Indian Patents
Title of Invention

HEMIASTERLIN DERIVATIVES
Abstract The present invention provides compounds having formula (I): and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R1-R7, X1, X2, R, Q, and n are as defined herein.
Full Text HEMIASTERLIN DER1VATIVES AND USES THEREOF
PR1OR1TY CLAIM
[000l] This Application claims pR1oR1ty to U.S. Patent Application No.: 10/667,864 filed September 22, 2003, which is a Continuation-In-Part and claims the benefit under 35 U.S.C. § 120 of International Application No.: PCT/US03/08888, filed March 21, 2003, which claims pR1oR1ty to U.S. Provisional Patent Application Number 60/366,592, filed March 22,2002; the entire contents of each of the above-referenced applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Hemiasterlin (1) was first isolated from the sponge Hemiasterella minor (class, Demospongiae; order, Hadromedidia; family, Hemiasterllidae) collected in Sodwana Bay, South AfR1ca (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.

[0003] After the initial isolation and reporting of this compound, additional hemiasterlins were isolated, and several hemiasterlin deR1vatives 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 deR1vatives that could be prepared and evaluated for biological activity were limited.

WO 2005/030794 PCTAJS2004/030921
[0004] Clearly, there remains a need to develop synthetic methodologies to access and examine the therapeutic effect of a vaR1ety of novel deR1vatives 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),
and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R1-R7, X1, 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 DESCR1PTION OF CERTAIN PREFERRED EMBODIMENTS OF THE
INVENTION
[0006] In recognition of the need to access and further explore the biological activity of novel deR1vatives of Hemiasterlin, and this class of peptides in general, the present invention provides novel peptide compounds, as descR1bed 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, ovaR1an, stomach, brain, liver, pancreatic or esophageal cancer, lymphoma, leukemia and multiple myeloma. In certain other embodiments, the inventive compounds also find use in the
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prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.
[0007] 1) General DescR1ption of Compounds of the Invention
[0008] The compounds of the invention include compounds of the general formula (I) as further defined below:

wherein n is 0,1,2, 3 or 4;
X1 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;
R4 and R2 are each independently hydrogen, -(OO)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 R1, 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;
R5, R6 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 RF is an aliphatic, alicyclic, heteroaliphatic,
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WO 2005/030794 PCT7US2004/030921
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', SRQ', 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(aryi), alicyclic(heteroaryl) or
heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; and
pharmaceutically acceptable deR1vatives thereof.
[0009] In certain embodiments, compounds of formula (I) and compounds descR1bed in classes and subclasses herein, are not naturally occurR1ng Hemiasterlins.
[0010] In certain embodiments, compounds of formula (I) and compounds descR1bed in classes and subclasses herein, do not have the following structure:

[0011] In certain embodiments of compounds descR1bed directly above and compounds as descR1bed in certain classes and subclasses herein, the compounds do not compR1se more than four consecutive a-amino acid residues, and/or one or more of the following groups do not occur simultaneously as defined: (a) nisi;
X1 and X2 are each C(=O);
R1 and R.2 are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at 4

least one of R1 and R2 is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and neither are Ar, Ar-aliphatic- or Ar-alicyclic-, R1 and R2, taken together, may form a three- to seven-membered R1ng; wherein Ar is defined as substituted or unsubstituted phenyl, naphtyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl, benzofuryl, benzotbiophenyl., quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl or pyR1dyl;
R3 is hydrogen;
R4 is —CR4aR4bR4c wherein R4a and R4b are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at least one of R4a and R4b 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 R1ng; and R4C is hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ax-aliphatic-, Ar-alicyclic- and Ar; wherein Ar is as defined directly above;
R5, R6 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 -ORG, -SRG, -NRGRH, -NHCH(RK)CO2H, or -NRCH(RK)CO2H, wherein RQ and RH are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic or heteroalicyclic; RK is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, or a moiety having the structure -(CH2)NRK1RK2, wherein t=l-4 and RK1 and RK2 are independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic or-C(NH)(NH2);
(b) nisi;
X1 and X2 are each C(=O);
R1 is an optionally substituted methylene or -CH= group bonded to the indole moiety thereby forming a tR1cyclic moiety;
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WO 2005/030794 PCT/US2004/030921
R.2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when R1 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 R2 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 R1 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;
R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;
R6 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;
X1 and X2 are each C(=O);
R1 is hydrogen, an optionally substituted alkyl or acyl group, or an optionally substituted methylene or -CH= group bonded to the indole moiety thereby forming a tR1cycllc moiety;
R2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when R1 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

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 substiruent, or is absent when R1 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;
R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;
R6 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-5 -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) n is1;
X1 is C=O;
R1 is methyl;
R2 and R3, taken together, form apipeR1dine moiety;
R4 and R5 are each hydrogen,
R6 is -CH(CH3)CH2CH3;
R7 is -CH2OC(=O)CH2CH(CH3)2, -CH2OC(=O)CH2CH2CH3 or -CH2OC(=O)CH2CH3; and
-R-X2-Q together represent the moiety having the structure:

(e) n is1;
X1 is C=O;
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WO 2005/030794 PCT/US2004/030921
R1, R25 and R7 are each methyl;
R3 and R5 are each hydrogen;
R4 and R6 are each f-propyl; and
-R-X2-Q together represent the moiety having the structure:

wherein Rx is hydrogen, or 2-thiazolyl; and/or
(f) nisi;
X1 is CO;
R1 and R2 are each independently hydrogen or Ci-4alkyl;
R3 and R5 are each hydrogen;
R4 and R6 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 C1-4alkyl;
R" is C1-6alkylamino; hydroxy; C3-7cycloalkylamino optionally substituted by phenyl or benzyl; arylamino; C1-4alkoxy; 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,
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benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, ammo, di-
alkylamino, acylamino, alkoxycarbonylamino or halogen; aralkyioxy or
aralkyl both optionally substituted with one to three substituents selected
from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl,
alkylcarbonyloxy, eyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl,
phenoxy, tR1fluoromethyl, tR1fruoromethoxy, alkylthio, hydroxy,
alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino,
aminosulfonyl or benzyl; or aralkylaniino having C1-4alkylene 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, tR1fluoromethyl, tR1fluoromethoxy, 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, tR1fluoromethyl, tR1fluoromethoxy, 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, tR1fluoromethyl, tR1fluoromethoxy, 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:
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WO 2005/030794 PCT/US2004/030921
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 tR1ple bond;
C3-7cycloalkyl refers to a saturated, cyclic hydrocarbon group with 3-7 carbon atoms optionally substituted with alkyl, phenyl, amino, hydroxy or halogen;
C1-4alkylene refers to a biradical linear or branched hydrocarbon chain containing 1-4 carbon atoms;
Axalkyl, 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 O, 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 cycloalkyl 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;
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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 descR1bed in (a) above and compounds as descR1bed in certain classes and subclasses herein, the following groups do not occur simultaneously as defined:
n is 1; X1 and X2 are each C(=O); R1 and R2 are each independently hydrogen, methyl, ethyl, propyl, n-butyl, acetyl; or R1 and R2, taken together, form a moiety selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R3 is hydrogen; R4 is -CR4aR-4bRtc wherein R4a and R4b are each independently methyl, ethyl, n-propyl or n-butyl; or R48 and R4b, taken together, form a moiety selected from the group consisting of ß-cyclopropyl, (3-cyclobutyl, p-cyclopentyl, and P-cyclcohexyl; and R4C is phenyl, naphtyl, anthracyl or pyrrolyl; R5 and R7 are each independently hydrogen or methyl; R6 is a three to she carbon, branched alkyl group; and -R-X2-Q together represent the moiety h.aving the structure:

