -OC(O)R0, -C(O)N(R )2, -S(O)R 3 , -SO/N(R )2 -S(O)R 2 -SO 3 RE 2 , -NR 3 SO'iN(R )2, NR 3 SOR 2 , -V 0 -Ar', -Ve-OR , -V-O( haloalkyl), -Vo-SRw 1 , -'Ve-NO2,N -- CN, -Vo-N(R')2, -Vo-NR 1 C(O)Rw, -V-NRA CO) 2 . -VN(R)C(O)N(R )2 -VC(O)R 0, -VR-C(S)R , -V,-CO2R, -- OC()R -V 0 -C(O)N(R)r, V-S(O) 2 , -V-SO2N(R 1 ) 2 -V-S(O)R -V0-SO 3 R, -Vo R S2N(R)2,-VoNR SO2-R ,--eA OVNR),--oAi 1,,( 31 -S-VNR )2-(A-oAi NR)- (E2 RCO-oN R' -C(O)N(R )-V -N(R )2, -C(O)N(R 1 )-V-Ar', -S(O)2-e-N(R')2, -A -Si(M)VR ) V S2(-V,-A-S(O)-V-N (R ), -SC()-o-Ar, )N A3)1 1' S02-OAl -S(O-O-V-N(R)2, -S(O)O-Vo-Ar 1 ,- R -NR V N(R )2, -NR SO-V-Ar, -O-[CH21]p-O-, -S-[CH 2 ]p-S- and -[CH 2 ] 1 eaIch V 0 is idpnetya Cl-ClO aIlkyjlne group; eaich V, is idpnetya C2-CIO alky.lene group; Ar is an aryl group or a heteroaryl group, each of w 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, alkylcarhonyl and haloalkyl; and each R 3 0 is independently hydrogen: ii) an aryl group or a heteroaryl group. each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino. dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarhonyl, alkylcarbonyl and haloalkyl: or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino. alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and each R is independently R, -CO 2 R 3 , -SO 2 R4 or -C(O)R; 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 of halogen, =O, =S, =N(CI C6 alkyl), Cl-C6 alkyl, CI-C6 haloalkyl, hydroxy, Cl-C6 alkoxy, nitro, cyano, (CI-C6 alkoxy)carbonyl, (Cl -C6 alkyl)carbonyl, Cl -C6 haloalkoxy, amino, (Cl -C6 alkyl)amino and (Cl -C6 dialkyl )amino; and each R is independently: i) an aryl gm up or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino. alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl: or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen. amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; and 119 each p is independently 1, 2, 3 or 4; and each q is independently 3, 4, 5 or 6.
2. 3. The method of Claim 2, wherein: 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 Irom the group consisting of halogen, -OH, -CN, NCS, -NO 2 , -NIH, Cl-C6 alkoxy, CI-C6 haloalkoxy, aryl and heteroaryl; or' n aryl group or a hraryI group, each independently and optionally substituted with one or more substitents selected from the group consisting o halogen. -OH, -CN, NCS, -NO2 -NH2, CI-C6 alkoxy, lower haloalkoxy, Cl -C6 aliphatic group and C I-C6 haloaliphatic group; or R and R' taken together with the nitrogen atom of NRR' Irm a non aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH; -CN; -NCS; NO 2 ; -NI2; Cl-C6 alkoxy; Cl -C6 haloalkoxy; Cl-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO2, -N2,. CI-C6 alkoxy, Cl-C6 haloalkoxy, aryl and heteroaryl; and an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, -NCS, -NO 2 , -NI 2 , CI-C6 alkoxy, Cl-C6 haloalkoxy, C1-C6 aliphatic group and Cl -C6 haloaliphatic group.
