IL174479A

Hemiasterlin derivatives, pharmaceutical compositions comprising the same and uses thereof

Abstract

This record has no abstract on file.

Term

No projected expiry on record.

22 claims: 14 independent, 8 dependent

1
174479/4 Claims 1. A compound having the structure or a pharmaceutically acceptable salt, ester or salt of an ester thereof;wherein g is 0, 1,2 or 3;X2 is C(=O), CRaRb, or -SO2-;wherein each occurrence of RA and Rb is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;Rz is hydrogen, or an unsubstituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkyl(aryl), aryl or heteroaryl moiety;R5, R$ and R7 are each independently hydrogen, -(C=O)Re or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Re is independently hydrogen, OH, ORf, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two R5, R6 and R7 groups, taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety;wherein Rp is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;Rsa, R9a and Rioa are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;Rli and Rl2 are each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;and Q is NRQ Rq ;wherein RQ and RQ are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or R^ and RQ , taken together with the nitrogen atom to which they are attached, may form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety. 284 174479/4
4
The compound of any one of claims 1 to 3, wherein X2 is C=O and R2 is hydrogen, or unsubstituted, linear or branched, cyclic or acyclic, Ci_g alkyl or benzyl.
5
The compound of any one of claims 1 to 4, wherein R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, iso-propyl, -CH(CH3)CH2CH3, CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CHCdLfCCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.
6
The compound of any one of claims 1 to 5 wherein R2 is hydrogen, or unsubstituted Ci_g alkyl;Rg is tert-butyl, R7 and Rioa are each methyl and Rsa is iso- 285 174479/4 propyl;RLi and RL2 are each independently hydrogen, Ci_6 alkyl, heteroalkyl, aryl or heteroaryl.
7
The compound of any one of claims 1 to 6 wherein Q is selected from the group consisting of:—ORQ1 -OR01 '0., )r OR02 PO2RQ1 %—nrCHrQZ °%_orqi / )r 0RQ1 ’Α-λ A RZ a rO • O wherein each occurrence of r is 0,1 or 2;wherein each occurrence of RQ1 and RQ2 is independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety;or RQ1 and RQ2, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety;or a pharmaceutically acceptable salt, ester or salt of ester thereof.
8
The compound of any one of claims 1 to 7 wherein Q is:Ox , Vorq1 A J or a pharmaceutically acceptable salt, ester or salt of ester thereof.
9
The compound of any one of claims 1 to 7 wherein Q is:286 174479/4 Ο. V- nrq1rQ2 NH or a pharmaceutically acceptable salt, ester or salt of ester thereof.
10
The compound of any one of claims 1 to 7 wherein Q is:—ORQ1 NH or a pharmaceutically acceptable salt, ester or salt of ester thereof.
11
The compound of any one of claims 7 to 10, wherein each occurrence of RQ1 and RQ2 is independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety.
12
The compound of any one of claims 1 to 11 having the structure:or a pharmaceutically acceptable salt, ester or salt of an ester thereof.
14
The compound of claim acceptable ester of:compound is a pharmaceutically 287 174479/3
16
The compound of any one of claims 1 to 11 having a structure selected from:288 174479/3
17
A pharmaceutical composition comprising a compound of any one of claims 1 to 16, a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent.
21
A compound of any one of claims 1 to 16, and a pharmaceutically acceptable carrier or diluent, and optionally an additional therapeutic agent for use in the treatment of cancer.

Independent claims14

1,194 paragraphs in 78 sections, as filed

174479/3

HEMIASTERLIN DERIVATIVES, PHARMACEUTICAL COMPOSITIONS

COMPRISING THE SAME AND USES THEREOF

BACKGROUND OF THE INVENTION

Hemiasterlin (1) was first isolated from the sponge Hemiasterella minor (class, Demospongiae; order, Hadromedidia; family, Hemiasterllidae) collected in Sodwana Bay, South Africa (see, Kashman et al. U. S. patent 5,661, 175). It was reported that Hemiasterlin exhibited antitumor activity against several cell lines, including human lung carcinoma, human colon carcinoma and human melanoma.

After the initial isolation and reporting of this compound, additional hemiasterlins were isolated, and several hemiasterlin derivatives were synthesized and their biological activity was also investigated. It was subsequently reported that Hemiasterlin and certain analogs thereof exhibit antimitotic activity and thus are useful for the treatment of certain cancers (see, U. S. Patent No. 6,153, 590 and PCT application WO 99/32509). However, only a rather limited number of Hemiasterlin analogs were prepared, half of which were the natural products themselves, isolated from Cymbastela sp., or were obtained by modifications to the natural products. Thus the number and types of derivatives that could be prepared and evaluated for biological activity were limited. 1 WO 2005/030794 PCT/US2004/030921 [0004] Clearly, there remains a need to develop synthetic methodologies to access and examine the therapeutic effect of a variety of novel derivatives of Hemiasterlin, particularly those that are inaccessible by making modifications to the natural product It would also be of particular interest to develop novel compounds that exhibit a favorable therapeutic profile in vivo (e.g., are safe and effective, while retaining stability in biological media).

Summary of the Invention [0005] As discussed above, there remains a need to develop novel Hemiasterlin analogs to evaluate their potential as therapeutic agents for the treatment of cancer. The present invention provides novel compounds of general formula (I),

R3 R4 r5 o (I) and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R1-R7, Xi, X2, R, Q, and n are as defined herein. The inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

Detailed Description of Certain Preferred Embodiments of the Invention [0006] In recognition of the need to access and further explore the biological activity of novel derivatives of Hemiasterlin, and this class of peptides in general, the present invention provides novel peptide compounds, as described in more detail herein, which demonstrate antitumor activity. Thus, the compounds of the invention, and pharmaceutical compositions thereof, are useful for the treatment of cancer. In certain embodiments, the compounds of the present invention can be used for the treatment of diseases and disorders including, but not limited to prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer, lymphoma, leukemia and multiple myeloma. In certain other embodiments, the inventive compounds also find use in the 2 WO 2005/030794 PCT/US2004/030921 prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

[0007] 1) General Description of Compounds ofthe Invention [0008] The compounds of the invention include compounds of the general formula (I) as further defined below:

*3 R4 r5 o wherein n. is 0,1,2,3 or 4;

Xi and X2 are each independently CRaRb, C(=O), or -SO2-; wherein each occurrence of Ra and Rb is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

Ri and R2 are each independently hydrogen, -(C=O)Rc or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein each occurrence of Rc is independently hydrogen, OH, ORd, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein Rd is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; each occurrence of R3 and R4 is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any two Ri, R2, R3 and R4 groups, taken together, may form an alicyclic, heteroalicyclic, alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety;

Rs, Re and R7 are each independently hydrogen, -(C=O)Re or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Re is independently hydrogen, OH, ORf, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two R5, Re and R7 groups, taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; wherein Rf is an aliphatic, alicyclic, heteroaliphatic, 3 WO 2005/030794 PCT/US2004/030921 heteroalicyclic, aryl or heteroaryl moiety; or R7 may be absent when NR7 is linked to R via a double bond; R is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Q is ORq', SR.q', NRq'Rq”, N3, =N-OH, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein RQ and RQ are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or RQ and RQ , taken together with the nitrogen atom to which they are attached, may form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; and pharmaceutically acceptable derivatives thereof.

[0009] In certain embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, are not naturally occurring Hemiasterlins.

[0010] In certain embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the following structure:

[0011] In certain embodiments of compounds described directly above and compounds as described in certain classes and subclasses herein, the compounds do not comprise more than four consecutive α-amino acid residues, and/or one or more of the following groups do not occur simultaneously as defined: (a) nisi;

Xi and X2 are each C(=O);

Ri and R_2 are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, lieteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at 4 WO 2005/030794 PCT/US2004/030921 least one of Ri and R2 is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and neither are Ar, Ar-aliphatic- or Ar-alicyclic-, Ri and R2, taken together, may form a three- to seven-membered ring; wherein Ar is defined as substituted or unsubstituted phenyl, naphtyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl or pyridyl; R3 is hydrogen; R4 is -CRtaRfoRtc wherein Rta and Rib are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at least one of Ria and Rib is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and neither are Ar, Ar-aliphatic- or Ar-alicyclic-, R4a and R4b, taken together, may form a three- to seven-membered ring; and Ric is hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and Ar; wherein Ar is as defined directly above; R5, R$ and R7 are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and Ar; R is a moiety selected from the group consisting of: a linear, saturated or unsaturated, substituted or unsubstituted alkyl group containing one to six carbon atoms; and Q is -OR<j, -SRg, -NRgRh, -NHCH(Rk)CO2H, or -NRCH(Rk)CO2H, wherein Rg and Rh are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic or heteroalicyclic; Rk is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, or a moiety having the structure -(CH2)tNRKiRK2, wherein t=l-4 and Rki and Rk2 are independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic or -C(NH)(NH2); (b) nisi;

Xi and X2 are each C(=O);

Ri is an optionally substituted methylene or -CH= group bonded to the indole moiety thereby forming a tricyclic moiety; 5 WO 2005/030794 PCT/US2004/030921 R.2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when Ri is -CH= as defined above; R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; R4 is a moiety having the structure:

wherein Rw, Ry and Rz are each independently hydrogen, or optionally substituted alkyl or acyl, or Rz is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; Rx is hydrogen or an optional substituent, or is absent when Ri is an optionally substituted methylene or -CH= group as defined above; Y is an optional substituent; and m is 0,1,2, 3 or 4;

Rs is hydrogen, OH or an optionally substituted alkyl or acyl group;

Rg is hydrogen or an optionally substituted alkyl group; R7 is hydrogen or alkyl; and -R-X2-Q together represent an optionally substituted alkyl moiety; (c) nisi;

Xi and X2 are each C(=O);

Ri is hydrogen, an optionally substituted alkyl or acyl group, or an optionally substituted methylene or -CH= group bonded to the indole moiety thereby foiming a tricyclic moiety; R2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when Ri is -CH= as defined above; R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; R4 is a moiety having the structure:

6 WO 2005/030794 PCT/US2004/030921 wherein Rw, Ry and Rz are each independently hydrogen, or optionally substituted alkyl or acyl, or Rz is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; with the limitation that Ry and Rz are not simultaneously hydrogen; Rx is hydrogen or an optional substituent, or is absent when Ri is an optionally substituted methylene or -CH= group as defined above; Y is an optional substituent; and m is 0,1, 2, 3 or 4;

Rs is hydrogen, OH or an optionally substituted alkyl or acyl group;

Rg is hydrogen or an optionally substituted alkyl group; R7 is hydrogen or alkyl; and -R-X2-Q together represent an optionally substituted alkyl moiety or -Q'-C(O)X, wherein Q' is an optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH=CH-, -CH2C=-C- or phenylene moiety, wherein X is -OR', -SR' or -NR'R" and each occurrence of R' and R" is independently hydrogen or optionally substituted alkyl; (d) nisi;

Xi is C=O;

Ri is methyl; R2 and R3, taken together, form a piperidine moiety; R4 and R5 are each hydrogen,

Rgis-CH(CH3)CH2CH3; R7 is -CH20C(=O)CH2CH(CH3)2, -CH2OC(=O)CH2CH2CH3 or -CH2OC(=O)CH2CH3; and -R-X2-Q together represent the moiety having the structure:

(e) nisi;

Xi is C=O; 7 WO 2005/030794 PCT/US2004/030921

Rb R2, and R7 are each methyl; R3 and R5 are each hydrogen; R4 and Re are each z'-propyl; and -R-X2-Q together represent the moiety having the structure:

wherein Rx is hydrogen or 2-thiazolyl; and/or (f) nisi;

Xi is C=O;

Ri and R2 are each independently hydrogen or Ci^alkyl; R3 and Rs are each hydrogen; R4 and Re are each z'-propyl; R7 is methyl; and -R-X2-Q together represent a moiety having the structure: wherein v is 0, 1 or 2; R' is hydrogen or Ci^alkyl; R" is Ci.6alkylamino; hydroxy; C3.7cycloalkylamino optionally substituted by phenyl or benzyl; arylamino; Ci^alkoxy; benzhydrazino; heterocyclyl optionally substituted with one to three substituents selected from the group consisting of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, mono- or di-alkylamino, acylamino, alkoxycarbonylamino, phenyl or halogen; heterocyclylamino; heterocycloalkylamino with the heterocyclyc group optionally substituted with one to three substituents selected from the group consisting of benzyl, 8 WO 2005/030794 PCT/US2004/030921 benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, dialkylamino, acylamino, alkoxycarbonylamino or halogen; aralkyloxy or aralkyl both optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino, aminosulfonyl or benzyl; or aralkylamino having Ci^alkylene and the aryl group optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, carbamoyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; and R”' is hydrogen, alkyl optionally substituted with one to three substituents selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbonyloxy, carbamoyloxy or halogen; alkenyl; alkynyl; C3. 7cycloalkyl; aryl optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; aralkyl with the aryl group optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, carbamoyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; or heterocyclylalkyl; wherein the groups recited in paragraph (f) above are defined as follows: 9 WO 2005/030794 PCT/US2004/030921 |T~ lUi» Ιί >· «· alkyl refers to a straight-chain or branched-chain hydrocarbon group optionally substituted with hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyloxy, carbamoyl or halogen; alkenyl refers to a hydrocarbon chain as defined for alkyl above having at least one double bond; alkynyl refers to a hydrocarbon chain as defined for alkyl above having at least one triple bond; C3.7cycloalkyl refers to a saturated, cyclic hydrocarbon group with 3-7 carbon atoms optionally substituted with alkyl, phenyl, amino, hydroxy or halogen;

Ci^alkylene refers to a biradical linear or branched hydrocarbon chain containing 1-4 carbon atoms;

Aralkyl, refers to an aryl group attached to an alkylene group;

Heterocyclyl refers to saturated, unsaturated or aromatic monovalent cyclic radical having one to three heteroatoms selected from Ο, N and S, or combination thereof, optionally substituted with one or more occurrences of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, mono- or di-alkylamino, acylamino, alkoxycarbonylamino or halogen;

Amino refers to -NH2 and includes amino groups which are further substituted by lower alkyl groups, or nitrogen protecting groups know in the art;

Cycloalkylamino refers to cycloaikyl groups as defined above attached to a structure via an amino radical;

Arylamino is defined as aryl-NH-;

Aralkylamino is defined as aralkyl-NH-;

Carbamoyl refers to the group -C(=O)-NH2;

Carbamoyloxy refers to the group -O-C(=O)-NH-;

Alkylcarbamoyloxy refers to the group -O-C(=O)-NH-alkyl; 10 WO 2005/030794 PCT/US2004/030921

Alkylcarbonyloxy refers to the group -O—C(=O)-alkyl;

Aralkyloxy refers to the group -O—aralkyl; and

Alkylthio refers to the group ALkyl-S-.

[0012] In certain other embodiments of compounds described in (a) above and compounds as described in certain classes and subclasses herein, the following groups do not occur simultaneously as defined: n is 1; Xi and X2 are each C(=O); Ri and R2 are each independently hydrogen, methyl, ethyl, propyl, n-butyl, acetyl; or Ri and R2, taken together, form a. moiety selected fiom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R3 is hydrogen; R4 is -CRtalbbRfc wherein R4a and Rib are each independently methyl., ethyl, n-propyl or n-butyl; or R|a and Rib, taken together, form a moiety selected from the group consisting of β-cyclopropyl, β-cyclobutyl, β-cyclopentyl, and β-cyclcohexyl; and Rtc is phenyl, naphtyl, anthracyl or pyrrolyl; R5 and R7 are each independently hydrogen or methyl; Ri is a three to sex carbon, branched alkyl group; and -R-X2-Q together represent the moiety having the structure: R' R" wherein R' is methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl, or sec-butyl; R" is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl or sec-butyl; and Q is OH or OKq wherein Rg is a linear or branched one to six carbon alkyl group.

[0013] In certain other embodiments of compounds described in (a) above and compounds as described in certain classes and subclasses herein, the following groups do not occur simultaneously as defined: n is 1; Xi and X2 are each C(=O); Ri, R3 and R5 are each hydrogen; R2 is methyl; Rj is -CR^RtbRic, Ri is tert-butyl; and -R-X2-Q together represent the moiety having the structure: 0

Q R' R" 11 174479/3 wherein R' is isopropyl; R" is methyl; and Q is OH; and (a) R4a and Rib are each methyl; Ru is methyl or phenyl; and R7 is hydrogen or methyl; (b) Rta and Rib are each methyl; Rtc is hydrogen; and R7 is methyl; or (c) Ria and Rib are each hydrogen; Ric is phenyl; and R7 is methyl.

In certain other embodiments, compounds of formula a) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed on page 8 line 28 through page 25 line 9, page 28 line 1 through page 32 line 9 and page 39 line 16 through page 80 line 20 of WO 03/008378.

In certain other embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed on page 10 line 24 through page 17 line 18, page 17 line 26 through page 19 line 3, page 19 line 10 through page 20 line 3, page 20 line 17 through page 21 line 9, page 21 lines 14-29, page 22 lines 1-12, page 22 lines 16-18, page 22 lines 22-27, page 23 line 1 through page 24 line 21, page 24 line 26 through page 25 line 9, and page 28 line 1 through page 32 line 9 of WO 03/008378.

In certain other embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed in Nieman J. et al.," Synthesis and Antitumotic/Cytotoxic Activity ofHemiasterlin Analogues", Journal of Natural Products, 2003, 66(2): 183-199.

In certain other embodiments, compounds specifically and/or generically disclosed in WO 99/32509, WO 96/33211, WO 99/31122, WO 97/43305, JP 08 073444, DE 40 16994 and/or WO 01/18032 do not fall within the scope of the invention. 12 WO 2005/030794 PCT7US2004/030921 [0018] In certain other embodiments, compounds specifically and/or generically disclosed in Andersen et al, Tet. Lett., 38(3): 317-320, 1997; Billson, et al., Bioorganic &amp; Medicinal Chemistry Letters, 8: 993-998, 1998; Dragovich, et al., J. Med. Chem. 41: 2806-2818, 1998; Hauske, et al, J. Med. Chem. 35: 4284-4296, 1992; and/or Nieman, et al, J. Nat. Prod. 66: 183-189, 2003, do not fall within the scope of the invention.

[0019] In certain embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have any one or more of the following structure:

13 WO 2005/030794 PCT/US2004/030921

[0020] In certain other embodiments, compounds of formula (I) are defined as follows:

Xi and X2 are each independently CHRaRb, SO2 or C=O; wherein Ra and Rb are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

Ri and R2 are each independently hydrogen, or a linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl or acyl moiety, or an aryl or heteroaryl moiety; wherein the alkyl, heteroalkyl, and aryl moieties may be substituted or unsubstituted; or

Ri and R2, taken together, may form a saturated or unsaturated, substituted or unsubstituted cyclic ring of 5 to 8 atoms; each occurrence of R3 and R4 is independently hydrogen, or a linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl, lower -alkyl(aryl), lower -heteroalkyl(aryl) moiety, or an aryl or . heteroaryl moiety; wherein the alkyl, heteroalkyl, -alkyl(aryl), heteroalkyl(aryl), aryl and heteroaryl moieties may be substituted or unsubstituted; or R3 and R4, taken together, may form a saturated or unsaturated, substituted or unsubstituted cyclic ring of 3 to 8 atoms; the carbon atom bearing R3 and R4 may be of S' configuration; nis 1;

Rs is hydrogen or a protecting group; wherein the protecting group may be a nitrogen protecting group; 14 WO 2005/030794 PCT/US2004/030921

Re is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl moiety; the carbon atom bearing Re may be of S configuration; R7 is hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl moiety; or Rzmay be absent when NR7 is linked to R via a double bond; R is a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated alkyl moiety; or a heteroaliphatic moiety containing 1-10 carbon atoms, 1 to 4 nitrogen atoms, 0 to 4 oxygen, atoms and 0 to 4 sulfur atoms; whereby the heteroaliphatic moiety may be substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated; wherein (i) the alkyl moiety may have the structure: 89a

Rea RlOa ( wherein Rga, R9a and Rioa are each independently absent, hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl moiety; wherein any two R7, Rga, R9a and Rioa groups may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or an aryl or heteroaryl moiety; and wherein the carbon atom bearing Rga may be of S configuration; (ii) the heteroalkyl moiety may have the structure:

Reb RlOb 15 WO 2005/030794 PCT/US2004/030921 wherein Rsb, R9b> Riob and Rub are each independently absent, hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroaikyl or acyl; or a substituted or unsubstituted aryl or heteroaryl moiety; wherein any two R7, R8b, R-9b3 Riob and Rub groups may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroaikyl, alky(aryl) or heteroalkyl(aryl) moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; wherein NR7 and CRgb, CRgb and CR9b, CRjb and NRiob, and NRiob and CRub are each independently linked by a single or double bond as valency permits; and wherein the carbon atom bearing R8b may be of 5 configuration; (iii) or the heteroaikyl moiety may have the structure:

Rec Rioc wherein Rgc, R90, Rioc, Riic and Ri2c are each independently absent, hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroaikyl; or a substituted or unsubstituted aryl or heteroaryl moiety; wherein any two R7, Rgc, R9C Rioc, Rue and Ri2c groups may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroaikyl, alky(aryl) or heteroalkyl(aryl) moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; wherein NR7 and CRgc, CRgc and CRgc, CR9C and CRioc, CRio0 and CRnc are each independently linked by a single or double bond as valency permits; and wherein the carbon atom bearing Rgc may be of S' configuration; and Q is ORq', SRq', NRqRq", wherein RQ' and RQ" are each independently hydrogen or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroaikyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or wherein RQ and RQ , taken together, may 16 WO 2005/030794 PCT/US2004/030921 form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl or heteroalkyl moiety or a substituted or unsubstituted aryl or heteroaryl moiety; and pharmaceutically acceptable derivatives thereof.

[0021] In certain embodiments, the present invention defines certain classes of compounds which are of special interest. For example, one class of compounds of special interest includes those compounds having the structure of formula (T) in which R is -CH(Rga)C(R9a)=C(Rioa)- and the compound has the structure (Ia):

wherein R1-R7, Xj, X2, Q and n are defined in classes and subclasses herein;

Rga, Rc>a and Rioa are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and wherein any two R7, Rga, Rga and Rioa groups may form a substituted or unsubstituted, saturated or unsaturated alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety.

[0022] Another class of compounds of special interest, herein referred to as class (Ib), consists of compounds having the structure of formula (I) in which X2 is C=O and R is a heteroaliphatic moiety containing 1-10 carbon atoms, 1 to 4 nitrogen atoms, 0 to 4 oxygen atoms and 0 to 4 sulfur atoms, whereby the heteroaliphatic moiety may be substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated.

[0023] Another class of compounds of special interest consists of compounds having the structure of formula (I) in which Xi is C=O; n is 1; Ri and R4, taken together, form a cyclic heterocyclic or heteroaryl moiety; R3 is hydrogen or is absent when the carbon atom bearing R3 is linked to N or E via a double bond; and the compound has the structure (lc): 17 WO 2005/030794 PCT/US2004/030921

(Ic) wherein R2, R5-R7, R, X2 and Q are defined in classes and subclasses herein; each occurrence of G, J, L and M is independently CHR1V, CR1VRV, O, S, NRIVRV, wherein each occurrence of R1V and Rv is independently absent, hydrogen, -C(=O)RVI, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any two adjacent R2, R1V, Rv or R.VI groups, taken together, form a substituted or unsubstituted, saturated or unsaturated alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety; wherein each occurrence of Rvl is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; N and G, G and J, J and L, L and Μ, M and CR3, and CR3 and N are each independently linked by a single or double bond as valency permits; and g, j, 1 and m are each independently 0, 1, 2, 3, 4, 5 or 6, wherein the sum of g, j, 1 and mis 3-6.

[0024] Another class of compounds of special interest consists of compounds having the structure of formula (I) in which Xi is C=O; n is 1; R3 and R4 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; and the compound has the structure (Id):

wherein Ri, R2, R5-R7, R, X2 and Q are defined in classes and subclasses herein. 18 WO 2005/030794 PCT/US2004/030921 [0025] The following structures illustrate several exemplary types of compounds of class (Ia). Additional compounds are described in the Exemplification herein.

[0026] The following structures illustrate several exemplary types of compounds of class (lb). Additional compounds are described in the Exemplification herein. 19 WO 2005/030794 PCT/US2004/030921

[0027] The following structures illustrate several exemplary types of compounds of class (Ic). Additional compounds are described in the Exemplification herein.

[0028] The following structures illustrate several exemplary types of compounds of class (Id). Additional compounds are described in the Exemplification herein. 20 WO 2005/030794 PCT/US2004/030921

[0029] Other compounds of the invention will be readily apparent to the reader.

[0030] A number of important subclasses of each of the foregoing classes deserve separate mention; for example, one important subclass of class (Ia) includes those compounds having the structure of formula (Ia) in which X2 is C=O; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;

Rga, R9a and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and RiOa groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety; and 21 WO 2005/030794 PCT/US2004/030921

Xi is CRaRb, SO2 or C=O; wherein Ra and Rb are each independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

[0031] Another important subclass of class (la) includes those compounds having the structure of formula (Ia) in which Xi is C=O; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;

[0032] Another important subclass of class (Ia) includes those compounds having the structure of formula (Ia) in which Xi and X2 are each C=O; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CR^RhjRic; and the compound has the following structure:

wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and R<te and Rib are each independently hydrogen or lower alkyl or heteroalkyl, and Rtc is aryl or heteroaryl; and 22 WO 2005/030794 PCT/US2004/030921

Rga, R.9a and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and Rioa groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety.

[0033] Another important subclass of class (la) includes those compounds having the structure of formula (la) in which Xi and X2 are each C=O; Q is an optionally substituted nitrogen-containing cyclic moiety; and the compound has the following structure:

wherein R1-R7 and n are defined in classes and subclasses herein;

I

Rga, R9a and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and Rioa groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety; each occurrence of A, B, D or E is independently CHR1, CR’R", O, S, NR’R11, wherein each occurrence of R1 and R11 is independently absent, hydrogen, -C(=O)R-ni, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any two adjacent R‘, R“ or R111 groups, taken together, form a alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety; wherein each occurrence of RU1 is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; N and A, A and Β, B and D, D and E, and E and N are each independently linked by a single or double bond as valency permits; and a, b, d and e are each independently 0, 1, 2, 3, 4, 5, 6 or 7, wherein the sum of a, b, d and e is 4-7. 23 WO 2005/030794 PCT/US2004/030921 [0034] Another important subclass of class (la) includes those compounds having the structure of formula (la) in which Xi and X2 are each C=O; Q is an optionally substituted nitrogen-containing cyclic moiety; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CR4aR4bR4c; and the compound has the following structure:

wherem Ri, R2, R5-R7 , A, B, D, E, a, b, d and e are defined in classes and subclasses herein; R4a and Rib are each independently hydrogen or lower alkyl or heteroalkyl, and Rtc is a substituted or unsubstitued aryl or heteroaryl group;

Rga, R9a and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherem any two R7, Rga, R9a and Rioa groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety.

[0035] A number of important subclasses of each of the foregoing subclasses of class (la) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (la) in which: i- a. Ri and R2 are independently hydrogen or substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; ii- a. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower aJkyl, heteroalkyl, -alkyl(aryl) or acyl; iii- a. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; 24 WO 2005/030794 PCT/US2004/030921 iv- a. Rj is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert- butyl, ί-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2s -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; v- a. Rj and R2 are each hydrogen; vi- a. The carbon atom bearing R3 and R4 is of S' configuration; vii- a. R3 is hydrogen and R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl; viii- a. R3 is hydrogen and R4 is -CR4aR4bR4C; wherein Rta and R4b are independently hydrogen, or a substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl moiety and R4C is substituted or unsubstituted aryl or heteroaryl; ix- a. R3 is hydrogen and R4 is -CR4aR4bPh; wherein 1¼ and R4b are independently hydrogen, or a substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl moiety; x- a. R4 is a substituted or unsubstituted 3-indole moiety; xi- a. R3 is hydrogen; xii- a. Ri and R4, taken together, form a substituted or unsubstituted pyrrolidine group; xiii- a. Ri and R4, taken together, form a substituted or unsubstituted piperidine group; xiv- a. Rj and R4, taken together, form a substituted or unsubstituted thiazolidine group; xv- a. Ri and R4, taken together, form a substituted or unsubstituted morpholine group; 25 WO 2005/030794 PCT/US2004/030921 xvi- a. Ri and R4, taken together, form a substituted or unsubstituted thiomoipholine group; xvii- a. Ri and R4, taken together, form a substituted or unsubstituted indole group; xviii-a. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl; xix- a. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl; xx- a. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl; xxi- a. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -Ci-salkylSRa or -CRaRbRc; wherein Ra and Rb are independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or heteroaryl; xxii- a. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -Ci_6alkylSRa or -CR^Ph; wherein Ra is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rb And Rc are each independently substituted or unsubstituted 26 WO 2005/030794 PCT/US2004/030921 linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxiii-a. R3 and R4 are each ethyl; xxiv- a. R3 is phenyl and R4 is lower alkyl; xxv- a. R3 is phenyl and R4 is ethyl; xxvi- a. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl group; xxvii-a. R3 and R4, taken together, form a cyclohexyl group; xxviii-a. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group; xxix-a. R5 is hydrogen; χχχ-a. Rg is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; xxxi-a. Rg is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; xxxii-a. Rg is tert-butyl; xxxiii-a. The Rg-bearing carbon atom is of 5 configuration; xxxiv-a. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; xxxv-a. R7 is methyl; xxxvi-a. -[C(R3)(R4)]nN(Ri)(R2) together represent the moiety having the structure:

27 WO 2005/030794 PCT/US2004/030921 a) R2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; b) R2 is methyl, ethyl, propyl, butyl, pentyl, terf-butyl, z-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; c) R2 is methyl, ethyl, propyl or z-propyl; d) Rqi is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; e) Rqi is hydrogen, methyl or phenyl; f) Rgi and the substituents on L, taken together, form a substituted or unsubstituted phenyl group; g) Rmi and Rm2 are each independently hydrogen, hydroxyl, a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl moiety; a substituted or unsubstituted phenyl moiety, or Rm2 is absent when Rmi and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety; h) Rmi and Rm2 are each hydrogen; i) g is 1 or 2; and/or j) L is CH2, S or 0; xxxvii-a. -[C(R3)(Rt)]nN(Ri)(R2) together represent the moiety having the structure: 28 WO 2005/030794 PCT/US2004/030921

a) R.2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, z'-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; c) R2 is methyl, ethyl, propyl or z'-propyl; d) Rli and Ru are each independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; e) Rli and Ru are each hydrogen; f) Rli and Ru are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or g is 1 or 2; xxxvi-a. R is -CH(Rga)C(R9a)=C(Rioa)-; and a) R«a is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; b) Rga is z'so-propyl; c) The Rga-bearing carbon atom is of S configuration; 29 WO 2005/030794 PCT/US2004/030921 d) R.9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; e) Rga is hydrogen; f) Rioa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; g) Rioa is methyl; xxxvii-a. nisi; xxxviii-a. Xi is C=O; xxxix-a. Xi is CH2; xl-a. Xi is SO2; xli-a. X2isC=O; xlii-a. X2 is CH2; xliii-a. X2 is SO2; xliv-a. Q is ORQ, SRQ, NRQ RQ , N3, =N-OH, or a moiety selected from the group consisting of:

(RQ1)sZ

/RQ1V 30 WO 2005/030794 PCT/US2004/030921 wherein each occurrence of r is 0,1 or 2; s and t are independently an integer from 0-8; X is O, S, or NRK; each occurrence of R^1 and R^2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -COR1, -CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ, -CO(NORJ)RJ, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or -ZiRJ; wherein h is 1 or 2; and Zi is independently -O-, -S-, NRK, -C(O)-, wherein each occurrence of RJ and RK is independently hydrogen, CORl, COORl, CONRlRm, -NRlRm, -S(O)2RL, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and R^ and RQ are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; and xlv-a. Q is ORQ, SRQ, NRq Rq , N3, =N-0H, or a moiety selected from the group consisting of:

31 WO 2005/030794 PCT/US2004/030921 wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; each occurrence of R51 and R^2 is independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroaikyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ1 and RQ2, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety; and RQ and Rq are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroaikyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or xliv-a. Q is ORq , SRq , NRq Rq , N3, =N-OH, or a moiety selected from the group consisting of:

)r Λ

pO2RQ1 -NRQ1RQ2

N

'N

^N-°· RQ1 = H or Me RQ1= H or Me Rqz = H, Me or Ph

»,

OH -N l>r

'N

wherein each occurrence of r is 0, 1 or 2; and RQ and Rq are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroaikyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen 32 WO 2005/030794 PCT/US2004/030921 atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.