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, iso-butyl or sec-butyl; and Q is OH or ORG wherein RG is a linear or branched one to six carbon alkyl group.
[0013] hi certain other embodiments of compounds described in (a) above and compounds as descR1bed in certain classes and subclasses herein, the following groups do not occur simultaneously as defined:
n is 1; X1 and X2 are each C(=O); R1, R3 and R5 are each hydrogen; R2 is methyl; R4 is -CR4aR4bR4c, Rc is tert-butyl; and -R-X2-Q together represent the moiety having the structure:

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WO 2005/030794 PCT/US2004/030921
wherein R' is isopropyl; R" is methyl; and Q is OH; and
(a) R4a and R4b are each methyl; R4C is methyl or phenyl; and R7
is hydrogen or methyl;
(b) R4a and R45 are each methyl; R4C is hydrogen; and R7 is
methyl; or
(c) R4a and R4b are each hydrogen; R4C is phenyl; and R7 is
methyl.
[0014] ha certain other embodiments, compounds of formula (T) and compounds descR1bed 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, which is incorporated herein by reference in its entirety.
[0015] In certain other embodiments, compounds of formula (I) and compounds descR1bed 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. .
[0016] In certain other embodiments, compounds of formula (I) and compounds descR1bed 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/CytotoX1c Activity of Hemiasterlin Analogues", Journal of Natural Products, 2003, 66(2): 183-199, which is incorporated herein by reference in its entirety.
[0017] hi certain other embodiments, compounds specifically and/or geneR1cally 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.
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[0018] In certain other embodiments, compounds specifically and/or geneR1cally disclosed in Andersen et al, Tet. Lett., 38(3): 317-320, 1997; Billson, et al., Bioorganic & Medicinal Chemistiy 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.
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[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:


WO 2005/030794 PCT7US2004/030921

[0020] In certain other embodiments, compounds of formula (T) are defined as follows:
X1 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;
R1 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
R1 and R2, taken together, may form a saturated or unsaturated, substituted or unsubstituted cyclic R1ng 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 R1ng of 3 to 8 atoms;
the carbon atom beaR1ng R3 and R4 may be of S configuration; nis 1;
R5 is hydrogen or a protecting group; wherein the protecting group may be a nitrogen protecting group;
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R6 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 beaR1ng Rg 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 R7 may 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:

wherein R8a, R9a and R10a 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 R10a 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 beaR1ng R8a may be of S configuration;
(ii) the heteroalkyl moiety may have the structure:

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WO 2005/030794 PCT/US2004/030921
"wherein R8b, R9b, R10b and R11b are each independently absent, hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or acyl; or a substituted or unsubstituted aryl or heteroaryl moiety; wherein any two R7, R8b, R9b, R10b and R11b groups may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; wherein NR7 and CR8b, CR8b and CR9b, CR9b and NR10b, and NR10b and CR11b are each independently linked by a single or double bond as valency permits; and wherein the carbon atom beaR1ng R8b may be of S configuration;
(iii) or the heteroalkyl moiety may have the structure:

wherein R8c, R9c, R10c, R11c and R12C 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, R8c, R9c, R10c R11c and R12c groups may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; wherein NR7 and CR8c, CR8c and CR9c, CR9c and CR10c, CR10c and CR11c are each independently linked by a single or double bond as valency permits; and wherein the carbon atom beaR1ng R8c may be of S configuration; and
Q is ORQ', SRQ', NRQ'RQ", 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 heteroalkyl moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; or wherein RQ and RQ , taken together, may
16

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 deR1vatives 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 (I) in which R is -CH(R8a)C(R.9a)=C(R10a)- and the compound has the structure (la):

wherein R1-R7, X1, X2, Q and n are defined in classes and subclasses herein;
R8a, R9a and R10a are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a 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 X1 is C=O; n is 1; R1 and R4, taken together, form a cyclic heterocyclic or heteroaryl moiety; R3 is hydrogen or is absent when the carbon atom beaR1ng R3 is linked to N or E via a double bond; and the compound has the structure (Ic):
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WO 2005/030794 PCT/US2004/030921

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, NR1vRv, wherein each occurrence of Rw 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.V1 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 RV1 is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
N and G, G and J, J and L, L and M, 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, land mis 3-6.
[0024] Another class of compounds of special interest consists of compounds
having the structure of formula (I) in which X1 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 R1, R2, R5-R7, R, X2 and Q are defined in classes and subclasses
herein. 18

[0025] The following structures illustrate several exemplary types of compounds of class (la). Additional compounds are descR1bed in the Exemplification herein.

[0026] The following structures illustrate several exemplary types of compounds of class (Ib). Additional compounds are descR1bed in the Exemplification herein.
19

WO 2005/030794 PCTAJS2004/030921

[0027] The following structures illustrate several exemplary types of compounds of class (Ic). Additional compounds are descR1bed in the Exemplification herein.

[0028] The following structures illustrate several exemplary types of compounds of class (Id). Additional compounds are descR1bed in the Exemplification herein.
20


[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 (la) includes those compounds having the structure of formula (la) in which Xj is C=O; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;
R8a, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a 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
X1 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 (la) in which X1 is C=O; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;
R8a, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety; and
X2 is CRARB, SO2 or C=O; wherein RA and RB are each independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.
[0032] Another important subclass of class (la) includes those compounds having the structure of formula (la) in which X1 and X2 are each OO; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CR4aR4bR4c; and the compound has the following structure:

wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and
R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl, and R4Cis aryl or heteroaryl; and
22

R8a. R9a and R10a are each independently hydrogen, or an alkyl, heteroalkryl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryi), -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 X1 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;
R8a, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a 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 CR1R1i, 0, S, NR1R1i, wherein each occurrence of R1 and R1i is independently absent, hydrogen, -C(=O)R1ii, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any two adjacent R1, R1i or R1ii groups, taken together, form a alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety; wherein each occurrence of R1ii is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
N and A, A and B, 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 X1 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:

wherein Rj, R2, R5-R7 , A, B, D, E, a, b, d and e are defined in classes and subclasses herein;
R4a and R Rsa, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a 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. R1 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. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -aUcyl(aryl) or acyl;
iii-a. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
24

iv-a. R1 is hydrogen aad 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;
v-a. R1 and R2 are each hydrogen;
vi-a. The carbon atom beaR1ng 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 R4a 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 -CR1aR4bPh; wherein R4a 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;
X1-a. R3 is hydrogen;
X1i-a. R1 and R4, taken together, form a substituted or unsubstituted pyrrolidine group;
X1ii-a. R1 and R4, taken together, form a substituted or unsubstituted pipeR1dine group;
X1v-a. R1 and R4, taken together, form a substituted or unsubstituted thiazolidine group;
xv-a. R1 and R4, taken together, form a substituted or unsubstituted morpholine group;
25