3. 4. The method of Claim 3, wherein: -N(R2R3) is a 5- or 6-menIered non-aromatic nitrogen-containing heterocyclic group optionally substituted with one or more suhstituents selected from the group consisting of halogen, alkyl, haloalkyl, -OR 4 0 , -O(haloalkyl), SR, -NO2 -CN, -N(R 4 -)2, NR 4 C(O)R 4 , -NR 4 C(O)OR 4 2, -N(R41)C(O)N(R4), -C(O)R4, -C(S)R 4,1 -C(O)OR 4, -C((O)R41, -C(O)N(R4) -SO 2 N(R 4 1 )2, -S(O)R Ar 2 , V2-Ar2, -V 2 -O(haloalkyl), -V 2 -SR -V2-NO2, -V-CN -V2-N(R )2, -V-NRC(O)R4 -V2-NR4 CO2R 42 , -V 2 -N (R 4 1 )C( O)N(R 4 )2, -V 2 -C(O)R 4 , -V 2 -C(S)R4, 120 -V-RCO2R4, -V 2 -OC(O)R4, -V 2 -C(O)N(R4)-, -V 2 -S(O)R 42 , -V-SO 2 N(R 41 ) 2 , -V 2 -)S(O)R 4 2 , -V-SO 3 R 42 , -O-V-Ar 2 and -S-V-Ar 2 . each V2 is independently a Cl-C4 alkylene group; Ar 2 is an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl, amino, Cl-C6 alkylamino, CI-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl -C6 haloalkoxy, Cl-C6 alkoxycarhonyl, CI-C6 alkylcarbonyl and C-C6 haloalkyl; and each R 4 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, Cl -C6 alkyl, amino, C 1 -C6 alkylamino, Cl -C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl-C6 haloalkyl; or iii) an Cl-Cl0 alkyl grup optionally substituted with one or more substituents selected from the group consisting of halogen, amino, Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxv, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl; and each R 4 is independently R4m, -C0 2 R 40 , -SO 2 R 4 u or -CI(O)R4; 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, 0O =S,=N(Cl-C6 alkyl), CI-C6 alkyl, CI-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano. CI-C6 alkoxycarbonyl. CI-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, Cl-C6 alkylamino and CI-C6 dialkylamino; and each R 42 is independently: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from 121 the group consisting of halogen, Cl-C6 alkyl, amino, Cl-C6 alkylamino, C1-C6 dialkylamino, Cl-C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, C l-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and Cl-C6 haloalkyl; or ii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino. C-C6 alkyamino, C-C6 dialkyl amino, C1-C6 alkoxv, nitro. cyano, hydroxy, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl and CI-C6 haloalkyl.
4. 5. The method of Claim 4, wherein R 5 and R are each independently -H1I; -OH; a halogen; or a Cl-C6 alkoxy or Cl-C6 alkyl group.
5. 6. ihe method of Claim 5, wherein Y is -H.
6. 7. The method of Claim 5, wherein each of the aliphatic, the aryl and the heteroaryl groups represented by each of I\) R and R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , ArK-Ar 3 , -OR 0, -O(haloalkyl), -SR0 -NO 2 , -CN, -NCS, -N(R 51 )2 -NR C(O)R4, -NR C(O)OR , -N(R)C(O)N(R)2, C(O)R. (S)R -w OC(O)R ,CO (R 1 RS(O)R -SO N(I )2 -V 4 -O(haloalkl), -SR , -V NO -V 4 -CN, -V 4 -N(R )2 -V 4 -NR'C(O)R -V 4 -NR 5 CO2RE, -N(R 51 )C(O)N(RM 1 )2, -V 4 -C(O)R , , -VC(S)R. -V-CO2R~ V, -VOC(O)REu, -V 4 C(O)N(R" )2-, -Ve+S(O) 2 R, -Ve 3 SO 2 N'(R ')2 -V 4 -S(O)R, -VSO 3 R', -V 4 -NRS()2N(R)2, -V 4 rNR 'SO2RP, -O-V-r -O-V\N( )2, -S-V4-Ara, -S -V5N),-N(R-r a WN( )-V4N(Ri)2 -NR 5 C(O)-V 4 -N(RS)2, -NR C(O)-V-Ar, -C(O)-V IN(R )2, -C(O)-V 4 -Ar -C(S R)2, -, -)2, -C(O)O-VAr3, -- C()-V-N(RS2 - -C(O)- Ar, -(O)5N(R)VN(f2 -C(O)N(RS)-Ar, -S(O)2-VN(R I)2 -S(O)2'-VrAr3,-ONR)VNR) -SON(S)Vrr3,-SO)Ve(R)2, -S(O)-V4~a -S(O)2-0-Vr5N(RS)2 122 -S(O)2-O-V 4 -Ar3, -NR" SO2-V-N(R')2 -NRM SO 2 -V 4 -Ar 3 , -O-[CH2]p-O-, S-[C12]-S-, and -[CH2]1 each V 4 is independently a Cl-C1O alkylene group; each Vs is independently a C2-CO alkylene group; 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, alkyl, amino, alkylamino, dialklami no, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and each R50 is independently i) hydrogen; ii) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dial kylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyL alkylcarhonyl and haloalkyl; and each R) is independently R -CO2R 1, -SO2R or -C(O)R": or -N(R 5 )2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =, =N(CI-C6 alkyl), C-C6 alkyl, Cl-C6 haloalkyl, hydroxy, Cl C6 alkoxy, nitro, cyano, Cl-C6 alkoxycarbonyl, Cl-C6 alkylcarbonyl, Cl-C6 haloalkoxy, amino, Cl -CO alkylamino and Cl-C6 dialkylamino; and each R' 2 is independecntly: i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyL alkylcarhonyl and haloalkyl: or 123 ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino. alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; anId the non-aromatic heterocyclic group represented by -N(R4R ) is optionally substituted with one or more substituents selected from the group consisting of halogen, =0, =S, =N(Cl-C6 alkyl), Cl-C6 alkyl, Cl-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)amino; each p' is 1, 2, 3 or 4; and each q' is 3, 4, 5 or 6.