[0034] An important subclass of class (lb) includes those compounds having the structure of formula (lb) in which R is -C(Rgb)C(R9b)N(Riob)C(Rnb)-; and the compound has the following structure: R5 \.X! V?n 'N Ra R4 R5

R8b •?9b Rl1b

Q

N I

Rwb wherein R1-R7, n, Xi and Q are defined in classes and subclasses herein;

Rgb, R9b, Riob and Rub are each independently absent, hydrogen, -(O0)RL or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgb, R9b, Riob and Rub groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, CRgb and CR9b, CRgb and NRiob, NRiob and CRnb are each independently linked by a single or double bond as valency permits.

[0035] Another important subclass of class (lb) includes those compounds having the structure of formula (lb) in which Xi is C=O; R is -C(Rgb)C(R9b)N(Riob)C(Rnb)-; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CRtaRibRu; and the compound has the following structure:

'8b

N R9b Rl1b

R10b 0

Q wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and

Rta and Rh, are each independently hydrogen or lower alkyl and Rjc is aryl or heteroaryl; 33 WO 2005/030794 PCT/US2004/030921

Rgb, Rgb, Riob and Rnb are each independently absent, hydrogen, -(C=O)RL or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an ( aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgb, R9b, Riob and Rnb groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, CRgb and CRgb, CRgb and NRiob, NRiob and CRnb are each independently linked by a single or double bond as valency permits.

[0036] Another important subclass of class (lb) includes those compounds having the structure of formula (lb) in which R is-C(R8b)C(R9b)N(Riob)C(Rnb)-; Riob and Rub, taken together, form a substituted or unsubstituted cyclic heteroalkyl or heteroaryl moiety; and the compound has the following structure:

p (Si)q wherein R1-R7, n and Q are defined in classes and subclasses herein; p is 1,2,3 or 4; q is 0-12; each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rgb and Rgb are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein Rgb and Rgb, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 34 174479/2 NR7 and CRg, and CRgb and CRgb are each independently linked by a single or double bond as valency permits.

Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which n is 1 ; R is- C (Rgb)C(R9b)N(Rlob)C(Rnb)-; Riob and Rub, taken together, form a substituted or unsubstituted cyclic heteroalkyl or heteroaryl moiety; R4 is a moiety having the structure-CR4aR4bR4c; and the compound has the following structure:

wherein R1-R7, Xi and Q are defined in classes and subclasses herein; p is 1, 2, 3 or 4; q is 0,1, 2, 3,4, 5 or 6; each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Ria and R4b are each independently hydrogen or lower alkyl or heteroalkyl; and R4C is aryl or heteroaryl;

Rgb and Rgb are each independently hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein Rgb and Rgb, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, and CRgb and CRgb are each independently linked by a single or double bond as valency permits. 47-01\01661800 35 WO 2005/030794 PCT/US2004/030921 [0038] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which R is -C(R8C)C(R9c)C(R]oc)C(Rnc)OC(Ri2c)-; and the compound has the following structure:

wherein R1-R7, n, Xi and Q are defined in classes and subclasses herein;

Rgc, R90 Rioc, Riic and Ri2c are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic,-heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgc, Rgc, Rioc, Rile and Ri2c groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRecj CRsc and CRgc, CRgc and CRioc, and CRioc and CRnc are each independently linked by a single or double bond as valency permits.

[0039] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which Xi is C=O; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CRtaR^Rtc; R is -C(R8c)C(R9c)C(Rioc)C(Rnc)OC(Ri2o)-; and the compound has the following structure:

wherein Ri, R2, R5-R7 and Q are defined in classes and subclasses herein; R4a and Rtb are each independently hydrogen, or lower alkyl or heteroalkyl; and R4C is aryl or heteroaryl; 36 WO 2005/030794 PCT/US2004/030921

Rgc, R9c Rioc Riic and Ri2c are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rsc, R90 Rioc, Riic and Ri2c groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgc, CRgc and CR9C, CRgc and CRioc, and CRioc and CRnc are each independently linked by a single or double bond as valency permits.

[0040] A number of important subclasses of each of the foregoing subclasses of class (lb) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (lb) in which: i- b. Ri and R2 are independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; ii- b. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; iii- b. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; iv- b. Ri is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert- butyl, z-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; v- b. Ri and R2 are each hydrogen; vi- b. The carbon atom bearing R3 and R4 is of S' configuration; vii- b. R3 is hydrogen and R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, 37 WO 2005/030794 PCT/US2004/030921 heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl; viii- b. R3 is hydrogen and R4 is -CR4aRibR4c; wherein R)a and are independently hydrogen, or a substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl moiety and Ric is substituted or unsubstituted aryl or heteroaryl; ix- b. R3 is hydrogen and R4 is -CR^RwPh; wherein R4a and Rh, are independently hydrogen, or a substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl moiety; x- b. R4 is a substituted or unsubstituted 3-indole moiety; xi- b. R3 is hydrogen; xii- b. Ri and R4, taken together, form a substituted or unsubstituted pyrrolidine group; xiii- b. Ri and R4, taken together, form a substituted or unsubstituted piperidine group; xiv- b. Ri and R4, taken together, form a substituted or unsubstituted thiazolidine group; xv- b. Ri and R4, taken together, form a substituted or unsubstituted morpholine group; xvi- b. Ri and R4, taken together, form a substituted or unsubstituted thiomorpholine group; xvii- b. Ri and R4, taken together, form a substituted or unsubstituted indole group; xviii-b. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl; 38 WO 2005/030794 PCT/US2004/030921 xix- b. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl; xx- b. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl; xxi- b. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, ferf-butyl, i-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -Cj-galkylSR3 or -CRaRbRc; wherein Ra and Rb are independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or heteroaryl; xxii- b. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, feri-butyl, i-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci.6alkylORa, -Ci-ealkylSR8 or -CRbRcPh; wherein Ra is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rb And Rc are each independently substituted or unsubstituted linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxiii-b. R3 and R4 are each ethyl; xxiv- b. R3 is phenyl and R4 is lower alkyl; xxv- b. R3 is phenyl and R4 is ethyl; xxvi- b. R3 and R4, taken together, form a substituted or unsubstituted cycloaikyl group; xxvii-b. R3 and R4, taken together, form a cyclohexyl group; 39 WO 2005/030794 PCT/US2004/030921 xxviii-b. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group; xxix- b. R5 is hydrogen; xxx- b. R^ is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxxi- b. Ri is methyl, ethyl, propyl, butyl, pentyl, terf-butyl, z'-propyl, - CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; xxxii-b. Ri is teri-butyl; xxxiii-b. The Ri-bearing carbon atomis of 5” configuration; xxxiv-b. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxxv-b. R7 is methyl; xxxvi-b. -[C(R3)(R4)]nN(Ri)(R2) together represent the moiety having the structure:

b) R2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; c) R2 is methyl, ethyl, propyl, butyl, pentyl, teri-butyl, z'-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; d) R2 is methyl, ethyl, propyl or z'-propyl; 40 WO 2005/030794 PCT/US2004/030921 e) Rgi is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; f) Rgi is hydrogen, methyl or phenyl; g) Rgi and the substituents on L, taken together, form a substituted or unsubstituted phenyl group; h) Rmi and Rm2 are each independently hydrogen, hydroxyl, a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl moiety; a substituted or unsubstituted phenyl moiety, or Rm2 is absent when Rmi and the substitutents on L, taken together, form a

I substituted or unsubstituted aryl or heteroaryl moiety; i) Rmi and Rm2 are each hydrogen; j) g is 1 or 2; and/or k) L is CH2, S or 0; xxxviii-a. -C[(R3)(R4)]nN(Ri)(R2) together represent the moiety having the structure: rli rl2 ; and a) R2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; b) R2 is methyl, ethyl, propyl, butyl, pentyl, fe/i-butyl, z'-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; 41 WO 2005/030794 PCT/US2004/030921 c) R2 is methyl, ethyl, propyl or /-propyl; d) Rli and Ru are each independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; e) Rli and Rl2 are each hydrogen; f) Rli and Ru are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or g is 1 or 2; xxxvii-b. R is -C(Rgb)C(R9b)N(Riob)CRi ib- and a) R«b is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; b) Rsb is wo-propyl; c) The Rgb-bearing carbon atom is of S configuration; d) Rgb is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; e) Riob is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl; f) Riob is hydrogen, methyl or acetyl; g) Riob and Rub, taken together, form a substituted or unsubstituted pyrrolidine ring; or h) R9b and Rub, taken together, form a substituted or unsubstituted thiazole ring; xxxviii-b. R is -C(Rgc)C(R9C)C(Rioc)CRncOCRi2c- and a) Rgc is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; 42 WO 2005/030794 PCT/US2004/030921 b) Rgc is Lo-propyl; c) The Rgc-bearmg carbon atom is of S configuration; d) R9c and Rioc are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; e) CR90 and CRioc are linked via a double bond; f) CR9c and CRioc are linked via a double bond and R9c is hydrogen; or g) CR9c and CRioc are linked via a double bond and RiOc is methyl; xxxix-b. nisi; xl-b. Xi is C=O; xli-b. Xi is CH2; xlii-b. Xi is SO2; xliii-b. Q is ORQ, SRQ, NRQ RQ , N3, =N-OH, or a moiety selected from the group consisting of:

(RQ1)SZ

(R01)/

N

43 WO 2005/030794 PCT/US2004/030921 wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; X is O, S, or NRK; each occurrence of RQ1 and R^2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -COR1, -CO2Rj, -NRjCORj, -NRjCO2Rj, -CONRjRj, -CO(NORJ)RJ, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or -ZiRJ; wherein h is 1 or 2; and Zi is independently -O-, -S-, NRK, -C(O)-, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, -NRlRm, -S(O)2Rl, or an aliphatic; alicyclic, heteroaliphatic, _ heteroalicyclic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and RQ and R^ are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and R^ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; xliv-b. Q is ORq , SRQ, NRQ RQ , N3, =N-0H, or a moiety selected from the group consisting of: 44 WO 2005/030794 PCT/US2004/030921

wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; each occurrence of RQ1 and RQ2 is independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or R^1 and R^2, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety; and RQ and Rq" are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or xlv-b. Q is ORq , SRq , NRQ RQ , N3, =N-0H, or a moiety selected from the group consisting of: 45 WO 2005/030794 PCT/US2004/030921 -OMe

<ΝΛ>, S —OMe

)r OMe

CO2RQ1 —NRQ1RQZ

N

'N

)r RQ1 = H or Me RQ1= H or Me R02 = H, Me or Ph

’) r

OH ks

)r wherein each occurrence of r is 0, 1 or 2; and R5 and are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.

[0041] An important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; R is -CH(R8a)C(R9a)=C(Rioa)-; j is 0; 1 and m are each 1; Rj is hydrogen; G is CRgi; M is CRmiRm2> and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; g is 1,2, 3 or 4;

Rsa, R9a and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, Rsa, R9a and Rioa groups may 46 WO 2005/030794 PCT/US2004/030921 form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety; L is CRliRu, S, O or NRu, wherein each occurrence of Rli, Rl2 and Ru is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; each occurrence of Rgi, Rmi and Rm2 is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein any two adjacent Rli, Rl2, Rl3, Rgi, Rmi or Rm2 groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety.

[0042] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m are each 1; R is -CH(Rga)C(R9a)=C(RiOa)-; R3 is hydrogen; and the compound has the structure:

Q RL1 RL2 wherein R2, R5-R7 and Q are defined in classes and subclasses herein; g is 0,1,2 or 3;

Rga, Rga and Rioa are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and Rioa groups may form a cyclic alkyl, heteroalkyl, -allcyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;

Rli and Ru are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.

[0043] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; R is -C(Rgb)C(R9b)N(Riob)C(Rnb)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRgi, M is CRmiRm2, and the compound has the structure: 47 WO 2005/030794 PCT/US2004/030921

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; g is 1,2 or 3; L is CRliRl2, S, 0 or NRu, wherein each occurrence of Rli, Rm and Ru is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; each occurrence of Rgi, Rmi and Rm2 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; any two adjacent RLi, Rm, Ru, Rgi, Rmi or Rm2 groups, taken together, may form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety;

Rgb, R9b, Riob and Rub are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or 1 wherein any two adjacent Rgb, R9b, Riob and Rub groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, CRgb and CR9b, CR9b and NRiob, NRiob and CRnb are each independently linked by a single or double bond as valency permits.

[0044] Another important subclass of class (lc) includes those compounds having the structure of formula (lc) in which X2 is C=O; R is -C(Rgb)C(R9b)N(Riob)C(Rnb)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRgi, M is CRmiRmz; Riob and Rub, taken together, form a cyclic heteroalkyl group; and the compound has the structure: 48 WO 2005/030794 PCT/US2004/030921

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; p is 1,2,3 or 4; qis 0-12; each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rsb and R% are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein Rgb and Rgb, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, and CRgb and CR^ are each independently linked by a single or double bond as valency permits.

[0045] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m are each 1; R is -C(R8b)C(R9b)N(Riob)C(Rnb)-; R3 is hydrogen; and the compound has the structure:

Reb RlOb θ ^9b Rub

Q wherein R2, R5-R7 and Q are defined in classes and subclasses herein; g is 0,1,2 or 3; 49 WO 2005/030794 PCT/US2004/030921

Rli and Rl2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

Rgb, R9b, Riob and Rub are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two adjacent Rgb, R9b, Riob and Rub groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, CRgb and CRgb, CRgb and NRiob, NRiob and CRub are each independently linked by a single or double bond as valency permits.

[0046] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m are each 1; R is -C(Rgb)C(R9b)N(Riob)C(Rnb)-; R3 is hydrogen; Riob and Rub, taken together, form a cyclic heteroaikyl group; and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; p is 1,2,3 or 4; q is 0-12; g is 0,1,2 or 3;

Rli and Rl2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety; 50 WO 2005/030794 PCT7US2004/030921

Rsb and R9b are each independently hydrogen, -(C=O)RL or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein Rgb and R9b, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, and CRgb and CR9b are each independently linked by a single or double bond as valency permits.

[0047] Another important subclass of class (lc) includes those compounds having the structure of formula (lc) in which X2 is C=O; R is -C(Rsc)C(R9c)C(Rioc)C(Riic)OC(Ri2c)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRgi, M is CRMiRm2; and the compound has the following structure:

Q

O wherein Rj, R2, R5-R7 and Q are defined in classes and subclasses herein; g is 1, 2 or 3; L is CRliRu, S, Ο or NRu, wherein each occurrence of Rli, Rl2 and Ro is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; each occurrence of Rgi, Rmi and Rm2 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; any two adjacent Rli, Rl2, Rm, Rgi, Rmi or Rm2 groups, taken together, may form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety;

Rgc, R90 Rioc, Riic and Rj2c are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl 51 WO 2005/030794 PCT/US2004/030921 moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm» or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgc, R9C, Rioc, R-iic and Ri2c groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicychc, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CR8c, CRgc and CR9C, CR9C and CRioc, and CRiOc and CRuc are each independently linked by a single or double bond as valency permits.

[0048] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; R is -C(R«c)C(R9c)C(Rioc)C(Riic)OC(Ri2c)-; G, J and M are each CH2; j, 1 and m are each 1; R3 is hydrogen; and the compound has the following structure:

wherein Ri, R2, R5-R7 and Q are defined in classes and subclasses herein; gis 0,1,2 or 3;

Rli and Ru are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

Rgc, Rgc, Rioc, Riic and Ri2c are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgc, R-9c, Rioc, Riic and Ri2o groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicychc, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgc, CRgc and CRgc, CR90 and CRioc, and CRioc and CRnc are each independently linked by a single or double bond as valency permits. 52 WO 2005/030794 PCT/US2004/030921 [0049] A number of important subclasses of each of the foregoing subclasses of class (Ic) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (Ic) in which: i- c. R.2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; ii- c. R.2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; iii- c. R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; iv- c. R2 is methyl, ethyl, propyl, butyl, pentyl, teri-butyl, z-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2CCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; v- c. R2 is hydrogen; vi- c. R2 is hydrogen, methyl or benzyl; vii- c. R2 is methyl; viii- c. R2 is acyl, wherein the acyl group is a nitrogen proteting group; ix- c. R3 is hydrogen;

,JWML x-c. The moiety having the structure I forms a substituted or unsubstituted pyrrolidine group; 53 WO 2005/030794 PCT/US2004/030921

Xl-C. R2

Rs,

Xll-C.

The moiety having the structure · forms a substituted or unsubstituted piperidine group; R2 I r3

The moiety having the structure I forms a substituted or unsubstituted thiazolidine group;

Rs, «3ί3Ν"β (JV1 xiii- c. The moiety having the structure I forms a substituted or unsubstituted morpholine group; R2 I R3 (JW1 xiv- c. The moiety having the structure · forms a substituted or unsubstituted thiomorpholine group; R2 IR3, 'V’ xv- c. The moiety having the structure I forms a substituted or unsubstituted indole group; xvi- c. R5 is hydrogen; xvii- c. R$ is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xviii-c. R<5 is methyl, ethyl, propyl, butyl, pentyl, /er/-butyl, z'-propyl, - CH(CH3)CH2CH3, -CH2CH(CH3)2j cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; 54 WO 2005/030794 PCT/US2004/030921 xix- c. Re is tert-butyl; xx- c. The Re-bearing carbon atom is of S' configuration; xxi- c. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxii- c. R7 is methyl; xxiii-c. R is -CH(R8B)C(R9a)=C(Rioa)-; and a) Rga is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; b) Rga is wo-propyl; c) The Rea-bearing carbon atom is of 5 configuration; d) R9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; e) R9a is hydrogen; f) Rioa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or g) Rioa is methyl; xxiv-c. Ris-C(Reb)C(R9b)N(Riob)CRiib-and a) Rsb is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; b) Rgb is fio-propyl; c) The Rgb-bearing carbon atom is of 5 configuration; d) R9b is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; 55 WO 2005/030794 PCT/US2004/030921 e) Riob is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl moiety; f) Riob is hydrogen, methyl or acetyl; g) Riob and Rub, taken together, form a substituted or unsubstituted pyrrolidine ring; or h) Rgb and Rub, taken together, form a substituted or unsubstituted thiazole ring; xxv-c. R is -C(Rgc)C(R9c)C(Ri oc)CRi ioOCRi2C- and a) Rgc is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; b) Rgc is tio-propyl; c) The Rgc-bearing carbon atom is of S configuration; d) R9c and Rioc are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; e) CR9C and CRioc are linked via a double bond; f) CR9c and CRioc are linked via a double bond and R9c is hydrogen; or g) CR9c and CRioc are linked via a double bond and Rjoc is methyl; xxv-c,

The moiety having the structure moiety having the structure:

represents the 56 WO 2005/030794 PCT/US2004/030921

a) R2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; l) R2 is methyl, ethyl, propyl or z-propyl; m) Rqi is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; n) Rgi is hydrogen, methyl or phenyl; o) Rqi and the substituents on L, taken together, form a substituted or unsubstituted phenyl group; p) Rmi and Rm2 are each independently hydrogen, hydroxyl, a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl moiety; a substituted or unsubstituted phenyl moiety, or Rm2 is absent when Rmi and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety; q) Rmi and RM2 are each hydrogen; r) g is 1 or 2; and/or s) L is CH2, S or 0; 57 WO 2005/030794 PCT/US2004/030921

VL xxvi-c. The moiety having the structure ι represents the moiety having the structure:

g) R2 is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroaikyl, -alkyl(aryl) or acyl moiety; h) R.2 is methyl, ethyl, propyl, butyl, pentyl, feri-butyl, z'-propyl, - CH(CH3)Et, -CH(CH3)CH2CH2CH3, CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; i) R2 is methyl, ethyl, propyl or z'-propyl; j) Rli and Ru are each independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl; k) Rli and Ru are each hydrogen; l) Ru and Ru are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; and/or m) g is 1 or 2; xxvii-c. X2 is C=O; xxviii-c. X2 is CH2; 58 WO 2005/030794 PCT/US2004/030921 xxix- c. X2 is SO2; xxx- c. Q is ORq , SRq , NRq Rq , N3, =N-OH, or a moiety selected from the group consisting of: (RQ1)

"N

)r X ro

L/7’r QX (Rq’)Z (Rq’).Z ' X. V-OR02

'N

)r / (RQ1), ~v-NHR- / r\j XT IX Λ (,0,,/-7 (*”>/ X.

'N

N )r „x (R°’):

'N

Or u (RQ2)t (RQ1), wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; X is 0, S, or NRK; each occurrence of RQ1 and RQ2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -CORj, -CO2Rj, -NRjCORj, -NRjCO2Rj, -CONRjRj, -CO(NORj)Rj, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or -ZiRJ; wherein h is 1 or 2; and Zi is independently -O-, -S-, NRK, -C(O)-, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, -NRlRm, -S(O)2Rl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Rq and RQ are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and R^ , taken together with the nitrogen atom to 59 WO 2005/030794 PCT/US2004/030921 which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; xxxi-c. Q is OR?, SRQ, NRQ RQ , N3, =N-OH, or a moiety selected from the group consisting of: OR01 wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; each occurrence of RQ1 and RQ2 is independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or R^1 and RQ2, taken together with the nitrogen atom to which they are attached, form1 a substituted or unsubstituted heterocyclic moiety; and RQ and Rq" are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or Rq and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or xxxii-c. Q is ORQ, SRQ, NR^ RQ , N3, =N-OH, or a moiety selected from the group consisting of: 60 WO 2005/030794 PCT/US2004/030921 -OMe —OMe

)r OMe X. CO2RQ1

'N

»r RQ1 = H or Me , V-NRQ1RQ2 5

A J

N

)r RQ1=HorMe RQ2 = H, Me or Ph X. N" ~\ Q'

OH —Ν'

)r 'Ν'

[0050] An important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is -CH(Rga)C(R9a)=C(Ri0a)-; X2 is C=O; and

wherein R3 and R4 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; Rb R2, R5-R7 and Q are defined in classes and subclasses herein; and 61 WO 2005/030794 PCT/US2004/030921

Rsa, Ria and Rioa are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and RiOa groups may form an alicyclic, heteroalicyclic, alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety.

[0051] Another important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is -C(R8b)C(R9b)N(Riob)C(Rnb)-; X2 is C=O; and the compound has the following structure:

N 3 1x4 R5 O Rgb Riob θ

Rsb, R9b, Riob and Rub are each independently absent, hydrogen, -(C=O)RL or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rgb, R9b, Riob and Rub groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRgb, CRgb and CR9b, CR9b and NRiob, NRiob and CRnb are independently linked by a single or double bond as valency permits.

[0052] Another important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is -C(R8b)C(R9b)N(Riob)C(Riib)-; X2 is C=O; Riob and Rnb, taken together, form a cyclic heteroalkyl group; and the compound has the following structure: 62 WO 2005/030794 PCT/US2004/030921 Ο

p (Si)q wherein R3 and R4 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; Ri, R2, R5-R7 and Q are defined in classes and subclasses herein; p is 1,2, 3 or 4; q is 0-12; each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rgb and Rgb are each independently hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein Rsb and R9b, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRg, and CRgb and CR9b are independently linked by a single or double bond as valency permits.

[0053] Another important subclass of class (Id) includes those compounds having the structure of formula (Id) in which X2 is C=O; R is -C(R8c)C(R9c)C(Rioc)C(Rhc)OC(Ri2c)-; and the compound has the following structure:

O

Q 63 WO 2005/030794 PCT/US2004/030921 wherein R3 and R4 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; Ri, R2, R5-R7 and Q are defined in classes and subclasses herein;

Rgc, R90 Rioc» Rile and Ri2c are each independently absent, hydrogen, -(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two Rec, R9c, R100 Rile and Ri2c groups, taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and NR7 and CRsc, CRec and CR9C, CR9c and CRioc, and CRioc and CRu0 are each independently linked by a single or double bond as valency permits.

[0054] A number of important subclasses of each of the foregoing subclasses of class (Id) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (Id) in which: i- d. Ri and R2 are independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; ii- d. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl; iii- d. Ri is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl; iv- d. Ri is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert- butyl, z-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, - 64 WO 2005/030794 PCT/US2004/030921 C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; v- d. Ri and R2 are each hydrogen; vi- d. Ri and R2 are independently hydrogen or methyl; vii- d. Ri and R2 are each methyl; viii- d. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl; ix- d. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl; x- d. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl; xi- d. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, ferf-butyl, z’-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -Ci-6alkylSRa or -CRaRbRc; wherein Ra and Rb are independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or heteroaryl; xii- d. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, ferf-butyl, z-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -Ci-6alkylSRa or -CRbRcPh; wherein Ra is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl 65 WO 2005/030794 PCT/US2004/030921 and Rb And Rc are each independently substituted or unsubstituted linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xiii- d. R3 and R4 are each ethyl; xiv- d. R3 is phenyl and R4 is lower alkyl; xv- d. R3 is phenyl and R4 is ethyl; xvi- d. R3 and R4, taken together, form a substituted or unsubstituted cycloaikyl group; xvii- d. R3 and R4, taken together, form a cyclohexyl group; xviii-d. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group; xix- d. Rs is hydrogen; xx- d. Re is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxi- d. Re is methyl, ethyl, propyl, butyl, pentyl, terf-butyl, z'-propyl, - CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; xxii- d. Re is teri-butyl; xxiii-d. The Re-bearing carbon atom is of S configuration; xxiv- d. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; xxv- d. R7 is methyl; xxvi- d. R is -CH(R8a)C(R9a)=C(Rioa)-; and i) Rga is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; j) Rga is iso-propyl; k) The Rga-bearing carbon atom is of 5 configuration; 66 WO 2005/030794 PCT/US2004/030921 l) 1¼ is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; m) R.9a is hydrogen; n) Rioa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or o) Rioa is methyl; xxvii-d. R is -C(Rgb)C(R9b)N(Riob)CRi ib- and p) Rgb is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; , q) Rgb is iso-propyl; r) The Rgb-bearing carbon atom is of S configuration; s) R9b is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; t) Riob is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower , alkyl or acyl moiety; u) Riob is hydrogen, methyl or acetyl; v) Riob and Rub, taken together, form a substituted or unsubstituted pyrrolidine ring; or w) R9b and Rnb, taken together, form a substituted or unsubstituted thiazole ring; xxviii-d. R is -C(Rgc)C(R9C)C(Rioc)CRi icOCRi2c- and h) Rgc is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; i) Rgc is z'so-propyl; 67 WO 2005/030794 PCT/US2004/030921 j) The Rgc-bearing carbon atom is of S' configuration; k) R90 and RiOc are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; l) CR9C and CR100 are linked via a double bond; m) CR9C and CR.ioc are linked via a double bond and Rgc is hydrogen; or n) CR9C and CRioc are linked via a double bond and Rioc is methyl; xxix- d. X2 is C=O; xxx- d. X2 is CH2; xxxi-d. X2 is SO2; xxxii-d. Q is ORQ, SRQ, NRQ RQ , N3, =N-OH, or a moiety selected from the group consisting of:

wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; X is O, S, or NRK; each occurrence of RQ1 and R^2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -CORj, -CO2Rj, -NRjCORj, -NRjCO2Rj, -CONRjRj, 68 WO 2005/030794 PCT/US2004/030921 -CO(NORJ)RJ, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or -ZiRJ; wherein h is 1 or 2; and Zi is independently -0-, -S-, NRK, -C(O)-, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, C0NRLRM, -NRlRm, -S(O)2Rl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and wherein each occurrence of RL and Rm is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Rq and Rq are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroaikyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; xxxiii-d. Q is ORQ, SRq , NRq Rq , N3, =N-0H, or a moiety selected from the group consisting of:

wherein each occurrence of r is 0, 1 or 2; s and t are independently an integer from 0-8; each occurrence of RQ1 and R^2 is independently hydrogen, or a substituted or unsubstituted, linear or 69 WO 2005/030794 PCT/US2004/030921 branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ1 and RQ2, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety; and RQ and Rq” are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or xxxiv-d. Q is ORQ, SRQ, NRQ RQ , N3, =N-OH, =N-0H, or a moiety selected from the group consisting of: A.

'N

CO2RQ1 %-NrQ1rQ2

'N

»r RQ1 = H or Me

An-q RQ1= H or Me RQ2 = H, Me or Ph

OH

—N

'N

wherein each occurrence of r is 0, 1 or 2; and RQ and RQ are independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety. 70 WO 2005/030794 PCT/US2004/030921 [0055] As the reader will appreciate, compounds of particular interest include, among others, those which share the attributes of one or more of the foregoing subclasses. Some of those subclasses are illustrated by the following sorts of compounds: [0056] I) Compounds of the formula (and pharmaceutically acceptable derivatives thereof);

wherein R1-R2, Ria, R4b, R9a-Rioa and Q are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety. [0057] II) Compounds of the formula (and pharmaceutically acceptable

wherein A, B, D, E, a, b, d, e, R1-R2, Ria, Rib, and R9a-Rioa are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0058] It will also be appreciated that for each of the subgroups I-Π described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-a. through xliv-a. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0059] HI) Compounds of the formula (and pharmaceutically acceptable derivatives thereof); 71 WO 2005/030794 PCT/US2004/030921

Me Rgb Rub O R10b θ ORq wherein RrR2, Ria, Rib, R9b-Riib and Rg are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0060] IV) Compounds of the formula (and pharmaceutically acceptable derivatives thereof):

wherein A, B, D, E, a, b, d, e, R1-R2, R4a, R4b, and R^-Rub are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0061] V) Compounds of the formula (and pharmaceutically acceptable derivatives thereof):

wherein R1-R2, Ria, Rib, R9c-Ri2c and Rq are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0062] It will also be appreciated that for each of the subgroups HI-V described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-b. through xlv-b. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0063] VI) Compounds of the formula (and pharmaceutically acceptable derivatives thereof): 72 WO 2005/030794 PCT/US2004/030921

wherein L, Rga-Rioa, Rgi, Rmi and Rm2 are as defined above and in subclasses herein; g is 1 or 2; Q is ORQ, wherein RQ is hydrogen or lower alkyl; and R2 and Rg are independently substituted or unsubstituted linear or branched lower alkyl.

[0064] VH) Compounds of the formula (and pharmaceutically acceptable derivatives thereof);

Rli R|_2 wherein g, R9a-Rioa, Rli and Rm are as defined above and in subclasses herein; Xi is CH2 or C=O; R2 and Rg are independently substituted or unsubstituted linear or branched lower alkyl; and Q is OR^ or NR^ R^ wherein R^ is hydrogen or lower alkyl, or R^ and R^ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety, whereby each of the foregoing alkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic.

[0065] VIII) Compounds of the formula (and pharmaceutically acceptable derivatives thereof);

wherein A, B, D, E, L, a, b, d, e, p, Rgb, Rgi, Rmi and Rm2 are as defined above and in subclasses herein; g is 1 or 2; and R2 and Rg are independently substituted or unsubstituted linear or branched lower alkyl. 73 WO 2005/030794 PCT/US2004/030921 [0066] IX) Compounds of the formula (and pharmaceutically acceptable derivatives thereof); rq' ι

wherein p, R9b, Rli, Rl2, Rq and RQ are as defined above and in subclasses herein; and R2 and Rg are independently substituted or unsubstituted linear or branched lower alkyl.

[0067] It will also be appreciated that for each of the subgroups VI-IX described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-c. through xxxii-c. described above and classes, subclasses and species of compounds described above and in the examples herein. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, iso-propyl, sec-butyl or -CH(CH3)CH(CH3)2. In certain embodiments, for compounds of subgroups VI-IX above, Rg is ieri-butyl or iso-propyl. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, iso-propyl, sec-butyl or -CH(CH3)CH(CH3)2, and Rg is ierf-butyl or iso-propyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is methyl and Rg is feri-butyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is iso-propyl and Rg is ieri-butyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is sec-butyl and Rg is ieri-butyl or isopropyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is-CH(CH3)CH(CH3)2, and Rg is ieri-butyl.

[0068] X) Compounds of the formula (and pharmaceutically acceptable derivatives thereof);

74 WO 2005/030794 PCT/US2004/030921 wherein Rb R9a, Rioa and Rq are as defined above and in subclasses herein; and R3 and R4 are each independently an alkyl, heteroalkyl, heteroalkyl(aryl) or alkyl(aryl) moiety, or R3 and R4, taken together, form a cyclic alkyl or heteroalkyl moiety.

[0069] It will also be appreciated that for subgroup X described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-d. through xxxiv-d. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0070] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. It is to be understood that the invention encompasses every possible isomer such as geometric isomer, optical isomer, stereoisomer and tautomer based on asymmetric carbon, which can occur in the structures of the inventive compounds, and mixtures of such isomers, and is not limited to the specific stereochemistry shown for the compounds disclosed in the present specification. It will be further appreciated that the absolute stereochemistry of some of the compounds recited in the Exemplification herein has not been determined, and that when a stereochemistry was assigned for those compounds it is meant to be tentative and to indicate that a set of diastereomers exists for those compounds and/ot that a diastereomer was isolated in pure form. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.