WO 2005/030794 PCT7US2004/030921
xvi-a. R1 and R4, taken together, form a substituted or unsubstituted thiomorpholine group;
xvii-a. R1 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;
X1x-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;
xX1-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, -C1-6alkylORa, -C1-6alkylSRa 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;
xX1i-a. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tot-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, -C1-6alkylORa, -C1-6alkylSRa 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
26

linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xX1ii-a. R3 and R4 are each ethyl;
xX1v-a. R3 is phenyl and R4 is lower allcyl;
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;
xX1x-a. R5 is hydrogen;
xxx-a. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
xxX1-a. R6 is methyl, ethyl, propyl, butyl, pentyl, tot-butyl, z-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
xxX1i-a. R6 is tert-butyl;
xxX1ii-a. The Rg-beaR1ng carbon atom is of S configuration;
xxX1v-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(R1)(R2) together represent the moiety having the structure:
; and
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, 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) RGI is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or substituted or unsubstituted phenyl;

e) RGI 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) LisCH2,SorO;
xxxvii-a. -[C(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:
28

;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, tert-butyl, /-propyl, -
CH(CH3)Et, -CH(CH3)CH2CH2CH3,
CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2,
CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -
CHtEfh, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl
or cyclopropyl;

c) R2 is methyl, ethyl, propyl or j-propyl;
d) RLI and R12 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(R8a)C(R9a)=C(R10a)-; and
a) R8a is substituted or unsubstituted, linear or branched, cyclic
or acyclic, saturated or unsaturated lower alkyl;
b) R8a is iso-propyl;
c) The Rga-beaR1ng carbon atom is of S configuration;
29

WO 2005/030794 PCT/US2004/030921
d) R9a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower
alkyl;
e) K.9a is hydrogen;
f) R10a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower
alkyl;
g) R10a is methyl;
xxxvii-a. nisi;
xxxviii-a, X1 is C=O;
xxX1x-a. X1 is CH2;
xl-a. X1 is SO2;
xli-a. X2 is C=O;
xlii-a. X2 is CH2;
xliii-a. X2 is SO2;
xliv-a. Q is ORQ', SRQ', NRQRQ", N3, =N-0H,or a moiety selected from the group consisting of:

30

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 RQ2 is independently
hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -CORJ, -CO2RJ, -NRJCORJ -NRJCO2RJ, -CONRJRJ, -COCNOR^R1, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or
heteroaryl moiety, or -Z1RJ; wherein h is 1 or 2; and Z] 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 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', NRQRQ", N3, =N-OH, 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 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; 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
xliv-a. Q is ORQ', SRQ', NRQRQ', N3, =N-OH, or a moiety selected from the group consisting of:

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 R and RQ' , taken together with the nitrogen
32

atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.
[0034] An important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which R is -C(R8b)C(R9b)N(R10b)C(R11b)-; and the compound has the following structure:

wherein R1-R7, n, X1 and Q are defined in classes and subclasses herein;
R8b, R9b, R10b and R11b are each independently absent, hydrogen, -(O=0)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, R10b and R11b 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 CR8b, CR8b and CR9b, CR9b and NR10b, NR10b and CR11b are each independently linked by a single or double bond as valency permits.
[0035] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which X1 is C=O; R is -C(R.8b)C(R9b)N(R10b)C(R11b)-; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CR4aR4bR4c; and the compound has the following structure:

wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and
R4a and R4b are each independently hydrogen or lower alkyl and R4C is aryl or heteroaryl;
33

WO 2005/030794 PCT/US2004/030921
R8b, R9b, R10b and R11b 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 R8b, R9b, R10b and R11b 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 CR8b, CR8b and CR9b, CR9b and NR10b, NR10b and CR11b are each independently linked by a single or double bond as valency permits.
[0036] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which R is-C(R8b)C(R9b)N(R10b)C(R11b)-; R10b and R11b, taken together, form a substituted or unsubstituted cyclic heteroalkyl or heteroaryl moiety; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein; pis 1,2,3 or4; q is 0-12;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R9b 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 R8b 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
34

NR.7 and CR8, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.
[0937] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which n is 1; R is— C(R8b)C(R9b)N(R10b)C(R11b)-; R10b and R11b, 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, X1 and Q are defined in classes and subclasses herein;
pis 1,2,3 or4;
is 0,1,2, 3,4, 5 or 6;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl; and R4c is aryl or heteroaryl;
Rgb and Rc>b 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 R8b 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 CR8b, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.
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(R10C)C(RHC)OC(R12C)-; and the compound has the following structure:

wherein R1-R7, n, X1 and Q are defined in classes and subclasses herein;
Rgc, Rs>c, R10c, R11c and R12C 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, R9C, R10c, R11c and R12C 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 CR8c, CR8c and CR9c, CR9C and CR10c, and CR10c and CR11c 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 X1 is C=O; n is 1; R3 is hydrogen; R4 is a moiety having the structure -CR4aR4bR4C; R is — C(Rsc)C(R9c)C(R10c)C(R11c)OC(R12c)-; and the compound has the following structure:

wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
R4a and R4b are each independently hydrogen, or lower alkyl or heteroalkyl; and R4Cis aryl or heteroaryl;
36

R8c R9c R10c R11c and R12c 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, R9c R10c, R1lc and R12C 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 CR8c, CRgc and CR9c, CR9C and CR10c, and CR10c 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 (Ib) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (Ib) in which:
i-b. R1 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. R1 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. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
iv-b. R1 is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tot-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)2C=CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
v-b. R1 and R2 are each hydrogen;
vi-b. The carbon atom beaR1ng R3 and R4 is of 5 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 -CR4aR4bR4c; wherein R43 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-b. R3 is hydrogen and R4 is —CR4aR4bPh; wherein R4a and R4b 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;
X1-b. R3 is hydrogen;
X1i-b. R1 and R4, taken together, form a substituted or unsubstituted pyrrolidine group;
X1ii-b. R1 and R4, taken together, form a substituted or unsubstituted pipeR1dine group;
X1v-b. R1 and R4, taken together, form a substituted or unsubstituted thiazolidine group;
xv-b. R1 and R4, taken together, form a substituted or unsubstituted morpholine group;
xvi-b. R1 and R4, taken together, form a substituted or unsubstituted thiomorpholine group;
xvii-b. R1 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

X1x-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;
xX1-b. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-bntyl, 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, -CHOBfh, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci-6alkylORa, -C]^alkylSRa or -CR^'H0; 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;
xX1i-b. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-bxstyl, 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^alkylSRa 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 linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xX1ii-b. R3 and R4 are each ethyl; xX1v-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 cycloalkyl 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;
xX1x-b. R5 is hydrogen;
xxx-b. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xxX1-b. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, z-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
xxX1i-b. R6 is tert-butyl;
xxX1ii-b. The R6-beaR1ng carbon atom is of 5 configuration;
xxX1v-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(R1)(R2) together represent the moiety having the structure:
; and
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, 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, -
CHQSfh, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl
or cyclopropyl;
d) R2 is methyl, ethyl, propyl or z-propyl;
40