7. 8. The method of Claim 7, wherein: X is -(CR R )-Q-; Q is -0-, , -C(O)-, -C(S)-, -C(0)0-, -C(S)O-, -C(S)S-, -C(O)NRK-, -NR 5 -, -NRsC(O)-, -NR M C(O0)NR 5 -, -OC(O)-, -S0-, -SO-, -S(Oh-, -SO 2 NR-, or NR S0r 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 -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; or X is -(CRR6)m.-; and R4 a substituted or unsubstituted cyclic alkyl group, a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted hcteroaryl group, -CN, -NCS, -NO2 or a halogen; and n is 1,2,3,4,5 or 6.
8. 9. The mecth-od of Claim 8, wheeini the compound~ is represented by a strctra IbMu11a selected from the group consisting o1: 124 OH OH R1 N(R2R3 R N(RR R N(R 2 R 3 ) HN HN (CR 5 R 6 )m-R4/ (CR 5 R6)n--Q-R 4 O 0 OH OH R 1 N(R 2 R 3 ) Ri N(R 2 R 3 ) HN HN (CR'R 6 )n R 4 -- 0 -R 4 O 0 and OH R 1 N(R 2 R 3 ) HN N(R'R 4 ) 0 or a pharmaceutically acceptable salt thereof, wherein R' is -H or Cl -C6 alkyl.
9. 10. The method of Claim 9, wherein: R' is a phenyl group optionally substituted with one or more substituCnts selected from the group consisting of halogen. cyano, nitro, alkyl, haloalkyl, -ORE 0 , -SR 3 t), -N(R 3 )2, Ar', -V-OR, -V_-N(R)2, -Vo)-Ar', -O-Ve-Ar, -O--V-N(R 3 )2 -S-V 0 -Ar -S-V,-N(R 3 )2, -N(R' )-V 0 -Ar', -N(R3' )-V,-N(R 3 ) 2 , -O-[CH2]p-O-, -S-[CH2]p-S-, and -[CH2]L Arl is a )heyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl, amino, Cl-C6 alkylamino, 125 Cl-C6 dialkylarnino, C-C6 alkoxy, nitro, cyano, hydroxy, CI-C6 haloalkoxy, CI-C6 alkoxycarbonyl, Cl -C6 alkylcarbonyl and C -C6 haloa kyl and each R 3 ' is independently i) hydrogen: i) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl, arino. CI-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, yano,. hydroxy, Cl -C6 haloalkoxy, Cl -C6 alkoxycarbonyl, Cl -C6 alkyl arbonyl and C I C6 haloalkyl; or ii) an Cl-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C -C6 alkylamino, Cl -C dialkylamino, Cl -C6 alkoxy, nitro, cyano, hydroxy, Cl-C6 haloalkoxy, Cl-C6 alkoxycarbonyl, Ci-C6 alkylcarbonyl and Cl C6 haloalkyl; and each R 3 ' is independently R or )2is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, =O, =S. =N(CI-C6 alkyl), Cl-C6 alkyl, Cl-CO haloalkyl, hydroxy, Cl-C6 alkox, nitro cyano, Cl -CO alkoxycarb onyl, Cl -C6 alkylcarbonyl. Cl-C6 haloalkoxy, amino, C -C6 alkylamino and (l(-.b dialklanino.
10. 11. The method of Claim 10, wherein -N(R 2 R) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, CI-C5 alkyl, CI-C5 haloalkyl, hydroxyl, Cl-C5 alkoxy, nitro, cyano, CI-C5 alkoxycarbonyl, CI-C5 alkylcarbonyl or CI-C5 haloalkoxy, amino, CI-C5 alkylamino and Cl-C5 dialkylamino.