[0071] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. The invention also encompasses tautomers of specific compounds as described above. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically 75 WO 2005/030794 PCT/US2004/030921 acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

[0072] Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, ER spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

[0073] 2) Compounds and Definitions [0074] As discussed above, this invention provides novel compounds with a range of biological properties. Compounds of this invention have biological activities relevant for the treatment of diseases or other disorders such as proliferative diseases, including, but not limited to cancer. In certain other embodiments, the inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

[0075] Compounds of this invention include those specifically set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.

[0076] Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in 76 WO 2005/030794 PCT/US2004/030921 combination with one or more additional therapeutic agents. The phrase, “pharmaceutically acceptable derivative”, as used herein, denotes any pharmaceutically acceptable salfi ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

[0077] Numerous suitable prodrug moieties, and information concerning their selection., synthesis and use are well known in the art. Examples of prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities. Examples of such prodrug moieties include the following: 77

Ο—* ρ For the synthesis of the prodrug groups, see Borchardt, R.T. etal., 0-/ J. Org. Chem. 1997, 43, 3541-3852. )-NH2

*R R1 = all natural, unnatural amino adds

R1 = C1-C4 alkyl, cydoalkyl, oxyalkyl, aminoalkyl, etc. R2 = all natural, unnatural amino adds

For the synthesis of the prodrug groups, see Zhou, X-X. et al., PCT WO 99/51613.

For the synthesis of the prodrug groups, see Ezra, A. et al., J. Med. Chem. 2000, 43,3641-3652.

Ri, R8 = all natural, unnatural amino adds

Other examples of prodrug moieties of interest include prodrug moieties that can be attached to hydroxyl-containing functionalities. Such prodrug moieties a well-known in the art, and will be readily identified by a person skilled in the relevant art.

The present invention encompasses any prodrug form of the compounds described herein.

Certain compounds of the present invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999,. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term "protecting group", as used herein, it is meant that a particular functional moiety, e. g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a 78 174479/3 multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without-the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e. g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p- methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e. g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e. g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e. g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis "Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley &amp; Sons, New York: 1999.

It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the 79 WO 2005/030794 PCT/US2004/030921 term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and

I unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example of cancer. The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0080] The term “aliphatic”, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term “alkyl” includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms "alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. 80 WO 2005/030794 PCT/US2004/030921 [0081] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[0082] The term “alicyclic”, as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “alicyclic” is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2-cyclopentyl-n, cyclohexyl, -CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[0083] The term “alkoxy” (or “alkyloxy”), or “tbioalkyl” as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon 81 WO 2005/030794 PCT/US2004/030921 atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0084] The term “alkylamino” refers to a group having the structure -NHR’wherein R’ is alkyl, as defined herein. The term “aruinoalkyl” refers to a group having the structure NH2R’-, wherein R’ is alkyl, as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.

[0085] Some examples of sutstituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryioxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CH12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rxj -CO2(Rx); -CON(RX)2; -OC(0)RX; -OCO2Rx; -OCON^; -N(Rx)2; -S(O)2Rx; -NRX(CO)RX wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. 82 WO 2005/030794 PCT/US2004/030921 [0086] In general, the terms “aryl” and “heteroaryl”, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkyl or heteroalkyl moiety and thus also include -(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl, (heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and-(heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases “aryl or heteroaryl” and “aryl, heteroaryl, -(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and ~(heteroalkyl)heteroaryl” are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments of the present invention, “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiements of the present invention, the term “heteroaryl”, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0087] It will be appreciated that aryl and heteroaryl groups (including bycyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one, two or three of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; 83 WO 2005/030794 PCT/US2004/030921 heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -0(0)1^ -CO2(RX); -CON(Rx)2; -OC(O)RX; -OCO2Rx; -OCONCRx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally appbcable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0088] The term “cycloalkyl”, as used herein, refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic or hetercycbc moieties, may optionally be substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH20H; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -C02(Rx); -C0N(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRX(CO)RX wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. 84 WO 2005/030794 PCT/US2004/030921 [0089] The term “heteroaliphatic”, as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have have substituted with an heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched or linear unbranched. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0090] The term “heteroalicyclic”, as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups.

[0091] The terms “halo” and “halogen” as used herein refer to an atom selected fiom fluorine, chlorine, bromine and iodine.

[0092] The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like. 85 WO 2005/030794 PCT/US2004/030921 [0093] The term “heterocycloalkyl” or “heterocycle”, as used herein, refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quatemized, andL (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certain embodiments, a “substituted heterocycloalkyl or heterocycle” group is utilized and as used herein, refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; - OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -C0N(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRX(CO)RX wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substitutents described above and herein may be substituted or unsubstituted. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples, which are described herein.

[0094] As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and 86 WO 2005/030794 PCT/US2004/030921 branched groups. Similarly, the terms “alicyclic”, “heteroalicyclic”, “heterocycloalkyl”, “heterocycle”, and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. In addition, the terms “aliphatic(aryl)”, “heteroaliphatic(aryl)”, “aliphatic(heteroaryl)”, “heteroaliphatic(heteroaryl)”, “alicyclic(aryl)”, “heteroalicyclic(aryl)”, “alicyclic(heteroaryl)”, “heteroalicyclic(heteroaryl)”, “-alkyl(aryl)”, “heteroalkyl(aryl)”, H-alkyl(heteroaryl)”, “heteroalkyl(heteroaryl)”, and the like encompass substituted and unsubstituted, and saturated and unsaturated (i.e., non-aromatic portion of the moiety) groups. Additionally, the terms “cycloaikyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkynyl”, “aryl”, “heteroaryl” and the like encompass both substituted and unsubstituted groups, unless otherwise indicated.

[0095] 3) Synthetic Methodology [0096] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[0097] In one aspect, the present invention provides novel peptides having formula (I) as described above and in certain classes and subclasses herein. Examples of synthetic methods for preparing exemplary types of compounds of the invention are provided below, as detailed in Schemes 1-20, and in the Exemplification herein. It will be appreciated that the methods as described herein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting materials are well known to those skilled in the art. Although the following schemes describe certain exemplary compounds, it will be appreciated that the use of alternate starting materials will yield other analogs of the invention. For example, compounds are described below where Xi and X2 are each C=O, R5 is hydrogen, R$ is /erf-butyl and R7 is methyl; however, it will be appreciated that alternate starting materials and/or intermediates can be 87 WO 2005/030794 PCT/US2004/030921 utilized to generate compounds where, for example, Xi and X2 may be independently C=O, CH2, SO2, and R5-R7 may represent moieties other than those depicted herein, such as alkyl, heteroalkyl, aryl, heteroaryl, etc. It will also be appreciated that any available techniques known in the art can be used to make the inventive compounds or compositions including them. A person of ordinary skill in the art will recognize that suitable synthetic methods are not limited to those depicted in Schemes 1-20 below, and that any suitable synthetic methods known in the art can be used to prepare the inventive compounds.

[0098] In certain embodiments, the inventive compounds, have the general structure (I*) as shown in Scheme 1, where R, R' and Q are aliphatic, heteroaliphatic, aryl or heteroaryl moieties. In preferred embodiments, R, R' and Q are moieties such as those described in classes and subclasses herein. Examples of preferred structures for R, R' and Q are depicted in Scheme 1. 88 WO 2005/030794 PCT/US2004/030921

A f λ

H Μθ"Νγ\

I

„N N^zA- R,

Me R3 R4

O

Me O')

O

Rl1b X I Riob

Λ. 0Rg .Rg

5—N RH1 RG2 ^N^Rgs

Rgi 0

Rhi RH2 VN'Rg

Examples of compounds of this sort include, but are not limited to, compounds wherein: R·) = H or Me R3= Me, Et, or forms a 5-6 membered ring with R4 R4 = Me, Et, or forms a 5-6 membered ring with R3

Riob = H. Me, Ac or forms a 5-6 membered ring with R^

Rub= H. or forms a 5-6 membered ring with RiOb

Rg = H, Me, Et or forms a 5-6 membered ring with Rhi

Rm = H, Me, Et or forms a 5-6 membered ring with RG RH2 = H, CO2H, C02Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe Rd = H, Me, or forms a 5-6 membered ring with RG2 Rg2 = H, or forms a 5-6 membered ring with Rqi RG3 = H, CO2H, C02Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe

Scheme 1 [0099] In certain embodiments, the inventive compounds belong to class (la) and subclasses thereof, as described herein. Scheme 2 depicts the synthesis of exemplary compounds of this class (compounds of general structure 11). As shown 89 WO 2005/030794 PCT/US2004/030921 in Scheme 2, the dipeptide core can be constructed, for example, from N-Boc-N-methyl-valinal (2) and 7V-Boc-terf-leucine (4). The TV-terminal moiety of the compounds of the invention (Rr in Scheme 1) may be provided by (S)-TV-Boc-neo-phenylalanine (6). As depicted in Scheme 2, a variety of synthetic methods allow access to a variety of analogs, for example, carboxylic esters of general structure 7, carboxylic acid 8 or amides of general structure 11. The reader will appreciate that other synthetic methods known in the art can be used to prepare other derivatives.

Boc deprotection

Me O A H Ph^k"

Rg2 N^RG3

Rgi Λ η Ph-q^

Examples of compounds of this sort include, but are not limited to, compounds wherein:

Rg1 = H, Me, or forms a 5-6 membered ring with RG2 Rq2 = H, or forms a 5-6 membered ring with Rqi

Rq3 = H, CO2H, CO2Me, CONH2, CONHMe, CONHMez, CONHBn, CH2OMe

Scheme 2 [0100] An exemplary synthetic approach for the preparation of intermediate 6 is depicted in Scheme 3. The method afforded (S)-TV-Boc-neo-phenylalanine (6) in 20% overall yield. 90 WO 2005/030794 PCT/US2004/030921

65 "C (75%)

1. Pd/C, H2, EtOAc 1. KHMDS.THF, -78°C' 2. Trisylazlde, THF, -7B ’C ->. 3. HOAc (93%)

(Hl) ) o

UOH, H2O2 aq. THF ->. (76%)

1. NaH, Mel, DMF, 0 °C 2. Chiral HPLC separation

H (V)

O

Me (vii) z boc2o -► (83%) CH2N2 (96%) LIOH, aq. THF reflux -► (100% yield, 80% e.e.)

(73%, enanliomerically pure)

Scheme 3 [0101] In certain other embodiments, the inventive compounds belong to class (Ib) and subclasses thereof, as described herein. Schemes 4-6 depict the synthesis of exemplary types of compounds of this class (for example, Amine Esters, Amine Acids, Amine Amides and TV-Acetyl Amine Amides of general structure 18, 20, 23, respectively as seen in Schemes 4; See also Amine Esters, Amine Acids, Amine Amides and TV-Acetyl Amine Amides of general structure 25, 26 and 27, respectively in Scheme 5). In certain embodiments, R may be a nitrogen-containing heteroalkyl moiety (see Schemes 4 and 5) or an unsaturated oxygen-containing heteroalkyl moiety (see Scheme 6). Although Schemes 4-6 depict compounds comprising an TV-terminal moiety derived from (5)-TV-Boc-neo-phenylalanine (6), a person of ordinary skill in the art would appreciate that a wide variety of organic moieties other than those described in Schemes 4-6 may be used to construct the compounds of the invention. Similarly, Schemes 4-6 recite compounds where the C-terminal moiety may be carboxylic esters, carboxylic acids or amides. It is to be understood that the scope of the invention is not limited to these compounds, but rather encompasses derivatives and analogs of these compounds, or compounds obtained from different starting materials. 91 WO 2005/030794 PCT/US2004/030921

(22)

Amine Amides (23)

Examples of compounds of this sort include, but are not limited to, compounds wherein: Riob = H.Me, or forms a 5-6 membered ring with Ri1b R11b = H. °r forms a 5-6 membered ring with Riob Rg = H, Me, or forms a 5-6 membered ring with Rm Rm = H, or forms a 5-6 membered ring with Rg RH2 = H, CO2H, CO2Me, C0MH2, CONHMe, CONHMe2, CONHBn, CH2OMe

Scheme 4 92 WO 2005/030794 PCT/US2004/030921

Boc'

Me O S'"' I = u 11 ?

Me ι

1) AcOH, Pyr, DMF

2) HCI, MeOH

OMe 0 , (24)

1 MLIOH, MeOH ΓΥ OMe

(25)

_*NH (21) α h Rq NMM, DERC, DMF

Me'

Phq\ H N-Acetyl Amine Acids (26)

PhJ\ " 0 Ac « N-Acetyl Amine Amides (27)

Examples of compounds of this sort include, but are not limited to, compounds wherein: Rq = forms a 5 or 6 membered ring with Rm Rh1 = forms a 5 or B membered ring with Rq RH2=CO2Me, CONH2

Scheme 5

Boc'

Me ι ,CO2Et

DIBAL CHjCIj (3b,

DMF, NMM, HOAt, CMC

2) HCI, EtOH 01

2) HCI, EtOH

Me'

Ph"'']''"' CO2Et

LiOH

EtOH

NMM, DEPC, DMF (31)

[0102] In certain other embodiments, the inventive compounds belong to class (Ic) and subclasses thereof, as described herein. Schemes 7-10 depict the

Scheme 6 93 WO 2005/030794 PCT/US2004/030921 synthesis of exemplary types of compounds of this class (for example Amine Esters, Amine Acids and Amine Amides of general structure 42, 43 and 45, respectively, as seen in Scheme 7). In certain embodiments, the compounds of the invention comprise a nitrogen-containing heterocyclic TV-terminal moiety. For example, the heterocyclic moiety may be a piperidine ring (Schemes 7, 8 and 9) or a thiazolidine ring (Scheme 10). Examples of other suitable moieties are described in the Exemplification herein, or will be apparent to the person of ordinary skill in the art. As dicussed above, R may be a nitrogen-containing heteroalkyl moiety (Scheme 7) or an unsaturated alkyl moiety (Schemes 8,9 and 10). 94 WO 2005/030794 PCT/US2004/030921

Boc. 1 n co2h

H

I + CIH2hL .COoMe NMM, HOW,

T CMC, DMF

(35) >?2 ^Ν^,ΟΟ,Η (38)

HCl, MeOH

NaBHj

NMM, HOAt, CMC, DMF

MbOHZTHF

0-5’C

Examples of compounds of this sort include, but are not limited to, compounds wherein: R2 = methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl R10b = H, Me, or forms a 5-6 membered ring with Rnb R11b = H, or forms a 5-6 membered ring with R10b

Rg = H, Me, OMe, or forms a 5-6 membered ring with Rm

Rm = H, i-Pr, or forms a 5-6 membered ring with RG

Rh2 = OH. OMe, OBn, O-iPr, O-cyclo-Bu, O-cyclo-Pent, O-cyclo-Hex, NH2, NHBn, NH(2-Naphth)

Scheme 7 95 WO 2005/030794 PCT/US2004/030921

I

-N. .CO,H BOC X (46)

Me aorb Λ C0,Me c ->- BO(7 X ->. a (96%) (unpurified) b. (10D%) (4η

BOCX

Ν. .CHO (2)

81%

(62%)

Conditions: a) K2CO3, CH3I, DMF; (b)TMS-diazomethane, MeOH, CH2CI2; (c) DIBAL, PhCH3, -78 °C; (d) Ph3P=C(CH3)CO2Et, CH2CI2; (e) HCl in 1,4-dioxane; (f) BOC-Tle-OH, CMC, HOAt, NMM, DMF; (g) N-(R2)pipecolic acid, CMC, HOAt, NMM, DMF (h) LiOH, aq. MeOH; (i) HCI-L-Pro-OMe, DEPC, NMM, DMF

Compounds of this type include compounds where R2 = methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3t -CH(CH3)CH2CH2CH3, -CHzCH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C=CH, cydohexyl, cyclopentyl, cyclobutyl or cyclopropyl

Scheme 8 96 WO 2005/030794 PCT/US2004/030921

Methyl pipecolic acid analogs

Trans Route -►

Boc^O, Et3N, MeOH

Boc

Quant

^N^xCO2H Mel, K2CO3, DMF Y. (55)

Boc

L s-BuU, TMEDA ether, -78‘C ILCO2(g) (2,4-syn)

Only one enantiomer shown 88.7%.

Boc .N^COzMe I (56) 65.0%

NaOMe, MeOH

Each cis and trans isomer may be individually subjected to the same reaction sequence

Me -NyCO^ H2 Μ(0Η)2 Τ (“ί

H2CO, MeOH TFACHjOj u fT^°' n2j>co2h

Boc N ^..CO2Me (59a) (57) (2,4-anti)

Only one enantiomer shown 78.5%

Quant (2,4-syn)

Only one enantiomer shown

Only one enantiomer shown

Boc

N ..-CO2H

KOH

2:1 EtOH/H2O (SB)

Quant.

Quant 'Ψ* Me 0 X (49) HBTU, DIEA, CHhCfe

Me Ο ψ Me

msVxY (51b) (Two diastereomers separated by flash chromatography) + 95.6% C02Et

Scheme 9 [0103] The skilled practitioner will recognize that the synthetic methodology may be applied to pipecolic acid analogs other than those depicted in Scheme 9. For example, the methodology may be used for pipecolic acid analogs having a different substitution pattern on the piperidine ring (e.g., other than 4-methyl) and/or analogs where the piperidine nitrogen atom may be substituted with a group other than methyl (e.g., ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, - 97 WO 2005/030794 PCT/US2004/030921 CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl).

[0104] In certain other embodiments, the inventive compounds belong to class (Id) and subclasses thereof, as described herein. One skilled in the art would appreciate that the exemplary heterocyclic starting materials described in Schemes 7-10, that are used in the preparation of compounds of class (Ic) (namely compounds 38, 60 or 65) could be substituted for acyclic α-amino acid moieties to access compounds of class (Id), as illustrated in Scheme 11 below: 98 WO 2005/030794 PCT/US2004/030921

UOH

Me Ο Ι^Χ^ΟΗ R/R. (27)

R3 R4

CMC, HOAt NMM, DMF

Me Ο γ Me O "φΑ " Ά'5" R3 R4 Η O Me

Examples of compounds of this sort include, but are not limited to, compounds wherein:

Ri = H or Me

R3= Me, Et, or forms a 5-6 membered ring with R4 R4 = Me, Et, or forms a 5-6 membered ring with R3 Riob = H, Me, or forms a 5-6 membered ring with R11b R11b = H, or forms a 5-6 membered ring with R10b RG = H, Me, or forms a 5-6 membered ring with Rm RH1 = H, or forms a 5-6 membered ring with RG

Rh2 = H, CO2H, CO2Me, CONH2l CONHMe, CONHMe2l CONHBn, CH2OMe

Scheme 11 [0105] For example, reaction of diethylglycine (72) with amine HCl salt 49 gives the TV-terminal gem-diethyl ethyl ester 73, or the corresponding carboxylic acid 74, after hydrolysis under suitable conditions (Scheme 12). 99 WO 2005/030794 PCT/US2004/030921

(74)

Scheme 12 [0106] In certain other embodiments, there is provided a method for preparing compounds of formula VIA:

wherein L, Q, R9a-Rioa, Rgi, Rmi and Rm2 are as defined above and in subclasses herein; g is 1 or 2; and R2 and Rs are independently substituted or unsubstituted linear or branched lower alkyl.

[0107] In certain other embodiments, the method comprises steps of: (a) reacting two compounds having the structures: 100 WO 2005/030794 PCT/US2004/030921

H2N

O

Me ι

under suitable conditions to form a compound having the structure: R2 0 Rg Me 0 v RM1 (b) oxidizing the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) subjecting the compound formed in step (b) to suitable olefin-forming conditions to form a compound having the structure: R2 0 Re Me H 0 (d) subjecting the compound formed in step (c) to suitable diversification reactions to generate the desired compound having the structure:

wherein L, Q, R9a-Rio<b Ron Rmi and Rm are as defined generally above and in claases and subclasses herein; g is 1 or 2; RQ is hydrogen, lower alkyl or an oxygen protecting group; and R2 and R^ are independently substituted or unsubstituted linear or branched lower alkyl. 101 WO 2005/030794 PCT/US2004/030921 [0108] In certain embodiments, RQ is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety.

[0109] In certain embodiments, in the step of oxidizing, the conditions comprise swem oxidizing conditions. In certain embodiments, in the step of oxidizing, the conditions comprise Dess Martin oxidizing conditions.

[0110] In certain embodiments, in step (c), the olefin-forming conditions comprise Ph3P=C(Rioa)C02RQr; wherein RQ is hydrogen, lower alkyl or an oxygen protecting group; and Rioa is as defined generally above and in classes and subclasses herein.

[0111] In certain other embodiments, the method comprises steps of: (a) reacting two compounds having the structures: R6 Me

h2»V 3X1

R2 O

RisriQ '0H R” and L R.> 'M1 under suitable conditions to form a compound having the structure: R2 O Rg Me RX1 rX2

Yl YO wherein R and R are independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; (b) converting the compound formed in step (a) under suitable conditions to form a compound having the structure:

R2 O Re Me Η O

° A rmi ; (c) subjecting the compound formed in step (b) to suitable diversification reactions to generate the desired compound having the structure: 102 WO 2005/030794 PCT/TIS2004/030921

wherein L, Q, R9a-Rioa, Rgi, Rmi and Rm2 are as defined generally above and in claases and subclasses herein; g is 1 or 2; Rq is hydrogen, lower alkyl or an oxygen protecting group; and R2 and Rs are independently substituted or unsubstituted linear or branched lower alkyl.

[0112] In certain embodiments, the step of converting comprises steps of: (i) subjecting the compound having the structure: R? O Ra Μθ nKM2 RM1 /\ x2

to ozonolysis conditions to form an aldehyde having the structure: R2 O Re Me H L"£RM2 0 Rmi ; and (ii) subjecting the compound formed in step (i) to suitable olefin-forming conditions to form a compound having the structure: L-W 0 Λ R™ KM1 [0113] In certain embodiments, in step (ii), the olefin-forming conditions comprise Ph3P=C(Rioa)C02R% wherein R^ is hydrogen, lower alkyl or an oxygen protecting group; and RiOa is as defined generally above and in classes and subclasses herein.

[0114] In certain embodiments, the step of converting comprises a step of: subjecting the compound having the structure: 103 WO 2005/030794 PCT/US2004/030921 to cross-olefm-metathesis conditions in the presence of CH2=C(Rioa)C02RQ' to form a compound having the structure:

R2 O Re Me Η O R2 o Rq Me l--Sr RM> ΓχΟ IVIC Γ71 w WAVtV..· ' 1 ° /\ R10a pRM2 [0115] It will be appreciated that the above methods are readily applicable to the preparation of compounds having the general structures:

wherein g, L, Q, R2, Rs-R^Rga-Rioa, Rgi, Rmi and Rm2 are as defined in classes and subclasses herein.

[0116] In certain embodiments, compounds of formula (VIA) may be prepared according to the methodology depicted in Scheme 13:

RQ' = protectiong group, lower alkyl, H

Scheme 13 [0117] Alternatively, or additionally, compounds of formula (VIA) may be prepared according to the methodology depicted in Scheme 14: 104 WO 2005/030794 PCT/US2004/030921

Me 0 BocN^Xh (97) 1. condensation

HN R*1 2. Add deprotection R*2 R*2 = independently H, alkyl, aryl, etc., or

(98)

Diversification

-*- Rq' = protectiong group, lower alkyl, H

Scheme 14 [0118] In certain embodiments, compound 92 may be prepared according to the methodology depicted in Scheme 15: H,N.

OH

BtsCI= |T^N^-SO2CI

Bts XOH Mel, K2CO3

Bts

Me ι ,N. .

OH L-Val'mol

PhSH, K2CO3

DMF, r.L

K2CO3, AcCN/H2O

DMF, 35° C (104) (105)

Vedejs J. Org. Chem. 2001, 66, 7355

Hlik

OH (106) 1.

BocHN

OH

HBTU, CH2Cl2, r.L 2. MeSOjH, 40° C l?6 “θ Η2Ν·'γ'Νγ"Ν>Η

O (92)

Scheme 15 [0119]

In certain other embodiments, compound 92 may be prepared according to the methodology depicted in Scheme 16: 105 WO 2005/030794 PCT/US2004/030921 N-protection Ζ'ΝΧ"ΌΗ

Methyl Iodide Η,Ν.

OH _,N„

OH Z= Protective group Z.B.. 034+ = Boc, CBz, etc.

Deprotection

Me hi(l

BocHN

OH

HBTU 2. Acid

Scheme 16

Re Me Η2Νχγ'ΝΧ>'0Η O A. (92) [0120] In certain embodiments, compound 95 may be prepared according to the methodology depicted in Scheme 17: R2 0 ^Y^0H + JLorU1 0RU1baslc hydrolysit R> 5 L—0 L—° (93) RU1 = Alkyl, aryl, etc L—U * pKM2 "Ml (107, AM' (108) 108

Me O hn^A,

R2 ο Rs Me H

HBTU R2 Ο Re Me O 72 “ >je 7= 7

Rgi-^Vn'V'/'U DIBAA L oRM2 ° or other suitable L rrM2 θ °M1 hvririrlfl rpanpntc Mi niwH u /\ or other suitable rmi hydride reagents (109) (95) U = ORU2, N(OMe)Me,etc., wherein RU2 Is alkyl, aryl, etc.

Scheme 17 [0121] In certain other embodiments, compound 95 may be prepared from intermediate 108 according to the methodology depicted in Scheme 18: 108

Me ORU1

LA? 0 A R2 0 Rs Me OR1 U1

Acetal cleavage RB1"+^

R2 O Re Me H

MAA

HBTU

rmT dRM2 rM1 (110) (95) RU1, RU2 = Alkyl, aryl, etc., Independently

Scheme 18 [0122] In certain embodiments, for the compounds depicted in Schemes 13- 18, Rg is substituted or unsubstituted, linear ot branched, cyclic or acyclic, or saturated or unsaturated lower alkyl. In certain exemplary embodiments, Rg is

I methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, - 106 WO 2005/030794 PCT/US2004/030921 CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. In certain other exemplary embodiments, Rg is tert-butyl.

[0123] In certain embodiments, for the compounds depicted in Schemes 13-18, Rioa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl. In certain exemplary embodiments, Rioa is linear or branched lower alkyl. In certain other exemplary embodiments, Rioa is methyl.

[0124] In certain embodiments, for the compounds depicted in Schemes 13- 18, the moiety having the structure:

has the following structure: ?2,

V ; wherein R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl. In certain exemplary embodiments, R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl. In certain other exemplary embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, z’-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -C(CH3j2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.

[0125] In certain embodiments, for the compounds depicted in Schemes 13- 18, Rg is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, z'-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; Rioa is methyl; R2 RG1 and the moiety having the structure:

Rmi has the following structure: ?2 o ; wherein R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, z’-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, - 107 174479/3 CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.

The exemplary methodologies depicted in Schemes 13-18 are not intended to limit the scope of the invention. Other synthetic approaches will be apparent to the skilled practitioner.

It will be appreciated that each of the reactions described in Schemes 2-18 above can be carried out using reagents and conditions as described for the synthesis of various types of exemplary compounds described above, or they may be modified using other available reagents or starting materials. For example, a variety of amide formation conditions, esterification, hydrolysis and aromatic nucleus functionalization conditions are well-known in the art and can be utilized in the method of the invention. See, generally, March, Advanced Organic Chemistry, 5th ed. , John Wiley &amp; Sons, 2001; and "Comprehensive Organic Transformations, a guide to functional group preparations", Richard C. Larock, VCH publishers, 1999;.

As mentioned above, it will be appreciated that the invention is not limited in scope to the compounds recited herein. Synthetic strategies or starting materials other than those described herein may be used to prepare compounds of general structure (I). It will also be appreciated that each of the components/starting materials used in the synthesis of the compounds of the invention can be diversified either before synthesis or alternatively after the construction of the peptide construct. As used herein, the term"diversifying"or"diversify"means reacting an inventive compound, as defined herein, at one or more reactive sites to modify a functional moiety or to add a functional moiety. For example, where an aromatic ring is present in the compound, the aromatic ring can be diversified (prior to or after reaction) to either add functionality (e. g., where hydrogen is present, a halogen or other functionality can be added) or to modify functionality (e. g., where a hydroxyl group is present on the aromatic ring, the aromatic ring can be diversified by reacting with a reagent to protect the hydroxyl group, or to convert it into an aliphatic or heteroaliphatic moiety). Described generally below are a variety of schemes to assist the reader in the synthesis of a variety of analogues, either by 108 WO 2005/030794 PCT/US2004/030921 diversification of the intermediate components or by diversification of the peptide construct.

[0129] In certain embodiments, the preparation of chemically diverse derivatives may be achieved by diversifying the C-terminal moiety of the compounds. For example, where the C-terminal moiety is a carboxylic acid, examples of chemical transformations suitable to achieve such derivatization include, but are not limited to, reduction to the corresponding aldehyde or alcohol, amidation, Wittig reaction, decarboxylation, esterification, addition of nucleophiles, conversion to ketones, imines, hydrazones, azides, etc... Examples of such transformations are depicted in Schemes 19 and 20. One skilled in the art will recognize that possible chemical transformations suitable to achieve diversification of the compounds of the invention are not limited to those depicted in Schemes 19 and 20. Rather, any suitable synthetic methods known in the art can be used to achieve desired chemical transformations. 109 WO 2005/030794 PCT/US2004/030921

Boc’

Me Ο 't Me

Ph^A (82)

co2h

LiOH

Boc'

Me O ΡΙιΆ

HCI. EtOH

Z-CK

Λ H Ph A"

1) NH3OH.HCI, NaOAc

2) TFA, DCM

(Ph)3PCHCO2Et

Scheme 19 110 WO 2005/030794 PCT/US2004/030921

Me' Η ϊ Ψ' = u 11 = 'OMe

Boc'

OH

1) PhT <6> NMM, HOAt CMC, DMF

Ph']'^

O (87)

2) HCI, MeOH

1) w o

Boc' γ^ΟΗ >j\ (4)

NMM, HOAt, CMC, DMF 2) HCI, MeOH

Boc'

OMe (28)

1) Hunnig’s base, DCM, MSCI

2) NaNj, DMSO

HCI, MeOH

OMe

TFA, DCM

Boc'

H A Βοε'Νγ'θΗ

1) Jj\ (4) NMM, ΗΟΑί, CMC, DMF

2) HCI, MeOH

Boe'

2) HCI, MeOH CIHoh

.R.A ΌΗ 1) PhT (®> Η ° A I,

NMM, HOAt, CMC, DMF N JL JL -N

Me' = h il

Ph'"]"'"· o (91)

Scheme 20 [0130] 4) Research Uses, Formulation and Administration [0131] According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having a pre-determined biological activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc. In certain exemplary embodiments, the inventive compounds are tested in assays to identify those compounds having cytotoxic or growth inhibitory effect in vitro, or cause tumor regression and/or inhibition of tumor growth in vivo.

Ill WO 2005/030794 PCT/US2004/030921

Compounds of this invention which are of particular interest include [0132] those which: • exhibit cytotoxic and/or growth inhibitory effect on cancer cell lines maintained in vitro or in animal studies using a scientifically acceptable cancer cell xenograft model; • preferably cause tumor regression in vivo\ • exhibit low sensitivity to MDR; • exhibit low cytotoxicity to non-dividing normal cells; and/or • exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability)., [0133] As detailed in the exemplification herein, in assays to determine the ability of compounds to inhibit the growth of tumor cell lines in vitro, certain inventive compounds exhibited IC50 values <10 μΜ. In other embodiments, compounds of the invention exhibit IC50 values < 5 μΜ. In other embodiments, compounds of the invention exhibit IC50 values < 1 μΜ. In other embodiments, compounds of the invention exhibit IC50 values < 750 nM. In other embodiments, compounds of the invention exhibit IC50 values < 500 nM. In other embodiments, compounds of the invention exhibit IC50 values < 250 nM. In other embodiments, compounds of the invention exhibit IC50 values < 100 hM. In other embodiments, compounds of the invention exhibit IC50 values < 50 nM. In other embodiments, compounds of the invention exhibit IC50 values < 25 nM. In other embodiments, compounds of the invention exhibit IC50 values < 10 nM. In other embodiments, compounds of the invention exhibit IC50 values < 7.5 hM. In other embodiments, compounds of the invention exhibit IC50 values < 5 nM. In other embodiments, compounds of the invention exhibit IC50 values < 2.5 nM. In other embodiments, compounds of the invention exhibit IC50 values < 1 nM. In other embodiments, compounds of the invention exhibit IC50 values < 0.75 nM. In other embodiments, compounds of the invention exhibit IC50 values < 0.5 nM. In other embodiments, compounds of the invention exhibit IC50 values < 0.25 nM. In other embodiments, compounds of the invention exhibit IC50 values <0.1 nM. In certain embodiments, compounds of the invention exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM -10 nM. 112 WO 2005/030794 PCT/US2004/030921 [0134] In certain other embodiments, compounds of the invention exhibit low sensitivity to MDR. In certain exemplary embodiments, compounds of the invention have a ratio [cell growth inhibition in MDR-positive cells] / [cell growth inhibition in MDR-negative cells] (i.e., resistance ratio) <10. In certain exemplary embodiments, compounds of the invention have a resistance ratio <9. In certain exemplary embodiments, compounds of the invention have a resistance ratio <8. In certain exemplary embodiments, compounds of the invention have a resistance ratio <7. In certain exemplary embodiments, compounds of the invention have a resistance ratio <6. In certain exemplary embodiments, compounds of the invention have a resistance ratio <5. In certain exemplary embodiments, compounds of the invention have a resistance ratio <4.