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 RMJ 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;
i) RMI and RM2 are each hydrogen; j) g is 1 or 2; and/or k) L is CH2, S or O;
xxxviii-a. -C[(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:
;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, tert-butyl, /-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, -CCCH^C^CH, cyclohexyl, cyclopentyl, cyclobutyl
or cyclopropyl;
41

WO 2005/030794 PCT/US2004/030921
c) R2 is methyl, ethyl, propyl or z-propyl;
d) RLI and RL2 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) RL1 and RL2 are each hydrogen;
f) RLI and RL2 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(R8b)C(R9b)N(R10b)CR11b- and
a) Rgb is substituted or unsubstituted, linear or branched, cyclic
or acyclic, or saturated or unsaturated lower alkyl;
b) R8b is fco-propyl;
c) The Rsb-beaR1ng carbon atom is of S configuration;
d) R9b is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;

e) R10b is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or acyl;
f) R10b is hydrogen, methyl or acetyl;
g) R10b and R11b, taken together, form a substituted or
unsubstituted pyrrolidine R1ng; or
h) R9b and R11b, taken together, form a substituted or unsubstituted thiazole R1ng;
xxxviii-b. R is -C(R8c)C(R9c)C(R10c)CR11cOCR12c- and
a) R8c is substituted or unsubstituted, linear or branched, cyclic
or acyclic, or saturated or unsaturated lower alkyl; 42

b) R.8c is iso-propyl;
c) The Rgc-beaR1ng carbon atom is of S configuration;
d) R9c and R10c are each independently hydrogen or substituted
or unsubstituted, linear or branched, cyclic or acyclic, or
saturated or unsaturated lower alkyl;
e) CR9C and CR10c are linked via a double bond;
f) CR9C and CRJOC are linked via a double bond and Rpc is
hydrogen; or
g) CR9C and CR10c are linked via a double bond and R10c is
methyl;
xxX1x-b. nisi;
xl-b. X1 is C=O;
xli-b. X1 is CH2;
xlii-b. X1 is SO2;
xliii-b. Q is ORQ', SRQ', NRQRQ", N3, =N-OH,or a moiety selected from the group consisting of:

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 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 —Z1RJ; wherein h is 1 or 2; and Z1 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 RQ , 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', NRQRQ", N3, =N-OH, or a moiety selected from the group consisting of:

44


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 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
xlv-b. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from the group consisting of:
45

WO 2005/030794 PCT/US2004/030921

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.
[0041] An important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is OO; R is -CH(R8a)C(R9a)=C(R1Oa)-; j is 0; 1 and m are each 1; R3 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; gis 1,2, 3 or 4;
Rsa, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl,
aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and R10a groups may
46

form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;
L is CRLIRL2, S, O orNRL3, wherein each occurrence of RLI, RL2 and RL3 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 RL1, Ru, 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(R8a)C(R9a):=C(R10a)-; R3 is hydrogen; and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; g is 0,1,2 or 3;
Rsa, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a groups may form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;
RLI and RL2 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(R8b)C(R9b)N(R10b)C(R11b)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRGJ, 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; gis 1,2 or 3;
L is CRL1RL2, S, O or NRL2, wherein each occurrence of RLI, RL2 and RL3 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, RL3, 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;
R8b, R9b, R10b and R11b 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 R8b, R9b, R10b and Rub groups, taken together, form a alicyclic or heteroalicycBc moiety, or an aryl or heteroaryl moiety; wherein RM is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR8b, CRsb and CR9b, CR9b and NR10b, NR10b and CR11b are each independently linked by a single or double bond as valency permits.
[0044] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; R is C(R8b)C(R9b)N(R10b)C(R11b)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRGI, M is CRMIRNE; R10b and R11b, taken together, form a cyclic heteroalkyl group; and the compound has the structure:
48


wherein R2, R5-R7 and Q are defined in classes and subclasses herein; pis 1,2,3 or4; q is 0-12;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R9b 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 R8b 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 CR8b, and CR8b and CR9b 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(R10b)C(R11b)-; R3 is hydrogen; and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; gisO, 1,2 or 3;
49

WO 2005/030794 PCT/US2004/030921
RLI and R11 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
R8b, R9b, R10b and R11b 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 R8b, R9b, R10b and R11b 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 CR8b, CRsb and CR9b, CR9b and NR10b, NR10b and CR11b 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(R8b)C(R9b)N(R10b)C(R11b)-; R3 is hydrogen; R10b and R11b, taken together, form a cyclic heteroalkyl group; and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein; pis 1,2,3 or4; q is 0-12; gisO, 1,2 or 3;
RLI and R12 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
50

R8b 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 R8b 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 CR8b, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.
[0047] Another important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C=O; R is C(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRGI, M is CRMIRNC; and the compound has the following structure:

wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein; gis 1,2 or 3;
L is CRLIRU, S, 0 or NR11, wherein each occurrence of RL1, RL2 and RL3 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, RL3, 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;
R8c, R9c, R10c, R11c and R12c 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 R8c, R9c, R10C, R11c and R12c 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 CR8c, CR8c and CR9c, CR9c and CR10c, and CR10c and CR11c 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(Rgc)C(R9c)C(R10c)C(R11c)OC(R12c)-; 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 R1, R2, R5-R7 and Q are defined in classes and subclasses herein; g is 0,1, 2 or 3;
RLI and R11 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
R8C, R9C R10c, R11c and R12c 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 R8c, R9c, R10c, R11c and R12C 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 CR8c, CR8c and CR9c, CR9c and CR10c, and CR10c and CR11c are each independently linked by a single or double bond as valency permits.
52

[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. 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;
ii-c. R2 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, terf-butyl, z-propyl, -
CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -
CHzCHCCHsk, -CH(CH3)CH(CH3)2, -C(CH3)2Et,
CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, 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;
x-c. The moiety having the structure > forms a substituted
or unsubstituted pyrrolidine group;
53

WO 2005/030794 PCT/US2004/030921
X1-c. The moiety having the structure forms a substituted
or unsubstituted pipeR1dine group;
X1i-c. The moiety having the structure forms a substituted
or unsubstituted thiazolidine group;
X1u-c. The moiety having the structure forms a substituted
or unsubstituted morpholine group;
X1v-c. The moiety having the structure forms a substituted
or unsubstituted thiomorpholine group;
xv-c. The moiety having the structure forms a substituted
or unsubstituted indole group;
xvi-c. R5 is hydrogen;
xvii-c. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xviii-c. R6 is methyl, ethyl, propyl, butyl, pentyl, ter/-butyl, i-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
54