11. 12. The method of Claim 11, wherein each of the aliphatic group, the aryl group and the heteroaryl group, represented by each of R, R 7 and RS independently is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl -C10 alkyl, Cl-C10 haloalkyl, Ar, Ar Ar, -0R, -0(haloalkyl), -SR', -NO2 -CN. -N(R)2 -N_()E C(O)R1, -C(O))OR, -O(O()R, -C(ON(R2, -V.;Ar3, 50 5055 -V-OR , -V-O(haloalkyl), -V 4 -SR -, -V 4 -N -V 4 -CN, -V 4 -N(R)2, -V 4 -NR 'C(O)R 126 50 it) 51 , - - 4 N R 5' 2 -VC ) -V-COR 4 -OC(O)R3u, -V 4 -C(O)N(R 1 )2-, -OV 4 -Ar 3 , -O-Vs-N(R )2, -S-V 4 Ar, -S-VsN(R )2, -N(R 5 )-V 4 -Ar, N(R")-VsN(R 5 )2, -NRiI C(O) 4 -N(R 5 )2, -NR C(O)-V 4 Ar 3 , -C(O)-V)N(Ru)2, -C(O)-V 4 -Ar 3 , -C(O)O-Vs-N(R ), -C(O)O-V 4 -Ar, -O-C(O )-V3N(R ) O-C(O)-V 4 Ar 5 , -C(O)N(R )-V\-N(R )2, -((O)N(R )- V Ar 3 , -O-[CHi,-O- and -[('H2l 1 -.
12. 13. The method of Claim 12, wherein the compound is represented by the following structural formula: OH R1 N( 2 R 2 3) HN (CH 2 )m-R 4 0 or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted aryl group or an optionally substituted heteroaryl group.
13. 14. The method of Claim 12, wherein the compound is represented by one of the following structural formulas: OH OH R1 N(R 2 R3) R4 N(R 2 R 3 ) HN HN 0 -(CH2)n---O-R4 )--(CH)ni- R4 0 or 0 or a pharmaceutically acceptable salt thereof. 127
14. 15. The method of Claim 12, w herein the compound is represented by one of the following structural formulas: OH OH R1 N(R 2 R 3 ) R 1 N(R 2 R 3 ) HN HN O--R 4 N(R 7 R 4 ) O or 0 or a pharmaceutically acceptable salt thereof
15. 16. The method of Claim 12, wherein the compound is represented by one of the following structural formulas: OH OH R1N(RRR N(R 2 R 3 ) HN HN 0- (CH2)k--R 0 N- (CH2)k-R 1 H O or 0 or a pharmaceutically acceptable salt thereof, wherein: k is 1, 2,3,4, 5or 6;and R is: i -H or ii) an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy. haloalkoxy. and haloalkyl, or 128 iii) a Cl -C6 alkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of with one or more substituents selected from the group consisting of halogen, cyano, nitro, Cl-C10 alkyl, Cl-C 10 haloalkyl, amino, Cl-Cl0 alkylamino, Cl-C10 dialkvlamino, aryl, heteroaryl, aryloxy, heteroarylo, h hydroxy, Cl-10 alkoxy, -O-[CH 2 p 1 -O- or -[CH2]r.
16. 17. The method of Claims 13-16, wherein -N(RR 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.
17. 18. The method of laim 17, wherein: R' is a phenyl group optionally substituted with one or more substituents selected from the group consisting of -OR3'), alkyl, and -O-[(CH2]-O-.
18. 19. The method of Claim 1, wherein the compound is selected from the group consisting of: OH 0 HN N O 0 (CH 2 ) 1 -0 A OH O N HNO (C H2)1-6 0 ,and 129 OH HNN 0 NH-(CH 2 ) 1 -6 A or a pharmaceutically acceptable salt thereof, wherein each ring A independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl anti alkoxy.
19. 20. The method of any one of Claims 1- 19, wherein the compound is a (IR, 2 R) stercoisomer, or a pharmaceutically acceptable salt thereof.
20. 21. The method of Claim 1, wherein the compound is represented by the follow ing structural fonnula: OH O .- Nf NH/ 0 0 ) OCH 3 or a pharmaceutically acceptable salt thereof.
21. 22. The method of Claim 1, wherein the compound is represented by the follow ing structural formula: 130 OH 0 F o N NH 0 OCH 3 , or a pharmaceutically acceptable sak ihereol
22. 23. A use of a compound as defined in any one of Claims 1-22 in the manufacture of a medicament for the treatment of polycystic kidney disease in a subject in need thereof.
23. 24. A compound as defined in any one of Claims 1-22 w\hen used in a method of treating polycystic kidney disease.
24. 25. A method as claimed in any one of Claims 1-22 a use as claimed in Claim 23 or a compound as claimed in Claim 24, wherein the polycystic kidney disease is an autosomal dominant polyeystic kidney disease. 131