[0135] In certain other embodiments, compounds of the invention exhibit low cytotoxicity to non-dividing normal cells. In certain exemplary embodiments, inventive compounds exhibit little or no cytotoxicity in non-dividing normal cells at concentrations > 1000 fold the concentration at which they inhibit cancer cell growth. In certain exemplary embodiments, inventive compounds exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μΜ.

[0136] In certain embodiments, inventive compounds exhibit stability in mouse serum.

[0137] In certain embodiments, inventive compounds exhibit a low mitotic block reversibility ratio. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 30. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 25. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 20. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 15. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 10. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 5. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 3. 113 WO 2005/030794 PCT/US2004/030921 [0138] In certain embodiments, compounds of the invention cause tumor regression in vivo. In certain exemplary embodiments, compounds of the invention cause tumor regression in vivo in suitable mouse tumor xenograph models. In certain exemplary embodiments, compounds of the invention cause reduction of tumor size to below 70% of the size at the start of compound administration in a suitable cancer cell xenograft model. In certain exemplary embodiments, compounds of the invention cause reduction of tumor size to below 65% of the size at the start of compound administration in a suitable cancer cell xenograft model. In certain exemplary embodiments, compounds of the invention cause reduction of tumor size to below 60% of the size at the start of compound administration in a suitable cancer cell xenograft model. In certain exemplary embodiments, compounds of the invention cause reduction of tumor size to below 55% of the size at the start of compound administration in a suitable cancer cell xenograft model. In certain exemplary embodiments, compounds of the invention cause reduction of tumor size to below 50% of the size at the start of compound administration in a suitable cancer cell xenograft model. In certain exemplary embodiments, compounds of the invention cause tumor regression in certain multidrug resistant xenograph models. [0139] In certain exemplary embodiments, compounds of the invention cause inhibition of tumor growth in vivo. In certain exemplary embodiments, compounds of the invention cause significant inhibition of tumor growth in suitable cancer cell xenograft models. In certain exemplary embodiments, compounds of the invention cause significant inhibition of tumor growth in suitable multidrug resistant cancer cell xenograft models. In certain exemplary embodiments, compounds of the invention cause inhibition of tumor growth in treated animals by > 50% compared to that of control aninals (i.e., “treated” tumor size < 50% “control” tumor size; or T/C value < 50%) in suitable cancer cell xenograft models. In certain embodiments, compounds of the invention have T/C values < 70%. In certain embodiments, compounds of the invention have T/C values < 65%. In certain embodiments, compounds of the invention have T/C values < 60%. In certain embodiments, compounds of the invention have T/C values < 55%.

[0140] In certain embodiments, compounds of the invention inhibit the growth of human cancer cells in vitro, exhibit low sensitivity to MDR (e.g., low 114 WO 2005/030794 PCT/US2004/030921 resistance ratio), exhibit low cytotoxicity to non-dividing normal cells, exhibit stability in mouse serum, have a low mitotic block reversibility ratio, cause tumor regression in vivo, and/or cause inhibition of tumor growth in vivo.

[0141] In certain embodiments, compounds of the invention inhibit the growth of human cancer cells in vitro, exhibit low sensitivity to MDR (e.g., low resistance ratio), exhibit low cytotoxicity to non-dividing normal cells, exhibit stability in mouse serum, have a low mitotic block reversibility ratio, cause tumor regression in vivo, and cause inhibition of tumor growth in vivo.

[0142] In certain embodiments, compounds of the invention have any one or more of the following properties: (i) exhibit growth inhibition ICso values in cultured human cancer cells in the range of 0.1 nM - 10 nM; (ii) have a resistance ratio preferably <10, preferably <9, preferably <8, preferably <7, preferably <6, preferably <5, more preferably <4; (iii) exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μΜ; (iv) exhibit stability in mouse serum; (v) exhibit mitotic block reversibility ratios of 1 to about 30, preferably of 1 to about 25, preferably of 1 to about 20, preferably of 1 to about 15, preferably of 1 to about 10, preferably of 1 to about 5, most preferably of about 1 to about 3; (vi) cause reduction of tumor size to below 70%, preferably below 65%, preferably below 60%, preferably below 55%, most preferably below 50%, of the size at the start of compound administration in suitable cancer cell xenograft models; and/or (vii) cause significant inhibition of tumor growth in suitable cancer cell xenograft model (e.g, T/C value preferably < 70%, preferably < 65%, preferably < 60%, preferably < 55%, most preferably < 50%).

[0143] In certain embodiments, compounds of the invention have the following properties: (i) exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM - 10 nM; 115 WO 2005/030794 PCT/US2004/030921 (ii) have a resistance ratio preferably <10, preferably <9, preferably <8, preferably <7, preferably <6, preferably <5, more preferably <4; (iii) exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μΜ; (iv) exhibit stability in mouse serum; (v) exhibit mitotic block reversibility ratios of 1 to about 30, preferably of 1 to about 25, preferably of 1 to about 20, preferably of 1 to about 15, preferably of 1 to about 10, preferably of 1 to about 5, most preferably of about 1 to about 3; (vi) cause reduction of tumor size to below 70%, preferably below 65%, preferably below 60%, preferably below 55%, most preferably below 50%, of the size at the start of compound administration in suitable cancer cell xenograft models; and (vii) cause significant inhibition of tumor growth in suitable cancer cell xenograft model (e.g., T/C value preferably < 70%, preferably < 65%, preferably < 60%, preferably < 55%, most preferably < 50%).

[0144] Examples of compounds exhibiting desired properties include ER- 805913, ER-805736, ER-807102, ER-807328, ER-806925, ER-807850, ER-807904, ER-807974, ER-808368, ER-808662, ER-808824, and salts thereof (See Table below).

[0145] As discussed above, compounds of the invention exhibit activity for the inhibition of tumor cell growth. As such, the inventive compounds as useful for the treatment of a variety of disorders, including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few. In certain embodiments, the inventive compounds are useful for the treatment of solid and non-solid tumors. In still other embodiments of interest, the inventive compounds are particularly useful for the treatment of breast cancer, prostate cancer, colon cancer, lung cancer, leukemia and lymphoma. 116 WO 2005/030794 PCT/US2004/030921 [0146] In certain embodiment, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the inventive compounds as useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).

[0147] Pharmaceutical Compositions [0148] As discussed above this invention provides novel compounds that have biological properties useful for the treatment of cancer. In certain embodiments, certain of the compounds as described herein act as inhibitors of tumor growth and thus are useful in the treatment of cancer and in the inhibition of tumor growth and in the killing of cancer cells. In certain embodiments, the inventive compounds are useful for the treatment of solid tumors or non-solid tumors. In still other embodiments of interest, the inventive compounds are useful for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few. The inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

[0149] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, the compounds are capable of inhibiting the growth of or killing cancer cells. In certain embodiments, 117 174479/3 these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be a cytotoxic agent or anticancer agent approved for the treatment of cancer, as discussed in more detail herein, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of an immune disorder or cancer. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a prodrug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with little or no undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium 118 WO 2005/030794 PCT/US2004/030921 salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesuifonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, trifluoroacetate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0151] Additionally, as used herein, the term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moeity advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0152] Furthermore, the term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic 119 174479/3 response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; com oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenffee water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as 120 WO 2005/030794 PCT/US2004/030921 sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0154] Uses and Formulations of Compounds of the Invention [0155] As described in more detail herein, in general, the present invention provides compounds useful for the treatment of cancer and proliferative disorders.

[0156] As discussed above, certain of the compounds as described herein act as inhibitors of tumor growth and thus are useful in the treatment of cancer and in the inhibition of tumor growth and in the killing of cancer cells. The invention further provides a method for inhibiting tumor growth and/or tumor metastasis. The method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the inventive compounds are useful for the treatment of solid tumors or non-solid tumors. In still other embodiments of interest, the inventive compounds are useful for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few.

[0157] As described in more detail herein, in general, the present invention provides compounds useful for the treatment of cancer, particularly solid and nonsolid tumors. Specifically, certain compounds of the invention have been shown to inhibit the growth of certain tumor cell lines in vitro, as described in more detail herein, and are useful for the treatment of cancer, including solid and non-solid tumors.

[0158] As discussed above, the inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting. For example, it is contemplated that the compounds of the invention will be useful as a coating for implanted medical devices, such as tubings, shunts, 121 174479/3 catheters, artificial implants, pins, electrical implants such as pacemakers, and especially for arterial or venous stents, including balloon-expandable stents. In certain embodiments inventive compounds may be bound to an implantable medical device, or alternatively, may be passively adsorbed to the surface of the implantable device. In certain other embodiments, the inventive compounds may be formulated to be contained within, or, adapted to release by a surgical or medical device or implant, such as, for example, stents, sutures, indwelling catheters, prosthesis, and the like.

In certain exemplary embodiments, the inventive compounds may be used as coating for stents. A stent is typically an open tubular structure that has a pattern (or patterns) of apertures extending from the outer surface of the stent to the lumen. It is commonplace to make stents of biocompatible metallic materials, with the patterns cut on the surface with a laser machine. The stent can be electro- polished to minimize surface irregularities since these irregularities can trigger an adverse biological response. However, stents may still stimulate foreign body reactions that result in thrombosis or restenosis. To avoid these complications, a variety of stent coatings and compositions have been proposed in the prior art literature both to reduce the incidence of these complications or other complications and restore tissue function by itself or by delivering therapeutic compound to the lumen. For example, drugs having antiproliferative and anti-inflammatory activities have been evaluated as stent coatings, and have shown promise in preventing retenosis (See, for example, Presbitero P. et al., "Drug eluting stents do they make the difference?", Minerva Cardioangiol, 2002,50 (5): 431-442; Ruygrok Ρ. N. et al., "Rapamycin in cardiovascular medicine", Intern. Med. J., 2003,33 (3): 103-109 ; and Marx S. O. et al., 'Bench to bedside: the development of rapamycin and its application to stent restenosis", Circulation, 2001,104 (8): 852-855,). Accordingly, without wishing to be bound to any particular theory, Applicant proposes that the inventive compounds, having antiproliferative effects, can be used as stent coatings and/or in stent drug delivery devices, inter alia for the prevention of restenosis. A variety of compositions and methods related to stent coating and/or local stent drug delivery for preventing restenosis are known in the art (see, for example, U. S. Patent Nos.: 122 174479/3 6,517,889; 6,273,913; 6,258,121; 6,251,136; 6,248,127 ; 6,231,600; 6,203,551; 6,153,252; 6,071,305; 5,891,507; 5,837,313 and published U. S. patent application No.: US2001/0027340). For example, stents may be coated with polymer-drug conjugates by dipping the stent in polymer-drug solution or spraying the stent with such a solution.

In certain embodiment, suitable materials for the implantable device include biocompatible and nontoxic materials, and may be chosen from the metals such as nickel-titanium alloys, steel, or biocompatible polymers, hydrogels, polyurethanes, polyethylenes, ethylenevinyl acetate copolymers, etc. In certain embodiments, the inventive compound, is coated onto a stent for insertion into an artery or vein following balloon angioplasty.

The invention may be described therefore, in certain broad aspects as a method of inhibiting arterial restenosis or arterial occlusion following vascular trauma comprising administering to a subject in need thereof, a composition comprising an inventive compound conjugated to a suitable polymer or polymeric material. In the practice of the method, the subject may be a coronary bypass, vascular surgery, organ transplant or coronary or any other arterial angioplasty patient, for example, and the composition may be administered directly, intravenously, or even coated on a stent to be implanted at the sight of vascular trauma.

In another aspect, the invention encompasses implants and surgical or medical devices, including stents and grafts, coated with or otherwise constructed to contain and/or release any of the inventive compounds disclosed herein. In certain embodiments, the compounds have antiproliferative activity. In certain other embodiments, the compounds inhibit smooth muscle cell proliferation.

Representative examples of the inventive implants and surgical or medical devices include cardiovascular devices (e. g. , implantable venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemaker wires, implantable defibrillators); neurologic/neurosurgical devices (e. g., ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions); 123 WO 2005/030794 PCT7US2004/030921 gastrointestinal devices (e.g., chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, implantable meshes for hernias, suspensions or solid implants to prevent surgical adhesions, including meshes); genitourinary devices (e.g., uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy); phthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk comeal transplants); otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains); plastic surgery implants (e.g., prevention of fibrous contracture in response to gel- or saline-containing breast implants in the subpectoral or subglandular approaches or post-mastectomy, or chin implants), and orthopedic implants (e.g., cemented orthopedic prostheses).

[0162] Implants and other surgical or medical devices may be coated with (or otherwise adapted to release) compositions of the present invention in a variety of manners, including for example: (a) by directly affixing to the implant or device an inventive compound or composition (e.g., by either spraying the implant or device with a polymer/drug film, or by dipping tbe implant or device into a polymer/drug solution, or by other covalent or noncovalent means); (b) by coating the implant or device with a substance such as a hydrogel which will in turn absorb the inventive compound or composition; (c) by interweaving inventive compound-or composition-coated thread (or the polymer itself formed into a thread) into the implant or device; (d) by inserting the implant or device into a sleeve or mesh which is comprised of or coated with an inventive compound or composition; (e) constructing the implant or device itself with an inventive compound or composition; or (f) by otherwise adapting the implant or device to release the inventive compound. In certain embodiments, the composition should firmly adhere 124 174479/3 to the implant or device during storage and at the time of insertion. The inventive compound or composition should also preferably not degrade during storage, prior to insertion, or when warmed to body temperature after insertion inside the body (if this is required). In addition, it should preferably coat the implant or device smoothly and evenly, with a uniform distribution of inventive compound, while not changing the stent contour. Within preferred embodiments of the invention, the inventive implant or device should provide a uniform, predictable, prolonged release of the inventive compound or composition into the tissue surrounding the implant or device once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stent thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated).

In the case of stents, a wide variety of stents may be developed to contain and/or release the inventive compounds or compositions provided herein, including esophageal stents, gastrointestinal stents, vascular stents, biliary stents, colonic stents, pancreatic stents, ureteric and urethral stents, lacrimal stents, Eustachian tube stents, fallopian tube stents and tracheal/bronchial stents (See, for example, U. S. Patent No.: 6,515,016). Stents may be readily obtained from commercial sources, or constructed in accordance with well-known techniques. Representative examples of stents include those described in U. S. Pat. No. 4,768,523, entitled "Hydrogel Adhesive"; U.S. Pat. No. 4,776,337, entitled "Expandable Intraluminal Graft, and Method and Apparatus for Implanting and Expandable Intraluminal Graft"; U.S. Pat. No. 5,041,126 entitled "Endovascular Stent and Delivery System"; U.S. Pat. No. 5,052,998 entitled "Indwelling Stent and Method of Use" ; U.S. Pat. No. 5,064,435 entitled "Self-Expanding Prosthesis Having Stable Axial Length"; U.S. Pat. No. 5,089,606, entitled " Water-insoluble Polysaccharide Hydrogel Foam for Medical Applications"; U.S. Pat. No. 5,147,370, entitled "Nitinol Stent for Hollow Body Conduits"; U.S. Pat. No. 5,176,626, entitled "Indwelling Stent"; U.S. Pat. No. 5,213,580, entitled "Biodegradable Polymeric Endoluminal Sealing Process"; and U.S. Pat. No. 5,328,471, entitled "Method and Apparatus for Treatment of Focal Disease in Hollow Tubular Organs and Other Tissue Lumens." 125 WO 2005/030794 PCT/US2004/030921 [0164] As discussed above, the stent coated with (or otherwise adapted to release) compositions of the present invention may be used to eliminate a vascular obstruction and prevent restenosis and/or reduce the rate of restenosis. Within other aspects of the present invention, stents coated with (or otherwise adapted to release) compositions of the present invention are provided for expanding the lumen of a body passageway. Specifically, a stent having a generally tubular structure, and a surface coated with (or otherwise adapted to release) an inventive compound or composition may be inserted into the passageway, such that the passageway is expanded. In certain embodiments, the stent coated with (or otherwise adapted to release) compositions of the present invention may be used to eliminate a biliary, gastrointestinal, esophageal, tracheal/bronchial, urethral or vascular obstruction.

[0165] In another aspect of the invention, methods for the treatment of cancer are provided comprising administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof. In certain embodiments, the inventive compounds are useful for the treatment of solid and non-solid tumors. It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of cancer. Thus, the expression “effective amount” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells, or refers to a sufficient amount to reduce the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular anticancer agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound 126 174479/3 employed; the specific composition employed ; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173,2001).

In certain other embodiments, methods are provided for using the inventive implants and other surgical or medical devices coated with (or otherwise adapted to release) compounds and compositions of the present invention. In certain embodiments, methods are provided for preventing restenosis, comprising inserting a stent into an obstructed blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the obstruction is eliminated and the inventive compound or composition is delivered in amounts effective to prevent restenosis and/or reduce the rate of restenosis. In other embodiments, methods are provided for preventing restenosis, comprising inserting a stent into an obstructed blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the obstruction is eliminated and the inventive compound or composition is delivered in amounts effective to inhibit smooth muscle cell proliferation.

Within other aspects of the present invention, methods are provided for expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the passageway is expanded. In certain embodiments, the lumen of a body passageway is expanded in order to eliminate a biliary, gastrointestinal, esophageal, tracheal/bronchial, urethral and/or vascular obstruction.

In certain embodiments, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway, the stent 127 WO 2005/030794 PCT/US2004/030921 having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the biliary obstruction is eliminated. Briefly, tumor overgrowth of the common bile duct results in progressive cholestatic jaundice which is incompatible with life. Generally, the biliary system which drains bile from the liver into the duodenum is most often obstructed by (1) a tumor composed of bile duct cells (cholangiocarcinoma), (2) a tumor which invades the bile duct (e.g., pancreatic carcinoma), or (3) a tumor which exerts extrinsic pressure and compresses the bile duct (e.g, enlarged lymph nodes). Both primary biliary tumors, as well as other tumors which cause compression of the biliary tree may be treated utilizing stents Implants and other surgical or medical devices may be coated with (or otherwise adapted to release) compositions of the present invention. One example of primary biliary tumors are adenocarcinomas (which are also called Klatskin tumors when found at the bifurcation of the common hepatic duct). These tumors are also referred to as biliary carcinomas, choledocholangiocarcinomas, or adenocarcinomas of the biliary system. Benign tumors which affect the bile duct (e.g, adenoma of the biliary system), and, in rare cases, squamous cell carcinomas of the bile duct and adenocarcinomas of the gallbladder, may also cause compression of the biliary tree and therefore, result in biliary obstruction. Compression of the biliary tree is most commonly due to tumors of the liver and pancreas which compress and therefore obstruct the ducts. Most of the tumors from the pancreas arise from cells of the pancreatic ducts. This is a highly fatal form of cancer (5% of all cancer deaths; 26,000 new cases per year in the U.S.) with an average of 6 months survival and a 1 year survival rate of only 10%. When these tumors are located in the head of the pancreas they frequently cause biliary obstruction, and this detracts significantly from the quality of life of the patient. While all types of pancreatic tumors are generally referred to as "carcinoma of the pancreas" there are histologic subtypes including: adenocarcinoma, adenosquamous carcinoma, cystadenocarcinoma, and acinar cell carcinoma. Hepatic tumors, as discussed above, may also cause compression of the biliary tree, and therefore cause obstruction of the biliary ducts. [0169] In certain embodiments, a biliary stent is first inserted into a biliary passageway in one of several ways: from the top end by inserting a needle through 128 WO 2005/030794 PCT/US2004/030921 the abdominal wall and through the liver (a percutaneous transhepatic cholangiogram or "PTC"); from the bottom end by cannulating the bile duct through an endoscope inserted through the mouth, stomach, and duodenum (an endoscopic retrograde cholangiogram or "ERCP"); or by direct incision during a surgical procedure. In certain embodiments, a preinsertion examination, PTC, ERCP, or direct visualization at the time of surgery is performed to determine the appropriate position for stent insertion. A guidewire is then advanced through the lesion, and over this a delivery catheter is passed to allow the stent to be inserted in its collapsed form. If the diagnostic exam was a PTC, the guidewire and delivery catheter is inserted via the abdominal wall, while if the original exam was an ERCP the stent may be placed via the mouth. The stent is then positioned under radiologic, endoscopic, or direct visual control taking particular care to place it precisely across the narrowing in the bile duct The delivery catheter is then removed leaving the stent standing as a scaffolding which holds the bile duct open. A further cholangiogram may be performed to document that the stent is appropriately positioned.

[0170] In certain embodiments, methods are provided for eliminating esophageal obstructions, comprising inserting am esophageal stent into an esophagus, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the esophageal obstruction is eliminated. Briefly, the esophagus is the hollow tube which transports food and liquids from the mouth to the stomach. Cancer of the esophagus or invasion by cancer arising in adjacent organs (e.g., cancer of the stomach or lung) results in the inability to swallow food or saliva. In certain embodiments, a preinsertion examination, usually a barium

I swallow or endoscopy is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope may then be positioned through the mouth, and a guidewire is advanced through the blockage. A stent delivery catheter is passed over the guidewire under radiologic or endoscopic control, and a stent is placed precisely across the narrowing in the esophagus. A post-insertion examination, usually a barium swallow x-ray, may be utilized to confirm appropriate positioning. 129 WO 2005/030794 PCT/US2004/030921 [0171] In certain embodiments, methods are provided for eliminating colonic obstructions, comprising inserting a colonic stent into a colon, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the colonic obstruction is eliminated. Briefly, the colon is the hollow tube which transports digested food and waste materials from the small intestines to the anus. Cancer of the rectum and/or colon or invasion by cancer arising in adjacent organs (e.g., cancer of the uterus, ovary, bladder) results in the inability to eliminate feces from the bowel. In certain embodiments, a preinsertion examination, usually a barium enema or colonoscopy is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope may then be positioned through the anus, and a guidewire is advanced through the blockage. A stent delivery catheter is passed over the guidewire under radiologic or endoscopic control, and a stent is placed precisely across the narrowing in the colon or rectum. A postinsertion examination, usually a barium enema x-ray, may be utilized to confirm appropriate positioning.

[0172] In certain embodiments, methods are provided for eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into a trachea or bronchi, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the tracheal/bronchial obstruction is eliminated. Briefly, the trachea and bronchi are tubes which carry air from the mouth and nose to the lungs. Blockage of the trachea by cancer, invasion by cancer arising in adjacent organs (e.g., cancer of the lung), or collapse of the trachea or bronchi due to chondromalacia (weakening of the cartilage rings) results in inability to breathe. In certain embodiments, preinsertion examination, usually an endoscopy, is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope is then positioned through the mouth, and a guidewire advanced through the blockage. A delivery catheter is then passed over the guidewire in order to allow a collapsed stent to be inserted. The stent is placed under radiologic or endoscopic control in order to place it precisely across the narrowing. The delivery catheter may then be removed leaving the stent standing as a scaffold on its own. A post-insertion 130 WO 2005/030794 PCT/US2004/030921 examination, usually a bronchoscopy may be utilized to confirm appropriate positioning.

[0173] In certain embodiments, methods are provided for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the urethral obstruction is eliminated. Briefly, the urethra is the tube which drains the bladder through the penis. Extrinsic narrowing of the urethra as it passes through the prostate, due to hypertrophy of the prostate, occurs in •virtually every man over the age of 60 and causes progressive difficulty with urination. In certain embodiments, a preinsertion examination, usually an endoscopy or urethrogram is first performed in order to determine the appropriate position for stent insertion, which is above the external urinary sphincter at the lower end, and close to flush with the bladder neck at the upper end. An endoscope or catheter is then positioned through the penile opening and a guidewire advanced into the bladder. A delivery catheter is then passed over the guidewire in order to allow stent insertion. The delivery catheter is then removed, and the stent expanded into place. A postinsertion examination, usually endoscopy or retrograde urethrogram, may be utilized to confirm appropriate position.

[0174] In certain embodiments, methods are provided for eliminating vascular obstructions, comprising inserting a vascular stent into a blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the vascular obstruction is eliminated. Briefly, stents may be placed in a wide array of blood vessels, both arteries and veins, to prevent recurrent stenosis at the site of failed angioplasties, to treat narrowings that would likely fail if treated with angioplasty, and to treat post-surgical narrowings (e.g., dialysis graft stenosis). Suitable sites include, but ar enot limited to, the iliac, renal, and coronary arteries, the superior vena cava, and in dialysis grafts. In certain embodiments, angiography is first performed in order to localize the site for placement of the stent. This is typically accomplished by injecting radiopaque contrast through a catheter inserted into an artery or vein as an x-ray is taken. A catheter may then be inserted either 131 WO 2005/030794 PCT/US2004/030921 percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering it through the vascular system under fluoroscopic guidance. A stent may then be positioned across the vascular stenosis. A post-insertion angiogram may also be utilized in order to confirm appropriate positioning.

[0175] Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 nig/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.

[0176] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. 132 WO 2005/030794 PCT/US2004/030921 [0177] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0178] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0179] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0180] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention 133 WO 2005/030794 PCT/US2004/030921 with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0181] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0182] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. 134 WO 2005/030794 PCT/US2004/030921 [0183] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include, polymeric substances and waxes.

[0184] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and

I eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used, to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [0185] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination 135 174479/3 regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anticancer agent), or they may achieve different effects (e.g., control of any adverse effects). For example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, γ-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999. See also the National Cancer Institute (NCI) website (www. nci. nih. gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www. fda. gov/cder/cancer/druglistffame-See Appendix A).

In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative). For purposes of the invention, the term "Palliative" refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and 136 174479/3 anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).

TREATMENT KITS

In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the phannaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.

Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration. EQUIVALENTS

The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. 137 174479/3

The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

The practitioner has a well-established literature of peptide chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention.

The various references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest.

Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof. For example, synthetic guidance may be found in J Org Chem., 2001,66: 7355-7364.

The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will he appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

It will be appreciated as described below, that a variety of inventive compounds can be synthesized according to the methods described herein. The 138 WO 2005/030794 PCT/US2004/030921 starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 “Chemistry of Carbon Compounds”, vols. 1-5 and supps, Elsevier Science Publishers, 1989; “Organic Reactions”, vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wiley and Sons, New York, NY; and Larock 1990, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd ed. VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.

[0196] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.

[0197] Certain exemplary compounds of the invention are listed below and are referred to by compound number as indicated.

Compound Structure ER-803840 (HEMIASTERLIN) .. Ο ''Ά Me O Me' N ΊΓ °H .yyh H 0 139 WO 2005/030794 PCT/US2004/030921 ER-803887 6 Ο Me 0 'y Ν H^V^OEt \ Η ° ER-803888 Me—fAf ό 0 Me 0 Λ/ύνΗ1'0Η \ ° Η ER-803889 ER-803890 0 Me 0 ΨΑ+γΠγΧ0Η cA" ' Me ER-803921 lyie 0 TFA· 0 ER-803995 H 0 H Me 0 ER-803996 Me— ό 0 Me 0 Α^'ΝΈγ'Ν'^/Ϊ!ΐΑ^·ΟΜβ 140 WO 2005/030794 PCT/US2004/030921

ER-803997 Higher Rf diastereomer A Me x Me—N jT 0 Ο Y7 Me O j ER-803998 Lower Rf diastereomer A Mex x Me— 0 Ο Ύ' Me O ΛνχΑ ER-803999 O Me O «•-/γΗ" 0 ER-804000 Ph. Ο X Me O H ° x ER-804001 Me—N/!5!7 Q O Me O WA X 0 XX 1 ^12-804002 /A H 0 Me—m q Z 141 WO 2005/030794 PCT/US2004/030921 ER-804332 Yvk Me Me I 1 -.N. IT s x 0 1 YYYh 1 H MY 0 M''' Me 0 X n Y XY^OH Ξ H II ER-804333 γ\ o , .. Me—N J 1 c ) H MY o Me o ER-804334 rS V XYy>H /¾¾. 0 Me·—N T o ER-804635 o Me yY JL Me Xf '^OH PlF r ER-804636 H ii s' Me O ΜβχΝχϊ· vN^ X YY>H J H II : Ph'Q ER-804762 ο Y s' Me 0 AV γΥ X, '''YoH H Ph^p^ 0 YY ER-805206 s' ftfle TY X YY>H ΓΥ 0 u ER-805230 «Ydt Kjle /YY 0 Y r H II z 0 Y\ 142 WO 2005/030794 PCT/US2004/030921

ι- ER-805231 PtYAh A o -A ο B ER-805257 •ΑΑγΙ Ph^ X Me rc ^OMe ER-805258 Ph^P^· / lyie Ti T ER-805268 Ph^ < Ifl. A Y ER-805316 jY s' IVIe ΥΎ 0 -γ ^OH ER-805324 «.-A y ΌΗ ό ό >< ER-805532 Me O aV 3 Ύ"Ύΐι H ER-805590 Me fY Ύ 0 ΎχΥ PlYp''''· 0 A ER-805594 γΤθ < Me vS A A^qH Ph'X|X' 0 A 143 WO 2005/030794 PCT/US2004/030921