X1x-c. R6 is tert-butyl;
xx-c. The R6-beaR1ng carbon atom is of S configuration;
xX1-c. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xX1i-c. R7 is methyl;
xX1ii-c. R is -CH(R8a)C(R9a)=C(R10a)-; and
a) Rga is substituted or unsubstituted, linear or branched, cyclic
or acyclic, or saturated or unsaturated lower alkyl;
b) R8a is iso-propyl;
c) The R8a-beaR1ng carbon atom is of S 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) R10a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl; or
g) R10a is methyl;
xX1v-c. R is -C(R8b)C(R9b)N(R10b)CR11b- and
a) R8b is substituted or unsubstituted, linear or branched, cyclic
or acyclic, or saturated or unsaturated lower alkyl;
b) R8b is wo-propyl;
c) The R8b-beaR1ng carbon atom is of S 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) R10b is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or acyl moiety;
f) R10b is hydrogen, methyl or acetyl;
g) R10b and R11b,, taken together, form a substituted or
unsubstituted pyrrolidine R1ng; or
h) R9b and R11b, taken together, form a substituted or unsubstituted thiazole R1ng;
xxv-c. R is -C(R8C)C(R9C)C(R10c)CR11cOCR12c- and
a) R8c is substituted or unsubstituted, linear or branched, cyclic
or acyclic, or saturated or unsaturated lower alkyl;
b) R8c is iso-propyl;
c) The R8c-beaR1ng carbon atom is of S configuration;
d) R9c and R10c are each independently hydrogen or substituted
or unsubstituted, linear or branched, cyclic or acyclic, or
saturated or unsaturated lower alkyl;
e) CR9C and CR10C are linked via a double bond;
f) CR9c and CR10c are linked via a double bond and R9c is
hydrogen; or
g) CR9C and CR10c are linked via a double bond and R10c is
methyl;
xxv-c. The moiety having the structure represents the
moiety having the structure:
56


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,
-CH^HCCH3)2, -CH(CH3)CH(CH3)2, -C(CH3)2Et,
CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl,
cyclopentyl, cyclobutyl or cyclopropyl;
1) R2 is methyl, ethyl, propyl or i-propyl;
m) RGI 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;
0) RGI 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) LisCH2, SorO;
57

WO 2005/030794 PCT/US2004/030921
xxvi-c. The moiety having the structure represents the
moiety having the structure:
;and
g) 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;
h) R2 is methyl, ethyl, propyl, butyl, pentyl, ferf-butyl, /-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, -CiCU&OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
i) R2 is methyl, ethyl, propyl or /-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;
1) RLI and RL2 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


xX1x-c. X2 is SO2;
xxx-c. Q is 0RQ', SRQ', NRQRQ", 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 NR ; each occurrence of RQ1 and RQ2 is independently hydrogen, halogen, -CN,
-SCOyi1, -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 Z\ is independently -O-, -S-, NR , -C(O)-, wherein each occurrence of R 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 RQ , taken together with the nitrogen atom to
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WO 2005/030794 PCT/US2004/030921
which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety;
xxX1-c. Q is ORQ, SRQ', NRQRQ", 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; 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, 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 R^ 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
xxX1i-c. Q is ORQ', SRQ', NRQ RQ", N3, =N-OH,or a moiety selected from the group consisting of:
60


wherein each occurrence of r is 0,1 or 2; and R^ 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 RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.
[0050] An important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is -CH(Rsa)C(R9a)=C(R1oa)-; X2 is C=O; and the compound has the following structure:

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; R1} R2, R5-R7 and Q are defined in classes and subclasses herein; and
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WO 2005/030794 PCT/US2004/030921
R8ib R9a and R1oa are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and wherein any two R7, Rga, R9a and R1oa groups may form an alicyclic, heteroalicyclic, alicyclicc(aryl), heteroalicyclic(aryl), aiicyclic(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(R1ob)C(Rnb)-; X2 is C=O; and the compound has the following structure:

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; R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
Rgb, R9b, R1ob 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, R1ob 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 CR8b, CRgb and CR9b, CR9b and NR1ob, NR1ob and CRHb 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(R1ob)C(Rnb)-; X2 is C=O; R1ob and Rub, taken together, form a cyclic heteroalkyl group; and the compound has the following structure:
62


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; R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
pis 1,2,3 or4; 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;
Rsb and R% 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 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(R1oc)C(Rnc)OC(R12c>; and the compound has the following structure:

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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; R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
Rgc, R9C, R1oc, R1ic and R12C 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 R1oc, R1ic and R12C 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 CR8c, CRgc and CR9c, CRpc and CR1oc, and CR1oc and CRnc 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. R1 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. R1 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. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
iv-d. R1 is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, /-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -
64

C(CH3)2Et, -CH(CH3)cyclobiityl, -CH(Et)2, -C(CH3)2€H, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
v-d. R1 and R2 are each hydrogen;
vi-d. R1 and R2 are independently hydrogen or methyl;
vii-d. R1 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;
X1-d. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, terf-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, -CHCEt^, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -Ci^alkylOR", -Ci^alkylSRa 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;
X1i-d. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-bntyl, /-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^alkylSRa or -CR^Ph; 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;
X1ii-d. R3 and R4 are each ethyl;
X1v-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 cycloalkyl 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;
X1x-d. R5 is hydrogen;
xx-d. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xX1-d. R$ is methyl, ethyl, propyl, butyl, pentyl, ferf-butyl, z-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;
xX1i-d. R6 is tert-butyl;
xX1ii-d. The R^-beaR1ng carbon atom is of S configuration;
xX1v-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(Rga)C(R9it)=C(R1oa)-; and
i) Rga is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
j) R8a is iso-propyl;
k) The R8a-beaR1ng carbon atom is of S configuration;
66

1) R9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
m) Rc>a is hydrogen;
n) Rjoa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or
0) R1oa is methyl;
xxvii-d. R is -C(R8b)C(R9b)N(R1Ob)CR1 lb- and
p) Rgb is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
q) Rgb is wo-propyl;
r) The Rgb-beaR1ng carbon atom is of S configuration;
s) R% is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
t) R1ob is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower . alkyl or acyl moiety;
u) R1ob is hydrogen, methyl or acetyl;
v) R1ob and Rub, taken together, form a substituted or unsubstituted pyrrolidine R1ng; or
w) Rpb and Rub, taken together, form a substituted or unsubstituted thiazole R1ng;
xxviii-d. R is -C(R8c)C(R9c)C(R1oc)CR1 icQCR12c- and
h) Rgc is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
1) R8c is iso-propyl;
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WO 2005/030794 PCT/US2004/030921
j) The Rgc-beaR1ng carbon atom is of S configuration;
k) R.9c and RJQC are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
1) CRpc and CR1oc are linked via a double bond;
m) CR9C and CR1oc are linked via a double bond and Rgc is hydrogen; or
n) CR9C and CR1oc are linked via a double bond and R1oc is methyl;
xX1x-d. X2 is C=O; xxx-d. X2 is CH2; xxX1-d. X2 is SO2;
xxX1i-d. Q is ORQ', SRQ', NRQRQ", 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 RQ2 is independently hydrogen, halogen, -CN,
-S(O)hRJ, -NO2, -CORJ, -CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ,
68

-CO(NORJ)RJ, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,
aryl or heteroaryl moiety, or -Z1RJ; 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 RQ , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety;
xxX1ii-d. Q is ORQ', SRQ', NRQRQ", 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; each occurrence of RQ1 and RQ2 is independently hydrogen, or a substituted or unsubstituted, linear or
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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
xxX1v-d. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, =N-OH, or a moiety selected from the group consisting of:

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

[0055] As the reader will appreciate, compounds of particular interest include, among others, those which share the attR1butes 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 deR1vatives thereof):

wherein R1-R2, R4a, R4b> R9a-R1oa 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 deR1vatives thereof).*

wherein A, B, D, E, a, b, d, e, R1-R2, R4* R4b, and R9a-R1oa 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-II descR1bed above, a vaR1ety of other subclasses are of special interest, including, but not limited to those classes i-a. through xliv-a. descR1bed above and classes, subclasses and species of compounds descR1bed above and in the examples herein.
[0059] ID) Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof):
71