ER-805599 0 j' Me '' 0 A-AVAm 0 A A<C1 ER-805697 aA Χνυι λ Me*^ N AA N \ Ph-b ° A ER-805701 0 jf Me O Me j] ]f NH2 ph-φ- ° A ER-805711 0 NK Me 0 Jk Jk A X JI Me "· ί β ιΓYy s X 0 A ER-805713 Me-AA Pl/jA 'Ν Me Ο γγν^ 0 Α\ ER-805734 λΰ Me^ N Ph^jA ' Μβ 0 ο Α\ Μβ ER-805735 O Me O mZS'Xs!|A|f'"VA^'"A »X 0 A A- ER-805736 ? ϊθ ft POjMe ° A A ER-805738 h ϊ 'ίΚ ? «Awvyv3* = Η J| = | /τ\ θ Me 1 ΡΙ<|\ ' \ I 144 WO 2005/030794 PCT/US2004/030921 ER-805847 o Ap ° ° ER-805865 ο 'Α ιγιθ o --omb Me' ι ηΛγνΥι fS 0 OMe ER-805876 AAiXjt A Mex Y N | > Ph'K H ° A 1 OH ER-805913 HC" t Jl 1 Γ X ER-805914 ««· η ϊ Y r y Me''"Υ^-ΥΧ/ ΥΥΎΥ^Ο Et jY' 'A CX’ ER-805925 h 8 Ψ r 8 ?°2H ph/^ 0 >\ ER-805938 h »Ψ r f r Ph-fx 0 ER-805968 1 η 11 = T I S 0 L~-' Phi 145 WO 2005/030794 PCT/US2004/030921 ER-805974 o lyie ο ΑΜθ I Me^ >ί χ PhA 0 1 Ν' ER-806004 aXXla Me >< hr >< ^ψ ΟΗ θΑ'A ER-806005 h 51 ϊ °A ER-806021 , 11 r j V" Me^N N '''jA "'s Ph-A 0 ER-806022 Ph^A" ° ER-806023 alXaa PhA ° ''N ER-806031 a lX™ Me" Ά^νΑΑ W^°:.:= Ph^A ° ER-806032 Αί^Αρ·· Ph^A ° 146 WO 2005/030794 PCT/US2004/030921 ER-806073 « ϊ Ψ r j ER-806085 Ο ''''ϊ γ® 0 0 0 ER-806086 0 /Κ ο PR ER-806105 Η ίί Τ ϊ® “· LΓϊ ΤΎ^°Γ ΡΙ,φ- 0 ° ER-806110 ^S^«X'VY"°'DrOH -zfs. 0 0 Phx|^ ' ER-806119 ζΑ ° 0 Ρκ|^ ER-806135 „ { ψ r Μβ^Νχ<ΧΝζ^γ'Νν^ν^·ΟΗ Phxj\ Η 0 ζΑ\ ER-806147 ztijiXvv^x Me^ Ν OEt PhzZjX' ° 147 WO 2005/030794 PCT/US2004/030921 ER-806180 ^Y ν ητ ηρ oh rVT' ° ER-806223 at ER-806318 HC|· «.-M-XvXoh Plkf^ H ° k ER-806356 »«’ Ψ Me O HCl · K | Jf Μβ·^^γχχΝ''ηΤ' ρκφ H ° Y\ ER-806371 Me O ''''Y Me 0 >Jk ._/ N >< OH /yl " S Λ ' \—/ Ph ' O2N ER-806395 H ° kf M® YrSiYYV' ph'ft " ° -Ά ER-806396 Me 0 γ Me B0C-NV^'N-JY'!,VC02Me Ph^x H ° yM ER-806397 Me 0 Me 0 ΒΟΟ^Νν^Ν·Χ^γ'ΝνΧχ/^'ΟΕ1 PhY[\ ° Y^ j 148 WO 2005/030794 PCT/US2004/030921 ER-806398 T® J MH T6 Pi<j\ H ° A ER-806399 H u "ι1*8 Μβ-ΝγΛΝΛγΝν'ε°2Μβ PhA H 0 Ax ER-806400 H ° V Me Τ Βΐ"'A0* Plf-f H 0 X-- ER-806409 utu Mex X^hT— VOH Ξ H = ptA[\ ER-806418 H Me 0 CO2Me ΜβχΝν^ΝΧ^γΝχΖ%%%1/^'ΝΧ\ Ph^k ° ER-806713 ,, 0 1 Me η n zU XjxxJvA mX X^ ν ητ ]| η Ph γ H ° a 1 U ER-806717 0 'k'' Me 0 νό'χΧ ER-806718 H—Cl ,. 0 Me 0 MA ER-806735 H—Cl 0 Me 0 /^An'YvaAoh U h ° AJ j 149 WO 2005/030794 PCT/US2004/030921 ER-806748 H—Cl I 0 Ar Me O ER-806749 H-CI , 0 Ά Me 0 ΛΛ JO-^X O' HJU” ER-806791 HCl· H ? 1 V® o H ER-806792 HCl· H ° 'y Me fNrNirN^Vc°2Et o H ER-806793 HCl· Η Ο 'γ Me fNrN ifNvXVc°2H o H ER-806794 HCl· H ° Af Me <NrNirNsrX<vCO2H o H ER-806822 HCI*H 0 1 ΑνΑ,Ν^^οο2ΕΙ &amp; Η°Λ ER-806823 hci‘h 0 Τ Μθ <Nv"J^NzSr|!j^<V'CO2H tf "ΎΧΎ ER-806824 hci’h 0 1 Me ^NY^NA<|lj'^Y'C02Et σΗοΛ 150 WO 2005/030794 PCT/US2004/030921 ER-806825 hc,’h 0 ] Me AH°A ER-806830 0 Ά Me 0 Μθ'ΛΝ/γΝγΥΛθΕ1 \,NH H 0 1 A ER-806831 H 0 '"γ Me O ΡκχΝγ^Ν^γΝγ^ΑοΕί S—j— H 0 ' ER-806853 0 Ά Me 0 ''ΝΧγΧ" \^NH H 0 Υ- ' A ER-806854 Me 0 Me 0 > A. JUAl Ο-Λ H I Λ ' o2n ER-806861 Aa JL H JL I PhA 0 x\ ER-806862 u 9 Ά Μθ 0 mXn A ''X Ph A 0 A A ER-806863 H ? Ψ Te ? Me^NY^N'z\xNVs'NxX;O2Me p«A H 0 Λ Me ER-806864 H ft T fe ft ?°*MB m/AnAAa PhA ° A 1 151 WO 2005/030794 PCT/US2004/030921 ER-806865 H ϊ Ψ “θ Me^NHs'NxS<N'y/xN^CO2Me ER-806866 0 Me'N^ ft 9 J Me 9 εω''Ι1'γ!!^Νγ\|Α^ Η2Νγ^Ν'^Ννζΐ!γ^0Εΐ ER-806867 Me O ψ Me 0 s-j— H O I ER-806868 Me 0 ''"'j Me O Ph~/NY^N s-j— H o y ER-806869 H 9 Ψ Me Mex'Ny^Nz\]xN'H'N^XCO2H pk> H ° A Μθ ER-806870 phH H ° /k Me ER-806871 h j? fe ft Me^Ny^N'^Y'Ny^NA Ph-j\ 0 xk ER-806879 O y^ Me η^Ύ/γ0"1 >t°yn^ ° 1 0 ER-806880 0 ''γ Me hnh h o y^ ι ER-806881 °Y° 0 "Ψ" Me 152 WO 2005/030794 PCT/US2004/030921 ER-806882 H J. ψ Me ER-806920 0 Yr Μβ η n AaXyx- 1 H II = | PYJ\ 0 Me ER-806921 h s 'ΊΗ w p A H 0 A 1 ER-806922 Me 0 Yf Me 0 Ph"o^NY^N'^YNV^Y^'0H 8η— H O 1 ER-806923 Me 0 Me 0 ρκγΝγ^Ν'^γΝγζ^ΑθΗ s-j— H ο 1 ER-806924 Me 0 Me 0 ρκγΝγΑ^γΝγγΑ>Η S—j— H 0 ' ER-806925 OMe AAAA ER-807000 HCI· 0 YK Me (Χ-γΑ.ΝΑγΝν^ΟΟ2Η HN J H 0 Ϋ 1 ER-807001 HCI· H 9 A ye 0-7 H °AT ER-807002 qA Me /Y^n\nvYC0^ Me"NJ H ο Λ ’ 153 WO 2005/030794 PCT/US2004/030921 ER-807077 [single diastereomer A AJ H ° A 1 ER-807078 single diastereomer Me 0 'A Me ER-807079 Me 0 A Me ER-807080 Me-NU H o A 1 ER-807081 [single diastereomer 0 'X Me ER-807096 OH XWx PhA o Me o ER-807101 Me 0 A Me Q"'JkX"AC02H ER-807102 Me 0 A Me ER-807133 jaW PhA 0 Me ° ER-807134 η ? Ψ r rv PhA ° A- 154 WO 2005/030794 PCT/US2004/030921 ER-807135 ρι,Α ° y- ER-S07145 nh2 ph^Y 0 /Y Me 0 ER-807146 Μβ. xN„Me Ph-M 0 YY Μβ o ER-807147 OMe Ph^Y ” Λ Me O ER-807148 OMe Ph-qY 0 Y\ Me 0 ER-807160 Me Ο γ” Me ER-807161 Me O kf Me ^••?Y^N^”>^YC02Et s—+— ο 1 ER-807180 Me 0 Me 0 cX j vX0Et ER-807192 Me O Me ^y\/yXC02Me 155 WO 2005/030794 PCT7US2004/030921 ER-807193 0 0 Me 0 ER-807194 Me 0 X 'K Me ° Y\ ER-807195 Me O X ""••(VS' A Me ER-807209 Me O S" τ ° ER-807210 Me O X L Me 'η|χΝ'γΧ^0Η ° /\ ER-807212 Me O γΝ'ΓγΑ'°κ o /\ ER-807213 οτΨ Me 0 γ"γγΑΕι 0 Y\ ER-807214 Me 0 A Me O rSn^™ o /\ ER-807215 Me 0 ψ AY Me 0 Ay'y’A. □ Y^ 1 156 WO 2005/030794 PCT/US2004/030921

Mb 0 0 ER-807217 AV Vy A/Y® 0 0 s'"' ER-807218 0 ER-807219 jd Ψ'6 «V h * / 0 ER-807222 h u 0 A- Al X Me p γΫγΧ» ER-807226 A Me Vy 0 M'' 0 ER-807228 A-A Ψ- r V' ο = H Ph-'O 0 / : 1 \ Me Me. NH j ER-807229 3 TO tf 21 ......A "A- Me A~ 0 A\ tftf Me 0 OMe J ER-807230 .aaA Ph-θ' H “A \ 2-3 >......< ” Me 0 ^-807231 mAA Λ H Pb-A tfr 0 A A^co2h I H 157 WO 2005/030794 PCT/US2004/030921 ER-807232 Ph-γ H x Ijfle 'YNsY^N'XX-CO2Me Π Me 0 γ I tl s'" Me 0 ER-807237 eX n YV 0 X XYXjEt Me Me 0 X / Me o ER-807238 cX yv XYXzEt SA - Me ER-807246 Me 0 X A C r o Ϋυ 0 Y XYXdH Me 0 X rW / Me 0 ER-807247 o=x \ z” /.....( XYXjEt ER-807248 o II Me I ί o 'ifn " γΧΥοΗ M ER-807249 0 II X j- 0 Η8Ν'^ΎΥγ "ST Ύγ>οΗ U* ER-807303 JvQ Ρ|ιγ H X CO2M6 9 X ER-807324 JX ριγ H A Me Vx co2h X> 158 WO 2005/030794 PCT/US2004/030921

ER-807328 nh2 H 9 SH PhA H 0 A k ER-807329 OH αΨΑύΑ"1 ph-q\ 0 m Me 0 ER-807332 Me 0 Af Me 0 /A JOx/%A ( \ ΓΎ Π OH <S γ 0 ER-807334 Η Ο A Me Me^NV^N‘VxNs?Xs'wz^'cO2Me PIT'S H 0 A Ac ER-807339 H ϊ I “e MexNXxN h A" lAAc ER-807341 Me Ο Me O Ο O rf™ ER-807342 Me O Me 0 <A i VA ER-807343 nh2 -vAwf Phf\ ° A\ AC O 159 WO 2005/030794 PCT/US2004/030921

ER-807344 OMe h ? ψ p °O γΛχίν ER-807345 OMe H s Τ' f Phq\ H ° Λ Ac 0 ER-807346 Me O gT Me 0 s-j— H o 1 ER-807347 Me 0 'NK' Me O /Νγ^Ν'Υ|χΝ'γ/:::γ^ΟΗ s-j— H O ER-807352 '"'I O Yp Me ER-807353 O Yp Me ER-807354 Ο Ψ Me ER-807355 Y ? Τ' r θΑΝ·^Ν^γθο2Η ER-807360 - Me O Me O /"/AW'- 0 A\ 1 ER-807361 Me Ο γ"' Me O 160 WO 2005/030794 PCT/US2004/030921 R-807362 Me ά it Me Ά 0 ✓Sa Η 0 ER-807364 Me ύ t; 0 Me -Α 0 <Ύ)Η ER-807365 Me if _ Η t ο Me Α Ο 'ΌΗ ER-807366 Me 5 •0 0 Me Α 0 Α^οη ER-807370 Me c 0 χ Λ' <· 0 Me .Ν___ Άγ·'· CO2Et ER-807371 Me 1 0 χ Χ^Ν' ) Η ο Me I CO2H ER-807374 σ 0 ζ 0 Me Α 0 AAqh ER-807375 Me ά Ν 1 Me ο Α 0 Α ''Ά, 0 Α^ΟΗ ER-807393 Ύ° σ d 0 Me 161 WO 2005/030794 PCT/US2004/030921

IeR-807413 Me 0 Me O Me. Jl JL i JL γ h iT^ Yy « ER-807414 Me 0 'Ap Me O Me. XN. UL -J. J. y N jri Y y °H ER-807417 y o H Me 0 γΝγγΛ°» 0 /\ ER-807418 Me Ο Y y cis Me 0 . /N. JL^ τ Ύγ™ ° y\ ER-807419 Me 0 ψ Me 0 Oh u ds ER-807420 A Me 0 . ^-N. ✓·*. JL· yry o /Y ER-807421 Me 0 > A Me O . -x'A A. Y AY o ER-807431 Γ ί Ψ r j U s VJy °H ER-807461 JrA ' Me 0 yyy 162 WO 2005/030794 PCT/US2004/030921 ER-807470 single diastereomer Γ i Ψ r i Xj « ί'χΧ" cis ER-807471 single diastereomer “e j τe t. ΧΑΫχΑ cis ER-807480 single diastereomer Me 0 Xp Me O ER-807481 single diastereomer Me O γ Me O ΧΧΑγγΜ Χγ'η 0 -- ER-807482 single diastereomer Me ο Y XA cis Me O y VA" ER-807483 single diastereomer Me ο Y xYy cis Y^ Me 0 v ^Y YYp ER-807484 Me Ο Ύ|· AA J 0" Y Me 0 . JL YYl 0H t ER-807487 Me Ο 'γ Me O a A IlAl <Ύ X A " \h 163 WO 2005/030794 PCT/US2004/030921 ER-807494 Me 1 N Q o Λ Ph X Me 'Xx ° 1 Xf ''OH H 0 Me 0 X j Me 0 J X ER-807495 A XN x" A "A- 'OH /trans u I A/ 0 h V cis 1:1 mixture of diastereomers ER-807499 Me 1 0 x Me 0 Me^ J X Ή J A "X X 'OEt r X H II 1 1 o l ER-807500 Me | 0 II Me 1 o Me^ J X s' vx 'OH c J o ER-807501 H Me 1 o Mex XX ,N A' 'OEt 0 ER-807502 H A Me I o Me^ XX 'N\x X 'OEt 0 ER-807503 Me | 0 II Me 1 0 Me^ J X s> vx A 'OH I 1 0 Me o j X Me 0 ER-807504 1 miA': 'N' J v 'X ''Xf OEt H n 0 V J ER-807529 H Me I 0 Mex XX ZN X ΌΗ -T" 0 164 WO 2005/030794 PCT/US2004/030921 ER-807530 Η 'X^ Me 9 A· 0 ER-807533 Me O Me CO2Me ϊΧύ ER-807534 ye ? 1 “e p°2H ΑίΧύ ER-807535 NH, °A Ijfle O A Me MsZ ΟκϊΧό ER-807540 o-T Me 0 xjx Me Απχό ER-807541 Me 0 A Me 0 ό^ϋ J AA* HO ER-807542 Me θ'"'' j-v HO X Me 0 YtA ER-807575 . Me Me 0 A Me Α ϊΧό 165 WO 2005/030794 PCT/US2004/030921 ER-807576 Me Q γ V Me rtf Ph ^NH 0U A VO ή ER-807577 Me 0 Ά A lyie 3 A Me ER-807602 Me 0 A Me 9 ΜεΑ-χ^Ν A 0 A* Jl o ER-807603 jX i h Ph-A Ax\, o ER-807619 = H Ph"A Aa\. O -A/tfoH ER-807620 P A H 0 Me ER-807621 rW A U " o A 1 Ph Me o s' Me ° ER-807622 Q'V A 0 /tf Ά/^-ΟΕί I Ph 1 166 WO 2005/030794 PCT/US2004/030921 ER-807625 Me Q Ph ο Ύ v ' Me A ° Y\ 0 ΌΗ Me I Me 0 ER-807626 Jl Q" Ph H A ° γ- ΌΗ Me I ο ' Me 0 ER-807739 1 0 A o /Y γ OEt Me Me j Η 'Ί s' Me 0 ER-807740 σ ΥΎ 0 Y" OEt I Me ER-807742 Me 0 As" Me *A ° Y· 0 xOEt ER-807743 Me o x 0 Me^'S< A 0 Y Ύ xOEt Me I 5 x Me 0 ER-807744 0" A 0 Y* Ύ- ΌΗ Me Me j 0 ER-807745 Q A 0 Y Ύ- ΌΗ I 1 Me 167 WO 2005/030794 PCT/US2004/030921 ER-807760 Me 1 o T V8 0 ·. Me ' γ Yv 0 Y -X, '"OH ER-807761 Me | 0 II Me 1 0 Me^Y \.....( '"OH ER-807796 Me I 0 A S Me 0 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. Ψ Ph H y‘y 0 OEt ER-807797 Me I o 11 s Me 0 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. Q Ph Jk. H Y*Y 0 Y T3Et Me I 0 ' Me 0 ER-807798 Q Λ H Yy ° Y OH Ph Me | 0 Η 1 Te 0 ER-807799 Mixture of two diastereomers 6 / Yv Ο /λ x ''OEt ER-807800 Me 0 Y 0 Me 0 ''N' CO2Me ER-807801 H 0 II s / Me 0 Me/Np< Λ H A ° X '"OEt 168 WO 2005/030794 PCT/US2004/030921 ER-807802 MeCL o A "TT Me V 0 . 0 1 yvoei ER-807803 H P x p Mex > <^r y- o S ER-807804 lyie Me OMe 0=4 vO O' H ίΧό ER-807805 Me ? j x Me OMe 0 Ύ-ΝΗ y ό A ER-807806 OMe 1 Me 1 .N H s' Me °Υ'ΝχΗ γχό ER-807807 OMe «Κ δ A x f V*W rXC ER-807808 OMe 0=4 Me 0 A ' Me ύοό ER-807809 OMe °-o _ Me A ο 'Ψ V Me ίϊ vv Ό 169 WO 2005/030794 PCT/US2004/030921 ER-807810 Ph I Me O Y 0=4 ΐ 'S Me °ν"^Χ Υχύ ER-807811 OMe ο=ζ Me 0. x II ' Me θν'Νχ'^ΟΗ A ίχΌ ER-807812 OMe ° ΓΛ cy° ΐ S Me Υχό Me | ο Me Ο 1 1 II ER-807820 single diastereomer A Λ ηΥι” Me I ο Me Ο ER-807821 single diastereomer r Λ ΑνυΤοη ER-807829 γ ΟΗ , οΆ Η' Υ%θ ϊΧϋ ΟΗ ER-807830 , Α Me O A ί jr Me 0,VNx/ τχό 170 WO 2005/030794 PCT/US2004/030921

ER-807831 Me O OH Me %--NxX*OH ER-807832 ,°H O=< Me O cY K Me V»H π?ό ER-807833 Me 0 4 (W NH O=\ X Me °vO ϊΧό ER-807839 / Me °%^Ns. ι § Me ϊΧύ ER-807840 Me 0 Y X o4°" " Me °VrC3 fro ER-807842 aa" Mex Υςζ I Me U ΥχΎ 0 OMe ER-807844 <xSr Y Me 0 5 YY°H 171 WO 2005/030794 PCT/US2004/030921 ER-807846 A N Me yS 0 Y 0 ΆΑΥ ER-807850 ο ά1 Η Η 1 N Me 0 • "Ά5 Y*-t 0 A AYoH ER-807860 Me o \JX i JI I Me 1 θ COjt-Bu j (7Π AY o ER-807861 r “e 0 Ά Me O °AH YYo ER-807863 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. Me o Av Me"' A ° A o A/Aa ER-807864 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. Me 0 \ Η ϊ8 Υί 0 Y 0 Me θ XL· Me ER-807874 A" rY --. X Yf OEt ER-807875 Me 0 ov Me AA 0 = 0 YXOEt ER-807877 Me θ \ ' Me 0 Cis-substituents on the piperidine ring. Two diastereomers (4:1). AA yS 0 Y XYqh 172 WO 2005/030794 PCT/US2004/030921

ER-807880 Me a o xj· A X Me A 0 Y 0 1 XoEt ER-807881 H Me/N Cr o x yA A H jx^ Me Yn 0 T 0 X^OEt U 1 ER-807882 H Me''1* Pr o x Λ' ΉH H Yn o = 1 ° Ύβ u ER-807883 H -.N Me'' 0 0 Λ- |x Me Yn 0 ή 0 XY)Et Me I 9 S X Me 0 ER-807884 c A Ά 0 1 ΖΧθΗ ER-807885 Me c ϊ X Me 0 A γΝη o : 1 Ύ)Η Me I X Me 0 ER-807886 c A A Y Ύ)Η ER-807888 H ΜεχΝ A A A H k r Yn ° T ° X^IH U 1 I 173 WO 2005/030794 PCT/US2004/030921 ER-807889 h s ψ f s I y 1ER-807890 H 5 ι “θ 5 Mex'N γ^Ν “^Y N Υγ^ΟΗ ER-807891 Η ° '"ί “θ ? CY Χγ ER-807899 Me 0 Y Me (τάχύ ER-807900 V® 9 'Ap iyie Vnh2 ER-807902 co2h Me Ο Ψ Me V™ cttya?0 ER-807904 5 \_ Me 0 Ύ Me °ΥΜ Υίτγχή 174 WO 2005/030794 PCT/US2004/030921 |eR-807905 %_ Me o A ryie °yO ίη χού ER-807906 3 Me 0 A Me crVixX ER-807907 3 ye ο Ά ye °v k ότπίΧό ER-807908 Me 0 A Me °y-OMe u ϋίΧό ER-807909 Me 0 "'γ Me CO2Me cA Aoo ER-807911 ”β ίί 1 Τθ n pOzH cyAxYd ER-807944 ΜβΟ2&amp;,„γ\ Wle 0 ψ Me °VNY (ΑΥτό 175 WO 2005/030794 PCT/US2004/030921

lER-807945 MeO2G„„- 1 Me 0 A Me SY'-/ ΑΑτό ER-807947 MeO2C.% H 0 A V® °YN^ ΎΎό ER-807948 MeO2C% Η oA^e Me/NAN'JNAI}A) ER-807949 HO2G% Me O A Me υ ϋ ϊΧό ER-807950 ϋθχίΗ ϋθ ν Α ϊλΟ ER-807951 Me 0 ΥΚ Me CO2Me Α ϊΤό ER-807953 η o A y® °yN^ MexNyAA^NyAA ρκϋ H ° Ύ ER-807954 HO2C. η o Aa °yn-/ ΜβχΝγΤΝΛγ-Νγ^Μ^\ pkA H 0 ER-807959 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. 0 YK Me 0 I T j « υΑ ° Y\ 1 J 176 WO 2005/030794 PCT/US2004/030921 [ER-807960 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. M® O AA mZ'AA X f. lV' O s' X o X ER-807961 V 0 X A / Me xA ° /tf 0 tfAoEt ER-807963 Me Ο V ι π 1 ' Me OMe ° V-x γθ CrV ER-807973 χ θ' X t r 0 Ay 0 /' ER-807974 A i r 0 Ay o /tf XAm ER-807975 X θ' X tf A”y o /' 0 ^Χ/Άη ER-807981 Me 0 A? X Me 0 ΧχΧΧΧ ° /A — ER-807982 xi Me Q ^-OMe •^nX ( ER-807983 Me 0 A/ xi X P CO2Me ΆΧ J OH j 177 WO 2005/030794 PCT/US2004/030921 ER-807986 (¥? OMe X Me ϋ Vs». A ER-807987 Me 0 A A? OMe °A Me rYx ER-807988 Me 0 A' An Me OMe o=\ An^AoH r Me ER-807989 OMe 0=4 Me 0 A AY if. mJ OCX ER-807990 pA· h OMe ' ν Ό ίΥΧϊ ”e ER-807991 «aaY PhA H 0 OMe Me Me O ER-807992 pwA H MeO2C„„ Z Me ϊΥύ ER-807994 ° Ή Me Y" 0 s' 0 178 WO 2005/030794 PCT/US2004/030921 ER-807995 yyXxy 5 Q 5 j X | ER-807996 y°H 0 > Ye 9 Ψ 1"e °y%e CrViX ER-807997 A Me o Me δΥϊΧί ER-807998 oAH ♦ Me 0 Ψ Me %-ΆΎθΗ Mxi ER-807999 oS°H Ijfle 0 ψ Me Xrx/ ER-808000 ho2g, h ? °yn ΜΥΝγΛ'Ν-λγΝν^ΝΛχ PhX H 0 A u ER-808001 OH H Q Y Me A Μβ-·Νγ^ΝΑ^·Νν^^·-Α^Ν'Μβ ph-γ- H ° A. Me ° ER-808002 OH h 9 "X Me Me^V^V>0H PlY|\ H o Y\ Me 0 179 WO 2005/030794 PCT/US2004/030921

ER-808007 Me Φ Me 0 A J Me yS ° Y 0 <Xx '^'OEt Me I 0 S' Me O ER-808008 0 A 'h yx 0 Y ''Xf 'x>Et Me ER-808010 H c S Me I O Me-^ OMe Ά A 0 N x^Xt 'Τ» ER-808011 o 4 X Me 0 η,ν^Λ OMe H /.....\ -z ' )=° ''Xf OEt ER-808012 H 0 x y'' Me j 0 X s A A 0 s' yy f>OEt ER-808013 / \ Et 0 Ϋ Me O H s ί « J A XfX)Et Me I O ' Me O ER-808029 .N 9 A YX 0 N Xf 'iJH Me Me I 0 / Me 0 ER-808030 0 A J yS 0 N <Xf 'xiH Me ER-808031 Me 1 0 tr H ' Me 1 O N Xf O X>Et I 180 WO 2005/030794 PCT/US2004/030921 ER-808032 Me ά 0 A γ Λ \ ζ-3 >.....< 0 Υ,χχ OEt 0 Υ Me 0 ER-808033 AA A A Me^ "Y N jf Y ΥΥ "OEt 0 Me 1 0 Me 0 ER-808034 ) .N 1 Ν ν^ύ Ύχ" ΌΗ Η II • ο Me 0 Υ Me 1 0 ER-808035 ό II A ΐΥ Νχχ ΥΥ ΌΗ ER-808037 H 0 II Ψ Me 0 Mo/NY Λ υΥ "OEt X Η 11 \ 0 MeSZ ER-808038 H 0 Ϋ Me ο ΜβχΙ\^ Υ ιΓ ζΝ^ γΥ "OEt Η II /'“χ > 0 vy ER-808057 H 0 II ψ Me 0 Me/N\ Λ υΑ "Λ γγ "OH f Λ Η II \ 0 A OMe ER-808058 0 A Me 0 I HzN X A . B Ν Xf ΎΥ'" ΟΗ B X Η II 0 \ 0 OMe Γ A Me 0 ER-808059 H I ϊ 1 \ zY Jl χ X .Ν 1 Υη ! γ Η 11 I \ , / 0 181 WO 2005/030794 PCT/US2004/030921 ER-808060 / \ Et 0 Me o Et^ A N /¾. JL N Y X N NF VX OH Η Ο Y H 0 1 ER-808061 jjjiixji Me XAKV ER-808062 0 Me 0 ΤγΎ YY™ ER-808063 -ΆΑχΛ ER-808065 T ff Ψ V® ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer. Γ"ϊ : t'Y16 ER-808066 T” ff ι" ve ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Me""'A> ° ER-808067 Te ff AK T® ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Me. ,N. JL N JL ER-808068 Te ff Ψ ve ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer γγΥνΥ0" ER-808071 Γ ff AK T® ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Γ"ΥΥ" Ύ ER-808072 Τθ ff AK v® ff Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer lY« Ϋ Ύ™ 0 x 1 182 WO 2005/030794 PCT/US2004/030921 lER-808073 16 H Ί Y Me O Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. (Single diastereomer Me. .N. Jl x XrX o YY 'OH ER-808074 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Me ° Y A ° γγ 'OH ER-808075 A X Me 0 ?yY 0 YY "OH MeS ER-808076 Η Ϊ S' X Me O ϊΥ 0 YY 'OH ER-808077 H «S' x Me o 0 YY 'OEt ER-808108 Me Ο γ Υί Me, NH Ο=ζ Me O<AY Άχ ER-808109 Me O .N^Jl 1 kJ H o o— Me χό ER-808110 Me 0 Sr Yi Me, N-Me °=\ iyie °γ-ϋ χο 183 WO 2005/030794 PCT/US2004/030921 ER-808111 k-Et [ 0=4 lyie 0 A Me °Υ-Ό AAco ER-808112 A lyie O A lyie AAz υ κ Αχό ER-808113 0 A («ie o A ve aO AAA ER-808114 0 A lyie ο A Me °AY AAa ER-808115 n-Hex NH A ve ο A ν® °νθ ΥΛχί ER-808116 /"Ο 0=4 lyie Ο Α Τβ AAA ER-808117 Α-χγ o=4 ye o A V18 AAa 184 WO 2005/030794 PCT/US2004/030921 ER-808118 To ryie ρ γ-- iyie kJ h 5 A A ER-808119 ho 0 A ye Ο Ύ yB CJsTa?O ER-808120 MeO WIIUMi/ J /lA-OMe 0 \ ye 9 1 Me όχγχό ER-808121 P\»OH > Γ1Ϋ r CXiXO ER-808122 Ph^-QH J" ipe O Y- ^0 θνΤ/ ER-808123 Θ A ye ρ γ' ye °Ύ^Α <A^nA'nA'nA tf> H 0 /k A ER-808124 ye Me-N NH °A_ ye ρ Ύ Me νΟ cxVxo 185 WO 2005/030794 PCT/US2004/030921 ER-808125 PMe j °=\ H 9 Y «yie γθ ylliXO ER-808126 Absolute stereochemistry is unknown. Single diastereomer OMe H 9 Y Me γθ "Ηίττγό ER-808131 η j? ""k τθ A /N. JL Λ .n /-. JL MH^"N ]]/ γγ vh ER-808139 .OMe 0 Me O ER-808140 Me o Me 0 cj ” xV^°Et ER-808141 Τθ H V Μβ ff ER-808142 .OMe h S I Te j? Me^Y^N^yNYA/ljEt Phy 0 Λ ER-808143 h u ^^k ™e u Μβ^Νγζ^ΝΧγ^Νγ/5γζΗ)Εί Phy H 0 \ ER-808144 H ? Y M® ° Μβ^Ν^^ΝΧγχΝγΖ,%γ^'θΕΙ Phy ° A 1 186 WO 2005/030794 PCT/US2004/030921 ER-808145 Me ο X/ .N. UL Λ 1 N 1 J H -OMe Me 1 γΝγ"γ o a. 0 I V>h | f® 0 4 X Me ° I ER-808146 . Jl 1 χΎχ 11 1 |X Vjh H fl : ο \ 1 M® 0 4 X Me 0 ER-808147 ί Jl 1 ynay 1 Vh H ll 0 x*x 1 -OMe u 0 f Me o ER-808148 ΛΑ ν' 1 V^H : H II - 1 PhXJX 0 A u P X Me o ER-808149 xi lA H Yn Ά PhXjx 0 \ 1 u 0 s X Me 0 ER-808150 χλ iA VA Ah : H I I PbXJX 0 Y\ 1 ER-808161 Me Ο X 1 Jl Me 0 1 II z o A < XL XL. ι ΥΛ1 0 χ^ Me o X Me C ER-808166 1 II N. JL 1 N J I N' II H Αγη O A\ υ Me o \ Me 0 ER-808167 1 II N Jl 1 ,| n A < X" AY /Υχ χΧΧ 1 J H 1 = Η 0 XX Me o X Me 0 ER-808168 1 II JL - ι II 1 N ΧΧΧχΧ 1 J H δ Ax k 187 WO 2005/030794 PCT/US2004/030921

ER-808169 Me 1 O H Y Me 1 1 0 / ? ι 1 yYY Ξ H ER-808170 Me i, ° y^ ΎΎ H II 0 Me 1 /NYY 0 * ER-808171 Me 1 ° Y '^X|Y H Me 1 o γ 0 ^-OMe γΥΑ OMe ER-808172 Me 1 χΝ 0 'y H aqY) ϊ Λ 1 H 6« ER-808173 Me 1 ° Y- H X Me γΆ o Ύ γ/ 1 H ER-808174 Me 1 ZN\, 0 Y H Y Me 1 0 I 0 Me 1 H ER-808175 Me 1 Yx 0 X yy-J H γ Me 1 ι Y/Nx 0 X O Ao ER-808176 Me 1 .n ° Y “"^lY H X Me 1 o Y o Ov-O(-Bu Ao ER-808177 Me 1 Y"s O 0 H S' Me 1 YN\z ο Λ. O ;--0H Ao ER-808178 Me 1 ° Y **^hr H X Me 1 O Y o Α^νΆ. .1 AA 188 WO 2005/030794 PCT/US2004/030921 ER-808179 Me 1 .N 0 Ύ H Me O Ak /CO2Me fX/V ER-808180 Me A 0 Ύ H X Me 0 x^OMe < II ' ϊχΐ ο ER-808181 Me 1 0 γΥ Υ Me Ο k χΝ. χχ Jk ^Me AX VV N II I 1 J H 0 Me ER-808182 Me 1 /N\ 0 Y 1 H X Me 0 ί#ό ER-808183 Me A 0 A" Y^N^ H X Me O °VOte I II ; .ti /x A X IaJ ER-808189 Ύ-.Γ ( A ° a k Me θΎ'Α/ χχό ER-808190 CY A ( y. ° ΓΛ k Me Vv ΎΧ'ό ER-808191 A ( Me 0 x A O=\ Τ' Ma ϊΧύ 189 WO 2005/030794 PCT/US2004/030921 ER-808192

ER-808193 ER-808194 ER-808195 ER-808196 ER-808197

Y'O

Ijfle θΥ'Ό'

A

le VO ird

Ph 190 WO 2005/030794 PCT/US2004/030921

IeR-808198 X Υχο ER-808199 ' \—. Ph Yi 0=4 ' Ma Oy-LJ Υχύ ER-808200 χ Y-N P” Yi o=4 ' Me °'·,Υ Υχ-ο ER-808201 Yi EtO-//Ph ' Me Υχύ ER-808202 MeO—A Yi 0=4 x Me Υχό ER-808203 Me p η A Jl J LJ H 4 X Me θνΌ Υχύ 191 WO 2005/030794 PCT/US2004/030921 jER-808204 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer A a \ z—3 \ / « o /XfOEt ER-808205 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer A \ z—3 \ / ” O VXfOEt ER-808206 A s' Me 0 qV ΥΎ ° 'XfXjEt ER-808207 o > H ll N Me o Άα A 0 N -''^XfXjEt ER-808208 Η H 9 ' Me 0 Ay" A ° N /VA’OH ER-808209 Y H s' Me o cA- ΥΎ 0 V X/VEt ER-808210 γ .° 4 X Me Ϊ A" y‘y ° X 'Xf'OEt ER-808211 h u Ί s' Me 1 O myn><V a A 0 N •'XfOH ER-808212 o x| / Me 0 A V OH y‘t 0 N Z'XfXOEt 192 WO 2005/030794 PCT/US2004/030921