WO 2005/030794 PCTAJS2004/030921

wherein R1-R.2, R4a, R1b, R9b-R1ib and RG are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.
[0O60] IV) Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof);

wherein A, B, D, E, a, b, d, e, R1-R2, Rja, R1b, and R9b-R1ib 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 deR1vatives thereof):

wherein R1-R2, R»a, R1b, R9c-R12c 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 III-V descR1bed above, a vaR1ety of other subclasses are of special interest, including, but not limited to those classes i-b. through xlv-b. descR1bed above and classes, subclasses and species of compounds descR1bed above and in the examples herein.
[0063] VI) Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof);
72


wherein L, IWR1oa, RGI> RMI and RJVG 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 R& are independently substituted or unsubstituted linear or branched lower alkyl.
[0064] VII) Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof):

wherein g, R9a-R1oa, RLI and Ru are as defined above and in subclasses herein; X1 is CH2 or C=O; R2 and R$ are independently substituted or unsubstituted linear or branched lower alkyl; and Q is ORQ or NR°- RQ wherein RQ is hydrogen or lower alkyl, or RQ 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 deR1vatives thereof):

wherein A, B, D, E, L, a, b, d, e, p, Rpb, RGI> RMI and RM2 are as defined above and in subclasses herein; g is 1 or 2; and R2 and K$ are independently substituted or unsubstituted linear or branched lower alkyl.
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WO 2005/030794 PCT7US2004/030921
[0066] DQ Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof):

wherein p, Rc^, RLI, RU, R^ and RQ are as defined above and in subclasses herein; and R2 and R^ are independently substituted or unsubstituted linear or branched lower alkyl.
[006V] It will also be appreciated that for each of the subgroups VI-IX descR1bed above, a vaR1ety of other subclasses are of special interest, including, but not limited to those classes i-c. through xxX1i-c. descR1bed above and classes, subclasses and species of compounds descR1bed above and in the examples herein. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, wo-propyl, sec-butyl or -CH(CH3)CH(CH3)2. hi certain embodiments, for compounds of subgroups VI-IX above, R6 is /erf-butyl or wo-propyl. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, wo-propyl, sec-butyl or — CH(CH3)CH(CH3)2, and Rg is tert-butyl or wo-propyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is methyl and R$ is tert-hvttyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is wo-propyl and R$ is ter/-butyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is .sec-butyl and Rg is tert-butyl or iso-propyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is-CH(CH3)CH(CH3)2, and R6 is fe/'f-butyl.
[0068] X) Compounds of the formula (and pharmaceutically acceptable deR1vatives thereof);

74

wherein R\, R^ R1oa 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 descR1bed above, a vaR1ety of other subclasses are of special interest, including, but not limited to those classes i-d. through xxX1v-d. descR1bed above and classes, subclasses and species of compounds descR1bed above and in the examples herein.
[0070] Some of the foregoing compounds can compR1se one or more asymmetR1c centers, and thus can eX1st in vaR1ous isomeR1c forms, e.g., stereoisomers and/or diastereomers. It is to be understood that the invention encompasses every possible isomer such as geometR1c isomer, optical isomer, stereoisomer and tautomer based on asymmetR1c 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 eX1sts 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 geometR1c 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.
[0O71] Furthermore, certain compounds, as descR1bed herein may have one or more double bonds that can eX1st 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 vaR1ous isomers, e.g., racemic mixtures of stereoisomers. The invention also encompasses tautomers of specific compounds as descR1bed above. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically
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WO 2005/030794 PCT/US2004/030921
acceptable deR1vatives of these compounds and compositions compR1sing one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
I0O72J Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may eX1st 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 vaR1ous modes of cooling, ranging from very fast to very slow cooling duR1ng 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, IR spectroscopy, differential scanning caloR1metry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their deR1vatives, their tautomeR1c forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
[0O73] 2) Compounds and Definitions
[0O74] 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 descR1bed herein, and are illustrated in part by the vaR1ous classes, subgenera and species disclosed elsewhere herein.
[0O76] Additionally, the present invention provides pharmaceutically acceptable deR1vatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in
76

combination with one or more additional therapeutic agents. The phrase, "pharmaceutically acceptable deR1vative", as used herein, denotes any pharmaceuticalry acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or deR1vative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise descR1bed herein, or a metabolite or residue thereof. Pharmaceutically acceptable deR1vatives thus include among others pro-drugs. A pro-drug is a deR1vative 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 vaR1ety of compounds, and mateR1als and methods for deR1vatizing 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 deR1vatives 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 pR1mary or secondary amine-containing functionalities. Examples of such prodrug moieties include the following:
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WO 2005/030794 PCT/US2004/030921
For the synthesis of the prodrug groups, see Borchardt, R. T. et al., J. Org. Chem. 1997, 43, 3641-3652.
R1 = all natural, unnatural amino acids
For the synthesis of the prodrug groups, see Zhou, X-X. et al., PCT WO 99/51613.
R1 = C1-C4 alkyl, cycloalkyl, oxyakyi,
aminoalkyl, eta
R2 = all natural, unnatural amino acids
For the synthesis of the prodrug groups, see Ezra, A. et al., J. Med. Chem. 2000, 43, 3641-3652.
R1, R2 = all natural, unnatural amino acids
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 descR1bed herein.
[0078J Certain compounds of the present invention, and definitions of specific functional groups are also descR1bed in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the PeR1odic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as descR1bed therein. Additionally, general pR1nciples of organic chemistry, as well as specific functional moieties and reactivity, are descR1bed in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as descR1bed herein, utilize a vaR1ety 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 temporaR1ly blocked so that a reaction can be carR1ed out selectively at another reactive site in a
78

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 nontoX1c reagents that do not attack the other functional
groups; the protecting group forms an easily separable deR1vative (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 (tR1methylsilyl ether), TES
(tR1ethylsilylether), UPS (tR1isopropylsilyl ether), TBDMS (t-butyldimethylsilyl
ether), tR1benzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few),
esters (e.g., formate, acetate, benzoate (Bz), tR1fluoroacetate, 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
deR1vatives, N-Alkyl and N-Aryl amines, imine deR1vatives, and enamine
deR1vatives, 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 vaR1ety of additional equivalent
protecting groups can be readily identified using the above cR1teR1a and utilized in
the present invention. Additionally, a vaR1ety of protecting groups are descR1bed in
"Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G.,
Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby
incorporated by reference.
[0079] It will be appreciated that the compounds, as descR1bed herein, may be substituted with any number of substituents or functional moieties. In general, the
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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 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 descR1bed 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 vaR1ables 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 integR1ty of the compound for a sufficient peR1od of time to be detected and preferably for a sufficient peR1od 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 geneR1c 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.
8o

[0081] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms, hi certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms, hi yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed hi the invention contain 1-8 aliphatic carbon atoms, hi still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms, hi 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 bR1dged 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, -CEt-cyclobutyl, cyclopentyl, -CH2-cyclopentyl-n, cyclohexyl, -Ctfe-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
[0083] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" 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, hi certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms, hi 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
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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, methyltbio, 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 "aminoalkyl" 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, hi 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-descR1bed aliphatic (and other) moieties of compounds of the invention include, 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; -CHI2; -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, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents descR1bed above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents descR1bed 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 descR1bed herein.
82

[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, -(heteroaUcyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryr' 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 R1ng system having one or two aromatic R1ngs 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 R1ng atoms of which one R1ng atom is selected from S, O and N; zero, one or two R1ng atoms are additional heteroatoms independently selected from S, O and N; and the remaining R1ng atoms are carbon, the radical being joined to the rest of the molecule via any of the R1ng atoms, such as, for example, pyR1dyl, pyrazinyl, pyR1midinyl, 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;
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WO 2005/030794 PCT/US2004/030921
heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2:NH2; -CH2SO2CH3; -C(O)RX; -CO2(RX); -CON(RX)2; -OC(O)RX; -OCO2RX; -OCONCR^; -NCR^; -SCO^R*; -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 descR1bed above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents descR1bed 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 descR1bed 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 hetercyclic 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; -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, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents descR1bed above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents descR1bed 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 descR1bed herein.
84

[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. hi 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(R.X); -CON(RX)2; -OC(O)RX; -OCC^R.; -
OCON(RX)2; -N(RX)2; -SCO^R,; -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 descR1bed above and herein may be substituted or unsubstituted,
branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl
substituents descR1bed 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 descR1bed 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 from fluoR1ne, chloR1ne, 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, tR1fluoromethyl, and the like.
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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 R1ng or a polycyclic group, including, but not limited to a bi- or tR1-cyclic group compR1sing fused six-membered R1ngs having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered R1ng has 0 to 1 double bonds and each 6-membered R1ng has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oX1dized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic R1ngs may be fused to an aryl or heteroaryl R1ng. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidiny 1, imidazolinyl, imidazolidinyl, pipeR1dinyl, 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; -CHCI2; -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, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents descR1bed above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substitutents descR1bed 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 descR1bed 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

branched groups. Similarly, the terms "alicyclic", "heteroalicyclic",
"beterocycloalkyF, "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)", "-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 "cycloalkyl", "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 vaR1ety 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 vaR1ety combinatoR1al 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 descR1bed above and in certain classes and subclasses herein. Examples of synthetic methods for prepaR1ng 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 descR1bed herein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting mateR1als are well known to those skilled in the art. Although the following schemes descR1be certain exemplary compounds, it will be appreciated that the use of alternate starting mateR1als will yield other analogs of the invention. For example, compounds are descR1bed below where Xj and X2 are each C=O, R5 is hydrogen, Rg is terr-butyl and R7 is methyl; however, it will be appreciated that alternate starting mateR1als and/or intermediates can be
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WO 2005/030794 PCT/US2004/030921
utilized to generate compounds where, for example, X] 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] hi certain embodiments, the inventive compounds, have the general structure (C) 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 descR1bed in classes and subclasses herein. Examples of preferred structures for R, R' and Q are depicted in Scheme 1.







88


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 R1ng with R4
R4 = Me, Et, or forms a 5-6 membered R1ng with R3
R1ob = H, Me, Ac or forms a 5-6 membered R1ng with R-|1b
R-iib = H, or forms a 5-6 membered R1ng with R^ob
RG = H, Me, Et or forms a 5-6 membered R1ng with RH1
RH1 = H, Me, Et or forms a 5-6 membered R1ng with RG
RH2 = H, CO2H, CO2Me, CONH2, COIMHMe, CONHMe2, CONHBn, CH2OMe
RG1 = H, Me, or forms a 5-6 membered R1ng with RG2
Re2 = H, or forms a 5-6 membered R1ng with RG1
RG3 = H, CO2H, CO2Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe
Scheme 1
[0099] In certain embodiments, the inventive compounds belong to class (la) and subclasses thereof, as descR1bed herein. Scheme 2 depicts the synthesis of exemplary compounds of this class (compounds of general structure 11). As shown
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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 JV-Boc-terf-leucine (4). The JV-terminal moiety of the compounds of the invention (R' in Scheme 1) may be provided by (S)-N-Boc-neo-phenylalanine (6). As depicted in Scheme 2, a vaR1ety of synthetic methods allow access to a vaR1ety 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 deR1vatives.

Scheme 2
[0100J An exemplary synthetic approach for the preparation of intermediate
6 is depicted in Scheme 3. The method afforded («S)-AT-Boc-neo-phenylalanine (6) in 20% overall yield.

90


Scheme 3
[0101] In certain other embodiments, the inventive compounds belong to
class (Ib) and subclasses thereof, as descR1bed herein. Schemes 4-6 depict the synthesis of exemplary types of compounds of this class (for example, Amine Esters, Amine Acids, Amine Amides and JV-Acetyl Amine Amides of general structure 18, 20, 23, respectively as seen in Schemes 4; See also Amine Esters, Amine Acids, Amine Amides and JST-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 compR1sing an //-terminal moiety deR1ved from (5)-JSf-Boc-neo-phenylalanine (6), a person of ordinary skill in the art would appreciate that a wide vaR1ety of organic moieties other than those descR1bed in Schemes 4-6 may be used to construct the compounds of the invention. Similarly, Schemes 4-6 recite compounds where Hie C-terminal moiety may be earboxylie 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 deR1vatives and analogs of these compounds, or compounds obtained from different starting mateR1als.
91




[0102] In certain other embodiments, the inventive compounds belong to
class (Ic) and subclasses thereof, as descR1bed herein. Schemes 7-10 depict the
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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 compR1se a nitrogen-containing heterocyclic N-terminal moiety. For example, the heterocyclic moiety may be a pipeR1dine R1ng (Schemes 7, 8 and 9) or a thiazolidine R1ng (Scheme 10). Examples of other suitable moieties are descR1bed 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


95

96
WO 2005/030794 PCTAJS2004/030921


Methylpipecolic acid analogs

[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 pipeR1dine R1ng (e.g., other than 4-methyl) and/or analogs where the pipeR1dine nitrogen atom may be substituted with a group other than methyl (e.g., ethyl, propyl, butyl, pentyl, tert-butyl, /-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -
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[0104] In certain other embodiments, the inventive compounds belong to
class (Id) and subclasses thereof, as descR1bed herein. One skilled in the art would appreciate that the exemplary heterocyclic starting mateR1als descR1bed 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 a-amino acid moieties to access compounds of class (Id), as illustrated in Scheme 11 below:




98


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

[0106] In certain other embodiments, there is provided a method for
prepaR1ng compounds of formula VIA:

wherein L, Q, IWR1oa, Roi, RMI and RM2 are as defined above and in subclasses herein; g is 1 or 2; and R2 and R$ are independently substituted or unsubstituted linear or branched lower alkyl.
[0107] In certain other embodiments, the method compR1ses steps of:
(a) reacting two compounds having the structures:
1OO


under suitable conditions to form a compound having the structure:

(b) oX1dizing 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:

(d) subjecting the compound formed in step (c) to suitable diversification
reactions to generate the desired compound having the structure:

wherein L, Q, Rpa-R1oa, 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 R$ are independently substituted or unsubstituted linear or branched lower alkyl.
101