JeR-808213 h s Y r » "Ύ? a ι"τι'β Ph ° ER-808214 Ph Y Me 0 γΥρ" p 1 ER-808215 Jjy Y OH Y Me 0 Y^YY^H 0 XX. ER-808216 y® 0 X-Y Me 0 I ER-808217 Y \ / O' jP 0 YY Me O V~° ΥχγΑό ER-808218 Y / O' J 0 γγ Me O V-° αΥΥό ER-808219 X s Y v | ρΛΧ"-Χ- Μ,."1---' ° ' ER-808220 Y °x ' Y Me o Υ A°" ° X\ ER-808221 i 8 Υ Γ 8 cXXxx1'0" 193 WO 2005/030794 PCT/US2004/030921 ER-808222 ?· X A-^ Me A-S o ~ X Xtf Xh ER-808223 Y 5 xV Me o χχ sV-v "ΧίΧΧϊΗ Η ο Ξ ER-808224 Y? X^ Me 1 N Xtf / H II ? 0 Ν' O Xstf^OEt ER-808225 Xi XX XX Me 1 X 'N Xtf O Ύ%η H S χ ER-808226 X' Ji \ N X Me I Az'nx/ Xi γχΛ I J H ο ER-808248 Me o / Jk o A^ Me AA o -γΑ^ΟΕΙ ER-808249 Me 0 ΟΛ A^ Me AA o ER-808251 Me o \ ^N. JL , tf N 1 J H X Me Ο θχ-ΟΗ k^k/^Jk x IxJ o ER-808253 xn N Jl X Me 1 YN^ ο χ^ 0 VOH tf Ύ xhtf 1 J H /ΧΥ ER-808292 xn .N. Ji J \ N 1 J H We 1 γΝχχ 0 /Y ' X^yph o %A Λό 194 WO 2005/030794 PCT/US2004/030921

ER-808293 if jr Dt C n' 1 J H \Y Me I 1 0 . 0 X-Ph o V ΥΎγ- Ύ> ER-808294 Yn Me 1 c CO °yo .N, Y. JL I N II H o a* ΎΥ- ό ER-808295 cO ΥΐΊ Me 1 0 -Ν. YL JL I N II H 0 Y^ ''YY*' '6 ER-808296 ΐη X Me 0 A M Γ N 1 J H 0 χΑ ΎγΥ' '0 Co ER-808297 Όϊ ' Me 1 0 Γ Τ v 1 J H κ/Ν\/ YY*- Ό ER-808298 =o / Ά Me > "-.^Ph 0 -N_ X . 1 N 1 J H 0 s yyt X> ER-808299 Yf Me 1 \y-Ph o I n 1 J H kA 0 > yyy ER-808300 Yf Y Me 1 Cr ^.N JL . 1 N 1 J H Ly 0 / YYY 195 WO 2005/030794 PCT/US2004/030921 ER-808301- 1 -"Yy-Ph i 0 y Me Ο °Ύ-° ER-808302 -- 'Y 0 γ/ Me O °v° ι y ji. y. a γγγτγο ER-808303 Ph ό y~-ph γ o y mb ο °γ-° ER-808304 "Η y_ph \ / . . O' 1 0 Y|Y Me 0 y-° ΥΥχΥό ER-808305 y \ / O' jP 0 Me 0 V° yyyo ER-808306 γ Y^ 0 'γ'' Me 0 γγγγ ER-808307 Q \ v 0» 0 Me 0 Y° Υτχ?τν ER-808308 $> \ / w o' Y 0 Me 0 V° 196 WO 2005/030794 PCT/US2004/030921 ER-808309 Υ 1 0 y Me 0 V Λ Jl X. Jl Λ fn X rw ER-808323 H J? Me'' ER-808324 Ά Τθ fi h2n Αγ ER-808325 H fi Y Te fi Jl A .N Jl Me J><f N VX Τ» J Y ° A 1 ER-808326 H fi Y f fi / χ; ° Α ι ER-808328 Y"rPh Me 0 Me 0 °'5y-° AAC Jx Jk ζχΛ A Α ϊχτ o ER-808329 0 Cyh f6 ? γ ° 0<x° r Νγίχ*|]'' "ύΎ^ϋ ER-808330 φθ 9 Y Me 0 V0 ER-808331 qQ f8 Η ^Y Μβ ° Α'θ 197 WO 2005/030794 PCT/US2004/030921 ER-808332 Me 1 0 H X Me 1 o ^A^ Qo 0 V Co ER-808333 Me 1 0 X Me I o °Y H ο γΥ Yd ER-808334 Me | o x "S' Me YPh 0 V H I 1 0 Υό ER-808335 Me 1 χ-Ύ 0 x ν' Me I ι •k/k V^Ph o °y-° 1 h 0 X ER-808336 Me 1 0 x x Me 1 j ^yph o °V° H 0 Υό ER-808337 Me 1 0 x X Me 1 t -"-\^-Ph 0 V H ΥΆ 0 fr. Υό ER-808338 Me 1 0 X Me 0 V° H I 1 \/N\. 0 M Υό Ph / 0 ER-808339 Me I 0 x Me X-Ph 0 V I .N H 1 ί Y/N. o A, Υό 198 WO 2005/030794 PCT/US2004/030921 ER-808340 Ύ I r'Ph Υ-"0 ER-808341 χ „ . z 0./ Me o Me O A*° χχχά ER-808342 A χΧχΧ ER-808343 O "Y Me O Y-° u ίγχνό ER-808344 •p O Me Ο Ύ-° ("Υκ ϊ“υΑΎ ER-808345 ϊ0 Η Α Μβ η θν*0 Λ ζΝ. ... X Λ CrXrryo ER-808357 single diastereomer Ύ1 Ψ ν ϊ Cj - ΤΧ'Λ ER-808358 single diastereomer Ύ ϊ Ψ r j y% 'γχΛ ER-808359 single diastereomer ί Τ'*Μβ ? χυχχχ 199 WO 2005/030794 PCT/US2004/030921 ER-808366 single diastereomer 5 Ψ V 5 u s VXT1™ ER-808367 X s Ψ r s cxVxA ER-808368 Ύ ! Ψ r « ϊ χΑ" ER-808383 Η Η ΙΠ ΐθ Π JI Λ Ν Χ3Χ X ΜχΧ\ Ν (k OEt ER-808384 η S ΙΠ τe 5 ER-808389 0 We 0 ER-808390 if Ο XX Me Ο 11 ΛΧλ Α χ «ΎχνΟ ER-808391 '"'k Ο Υ Me Ο X χ[Χ'η'Χ|Γ'Ν ER-808392 '''k ° Χ^ Me Ο J ER-808393 Ο ΑΧ Me 0 χ Χ^ν'|ιχΝΥ,5υζΑ''ν/ | 200 WO 2005/030794 PCT/US2004/030921

JeR-808394 Xv ί Τ N" 1 J H γΧ Me 1 1 Jl κι A ό a Ί ER-808395 ΌΊ .n JL I 1 T N X Me 1 \XNLX Xx 0 υά I J H o Ax ER-808396 Xv ι r " 1 J H A Me 1 AN\z o a A o X^'N/X ER-808397 T"r ,iL JL f N 1 J H A Me o a Ά 0 X^A ER-808398 if X- A 1 N 1 J H γΧ Me 1 Ή 0 ΆΑ o a ER-808399 Yf jl JL -x I N 1 J H A Me 1 L-N X 0 X^-N^X Ar ER-808400 A -il JL J ι n II H A Me 1 L „N n 0 XnX XPh ER-808401 YjT .il JL A 1 N Me 1 sXnlX c ϊϊ5τ 3 1 J H o Al, ^Ph ER-808402 Yn -il A J 1 N 1 J H A Me 1 ΙχΝ,- ° A Xx n Ah ER-808403 ΥίΊ -N JL -J ί N 1 J H A Me 1 L-N O -xA Ά O X Λό OMe 201 WO 2005/030794 PCT/US2004/030921

IeR-808404 Υι Y .n JL A Γ N ν' H II XX ° Me 1 Nvz'x o I Λό ER-808433 H 5 Ύ X Me 0 1 1 H o A\ xA OEt ER-808434 Η ί Af X Me 1 0 “Υ/ ° A χΧΥ ΌΗ ER-808435 H j? > Y Me 1 ° A 0 χΧΥ OEt ER-808436 h ii Af A. JL Jl Mex A N /===( / H Y Me 1 0 A 0 χΧ ΌΗ ER-808437 γΥ Me ο hX γ 0 ER-808447 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Me ο X X •Jy Me A 0 X ο χχΧ" OEt ER-808448 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Me o \ UM |y Me Ay ° X ο χΧ OEt ER-808449 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer Xx=: Jy Me YY ° X" ο -ΧΥ" OEt ER-808450 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer X °-Υ \ z—3 \.....( · 0 χΧ OEt 202 WO 2005/030794 PCT/US2004/030921 ER-808451 Υ® o A' Me O Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer x.,.0 "ί ER-808452 Γ 9 A 76 N Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer AAV/A™ ER-808453 A ? A τ® » Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer (ArY o Z\ 1 ER-808454 A" 9 Ά 7® π Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer AAs AaA™ ER-808475 9 A V® 9 Single diastereomer /As ΑχΑ ER-808476 Ύ ι ψ r s Single diastereomer (Α"γ ΥγΥ ER-808477 ^^^A 9 A τ® 9 Single diastereomer (A" s χΥ ER-808478 9 A τ® 9 Single diastereomer (AAA ER-808479 Ak ER-808480 203 WO 2005/030794 PCT/US2004/030921 ER-808481 Yn JL A Γ 'l N II H X Me A o xA 0 ΧΥΥ' A\xCO2Et T ER-808482 γη X Me I 0 J. JL I 1 1^ » II H νχΝ^ 'Αν Ύ^-COjEt ER-808483 Yr r Μ® | 0 Jl. JL . I V N II H | 1 Lx Ά Ί A XY^OH ER-808484 Yn so J I N II H Me 1 \xN 0 CO2t-Bu /Υ[ΥνΫ °Y ER-808485 Yr Me 1 ι 0 CO2Me xX JL I N II H JL/Ns, o . /XY 'Ν·"\ ER-808486 Yr Me 1 | 0 CO2t-Bu χ JL . 1 T^ N L J H AxN 0 / /%/Y M-z> ER-808487 1 Yr χΎ SO -r N L J H N Me 0 χ 0 ysY CO2Me '0 ER-808488 Yn Y Me 0 χΝκ X*L A 1 N L J H 0 xA x-\xC02h ER-808489 Yn ' Me 0 χΝ. JL A 1 N L J H s xN. A Y^COiH ER-808490 Yr X Me ο CO2Me χΝ. JL I N II H 0 / /XT •nA. 204 WO 2005/030794 PCT/US2004/030921 ER-808491 Single diastereomer A x Me ?r o /7 o VS )H ER-808492 Single diastereomer c X Me yY ο χ 0 )H ER-808493 o A 0 Single diastereomer σ xA As ° Ν' ΌΗ ER-808494 o Me 0 Single diastereomer σ 'X Ai O P'' -γ ΌΗ ER-808495 A O Me 3 0 AA VyA O 1 II ΌΗ ER-808552 7 9 > k Me o a Αχ A o •y OEt ER-808553 9 9 A k Me o σ A A A o y OEt ER-808563 7 O x k Me ' 0 a Αχ A o y ΌΗ ER-808564 7 9 k Me o a Αχ A o y ΌΗ 205 WO 2005/030794 PCT/US2004/030921

206 WO 2005/030794 PCT/US2004/030921

IeR-808676 Ο γ''' Me 0 Α» ϊ XX” ER-808677 | O < Me O cAXaA°k ER-808678 Τ} l t 5 iA^AvA® ER-808679 Ύ 0 I Ο Y Me o cA AAA°k ER-808680 χχ o Μθ 0 CX i χΑ ER-808681 o ] O Y^ Me O ER-808682 XX O p Me o cXXnxXob ER-808683 Xr 9 Υ'"' Me O CA-sAXh ER-808684 ] ° :: Me O Cj AAA” j 207 WO 2005/030794 PCT/US2004/030921 ER-808685 Y 0 Τ Ο γ Me o Q+γγγ ER-808686 Y 0 Τ O Me O ER-808687 Y j γ r s (Y'YyY" ER-808688 o | O Me o (Η'γΥΐΟΗ ER-808689 Y f IT » cY" i yy1'0" ER-808690 o Yp Me O ιΥ'ϊ ϊΥΛ°κ ER-808693 O Me Ο cj ΥχΥ* ER-808694 Ο Ύ Me Ο γγγγ ER-808695 "Υ"" Ο Ύ" Me Ο γ% ϊ γΥ°ε· 208 WO 2005/030794 PCT/US2004/030921

IeR-808696 SY 0 A Me 0 AVxA* IeR-808697 Ά fi ωθ ° Α-ΥχΑ jER-808698 A Ο A Me Ο Cj ηynxV"°h , ER-808699 ΥΥ Ο 'A Me ο I ΑΥχΑ ER-808700 Ά Ο A Me ο ΑΑΑ ER-808706 Single diastereomer ΤΓ Ο Ί''' Me Ο ΑυϋΑ ER-808707 Single diastereomer "Τ' t Ί* 0 ER-808708 Single diastereomer Ύ tyr j ER-80870 Single diastereomer 0 Me Ο (A Υ“VA“ ER-808710 Single diastereomer X"»1*5 Α ι γΑ 209 WO 2005/030794 PCT/US2004/030921

IeR-808731 X o ΥΓ H X Me 0 ΌΗ 1 ° /^ -y ER-808732 y o Λ J X Me ?Y 0 /tf y 0 ΌΗ ER-808774 Single diastereomer 'Ύ a o Λ Me 1 O X "y 0 Oh ER-808775 Single diastereomer XT Q o Λ Ms -y 0 “OH ER-808777 Single diastereomer o o Λ 5 ' Me ?Y o /tf y 0 "OH ER-808779 Single diastereomer σ o Λ 5 Me Vy o /tf yz 0 "OH ER-808780 Single diastereomer Q 0 Λ J tf Me Vy ° N--' yz 0 ΌΗ ER-808815 Single diastereomer Y ο H ' Me 1 0 /X y 0 OEt ER-808816 Single diastereomer .N c Ύ H tf Me 1 tf.N ο χ -y c Y)Et lER-808817 Single diastereomer χ. o x ’jj' 1 H 'γ Me 1 1 A. ZN ο p zy c \>Et 210 WO 2005/030794 PCT/US2004/030921 ER-808818 jf Ο dk Me o Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer xA Jk JUkyUk χ χ. γγ γγχΕί h/V ο 1 ER-808819 ° '''k Τ8 ? Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer ΧΝ Υ^ν·^^νΑχαΥχ'οει ER-808820 Ύ Η ^k ϊ® Π Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer ΑΧΑΧ Η ° χΚ ER-808821 '^'k ί? V τ® j? Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer ER-808822 ¥β o Ax' Me ο Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer θ'''''^Ν'^γΝνζγ^0ΕΙ ER-808823 Me ο ΑΧ Me Ο Cis-substituents on die piperidine ring, but absolute stereochemistry is unknown. Single diastereomer ER-808824 9 ΑΥ Μ® Ο χΝ 1 XXxkx^Ak I η ik 0Η ER-808825 kk 9 AY Me ο xNAk -A/Axxkk X 1 Ν lk θΗ ER-808826 θ \χ 0 Single diastereomer χΧ Jk xk Jk xs^ Λ X Ν (k °Η 211 WO 2005/030794 PCT/US2004/030921 ER-808827 0 A' Me 9 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer χ\Χ z\AxX < Y N Y< Υγ XOH . M..-U . " ΐ A I ER-808828 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer 0 Me 9 zN. AL zL zX xA I Ih'iA Yqp oh ER-808829 Ο YY Me 0 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer y.,-U H ί A ! ER-808830 ν ΑΧ t® 9 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer χ^χχ^χχ γγχΑΗ ER-808831 ¥θ Ο '"Ύ Me Ο Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer A ,Α JL ν χ\ ζΑ < Υ V^X"OH υΑυΑ Η ° χΑ ’ ER-808832 ρ ο Me Ο Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer ϊ"αχ^°η ER-808861 Χτ 0 Υ Me 0 Υ"νΎμ ΑΧ 1 Hlf^ η SMe ER-808862 '''Χ 0 ΥΥ Me 0 X ζΜ. ζΑ A A Χ5>. Α Α ^οη I Ι^ηιΓ^ γ Υ/ν ER-808863 ^Χ Ο X Me 0 zXNsAk ζΥ ζ4 ζΑ Η ΦΑ Η ο · ι Η 212 WO 2005/030794 PCT/US2004/030921

IeR-808864 Y 0 YY Me ii 1 ι U. Y X M ΤΓ H II 0 X o ΥΑ H ER-808865 Ys Me ° f 1 I X zN. / n AA Η II : 0 Y AY 1 H Y)H ER-808866 YY Me 1 . Y X n AA N Η II = o /X Ο γ·Ν Z%zAnAsY 1 H ER-808867 Y z-N^z O Y' Me II ι Ά Y X n yr H II ο s o ν^γΥ A H ER-808868 Yi JlO 3 YY Me 1 ι L Y. x. N AA H II o / o ΥΥγΝ A3 N H ER-808869 Ys YY Me 1 1 0 . z N Ar X Η II = 0 Y Ll ER-808870 Ll Υ,Χ YA Me 1 . Y x n AA X Η II Ξ 0 Y o Yf-N 1 H zL-OH ER-808871 Ys YY Me I ι . A zN. N AA X H ί A A YY H A ER-808872 Ys Me 0 . Y z-N. Z n AA >S H II = ° zY Yy 1 H -\zO L> ER-808873 Li zN\Y YY Me I 1 Y zN. Z n AA ^A Η II = 0 Y γ. 1 H A 213 WO 2005/030794 PCT/US2004/030921 ER-808874 Ά 0 ΥΥ” Me .0 Cy h o * I H NOj ER-808875 kX 0 XX Me Ο XX ER-808876 XX 0 XX Me O ΧχΑ^ν'^Α’ΤΧ kk H O XX 1 k^Nxx-Ph ER-808877 no2 XX Ο YX Me O ER-808878 Α Ο XX Me O Xi Χ'Ύ’Χ['ηΧγ'ζΧ'χχΧ''— ER-808879 YY yX yo JkJ* ER-808880 j| ^X V® Π ER-808881 XX j? '''X^ V® j? |'''Ν^ζ^ΝχηΧ'γζΥχχχ’'χ·ρΐι ER-808882 Ti Y I I Τ' Υ*/Μ^·Ν'^χζ'ΝχΥ,ΥχηΝ-^'ρ|, CN ER-808883 γ Ϊ Y y® ? Cl 214 WO 2005/030794 PCT/US2004/030921 ER-808884 Yj y τθ 9 N SS H II 0 Vk/^’N'k = j H ER-808885 vn A Me 1 /—ph o. / o V-° 1 't n 1 J H o A A6 | ER-808886 Yr A Me s rf A. JL 1 N 1 J H ° Y ER-808887 Yr Γ Me ϊ rf Jr JL x k ✓’k <ksY^NY/YCi 1 H II H ° Y ER-808888 m Me 0 Ji. JL 1 1 T N 1 J h 1 H IJL ER-808889 / o= y J Me 1 ι ,S ( N”" A. /%YNYY 1 J H O 0 ER-808890 Yn Me o JL 1 I N \/N\/ 0 Ax 1 H LA XI ER-808891 Ύ JL , f Τ N 1 J H Y^ Me 1 \YN\Y 0 γΧ 0 %AnA Cl Υ Ckk 1 u ER-808892 Yi' ^Y Me ?$) ι N 1 J H O s ER-808893 Yn I N 1 J H S' Me 1 k/N ° Y XQ Ί 2 k) 215 WO 2005/030794 PCT/TJS2004/030921 ER-808894 Y x-N. ° A H 9 1 |Y Me 1 0 X ? γΊι -x Χγ H OMe ER-808895 Y ° A H Me 1 ^χΝ 0 ^A Xz 0 Ph A A xph x v ER-808896 Y ° A ”"nz H Y Me 1 O Y \ γ ER-808897 Y 0 Y H s' Me 1 ο ^A Χγ O A Z~\ zPh L„ ER-808898 Y ji ° Y H Me 1 .jj.. o A Xz 0 JI .— ..OH X Y Η 1 ΌΗ ER-808899 Y 0 Y H Me 1 χχΝ Ο Xx Xz OH ii ( XnAa>h H ER-808900 Y Jl ° A Xi H Y Me 1 \χΝ. ο χ. Xz 0 HO"— A /> ' X H ER-808901 Y ,N ° Y H ' Me 1 0 X Xz 0 A Z\ χΟΗ X H ER-808902 Y x-Nxx< ° Y H X Me 1 ο X γ o 9 •*ln/xA H ER-808903 Y ,Νχ AX' 1 H A Me I ι Aa o . 0 /x Λ χΜβ AY n s Ξ Η 1 216 WO 2005/030794 PCT/US2004/030921 ER-808904 xy 1 J H Ή Me 1 Λ o s o n y 1 ER-808905 Yn .Ν. Jl J Γ n II H Me 1 ° 1 C .✓Ν. s'"· 1 H SMe ER-808906 Yn y-N. >L Jl ι N Me 1 ι H ,Ν.ζ, J h 5 L j H 0 lER-808907 Yn Me O y. jl i 1 N 1 1 J H o 1 Me ER-808908 Yn Me | 0 -N. Jl Jl 1 N -Νγχ '5ϊ*ϊ<'·'νχ'Τ:ο2ι-βιι H L J h 0 SMe ER-808909 Yn Me i 1 N ZN. L J h 0 1 H 0 ER-808910 Yn Me o .ό JL 1 Γ N J H M L J h 0 ER-808911 Yn Me 1 zN. 0 -. X YY z-CN L J H 0 y γ ' YCN ER-808912 Yr x JL z 1 N Me 1 XNX. 0 NY\ X i > 1 1 H c ) J ER-808913 Yn Me 1 ° xx 1 N /N. . /ϊγζΧΝ/^/ ι ι h 0 217 WO 2005/030794 PCT/US2004/030921 ER-808914 vn JL JL Λ r n 1 J H 0 Me 1 J Ά H ER-808915 Yf Me I 0 JL JL r Ν' 1 J H Ο ^χ ΑγΥ'"\ γ 1 L? ER-808916 Yn Me 1 0 JL Jl X I N L J H 0 -Νχχ LA IeR-808917 YjT Me I -OH 1 O { -.ν. JL X χΝ X X xOH I N 1 J H 0 H f>h IeR-808918 Yn Me 1 0 xO < Z N 1 J H 0 N\X Xz' V ER-808919 Yn Me 1 o 1 N χΝ. X L J h 0 1 Me ER-808920 Yn Me 1 o |Ά 1 N ,N ^xNx^'C02Me 0 IeR-808921 Me L O Ph 1 "τ N 1 J H 0 γ° V Me 0 ER-808922 xN. JL JL 1 AN 1 N Π ι ι h ii NOj |eR-808923 Yn al JL Λ Me 1 N -Ph XX 1 N Ά-- Ί4 ^CO2Me _ 0 218 WO 2005/030794 PCT/TJS2004/030921 ER-808987 Y O' o Λ Υ"Ύ ° Xs o OEt ER-808988 Y 0 0 1 j ' r o zx H Yr ° Y -OX 'OH ER-808990 Y -N 0 'ti H ' 0 Χχ-Νχχ ° Y o YX" OEt ER-809040 Single diastereomer A o X' H Y Me 1 o / c υΆ l OEt ER-809041 7 O Me o ΊΓ H 1 X/N ο χ YX" OEt ER-809043 Y .N O ' r o Y H •x o a AY "OH ER-809044 Y .N O x r o Y H O Y* χ%Υ· ΌΗ ER-809045 Single diastereomer A .N 3 X Yr H Ύ \ z—3 \ / «> γ o X ER-809046 7 O s' Me 0 ZN\> Y H 1 χ^Ν ο A ''kY ΌΗ ER-809054 V -N. JL 1 N 1 J H 1 Me >X 1 V o H yyy 219 WO 2005/030794 PCT/US2004/030921

ER-809055 Yd .N. J r τ X 1 J H V Me 1 0 J MeS j”1 Ύ 0 %/H ER-809056 y Me V 0 s' F o k o y-NH χ/χι-Ϋ ER-809057 V Me V 0 x „ y 0 yNH Υγ'ΝΫ ER-809058 XV Γ N I J H X Me ο χΐ o S/h) lA ho ER-809059 (¼ Ά τ® Y' 0 s Q o °y-NH ER-809060 X Jk \ N 1 J H "IT Me 1 0 0 Y o yNH cXo ER-809061 X V Me V 0 s V o yNH x’y'V'X ER-809062 Yii . ZN\X ztf ' < 'X^'X'' 1 J H ' Me 1 s/Nxz- 0 Y) ° ‘vA, : Me Υύ ER-809063 Me vi 0 s^ V 0 yNH -y-viX 220 WO 2005/030794 PCT/US2004/030921 ER-809064 _ cA J Me ks 0 N Y 0 VNH ΥνΛ ER-809065 I N II H 7 Me o A 0 °AH Y5 ER-809066 Yr L r ,Ph OH o Y 0 V-NH k tY Y γ YnX kJ H 0 A ΝΟχ / ER-809067 <0 Yd xJk Jl r n 1 J H S Me 1 AV o c Y Ph 0 ? 0 V-nh ER-809068 ΪΙΥ L r k Τι Y > x Y%X kJ H O ER-809069 Γ N 1 J H ' Me 0 rW O vO''· ό i ER-809070 Q Yr T r o r O V-NH k T s T x /X kA kJ H 0 X ER-809071 Yjd S' Me -COjEt ° vL k ι « YNY Xf kJ " 0 /k 221 WO 2005/030794 PCT/US2004/030921 ER-809072 X" f Me j Ά T o/SA kJ H 0 ER-809073 Cf r τ n kJ H 0 Me k YPh o 1 0 V\ XJ Cl J ER-809074 Jx YjS Γ N 1 J H Me 0 V" γΧόό ER-809075 =o / f Me o 1 o V'NH rn T 'N\z Χαά kJ H 0 ER-809076 Cf Γ n' kJ H 0 Me 1 ,N YPh 0 V Χό ER-809077 k X' t Me ο Ά» r τ K' Ϊ 'NXx ·Ύ"νΑ kJ h 0 ER-809078 c X' f Me 0 %JH r τ s' Ϊ 'NXz· Ο/υΑ χ h 0 ER-809079 XI II H o=\ ' \...../-> /X X“ □ %-NH Λό 1 222 WO 2005/030794 PCT/US2004/030921 ER-809080 γ ψ A γ 0 γ Me o V-NH J. JI Λ Ji JL J X ik ER-809081 , . Nr Ύ 0 Y Me 0 ΥΥΥό ER-809082 Co Y 0 Ψ Me 0 VH rYΥΥό ER-809083 γ o A mb ο ΑτοΧ ER-809084 y . ψ r .. gY YY ER-809085 Ph u \ x 1 o / 0Me Y 0 Y Me 0 YN« YrrvY ER-809086 Ph HO-Α ,.,.Ph Y 0 Υ MB 0 YnH YmYAq ER-809087 γ ο γ mb^^v^ Υγγό 223 WO 2005/030794 PCT/US2004/030921 ER-809088 <Ph ί Y1Ψ j Y\ Υ ΥχΥό L ER-809089 x-OH J . ο 1 0H Y 0 ψ Me 0 YNH ΥΥχΥο ER-809090 O’ Υ 0 Ύ Me o “V'NH YYY6 ER-809091 HO Υ ο Ψ ., 5 ΥΥχτΥ ER-809092 Υ 1 "Ή f 1 °vN'—1 ΥΥ/ό ER-809093 OH Y. Ψ » o V· ΥΥχτΥ ER-809094 Me Υ 0 Y Me 0 %Υη γΥ·γγ ER-809095 o J Υ Ο Ψ 0 °Y-NH ΥΥν-ό 224 WO 2005/030794 PCT/US2004/030921 ER-809096 A ° A ΑΑΥΑό SeR-809097 MeS Υ|^ 0 S’' Me o V—NH I ASAo ER-809098 ^CO2Et Yf 0 fS Me O °V-"Ns„ III II ί Me AAoA ER-809099 ^-CO2t-Bu A O A Me o A AVyAo ER-809100 MeS Y A μ. o “A ΑΑγύό ER-809101 CN A 9 A V® 9 A JL JL λ JL -- ™ cysVyVo ER-809102 A™ A ° A «® ° °vn" AYrW ER-809103 , A A 9 Τ M® 9 VNH aAaa 225 WO 2005/030794 PCT/US2004/030921

ER-809104 'X 0 '"A Me 0 °Y-NH (ΥΧγΥό ER-809105 Λ Y ο Ψ Me 0 X™ ΧχΧό ER-809106 τ® ? X^X ΧχχΥό ER-809107 , A X 0 X Me 0 Χχχό ER-809108 Ph hoyX X 0 X Me 0 X™ XsVrYo ER-809109 γ Ύ ? s Άϋ. ΥγΧ ER-809110 γ Y-COjMe ^Y" 0 Me 0 XNH xXyd ER-809111 0 X 0 X Me 0 °yO qX s YrX 226 WO 2005/030794 PCT/US2004/030921

IeR-809112 Yd Jl J r τ N 1 J h OH I Ph.,, J S Me 1 o Vy 0 \,NH Υό ER-809113 YsY r yAy I h II o Me 1 O °V-NH Υ Ph L^-COjMe 0 °yNH Υό ER-809114 Yii Jk A r 'r N 1 J H ' Me 1 V\/ 0 Vx ER-809115 Yd -A J r 'r n 1 J H S Me 1 χΧ* 0 V* No Y —o z ER-809116 XV Me o vO Cj " Y Y 0 Ν' ER-809117 XV ' Me : Me U " Y Y 0 N'·' ER-809118 Xa> k Μ· ° VNH U s Y > 0 V* ER-809119 7 OH y XV S Me 0 °ΎΗ II ? CP Y Y 0 N^ ER-809120 Yx tx o Y 0 V-NH I Cj 5 Y > 0 V 227 WO 2005/030794 PCT/US2004/030921 ER-809121 YH /N. Jl JL I N II H Me 1 ο 0 Ο » VNH Ύ ER-809122 Yi" X Jl „ 1 N 1 J H •γ Me 1 ΧΑ 0 /J. 0 : Me Λό ER-809123 γχ 0 Υ" 0 Ον-*Η ER-809124 Y k ? 0 X Ή ° °kc i Me •Ήΐ'Υ ER-809125 y s' Me yY ° Yx 0 3 Yik ER-809126 Y L·' Me Y\ 0 Η .A 0 Υ^Η Χ^Ν'Χ\ ER-809127 γ Me yY Ο /Ϋ γ- ο "Ύ ο Ή Y ER-809128 s' Me yY O Ύ ο Η ο %-ΝΗ ΗιΎ> Β 228 WO 2005/030794 PCT/US2004/030921

ER-809129 A X Me 0 Y .F 0 XN'm ί Me tYnA ER-809130 Ό 3 X Τ' r 0 / O V-nh Y T > -'άΥχΆ. kJ ° Y ER-809131 Y ° A i j x Γ o A 0 V-NH Γτ Ύ γΥ χΥνΆ. kJ H ° Y ER-809132 Y ° I 1 j Me o °Yz.nK^ 'J vy xJY-\ kJ 0 Y ER-809133 Ό 3 Τ' r o r O VNH Γ t V L Ύ/%Υ kJ H 0 Y ER-809134 Me Y Y ° A 1 j ( Γ 0 ( γ A vv vST kJ 0 Y ER-809135 Y ° A i j Me . K ff ί Me Kt 'J γΥ Ύ%λ kJ 0 Y ER-809136 Y ° A i j x Γ O cCnXX r γ nJ TV ΆγΑι'Χ kJ 0 Y 229 WO 2005/030794 PCT/US2004/030921

IeR-809137 P 1 Y 0 A Me o °V<H γΑχΑο ER-809138 Λ Υ O A Me 0 Y Y:YOY | ER-809139 Y 0 A Me o ΦΎγό ER-809140 Y 9 '''Α Me 9 °X'ICZ^ JL J. Jk s OmJu o ER-809141 V" o 'ψ' ” S ER-809142 I Y 9 A ». O V"H ΥΥΥύ ER-809143 / MY ER-809144 myL 230 WO 2005/030794 PCT/US2004/030921

1 ER-809145 A / Me 1 n 0 A-nh Y' 0 X /V ER-809146 Ai o V Me 1 0 \Uh < n II H ο /s AZ '0 ER-809147 ' YiT ' Me . Y o V«H AY u " T 0 Y ER-809148 γη ' Me I ? vO Γ ί H y\ cj H 0 V ER-809149 Yr k r n 0 ν-ΝΗ V -A CJ " II 0 z = 1 I 7 ER-809150 „ yO Me 0 °V-NH Λ- 0 AZ ^rrX ER-809151 . V Me 0 A-nh ?Y 0 Ά -nA ER-809152 x r Y 0 '« ii s Me La U “ T 0 X 231 WO 2005/030794 PCT/US2004/030921 ER-809153 .9 Y Η Y Γ H γ» ΥγΥ ER-809154 Av? ER-809155 Y Y ο Ψ Ma o °V CY-γ YY> ER-809156 Y 0 A Me cY» ί ΥΥό ER-809157 Y AVo ER-809158 Υγ k Y 0 Ψ Me 0 YYYo ER-809159 Y 0 Ψ Me Yy'YYo 232 WO 2005/030794 PCT/US2004/030921 ER-809160 X Me I MeOjC-, fl o y O Y o Yz ER-809161 Yl H Me 1 o a o χΑ,Β Ί ER-809162 &amp; Y X Me A o o ΧΧθΗ ER-809163 A H x Me 1 o I o /'XXOH ER-809164 X" Yxz* O X X Me | ι o ir H Υ --Ν. 0 YYoh s ER-809165 'Ύ a X C ϊ* 0 A Y' /XXoH s ER-809166 -’Ύ σ 0 Y Me X o 0 YXYh Y ER-809167 X o ίΥ H X Me 1 O 0 YVOH Y ER-809240 X K 0 Me 0 VOH -"v-AsA ER-809241 Yi ''bY H Me 1 ο > o /SXe Ί 233 WO 2005/030794 PCT/US2004/030921 |eR-809242 X Me rV 0 Y 0 1/ YDEt ER-809243 υπ Y N 1 J H ' Me 1 o L, 0 T3Et ER-809244 vn ^N. JL J Y N 1 J H Y Me 1 L /N ° X Ί O C^OEt ER-809245 X Me kv> O 1 O C^OEt ER-809246 r ay ' Wle Y/Yz O ZS« o L ER-809247 X A 0 γ"" Ί o '^OEt ER-809268 / Me vS 0 x 5 Vy>Et ER-809269 H ? i Me 1 0 Y|SJ As 0 V Y% /oh ER-809282 Η ? I / Me 0 Y 0 X· -z%] •'XlEt 234 WO 2005/030794 PCT/US2004/030921

ER-809283 A A < 0 Me X -Xz 0 "OH ER-809284 ii A Me 0 a γ Ύ 0 Ύ -Xz 'OEt ER-809285 9 A Me o A Y I o zY -Χγ "OH ER-809300 A j Me -A -Xz o 'OEt ER-809301 Aj> A J 0 Me -A -Xz 0 "OH ER-809302 A Me Ύ 0 γ A 0 -Xz 'OEt ER-809303 A 5 Me 0 γ A 0 -N\x -Xz "OH ER-809304 J Me -Y o A <p T o -Xz 'OEt I ER-809305 A jA A Me o 1 γ A 0 -NYz -Xz "OH 235 WO 2005/030794 PCT/US2004/030921

IeR-809306 Uk X < 0 Me '"χχ Άχ 0 OEt ER-809308 0 A A 0 Me Ά Ύ Ο "ΟΗ ER-809309 X 0 Me 'N\X Άχ Ο "OEt ER-809310 X X 0 Me Ά Ύ Ο "ΟΗ ER-809311 X 0 Me 'N\X Ύ Ο 'OEt ER-809312 X X 0 Me 'NXX Άγ Ο "ΟΗ ER-809313 0 Me 'NSX Ύ 0 'OEt ER-809314 La „c X 0 Me Ύ Ο "ΟΗ 236 WO 2005/030794 PCT/US2004/030921

ER-809315 X Γ Te o 'OEt 0 z ί' ER-809316 o< Me Λ y c 0 "OH ER-809317 1 H Me 0 X If 0 z>X Ύ 'OEt ER-809318 .c ξ 0 Me Ύ o "OH ER-809319 LXp ζ. 0 Me 'N\Z ύ o 'OEt ER-809320 L-p <y ξ 0 Me ,Ν^ 0 "OH ER-809321 H 0 Y Me | 0 Yf Av 1 H 0 •N\y χ- 'OEt ER-809322 H ο Y II Me | 0 L 0 χ "OH ER-809323 V? 0 Y II Me I 0 <y Y' 'OEt 1 Γ ] 0 ER-809324 Lh O 1 Me | o <X"ir 1 H 0 -N\y Y” 'OH I 237 WO 2005/030794 PCT/US2004/030921

IeR-809325 1 θ AT Me Q H I 1 Η ll OEt ER-809326 I 0 Me Q YaY An ER-809638 γ«ψ ° γΥs XX ER-809640 O^akBYY1'oH ER-809641 Single diastereomer YTiX- i Cj “ jYi 0H ER-809642 Single diastereomer Yf S Ψ Η j? Cj a ιYi°" ER-809643 Single diastereomer Ax ° f? γΥ» j ER-809644 Single diastereomer AAaX10" ER-809645 XX ί? y ? χ jl zX y. jl. ι h iT OEt ER-809646 XX i? Y 9 1 h if YYOH ER-809647 Single diastereomer Ύ η XX » QYr Υγ oet 238 WO 2005/030794 PCT/US2004/030921

ER-809648 Single diastereomer ° y -y- 0 ''TM ' N H 0 ER-809649 Single diastereomer V -N H 0 H ,N y O ^OEt ER-809650 Single diastereomer V H 0 -y O ''oH 0 x~ y V Me 1 ,/,/ O Yx y ° Ύ*0Ε1 0 z* y y V o Vie 1 y X o °Y ό ass. z V "X J 'Ύ σ 0 V 0 Me 1 .N. -y o 11 1 VYoEt 0 z -Z -ν σ 0 V | Me 1 ι V/N. 0 Ν' -y 0 ZYoH o ass. 1 N V r O' 0 V 0 Me 1 N. y 0 ✓V^Et I 239 WO 2005/030794 PCT/US2004/030921

0 J j 0 oAxY 0 γ S Ψ » ί V 9 Ve h Z" N'VZX''zU'"|jxA''cOiMe MbOjG Υ ϊ A 9 Y 'Ov-O JJ H ϊγΐ Y MeOaCu Ύι+f t MY? ΟΥρΌ k , MeOjC. 'ι' ί T If 8 ’v“ Ci Z"> crtyc A

[0198] General Reaction Procedures: [0199] Unless mentioned specifically, reaction mixtures were stirred using a magnetically driven stirrer bar. An inert atmosphere refers to either dry argon or dry nitrogen. Reactions were monitored either by thin layer chromatography (TLC), by proton nuclear magnetic resonance or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.

[0200] Listed below are abbreviations used for some common organic reagents referred to herein: 240 WO 2005/030794 PCT/US2004/030921 [0201] BOC or BOC2O: Di-teri-Butyl dicarbonate [0202] CMC: l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p- toluenesulfonate [0203] DCM: Dichloromethane [0204] DEPC: Diethylphosphoryl cyanide (Diethyl cyanophosphonate) [0205] DIBAL: Diisobutylaluminum hydride [0206] DIEA: Diisopropylethylamine [0207] DMF: ΛζΑ-Dimethylformamide [0208] DMSO: Dimethylsulfoxide [0209] Ether: Diethyl ether [0210] HBTU: 0-(1 -77-benzotriazol-1 -yl)-WJVJVJV- tetramethyluronium hexafluorophosphate [0211] HOAt: 1 -Hydroxy-7-azabenzotriazole [0212] LAH: Lithium aluminum hydride [0213] MSA: Methane sulfonic acid [0214] NMM: N-Methyl Morpholine [0215] TBME: Terf-butyl methyl ether [0216] TFA: Trifluoroacetic acid [0217] THF: Tetrahydrofuran [0218] TMEDA: Tetramethylethylenediamine [0219] General Work Up Procedures: [0220] Unless mentioned specifically, reaction mixtures were cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride. Desired products were extracted by partitioning between water and a suitable water-immiscible solvent (eg. ethyl acetate, dichloromethane, diethyl ether). The desired product containing extracts were washed appropriately with water followed by a saturated solution of brine. On occasions where the product containing extract was deemed to contain residual oxidants, the extract was washed with a 10% solution of sodium thiosulphate in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing 241 WO 2005/030794 PCT/US2004/030921 procedure. On occasions where the product containing extract was deemed to contain residual acids, the extract was washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character). On occasions where the product containing extract was deemed to contain residual bases, the extract was washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character). Post washing, the desired product containing extracts were dried over anhydrous magnesium sulphate, then filtered. The crude products were then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45°C).

[0221] On occasions where triphenylphosphine oxide was a major byproduct of the reaction, the reaction mixture was added directly to a large volume of well-stirred hexane. The resultant precipitate of triphenylphosphine oxide was removed by filtration and the filtrate processed in the usual manner.

[0222] General Purification Procedures: [0223] Chromatographic purification refers either to flash column chromatography on silica, using a single solvent or mixed solvent as eluent, or HPLC on a Cl 8 column. Suitably purified desired product containing elutes were combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45 °C) to constant mass. Final compounds were prepared for biological testing by either a) dissolved in 50% aqueous acetonitrile, filtered and transferred to vials, then freeze-dried under high vacuum; or b) dissolved in methanol, filtered and transferred to vials, then concentrated to dryness using a Centrifugal vacuum evaporator.

[0224] Example 1: Preparation of Amine Esters 18, Amine acids 20 and

Amine Amides 23

Boc’

(18) [0225] (20)

Preparation of Compound 13 (23) 242 WO 2005/030794 PCT/US2004/030921

[0226] To a solution of Compound 12 (205mg) in DMF (3.8ml), at room temperature, was added (S)-N-Boc-neo-phenylalanine (6) (140mg), NMM (0.30ml), HOAt (0.124g), and CMC (1.16g). The reaction mixture was shaken at room temperature for 24hr. Aqueous workup followed by chromatographic purification gave Compound 13 (153mg, 61%).

[0227] Preparation of Compound 14

[0228] To a solution of compound 13 (153mg) in methanol (20ml), at 0°C,

I was added sodium borohydride (3.18g) portionwise with shaking over a 3 day period. The reaction mixture temperature was maintained between 0° - 5°C. On occasion where the reaction mixture turned into a solidified mass, THF was added to aid agitation. The reaction mixture was allowed to warm to room temperature then re-cooled to 0°C and worked up in the usual manner to give compound 14 (140mg, 96%).

[0229] Preparation of Compound 15

[0230] To a solution of compound 14 (50mg) in THF (3ml), at room temperature, was added Dess Martin periodinane (204mg) in one portion. The resultant suspension was stirred vigorously for 4.5hr. An aqueous work up gave 243 WO 2005/030794 PCT/US2004/030921 crude compound 15 (50mg) which was used immediately in the next stage without purification.

[0231] General Procedure for the Preparation of Amine Esters 18

[0232] To a solution of compound 15 (1 equivalent) in a suitable volume of 1,2-dichloroethane, at room temperature, was added 4A molecular sieves (crushed and dried) (equal mass to that of the amine hydrochloride). A suitably chosen amine hydrochloride (16) (10 equivalents) was added with vigorous stirring followed by sodium triacetoxyborohydride (1.5 equivalents). The reaction mixture was stirred at an appropriate temperature (20°-50°C) until compound 15 was consumed to a satisfactory degree. Aqueous work up followed by chromatographic purification gave the corresponding TV-Boc Amine Ester 17. Deprotection of the TV-Boc moiety under suitable conditions would give the corresponding TV-terminal free amine 18. [0233] General Procedure for the Preparation of Amine Acids 20

[0234] To a solution of the TV-Boc Amine Ester 17 in a suitable mixture of THF and methanol, was added ITU lithium hydroxide solution (10-50 equivalents). When the TV-Boc Amine Ester 17 was hydrolyzed to a satisfactory degree, the reaction mixture was given an aqueous work up. The TV-Boc Amine Acid 19 was purified chromatographically. Deprotection of the TV-Boc moiety under suitable conditions would give the corresponding TV-terminal free amine 20.

[0235] General Procedure for the Preparation of Amine Amides 23 244 WO 2005/030794 PCT/US2004/030921 ΛΛ, pX Η

Riob Ο (23) [0236] To a solution of the TV-Boc Amine Acid 19 in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (21) (20 equivalents) was added followed by DEPC (20 equivalents). When the TV-Boc Amine Acid 19 was consumed to a satisfactory degree the TV-Boc Amine Amide 22 was isolated either by direct chromatographic purification of the reaction mixture, or by an aqueous work up followed by chromatographic purification. Deprotection of the TV-Boc moiety under suitable conditions would give the corresponding TV-terminal free amine 23.

[0237] Example 2: Preparation of N-Acetyl Amine Amides 27 [0238]

RH2 rg

Preparation of Compound 24

OMe [0239] To a solution of aldehyde 13 (50mg) in 1,2-dichloroethane (2ml), at room temperature, was added 4A molecular sieves (crushed and dried) (50mg). Glycine methyl ester hydrochloride (120mg) was added with vigorous stirring followed by sodium triacetoxyborohydride (205mg). The reaction mixture was stirred at 40°C) for two hours. Aqueous work up followed by chromatographic purification gave compound 24 (31mg, 46%).

[0240] Preparation of compound 25 245 WO 2005/030794 PCT/US2004/030921

[0241] To a solution of compound 24 (5.5mg) in DMF (0.4ml), at room temperature, was added pyridine (0.006ml) followed by acetic anhydride (0.004ml). The reaction mixture was shaken for three hours at room temperature then concentrated in vacuo to dryness. The residue was dissolved in saturated HCI in methanol (1ml) and stood at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to give compound 25 (4mg, 90%).

[0242] Preparation of compound 26

[0243] To a solution of compound 25 (3.35 mg) in methanol (0.2 mL), was added 1 M lithium hydroxide solution (0.118 mL). The reaction mixture was stirred at room temperature for 5 hr. Chromatographic purification followed by treatment with methanolic HCI gave the hydrochloride salt of compound 26 (1.95mg, 61%). [0244] General Procedure for the Preparation of TV-Acetyl Amine Amides 27

^xrN'

Ac O RH2

Rg [0245] To a solution of compound 26 (1 equivalent) in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (21) (20 equivalents) was added followed by DEPC (20 equivalents). When compound 26 was consumed to a satisfactory degree the TV-Acetyl Amine Amide (27) was isolated by direct chromatographic purification of the reaction mixture. 246 WO 2005/030794 PCT/US2004/030921

Example 3: Preparation of compound 33 [0246]

[024η (33)

Preparation of Compound 28

Me ι

Boc' 1“

ΌΗ (28)

[0248] To a solution of compound 3b (1.94 g) in dry DCM (20 mL), at 0°C under an inert atmosphere, was added a 1 M solution of DIBAL (32 mL) dropwise. The reaction mixture was stirred at 0°C for 2.5 hr then methanol (4.4 mL) was added dropwise followed by a saturated solution of ammonium chloride (8.8 mL). DCM (200 mL) was added and the reaction mixture stirred vigorously at room temperature for 30 min. Filtration followed by concentrated in vacuo gave crude compound 28 (1.08 g, 65%).

[0249] Preparation of Compound 29

Me (29) [0250] To a solution of compound 28 (207 mg) in THF (5 mL), at 0°C under an inert atmosphere, was added sodium hydride (60% dispersion in mineral oil; 160 mg) portionwise. The reaction mixture was stirred at 0°C for 45 min then treated with ethyl bromoacetate (0.47 mL). The reaction mixture was allowed to warm to room temperature. An aqueous work up followed by chromatographic purification gave an intermediate Boc compound (185 mg, 67%). The intermediate Boc compound (139 mg) was dissolved in ethanol (2 mL) and treated with saturated HCl in ethanol (2 mL). The reaction mixture was stood at room temperature for 10 min then concentrated in vacuo to dryness to give compound 29 (114 mg). 247 WO 2005/030794 PCT/US2004/030921 [0251] Preparation of compound 30

[0252] To a solution of compound 29 (114 mg) in DMF (1.8 mL), at room temperature, was added (S)-TV-Boc-tert-leucine (4) (283 mg), NMM (0.135 mL), HOAt (56 mg), and CMC (518 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (42 mg, 22%). The intermediate Boc compound (42 mg) was dissolved in saturated HCI in ethanol (5 mL) and stood at room temperature for 10 min. Concentration in vacuo gave compound 30 (37mg). [0253] Preparation of compound 31

[0254] To a solution of compound 30 (24 mg) in DMF (0.26 mL), at room temperature, was added (S)-N-Boc-neo-phenylalanine (6) (38 mg), NMM (0.014 mL), HOAt (8.3 mg), and CMC (52 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (38 mg, 64%). The intermediate Boc compound (38 mg) was dissolved in saturated HCI in ethanol (5 mL) and stood at room temperature for 10 min. Concentration in vacuo gave compound 31 as its HCI salt.

[0255]

248 WO 2005/030794 PCT/US2004/030921 [0256] A solution of compound 31 (4 mg) in ethanol (2 mL) was treated with 1 M lithium hydroxide (0.5ml). The reaction mixture was stirred at room temperature for 1.5 hr. Aqueous work up followed by chromatographic purification gave compound 32 (2.9mg, 76%).

[0257] Preparation of compound 33

[0258] To a solution of compound 32 (1.9 mg) in DMF (70 μΐ), at room temperature, was added NMM (3.8 μΐ), pyrrolidine (2.8 μΐ), and DEPC (5.2 μΐ). The reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was purified chromatographically to give compound 33 (1.2 mg, 58%). [0259] Example 4: Preparation of Amine Esters 42, Amine Acids 43 and

Amine Amides 45

(42) (43) (45) [0260] Preparation of compound 39

[0261] To a solution of compound 12 (1.25 g) in DMF (21 mL), at room temperature, was added (R)-TV-methylpipecoline hydrochloride (38) (0.38 g), NMM (1.4 mL), HOAt (0.575 g), and CMC (5.37 g). The reaction mixture was shaken at room temperature for 24 hr. Aqueous workup gave compound 39 (0.511 g, 63%). [0262] Preparation of compound 40 249 WO 2005/030794 PCT/US2004/030921

[0263] To a solution of compound 39 (0.8 g) in methanol (8 mL), at 0°C, was added sodium borohydride (7.9 g) portionwise over a 3 day period. The reaction mixture temperature was maintained between 0° - 5°C. On occasion where the reaction mixture turned into a solidified mass, THF was added to aid stirring. The reaction mixture was allowed to warm to room temperature then re-cooled to 0°C and quenched with saturated sodium bicarbonate solution. Aqueous workup gave compound 40.

[0264] Preparation of compound 41

[0265] To a solution of compound 40 (50 mg) in THF (3 mL), at room temperature, was added Dess Martin periodinane (225 mg) in one portion. The resultant suspension was stirred vigorously for 4 hr. An aqueous work up gave crude compound 41 (55 mg) which was used immediately in the next stage without purification.

[0266] General Procedure for the Preparation of TV-terminal N-heterocyclic

Amine Esters 42

[0267] To a solution of compound 41 (300 mg) in 1,2-dichloroethane (10 mL), at room temperature, was added 4 A molecular sieves (crushed and dried) (1.5 g). The amino acid ester hydrochloride (16) (10 equivalents) was added and the reaction mixture stirred vigorously for ~10 min. Sodium triacetoxyborohydride 250 WO 2005/030794 PCT/US2004/030921

(43) (290 mg) was added in one portion and the reaction mixture stirred vigorously at room temperature. When compound 41 was consumed to a satisfactory degree, the reaction mixture was given an aqueous work up. The TV-terminal N-heterocyclic Amine Esters 42 was purified cbromatographically, except in cases where it was deemed unnecessary.

[0268] General Procedure for the Preparation of TV-terminal N-heterocyclic

Amine Acids 43

Me c [0269] To a solution of the TV-terminal N-heterocyclic Amine Esters (42) in a suitable mixture of THF and methanol, was added 1 M lithium hydroxide solution (10-50 equivalents). When the TV-terminal N-heterocyclic Amine Esters 42 was hydrolyzed to a satisfactory degree, the reaction mixture was given an aqueous work up. The TV-terminal N-heterocyclic Amine acid 43 was purified chromatographically, except in cases where it was deemed unnecessary.

[0270] General Procedure for the Preparation of TV-terminal N-heterocyclic

Amine Amides 45

[0271] To a solution of the TV-terminal N-heterocyclic Amine acid 43 in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (44) (20 equivalents) was added followed by DEPC (20 equivalents). When the TV-terminal N-heterocyclic Amine acid 43 was consumed to a satisfactory degree the TV-terminal N-heterocyclic Amine Amide 45 was isolated either by direct chromatographic purification of the reaction mixture, or by an aqueous work up followed by chromatographic purification. 251 WO 2005/030794 PCT/US2004/030921

[0273] [0274] (51) (52)

Step 1: Preparation of Compound 49:

I N -C°2Me

Preparation of compound 47:

BOC (47)

Procedure a.

Compound 46 (1.0405 g, 4.4984 mmol) was dissolved in DMF (8.0 [0275] [0276] mL). K2CO3 (0.6258 g, 4.5279 mmol) was added. Methyl iodide (0.6 mL, 9.6379 mmol) was added. The milky suspension was stirred at room temp under nitrogen for 3 days. Standard aqueous workup yielded ester 47 as a colorless oil (1.0590 g, 96%).

[0277] Preparation of compound 2:

I

.N. .CHO BOCX Y (2) [0278] Compound 47 (0.9447 g, 3.8509 mmol) was dissolved in toluene (15 mL), and the solution was cooled to -78 °C under nitrogen. DIBAL (6.0 mL, 6.00 mmol, 1.0 M in hexanes) was added via syringe over 5 min. The solution was stirred for 1 h, and was quenched with MeOH (1.0 mL) at -78 °C. The bath was removed and 5.0 mL of saturated potassium sodium tartrate solution was added. The mixture was stirred for ca. 1 h, and was filtered through Celite. The filtrate was 252 WO 2005/030794 PCT/US2004/030921 washed with H2O and brine, and dried over Na2SC>4, filtered, and evaporated to give compound 2 (0.8413 g, 101%) sufficiently pure for the next step.

[0279] Preparation of compound 3 b:

[0280] Compound 2 (0.8413 g, 3.8509 mmol) was dissolved in CH2C12 (5.0 mL) and (carbethoxyethylidene)triphenylphosphorane (1.8212 g, 5.0254 mmol) was added. The solution was stirred at room temp under nitrogen overnight. The solution was evaporated, and the residue was diluted with EtOAc (70 mL) and washed with H2O (2 x 25 mL) and brine (25 mL), and dried over Na2SO4, filtered, and evaporated to give an oil. Purification by Flash Chromatography on SiO2 (FC) gave pure compound 3b (0.7863 g, 68%).

[0281] Preparation of compound 48:

[0282] Compound 3b (0.7863 g, 2.6262 mmol) was dissolved in CH2C12 (1.0 mL) and triethylsilane (0.460 mL, 2.880 mmol) was added. Trifluoroacetic acid (TFA) (2.5 mL) was added at room temp. After 30 min (complete reaction as judged by HPLC), the solution was evaporated to give a solid (1.1307 g). This solid was dissolved in CH3CN (ca. 10 mL) and 5.5 N HCl (2.4 mL, 13.2 mmol) was added. Evaporation gave the HCl salt, compound 48 (0.618 g, 100%).

Preparation of compound 5b:

[0283] Compound 48 (0.390 g, 1.6543 mmol), L-N-BOC-t-butylglycine (1.0106 g, 4.3694 mmol), CMC (1.9704 g, 4.6518 mmol), HOAt (0.5905 g, 4.3384 253 WO 2005/030794 PCT/US2004/030921 mmol), and NMM (0.490 mL, 4.4567 mmol) were combined, and DMF (4.0 mL) was added. The solution was stirred at room temp under nitrogen for 25 h. The solution was diluted with EtOAc (70 mL) and was washed with H2O (2 x 25 mL), aq. pH 7.2 phosphate buffer (25 mL), H2O (25 mL), and brine (25 mL), and dried over MgSO4, filtered, and evaporated to give a solid which was purified by FC to give compound 5b (0.4239 g, 62%).

[0284] Preparation of compound 49:

[0285] Compound 5b (0.1159 g, 0.2809 mmol) was dissolved in CH2C12 (3.0 mL) and triethylsilane (0.050 mL, 0.3130 mmol) was added. Trifluoroacetic acid (TFA) (2.5 mL) was added at room temp. After 30 min (complete reaction as judged by HPLC), the solution was evaporated to give a solid. This solid was dissolved in CH3CN (ca. 5 mL) and 5.5 N HCI was added (0.3 mL, 1.65 mmol). Evaporation gave the HCI salt, compound 49 (0.0662 g, 100%).

[0286] Step 2: Preparation of Compound 51: [0287] Preparation of compound 50:

(50) [0288] Compound 49 (0.0774 g, 0.2219 mmol), (7?)-N-methylpipecolic (0.0705 g, 0.3925 mmol), CMC (0.1752 g, 0.4136 mmol), HOAt (0.0344 g, 0.2527 mmol), and NMM (0.063 mL, 0.5730 mmol) were combined, and DMF (2.0 mL) was added. The solution was stirred at room temp under nitrogen for 20 h. The solution was purified directly by RP HPLC to give compound 50 (0.0989 g, 81%). [0289] Preparation of compound 51: 254 WO 2005/030794 PCT/US2004/030921

[0290] Compound 50 (0.0989 g, 0.2086 mmol) was dissolved in 1:1 H2O/MeOH (14 mL) at room temp. LiOH (0.0537 g, 2.2422 mmol) was added. The suspension was stirred at room temp. 19 h. The solution was acidified with 5.5 N HCl (0.50 mL), and purified by RP HPLC to give the TFA salt of 11 (0.0978 g, 90%). This was dissolved in CH3CN (ca. 5 mL) and treated with 5.5 N HCl (ca. 1 mL, 5.5 mmol) and evaporated to give the HCl salt of compound 51 (0.0667 g, 72%).

[0291] Step 2: Preparation of Compound 52:

hydrochloride (0.0263 g, 0.1588 mmol) were dissolved in DMF (1.0 mL) at room temp, under nitrogen. DEPC (0.017 mL, 0.1120 mmol) was added via syringe. NMM (0.025 mL, 0.2274 mmol) was added via syringe. The solution was stirred overnight, quenched with H2O (1.0 mL), and purified by RP HPLC to give the TFA salt of compound 52. This was dissolved in CH3CN (ca. 3 mL) and treated with 5.5 N HCl (0.10 mL, 0.55 mmol) and evaporated to give the HCl salt of compound 52 (0.0078 g, 100%).

[0293] Example 6: Preparation of compound 62a

[0294] Preparation of compound 54 255 WO 2005/030794 PCT/US2004/030921

Boc

(54) [0295] To a solution of 4-methylpiperidine (53) (600 pL, 5.0 mmol) in

MeOH (20 mL) was added Et3N (770 pL, 5.5 mmol) followed by Boc2O (1.2 g, 5.5 mmol) at 0°C. After 15 minutes, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction solution was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 54 (926.5 mg) quantitatively as a colorless oil.

[0296] Preparation of compound 55

Boc M co2h (55) [0297] A solution of compound 54 (926.5 mg, 5.0 mmol) in Et2O (10.5 mL) was cooled to -78°C and treated with TMEDA (755 pL, 5.0 mmol) followed by slow addition of a 1.3 M cyclohexane solution of sec-butyllithium (4.6 mL, 6.0 mmol) over a 30 minute period. The reaction solution was then warmed to -20°C and maintained at that temperature for 30 minutes, after which the solution was recooled to -78°C and purged with gaseous carbon dioxide for 15 minutes. The reaction solution was then slowly warmed to 0°C and poured into a biphasic mixture of 1JVHC1 (100 mL) and EtOAc (50 mL). The reaction solution was then extracted several times with EtOAc. The EtOAc extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 55 (1.07 g) in 89% yield as a colorless oil (a mixture of two cis enantiomers).

[0298] Preparation of compound 59a

256 WO 2005/030794 PCT/US2004/030921 [0299] To a solution of compound 55 (292 mg, 1.2 mmol) in CH2CI2 (2.4mL) at 0°C was added TFA (2.4 mL). After 15 minutes, the reaction solution was wanned to r.t. and stirred for 3 hours. The reaction mixture was then concentrated in vacuo to provide compound 59a (309 mg) quantitatively as a light yellow oil.

[0300] Preparation of compound 59b

[0301] (59b)

Step 1: Preparation of compound 56

Boc ,lXcO2Me

(56) [0302] To a solution of compound 55 (780 mg, 3.2 mmol) in DMF (6.4 mL) was added K2CO3 (663 mg, 4.8 mmol) followed by Mel (300 pL, 4.8 mmol). The reaction solution was allowed to stir overnight. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (4% EtOAc in hexanes) yielded 535 mg (65 %) of compound 56 as a colorless oil.

[0303] Step 2: Preparation of compound 57

Boc ppxCO2Me (57) [0304] To a solution of compound 56 (463 mg, 1.8 mmol) in MeOH (2.6 mL) was added a 25 wt % solution of NaOMe in MeOH (100 pL). The solution was allowed to stir overnight. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel 257 WO 2005/030794 PCT/US2004/030921 chromatography (4% EtOAc in hexanes) yielded 363.6mg (79%) of racemic compound 57 as a colorless oil.

[0305] Step 3: Preparation of compound 58

Boc

(>yco2H (58) [0306] To a solution of compound 57 (360 mg, 1.4 mmol) in a 2:1 mixture of H2O (2.75mL) and EtOH (5.50 mL) was added KOH pellets (786 mg, 14 mmol) and the reaction solution was stirred at room temperature until complete by TLC. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 58 (341 mg) quantitatively as a white solid.

[0307] Step 4: Preparation of compound 59b

To a solution of compound 58 (292 mg, 1.2 mmol) in CH2C12 (2.4 mL) at 0°C was added TFA (2.4 mL). After 15 minutes, the reaction solution was warmed to r.t. and stirred for 3 hours. The reaction mixture was then concentrated in vacuo to provide compound 59b (309 mg) quantitatively as a light yellow oil.

[0308] Preparation of compounds 60a and 60b

N CO2H (60a and 60b) [0309] To a solution of compound 59a (or 59b) (283 mg, 1.1 mmol) in

MeOH (5 mL) was added Pd(OH)2 (75 mg) followed by a 37 wt % solution of formaldehyde in H2O (300 pL). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to provide compound 60a (or 60b) (173 mg) quantitatively as a white solid.

[0310] Preparation of compounds 61a and 61b

258 WO 2005/030794 PCT/US2004/030921

(61a and 61b) [0311] To a solution of compound 60a and 60b (11.0 mg, 0.07 mmol) in CH2CI2 (350 pL) was added HBTU (40mg, 0.11 mmol) and DIEA (37 pL, 0.21 mmol). After 5 minutes, amine 49 (22.0 mg, 0.07mmol) was added. The reaction mixture was stirred for 30 minutes, filtered, and concentrated. Purification of the residue by silica gel chromatography (2% EtOH in CH2C12) yielded 15.1 mg (96 %) of each diastereomer 61a and 61b as colorless oils.

[0312] Preparation of compound 62a

[0313] To a solution of diastereomer 61a (9.0 mg, 0.02 mmol) in a 2:1 mixture of H2O (80 pL) and EtOH (160 pL) was added LiOHH2O (840 mg, 0.20 mmols). The reaction solution was allowed to stir overnight. The reaction mixture was then acidified with 1 N HCl until the pH = 6.00. The solution was then extracted several times with CH2C12. The CH2C12 extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 62a (8.4 mg) quantitatively as a white solid.

[0314] Example 7: Preparation of compound 67b

[0315] Preparation of compound 64

259 WO 2005/030794 PCT/US2004/030921 (64) [0316] To a suspension of L-penicillamine (63) (300 mg, 2.0 mmol) in methanol (10 mT.) was added benzaldehyde (233 mg, 2.2 mmol) followed by sodium bicarbonate (336 mg, 4.0 mmol). The mixture was heated to reflux with stirring for 16 L After cooling to r.t., it was acidified to pH 5 with 1 TV HCl and extracted with ethyl acetate three times. The organic phase was concentrated to give a yellow solid as the crude product 64 (469 mg, 99%) [0317] Preparation of compound 65

[0318] To a solution of crude 64 (47 mg, 0.2 mmol) in THF (1 mL) was added aq. 37% formaldehyde solution (49μ1, 0.6 mmol) followed by NaBFL (38 mg, 0.6 mmol). The mixture was stirred at r.L for 24 h. After acidifying to pH 5 and extracting with ethyl acetate, the organic phase was dried and concentrated to give crude product 65 (67 mg, >100%).

[0319] Preparation of compounds 66a and 66b

Ph Y

PhΎ H

(66a)

[0320] To a mixture of 65 (29 mg, 0.115 mmol), amine HCl salt 49 (15 mg, 0.043 mmol), CMC (55 mg, 0.129 mmol), and HOAt (3 mg, 0.022 mmol) was added DMF (0.5 mL) followed by NMM (6ml, 0.055 mmol). The mixture was stirred at r.t. for 24 h. The reaction was quenched by adding water (0.5 mL) and methanol (0.5 mL). The products 66a (32%), and 66b (75%) were obtained after separation by RP HPLC (0-100% B in 30 min. A: 5% MeCN+0.15% TFA in H2O; B: 0.15% TFA in MeCN) and lyophilization.

[0321] Preparation of compounds 67b 260 WO 2005/030794 PCT/US2004/030921

To a solution of 66b (4 mg, 0.0073 mmol) in methanol (0.5 mL) was added aq. LiOH (ITU, 0.5 mL). The mixture was stirred for 16 h and acidified with 1TV HCl. Product 67b (2.79 mg, 74%) was obtained after RP HPLC purification and

h 0 boc'xoh (69)

[0324] To a solution of diethylglycine (68) (131 mg, 1.0 mmol) in 1 TV

NaOH (1.5 mL) was added a solution of di-T-butyl-dicarbonate (436 mg, 2.0 mmol) in dioxane (1.0 mL). The mixture was stirred for 16 h. It was acidified to pH 3 with 1 TV HCl and extracted with ethyl acetate three times. The organic phases were combined, dried, and concentrated to yield crude product 69 (135 mg, 58%).

[0325] Preparation of compound 70

[0326] To a solution of crude 69 (135 mg, 0.58 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added trimethylsilyldiazomethane (2 TU in hexanes, 2.0 mmol). The solution was stirred at r.t. for 1 h. Evaporation gave crude product 70 (0.58 mmol). 261 WO 2005/030794 PCT/US2004/030921 [0327] Preparation of compound 71

[0328] To a mixture of sodium hydride (160 mg 60%, 4 mmol) in DMF (1 mT.) was added a solution of compound 70 (0.58 mmol) in DMF (1 mL) followed by methyl iodide (188 μΐ, 3 mmol). The mixture was stirred at room temperature for 24 h. Water was added to quench the reaction. The product 71 (118 mg, 78% 2 steps) was extracted with ethyl acetate and purified by flash column chromatography (silica, ethyl acetate/hexanes).

[0329] Preparation of compound 72

HN

OH HCl (72) [0330] A solution of compound 71 (118 mg, 0.46 mmol) in cone. HCl (1 mT.) was stirred at room temp, for 24 h. Product 72 was obtained after evaporation of volatiles.

[0331] Preparation of compound 73

[0332] To a mixture of compound 72 (30 mg, 0.166 mmol), amine 49 HCl salt (39 mg, 0.166 mmol), CMC (141 mg, 0.332 mmol), and HOAt (14 mg, 0.103 mmol) was added DMF (1.5 mL) followed by NMM (6ml, 0.128 mmol). The mixture was stirred at room temp, for 24 h, The reaction was quenched by adding water (0.5 mL) and methanol (0.5 mL). Product 73 (27 mg, 34%) was obtained after separation by RP HPLC (0-100% B in 30 min. A: 5% MeCN+0.15% TFA in H2O; B: 0.15% TFA in MeCN) and lyophilization. 262 WO 2005/030794 PCT/US2004/030921 [0333] Preparation of compound 74

[0334] To a solution of compound 73 (18 mg) in methanol (0.5 mL) was added aq. LiOH (1 M, 0.5 mL). The mixture was stirred for 16 h and then acidified by 1 N HCI. Product 74 (12.3 mg, 73%) was obtained after RP HPLC purification and lyophilization.

[0335] Example 9; Preparation of componnd 78

[0336] Preparation of compound 76

[0337] To a solution of compound 75 (123 mg) in dry DCM (1 mL), at 0°C under an inert atmosphere, was added a 1M solution of DIBAL (1.6 mL) dropwise. The reaction mixture was stirred at 0°C for 2 hr then allowed to warm to 10°C then re-cooled to 0°C. Methanol (0.22 mL) was added dropwise followed by a saturated solution of ammonium chloride (0.44 mL). DCM (20 mL) was added and the reaction mixture stirred vigorously at room temperature for 30 min. Filtration followed by concentrated in vacuo gave compound 76 (73 mg, 65%).

[0338] Preparation of compound 77 263 WO 2005/030794 PCT/US2004/030921

[0339] To a solution of compound 76 (3 mg) in acetonitrile (0.6 mL) was added Dess Martin periodinane (3.1 mg). The reaction mixture was stirred at room temperature for 1 hr then diluted with diethyl ether (2 mL). The resultant suspension was filtered through a 0.25 pm PTFE syringe filter and concentrated in vacuo to give crude compound 77 (4 mg).

[0340] Preparation of compound 78

[0341] To a solution of compound 77 (3 mg) in DCM (0.5 mL), at room temperature, was added ethyl carbethoxymethylidene triphenylphosphorane (21 mg). The reaction mixture was stirred at room temperature for 16 hr then concentrated in vacuo to dryness. Chromatographic purification gave compound 78 (1.48 mg, 44%).

[0342] Example 10: Preparation of compound 81

[0343] Preparation of compound 79

264 WO 2005/030794 PCT/US2004/030921

[0344] To a solution of compound 7b (10 mg) in dry DCM (0.5 mL), at 0°C under an inert atmosphere, was added a 1 M solution of DIBAL (0.085 mL) dropwise. The reaction mixture was stirred at 0°C for 1.5 hr then methanol (0.012 mL) was added dropwise followed by a saturated solution of ammonium chloride (0.024 mL). DCM (5 mL) was added and the reaction mixture stirred vigorously at room temperature for 20 min. Filtration followed by concentrated in vacuo gave crude compound 79 (9 mg, 95%).

[0345] Preparation of compound 80

Me Ο γ Βοοζ'Νγ7"Νχγ PhY H ° (80) [0346] To a solution of compound 79 (5 mg) in THF (0.5 mL) was added sodium bicarbonate (3.6 mg) and Dess Martin periodinane (7.2 mg). The reaction mixture was stirred at room temperature for 3hr then concentrated in vacuo to give crude compound 80.

[0347] Preparation of compound 81

[0348] To a solution of compound 80 (4.8 mg) in ethanol (0.5 mL), at room temperature, was added hydroxylamine hydrochloride (4 mg) and sodium acetate (6 mg). The reaction mixture was stirred at 40°C for 1.5 hr then concentrated to dryness. The residue was dissolved in DCM (0.2 mL) and treated with TFA (0.2 mL) and stood at room temperature for 10 min. Concentration in vacuo to dryness followed by chromatographic purification gave compound 81 (2.04 mg).

[0349] Example 11: Preparation of compound 87 265 WO 2005/030794 PCT/US2004/030921

[0350] Preparation of compound 84

Me ι

Boc' N AAoMe (84) [0351] To a solution of compound 28 (335 mg) in THF (10 mL), at 0°C under an inert atmosphere, was added sodium hydride (65% dispersion in mineral oil; 144 mg) portionwise. The reaction mixture was stirred at 0°C for 30 min then treated with methyl iodide (0.405 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 hr. An aqueous work up followed by chromatographic purification gave compound 84 (254mg, 72%).

[0352]

Preparation of compound 85 CIHoh

OMe (85) [0353] Compound 84 (189 mg) was treated with saturated HCI in methanol (5 mL). The reaction mixture was stood at room temperature for 2 hr then concentrated in vacuo to dryness to give compound 85 (145mg).

[0354] Preparation of compound 86

[0355] To a solution of compound 85 (145 mg) in DMF (3 mL), at room temperature, was added (S)-N-Boc-tert-leucine (483 mg), NMM (0.230 mL), HOAt (95 mg), and CMC (884 mg). The reaction mixture was shaken at room temperature 266 WO 2005/030794 PCT/US2004/030921 for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (249 mg, 93%). The intermediate Boc compound (60 mg) was dissolved in methanol (1 mL) and treated with saturated HCI in methanol (3 mL) and stood at room temperature for 30 min. Concentration in vacuo gave compound 86 (49mg).

[0356] Preparation of compound 87

Me' OMe (87) [0357] To a solution of compound 86 (49 mg) in DMF (0.44 mL), at room temperature, was added (S)-N-Boc-neo-phenylalanine (94 mg), NMM (34 μΐ), HOAt (21 mg), and CMC (130 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (41 mg, 47%). The intermediate Boc compound (5.5 mg) was dissolved in DCM (1 mL) and treated with TFA (1 mL). The reaction mixture was stood at room temperature for 30 min then concentrated in vacuo to dryness. The residue was dissolved in saturated HCI in methanol (1 mT.) and stood at room temperature and then concentrated in vacuo to give compound 87 (4.39 mg, 89%).

[0358] Example 12: Preparation of compound 91

Me' [0359] [0360] (91)

Preparation of compound 88

Boc' (88)

To a solution of compound 28 (344mg) in 0.5 MHunnig’s base in 267 WO 2005/030794 PCT/US2004/030921 DCM (8 mL), at 0°C under an inert atmosphere, was added methane sulphonyl chloride (0.207 mL) dropwise. The reaction mixture was stirred at 0°C for 1.5 hr then subjected to an aqueous work up followed by chromatographic purification to give an intermediate mesylate (444 mg). The intermediate mesylate was dissolved in DMSO (2 mL) and treated with sodium azide (258 mg). The reaction mixture was heated at 40°C for 6 hr. An aqueous work up gave compound 88 (306 mg, 82%).

[0361] Preparation of compound 89

(89) [0362] Compound 88 (140mg) was dissolved in DCM (1 mL) and treated with TFA (1 mL). The reaction mixture was stood at room temperature for 30 min then concentrated in vacuo to dryness. The residue was dissolved in saturated HCI in methanol (1 mL) and stood at room temperature and then concentrated in vacuo to give compound 89 (109 mg).

[0363] Preparation of compound 90

[0364] To a solution of compound 89 (109 mg) in DMF (2 mL), at room temperature, was added (S)-N-Boc-tert-leucine (347 mg), NMM (0.165 mL), HO At (68 mg), and CMC (635 mg). The reaction mixture was stirred at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (173 mg, 87%). The intermediate Boc compound (51 mg) was dissolved in methanol (1 mL) and treated with saturated HCI in methanol (3 mL) and stood at room temperature for 30 min. Concentration in vacuo gave compound 90 (43mg).

[0365] Preparation of compound 91 268 WO 2005/030794 PCT/US2004/030921

[0366] To a solution of compound 90 (42 mg) in DMF (0.37 mL), at room temperature, was added (S)-N-Boc-neo-phenylalanine (79 mg), NMM (28 μΐ), HOAt (17 mg), and CMC (108 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (88 mg). The intermediate Boc compound (88 mg) was dissolved in saturated HCl in methanol (5 mL) and stood at room temperature for 30 min and then concentrated in vacuo to give compound 91 (70 mg, 89%).

[0367] Example 13: General Procedure for the preparation of C- terminal acid compounds:

R2 = Me or Et Ri = see examples below

[0368] To a solution of the corresponding methyl or ethyl ester (e.g., compound 7b) in a suitable mixture of methanol and tetrahydrofuran, at room temperature, was added aqueous 1 Ai lithium hydroxide (10-50 equivalents). The 269 WO 2005/030794 PCT/US2004/030921 reaction mixture was stirred or shaken or stood at room temperature until the starting ester had been satisfactorily hydrolyzed. The usual workup followed by chromatographic purification gave the desired C-terminal acid compound (e.g, compound 82).

[0369] Example 14: Preparation of compound ER-807974

[0370]

Preparation of compound ER-807641

BocN^COaH [H2N(OMe)Me]CI

N-Boc-N-Me-L-Val-OH 46 HBTU, DIEA, 0°C MeCN 85-87%

Me O

Bochl^JL^.Me /X OMe ER-807641 [0371] To a stirred solution of N-Boc-N-Me-L-Valine (200 g, 0.86 mols), Ν,Ο-demethylhydroxylamine (92.8 g, 0.95 mols, 1.1 eq) and DEEA (316.3 mL, 1.82 mol, 2.1 eq) in CH3CN (2 L) at 0 °C was added HBTU (360.7 g, 0.95 mols, 1.1 eq) in portions. The solution was stirred at 0°C for additional 15 min and then for 1 h at 25 °C. Reaction was monitored by TLC (HepL/EtOAc 1:1) and deemed completed when no 46 was observed. The solution was concentrated by rota-vap and then diluted in TBME ( 1 L). The organic solution was washed with HCl (IN, 500 mL), water (250 mL), NaHCO3 (sat. 250 mL) and brine (250 mL). The organic solution was dried over MgSO4 (~120 g). The solution was filtered through a silica gel bed (~200 g) and concentrated. Crude amide ER-807641 was used without any further purification.

[0372] Preparation of compound ER-808993

Me O

BocN^JL.-.Me ; N A OMe

BocAcHO ER-807641 ER-808993 [0373]

To a stirred solution of amide ER-807641 (207 g, 755 mmol, leq.) in

LAH -

THF, -50° C 89-93% 270 WO 2005/030794 PCT/US2004/030921 dry THF (2070 mL) at -78 °C was added a solution of L1AIH4 (1.0M/THF, 754 mL, 755 mmol, 1.0 eq.). The solution was stirred at -78 °C for 1 h. Reaction was quenched at -78 °C by addition of reaction solution to a suspension of Na2SO4.10H2O (243 g) in TBME ( 1.5 L). The slurry was allowed to warm up to ~15 °C and was then filtered through a Celite pad. The filtrate was concentrated, and the crude aldehyde ER-808993 was obtained as a clear oil and used without further purification.: 157.9 g (97%).

[0374] Preparation of compound ER-808995-01

Bocff.CHO ER-808993

55% (2 steps) 1) MSA, EtOA^

2) HCl, TBME

OEt ER-808995-01 [0375] Part A: [0376] To a stirred solution of aldehyde ER-808993 (138 g, 641 mmol, leq.) in dry THF (1.4 L) at 25 °C was added Ph3P=CMeCO2Et (256 g, 705.1 mmol, 1.1 eq.). The solution was stirred at r.t for 18 h. Reaction was not completed after that time. The solution was heated to reflux for 5 h, after which TLC showed no aldehyde remaining. The solution was cooled to room temp and heptane (1.5 L) was added. Precipitation of by-product Ph3P=O was observed. The mixture was filtered through a silica gel (200 g) plug. The filtrate was concentrated to a minimum volume (~50 mL), and the residue was dissolved in EtOAc (800 mL).

[0377] PartB: [0378] To a stirred solution of crude ER-808994 in EtOAc (800 mL) was added MSA (80 mL). The mixture was stirred at r.t. for 45 min. (until complete by TLC). The amino-ester MSA salt was extracted from organic solution with water (2 x 300 mL). The aqueous layer was neutralized to pH 7-8 with sat. NaHCO3 (300 mL). The resultant solution was extracted with EtOAc (2 x 400 mL), washed with brine (300 mL), dried over MgSO4, and filtered. The EtOAc solution of the free amino-ester was bubbled with HCl (gas), and the HCl salt of ER-808995 precipitated and was collected by filtration under N2.

[0379] Preparation of compound ER-803921-01 271 WO 2005/030794 PCT/US2004/030921

HN

0Et +BocHN

HBTU DIEA, CH2CI2

ER-808996 1) MSA, EtOAc ->- 2) HCI, TBME 85-90% (2 steps)

ER-808995 N-Boc-tBu-L-Leu

Overall Yield: 39% ER-803921-01 (6 chemical steps) [0380] To a stirred solution of ER-808995 (61.2 g, 259.6 mmol, leq.), N-Boc-tBu-Gly-OH (90.1 g, 389.4 mmol, 1.5 eq) and DIEA (158 mL, 906.6 mmol, 3.5 eq) in dry DCM (612 mL) at 25 °C was added HBTU (147.7 g, 389.4 mmol, 1.5 eq.). The solution was stirred at room temp for 4 h After concentration, the solid residue was suspended in TBME (250 mL). The mixture was filtered through a silica gel bed (~120 g), and the filtrate was washed with a solution of aq. HCl (IN, 200 mL), water (200 mL) and NaHCO3 (sat, 200 mL). The organic layer was dried over MgSOzj, filtered and concentrated. The N-Boc-amino-ester ER-808996 was isolated as an oil. This intermediate was re-dissolved in EtOAc (120 mL) and MSA (75 mL) was added. The solution was stirred at room temp for 1 h, at which time the reaction was deemed complete by TLC. The amino-ester MSA salt was extracted with water (2 x 250 mL), followed by neutralization with a solution NaOH (ca.50%, 300 mL) to pH~8-9. The free amine was extracted with TBME (2 x 30 mL). The combined organic solution was washed with water (200 mL) and brine (200 mL). After drying over MgSO4 and filtration, HCl (g) was bubbled to obtain the hydrochloride salt of ER-803921 as a white solid collected by filtration at ca. 5 °C.

[0381] Preparation of compound ER-808998

NH

CO2H

Me2CO, H2 ->

Pd(OH)2 88%

N-iPr-pipecolic acid ER-808998 D-pipecolic acid [0382] A stirred suspension of D-pipecolic acid (100.0 g, 0.77 mol, leq.) and Pd(OH)2 (20% wt. Pd, 10 g) in a mixture MeOH/acetone (2:1 v/v, 1.5 L) was submitted to hydrogenation (H2 60 psi) for 24 h. Reaction was monitored by TLC (ethanol) and deemed complete when no D-pipecolic acid was observed. The mixture was filtered through a Celite (~50 g) bed. The clear filtrate was concentrated to ca. 100 mL and TBME (50 mL) was added. ER-808998 was filtered as a white crystalline solid in 88% yield. 272 WO 2005/030794 PCT/US2004/030921 [0383] Preparation of compound ER-807961

[0384] To a stirred solution of dipeptide ER-803921 (5.0 g, 16.8 mmol, 1 eq.), N-iPr-pipecolic acid ER-808998 (3.7 g, 21.8 mmols, 1.3 eq.) and HBTU (8.3 g, 21.8 mmols, 1.3 eq.) in 50 mL DCM was added DIEA (7.3 mL, 41.9 mmols, 2.5 eq.) dropwise at 25°C. The mixture was stirred for 18 h (overnight) at which time reaction was deemed complete by TLC (heptane/EtOAc 1:1). The mixture was concentrated under vacuum and TBME (50 mL) was added. The residual “thick” oil was separated from the ethereal solution by filtration through a Celite pad. The filtrate was washed with aq HCl ( 1M, 3 x 25 mL). The combined aqueous phases were neutralized with NH4OH to pH 8-9 in the presence of EtOAc (25 mL). The aqueous layer was separated and back-extracted with TBME (25 mL). The combined organic phase was washed with brine and dried over MgSO/j, filtered, and concentrated to give tripeptide-amino-ester ER-807961 in 93% yield.

[0385] Preparation of compound ER-807974

To a stirred solution of ester ER-807961 (5.0 g, 16.8 mmol) in 5:1 THF/H2O (50 mL) was added LiOH (3.50 g, 83.8 mmol), and the mixture was stirred at room temperature for 20 h. The reaction was monitored by TLC (ethanol) and deemed complete when no ER-807961 was observed. The suspension was acidified with H2SC>4 (-0.50 mL) to pH 7. The mixture was extracted with EtOAc (3 x 25 mL). The combined organic solution was washed with brine (20 mL), dried over MgSOzj, filtered, and concentrated. The residue was triturated with TBME: 1.8 g (83%) of thick oil free-base ER-807974 was obtained.

[0386] Example 15: Preparation of compound ER-808367 273 WO 2005/030794 PCT/US2004/030921

ER-808367

[0387] Preparation of compound 2Z

N^CO2H

2Z CO2H H2,2-butanone -j

Pd(OH)2l MeOH

1Z

[0388] To a suspension of D-pipecolic acid 1Z (750 mg, 5.81 mmol) in

MeOH (23.2 mL) and 2-butanone (11.6 mL) was added Pd(OH)2 (175 mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to give a crude white solid. The crude product was subjected to flash chromatography (SiO2) eluting with 100% EtOH. This provided compound 2Z (721 mg, white solid) as a mixture of diastereomers in 67% yield.

[0389] Preparation of compounds 3Z and 4Z

Separate diastereomers by flash chromatography [0390] To a solution of 2Z (650 mg, 3.51mmol) in DMF (8.8 mL) was added K2CO3 (728mg 5.27mmol) and p-nitrobenzylbromide (l.lg, 5.27mmol). The reaction mixture was allowed to stir overnight. The reaction solution was diluted with water and extracted several times with diethyl ether. The ether extracts were combined, washed with water and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture of diasteomers was then 274 WO 2005/030794 PCT/US2004/030921 separated by flash chromatography eluting with 8% EtOAc in hexanes to give each diastereomer as a pale yellow oil. Compound 3Z (360mg) was obtained in 32% yield with an Rf = 0.590 (SiO2) using 30% EtOAc in hexanes. Compound 4Z (652mg) was obtained in 58% yield with an Rf = 0.482 (SiO2) using 30% EtOAc in hexanes.

[0391] Preparation of compound ER-809439

ER-809439 ER-809447 [0392] To a solution of compound 3Z (320mg, 1.0 mmol) in MeOH (10 mL) was added Pd(OH)2 (50mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere for 3 hours. The reaction solution was then filtered through a bed of celite, and concentrated to provide compound ER-809439 (185mg) as a white solid, quantitatively. Compound ER-809439, Rf = (SiO2,0.292,100% EtOH).

[0393] Preparation of compound ER-809447 [0394] A procedure similar to that used for the preparation of compound ER- 809439 was used. Compound ER-809447, Rf = (SiO2,0.292, 100% EtOH).

[0396] Compound 49 (9.6mg, 0.03 lmmol), N-sec-butylpipecolic ER-809439 (5.2mg, 0.028 mmol), HBTU (12.9mg, 0.034 mmol), were combined. DMF (0.28mL) was added, followed by DIEA (14.9mL, 0.084mmol). The solution was stirred at room temperature under nitrogen for 20 h. The solution was purified directly by RP HPLC to give the TFA salt of compound ER-808357 (13.6mg, 82%). 275 WO 2005/030794 PCT/US2004/030921

ER-808357 ER-808367 [0398] The TFA salt of compound ER-088357 (10.4 mg, 0.018 mmol) was dissolved in 1:2 H2O/EtOH (0.072 mL/0.144 mL) at room temperature. LiOH (7.5 g, 0.18mmol) was added. The suspension was stirred at room temperature for 19 hours. The solution was purified directly by RP HPLC to give the TFA salt of compound ER-808367 (10.1 mg, quantitative).

[0399] Example 16: Preparation of compound ER-808368

[0401] A procedure similar to that used for the preparation of compound ER- 808357 was used.

[0403] A procedure similar to that used for the preparation of compound ER- 808367 was used. 276 WO 2005/030794 PCT/US2004/030921

Example 17: Preparation of compound ER-808662 [0404] [0405]

co2h [0406] To a suspension of D-pipecolic acid 1Z (1.00 g, 7.74 mmol) in

MeOH (31 mL) and 3-methyl-2-butanone (15.5 mL) was added EtjN (1.1 mL) and Pd(OH)2 (250 mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to give a crude white solid. The crude product was subjected to flash chromatography (S1O2) eluting with 100% EtOH. This provided compound 5Z (377.9 mg, white solid) as a single diastereomer in 24.5% yield. Rf = (S1O2,0.280,100% EtOH).

[0408] ER-808656 A procedure similar to that used for the preparation of compound ER- 808357 was used.

[0409]

Preparation of compound ER-808662

277 WO 2005/030794 PCT/US2004/030921 [0410] A procedure similar to that used for the preparation of compound ER- 808367 was used.

[0411] Compounds ER-809638 through ER-809650 were made according to the procedures for ER-808368 or ER-808662 with the one change: N-BOC-L-Valine was used in place of N-BOC-N-Methyl-L-Valine (46). Compounds ER-808998, ER-809439 and 5Z were used as required.

[0412] Example 18: Preparation of compound ER-808824

ER-808824

[0413] Preparation of compound 6Z

[0414] Compound 48 (325.5mg, 1.38mmol), L-N-BOC-valine (300.0mg, 1.38 mmol), HBTU (628.3mg, 1.66 mmol), were combined. CH2CI2 (7mL) was added, followed by DIEA (0.72mL, 4.14mmol). The solution was stirred at room temperature under nitrogen for 1 hour. The solution was concentrated in vacuo, and the crude was purified by flash chromatography (S1O2) eluting with 4% EtOAc in hexanes. This provided compound 6Z (476.8mg) as a colorless oil in 86.7% yield.

[0416] Compound 6Z (450mg, 1.13mmol) was dissolved directly in 4N HCl/dioxane (2.8mL). The reaction was stirred for overnight and then concentrated in vacuo to give compound 7Z (374.8mg) as a white solid, quantitatively. 278 WO 2005/030794 PCT/US2004/030921

ER-809439 [0417]

ER-808815 [0418] A procedure similar to that used for the preparation of compound ER- 808357 was used.

[0420] A procedure similar to that used for the preparation of compound ER- 808367 was used.

[0421] Example 19: Biological Assays: [0422] In certain embodiments, compounds of the invention were tested for in vitro and in vivo activity. Screening methods included standard in vitro cell growth inhibition assays using a panel of human cancer cell lines, a U937 (ATCC accession number CRL 1593) mitotic block reversibility assay, mouse serum stability assay, MDR assay, and cytotoxicity assay. In certain other emdodiments, compounds of the invention were evaluated in tumor xenograft in vivo growth inhibition assays.

[0423] In vitro potency was determined in the MDA-MB-435 cell growth inhibition assay, and active compounds (ICso < 20 nM) were evaluated in the reversibility, MDR, and mouse serum stability assays. In addition, the active compounds were tested in the IMR-90 cytotoxicity assay and in additional cell growth inhibition assays in a panel of human cancer cell lines, both solid and nonsolid tumors.

[0424] Cell growth inhibition assay: Cultured human cancer cells (including breast, prostate, colon, lung, leukemia, lymphoma and other) were plated in 96-well plates and grown in the continuous presence of test compounds for 72 or 96 hours. 279 174479/3

The human cell lines used in this cell growth inhibition assay, include, but are not limited to, the following solid tumor cell lines and non-solid tumor cell lines: DLD-1 colon cancer cells (ATCC accession number CCL-221), DU 145 prostate cancer cells (ATCC accession number HTB-81), H460 non small cell lung cancer, HCT-15 colon cancer cells (ATCC accession number CCL-225), HEL erythroleukemia cells, HL-60 promyelocytic leukemia cells (ATCC accession number CCL-240), K562 leukemia (ATCC accession number CCL-243), LOX melanoma, MDA-MB-435 breast cancer cells, U937 lymphoma cells (ATCC accession number CRL 1593), PANC-1 pancreatic cancer (ATCC accession number CRL-1469), HCC-2998 colon cancer (NCI-Frederick Cancer DCTD Tumor/Cell Line Repository), HCT 116 colon cancer (ATCC accession number CCL-247), HT-29 colon cancer (ATCC accession number HTB-38), LoVo colon cancer (ATCC accession number CCL-229), SW-480 colon cancer (ATCC accession number CCL-228), SW-620 colon cancer (ATCC accession number CCL-227) and COLO-205 colon cancer (ATCC accession number CCL-222). For monolayer cultures, growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139 : 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340 plate reader and absorbances at 405 nm were subtracted from absorbances at 620 nm. For suspension cultures, growth was assessed using a 3-(4, 5-dimethylthiazol-2-yl) -2, 5- diphenyl tetrazolium bromide-based assay (Mosmann et al, J. Immunol. Methods, 65: 55-63, 1983) modified as follows. After 4 days of incubation with test compounds, sterile-filtered 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide was added to each well (final concentration, 0.5 mg/ml), and plates were incubated at 37 C for 4 h. Acid-isopropanol (0.1 N HCl in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dissolved by gentle mixing. Absorbances at 540 nm were measured on a Titertek Multiscan MCC/340 plate reader.

Mitotic block reversibility assay was performed as described (See, Patent US 6,214, 865 BI, by B. Littelfield et al, 4/10/01). 280 WO 2005/030794 PCT/US2004/030921 [0426] Briefly, U937 (ATCC accession number CRP 15.93) were exposed to various concentration of compounds for 12 hours. The compounds were washed away and the cells were allowed to recover for an additional 10 hours. The cells were collected by centrifugation and fixed overnight in 70% ethanol. The cells were washed in PBS, incubated with RNase A and stained with propidium iodide. Single channel flow cytometry was performed on a Becton Dickinson FACScan; the collection and analysis of data were performed using Becton Dickinson CELLQuest software. Doublet events were eliminated from analyses by proper gating on FL2-W/FL2-A primary plots before histogram analysis of DNA content (measured as FL2-A).

[0427] Determination of activity in vitro utilizing the MDR assay. This is a modification of the standard cell growth inhibition assays described above. Two cultured himan cancer cell lines were used: human uterine sarcoma MDR negative MES-SA cells (ATCC accession number CRL-1976) and human uterine sarcoma MDR-positive MES-SA/Dx5 cells (ATCC accession number CRL-1977). Cells were plated in a 96-well microtiter plates at a density of 7500 cells / well. The cells were incubated in the presence or absence of test compounds for 96 hours. Cell growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340 plate reader and absorbances at 405 nm were subtracted from absorbances at 620 nm. The ratio of the concentrations of the compounds inhibiting the growth of cells by 50% was calculated and used to estimate the sensitivity of the compounds to MDR (multidrug-resistance, or P-glycoprotein-mediated drug efflux). In some cases, a different pair of cell lines was used: MDR-negative murine leukemia cells P388/S, and MDR-positive murine leukemia cells P388/VMDRC.04. Cells were plated in a 96-well microtiter plates at a density of 4000 cells / well. The cells were incubated in the presence or absence of test compounds for 72 hours. Cell growth was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide-based assay (Mosmann et al, J. Immunol. Methods, 65: 55-63, 1983) modified as follows. After 3 days of incubation with test compounds, sterile-filtered 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide was added to 281 WO 2005/030794 PCT/US2004/030921 each well (final concentration, 0.5 mg/ml), and plates were incubated at 37°C for 4 h. Acid-isopropanol (0.1 N HCI in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dis-solved by gentle mixing. Absorbances at 540 nm were measured on a Titertek Multiscan MCC/340 plate reader.

[0428] Stability to esterase degradation was determined in the mouse serum stability assays. The enzymatic activity of mouse serum can result in inactivation of compounds in vivo despite their promising in vitro activity. A modification of the standard cell growth inhibition assays described above was used to determine stability of the test compounds to esterase degradation. Human breast carcinoma cell line MDA-MB-435 or human prostate carcinoma cell line DU 145 were used. The cells were plated in a 96-well microtiter plates at a density of 7500 cells / well. Prior to adding the test compounds to cells in the cell growth inhibition assay, the test compounds were incubated in 100% mouse serum or normal growth medium for 6 hours at 37 °C. After that, the test compounds were added to the 96-well microtiter plates containing the cells. The cells were incubated in the presence or absence of test compounds for 96 hours. Cell growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340. Ability of test compounds to inhibit cell growth after compounds’ exposure to mouse serum esterases was assessed.

[0429] Cytotoxicity assay. To determine toxicity of compounds against

normal, non-dividing cells, quiescent IMR-90 normal human fibroblasts (ATCC accession number CCL-186) were used. IMR-90 cells were plated in a 96-well microtiter plate format and grown to confluency (for 72 hours). After the 72-hour growth, the cells were washed and the medium was replaced from normal medium containing 10% fetal bovine serum to medium containing low concentration of serum (0.1%). Cells were made quiescent by incubation in 0.1% serum-containing growth medium for additional 72 hours. Cells were incubated with the test compounds for 24 hours. Cellular ATP levels were measured using a ViaLight HS 282 WO 2005/030794 PCT/US2004/030921 kit (LumiTech Ltd). A cytotoxic compound carbonyl cyanide was used in all assays as a positive control for cytotoxicity.

[0430] Determination of antitumor activity in vivo in mice. In vivo tumor xenograft studies were performed in immunocompromised (nude) mice. Mice (female Ncr athymic) were implanted subcutaneously with human tumor xenografts (including breast MDA-MB-435, colon COLO-205, HCT-15, HCT-116, HCC-2998, HT-29, SW-620, DLD-1, LoVo, melanoma LOX, lung H522, pancreatic PANC-1). After the xenografts reached an average size of 75-200 mm3 or 400-600 mm3, the animals were weighed and randomly divided into groups of 8-10 on the first day of compound administration. Test compounds were administered intravenously or intraperitoneally. Tumor and body weight measurements were done twice weekly. 283

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CA2479764A1	Canada	A1	2003-10-09
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AU2003228354A1	Australia	A1	2003-10-13
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EP1490054A2	European Patent Office (EPO)	A2	2004-12-29
AU2004276261A1	Australia	A1	2005-04-07
CA2539823A1	Canada	A1	2005-04-07
WO2005030794A2	World Intellectual Property Organization (WIPO)	A2	2005-04-07
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EP1664088A2	European Patent Office (EPO)	A2	2006-06-07
US7064211B2	United States of America	B2	2006-06-20
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