158

1 60
WO/ 2005/030794 PCT7US2004/030921


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[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 oX1dizing, the conditions
compR1se swem oX1dizing conditions. In certain embodiments, in the step of oX1dizing, the conditions compR1se Dess Martin oX1dizing conditions.
[0110] hi certain embodiments, in step (c), the olefin-forming conditions
compR1se Ph3P=C(R1oa)C02RQ'; wherein RQ is hydrogen, lower alkyl or an oxygen protecting group; and R1oa is as defined generally above and in classes and subclasses herein.
[0111] hi certain other embodiments, the method compR1ses steps of:
(a) reacting two compounds having the structures:

under suitable conditions to form a compound having the structure:

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:

(c) subjecting the compound formed in step (b) to suitable diversification
reactions to generate the desired compound having the structure:

102


wherein L, Q, R^-R1o*, 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 R$ are independently substituted or unsubstituted linear or branched lower alkyl.
[0112] In certain embodiments, the step of converting compR1ses steps of:
(i) subjecting the compound having the structure:

to ozonolysis conditions to form, an aldehyde having the structure:
;and
(ii) subjecting the compound formed in step (i) to suitable olefin-forming conditions to form a compound having the structure:

10113J In certain embodiments, in step (ii), the olefin-forming conditions
compR1se Ph3P=C(R1oa)CC>2RQ'; wherein RQ is hydrogen, lower alkyl or an oxygen protecting group; and Rjoa is as defined generally above and in classes and subclasses herein.
[0114] In certain embodiments, the step of converting compR1ses a step of:
subjecting the compound having the structure:
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to cross-olefin-metathesis conditions in the presence of CH2=C(R1oa)C02RQ' to form a compound having the structure:

[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, R5-R7, R9a-R10a> 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:


[0117] Alternatively, or additionally, compounds of formula (VIA) may be
prepared according to the methodology depicted in Scheme 14:
104


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

[0119] In certain other embodiments, compound 92 may be prepared
according to the methodology depicted in Scheme 16:
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[0120] In certain embodiments, compound 95 may be prepared according to
the methodology depicted in Scheme 17:

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

[0122] In certain embodiments, for the compounds depicted in Schemes 13-
18, R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl. In certain exemplary embodiments, R$ is methyl, ethyl, propyl, butyl, pentyl, tert-bvtyl, /-propyl, -CH(CH3)CH2CH3, -
106

CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. Li certain other exemplary embodiments, R$ is ter/-butyl.
[GI23] In certain embodiments, for the compounds depicted in Schemes 13-
18, R1oa is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl. hi certain exemplary embodiments, R1oa is linear or branched lower alkyl. hi certain other exemplary embodiments, R1oa is methyl.
[0124] hi certain embodiments, for the compounds depicted in Schemes 13-
18, the moiety having the structure: has the following structure:
wherein R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl. hi 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, tertf-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)2C^CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.
[0125] In certain embodiments, for the compounds depicted in Schemes 13-
18, R6 is nieihyl, ethyl, propyl, butyl, pentyl, tert-bnty\, /-propyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; R1Oa is methyl;
and the moiety having the structure: has the following structure:
wherein R2 is methyl, ethyl, propyl, butyl, pentyl, terf-butyl, /-propyl, -CH(CH3)Et, -CH(CH3)CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)2, -
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CH(CH3)CH(CH3)2, -C(CH3)2Et, -CH(CH3)cyclobutyl, -CH(Et)2, -C(CH3)2OCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.
[0126] 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.
[0127] It will be appreciated that each of the reactions descR1bed in Schemes
2-18 above can be carR1ed out using reagents and conditions as descR1bed for the
synthesis of vaR1ous types of exemplary compounds descR1bed above, or they may be
modified using other available reagents or starting mateR1als. For example, a vaR1ety
of amide formation conditions, esteR1fication, 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, 5*
ed., John Wiley & Sons, 2001; and "Comprehensive Organic Transformations, a
guide to functional group preparations", R1chard C. Larock, VCH publishers, 1999;
the entire contents of which are incorporated herein by reference.
[0128] As mentioned above, it will be appreciated that the invention is not
limited in scope to the compounds recited herein. Synthetic strategies or starting mateR1als other than those descR1bed herein may be used to prepare compounds of general structure (I). It will also be appreciated that each of the components/starting mateR1als 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 R1ng is present in the compound, the aromatic R1ng can be diversified (pR1or 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 R1ng, the aromatic R1ng can be diversified by reacting with a reagent to protect the hydroxyl group, or to convert it into an aliphatic or heteroaliphatic moiety). DescR1bed generally below are a vaR1ety of schemes to assist the reader in the synthesis of a vaR1ety of analogues, either by
108

diversification of the intermediate components or by diversification of the peptide construct.
[0129J In certain embodiments, the preparation of chemically diverse
deR1vatives may be achieved by diversifying the C-tenninal moiety of the compounds. For example, where the C-terminal moiety is a carboxylic acid, examples of chemical transformations suitable to achieve such deR1vatization include, but are not limited to, reduction to the corresponding aldehyde or alcohol, amidation, Wittig reaction, decarboxylation, esteR1fication, 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.
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[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 cytotoX1c or growth inhibitory effect in vitro, or cause tumor regression and/or inhibition of tumor growth in vivo.
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WO 2005/030794 PCT/US2004/030921
[0132] Compounds of this invention which are of particular interest include
those which:
• exhibit cytotoX1c 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 cytotoX1city to non-dividing noirmal 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 112

[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) [0135] In certain other embodiments, compounds of the invention exhibit
low cytotoX1city to non-dividing normal cells. In certain exemplary embodiments, inventive compounds exhibit little or no cytotoX1city 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 cytotoX1city in non-dividing normal cells at concentrations in the range of up to 1-10 \M.
[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. hi certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 25. hi certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 20. hi certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 15. hi 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. hi certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 3.
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[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, hi 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 size; or T/C value embodiments, compounds of the invention have T/C values embodiments, compounds of the invention have T/C values embodiments, compounds of the invention have T/C values embodiments, compounds of the invention have T/C values [0140] hi certain embodiments, compounds of the invention inhibit the
growth of human cancer cells in vitro, exhibit low sensitivity to MDR (e.g., low
114

resistance ratio), exhibit low cytotoX1city 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 cytotoX1city 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] hi certain embodiments, compounds of the invention have any one or
more of the following properties:
(i) exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM - 10 nM;
(ii) have a resistance ratio preferably (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 preferably [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;
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WO 2005/030794 PCT/US2004/030921
(ii) have a resistance ratio preferably (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 preferably [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 vaR1ety 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, ovaR1an cancer, pancreatic cancer, prostate cancer and gastR1c 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

[0146] In certain embodiment, the method involves the administration of a
therapeutically effective amount of the compound or a pharmaceutically acceptable deR1vative 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, ovaR1an cancer, pancreatic cancer, prostate cancer and gastR1c cancer, bladder cancer, uteR1ne 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 descR1bed 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, ovaR1an cancer, pancreatic cancer, prostate cancer and gastR1c 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 compR1se any one of the compounds descR1bed herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable deR1vative thereof), and optionally compR1se a pharmaceutically acceptable carR1er. In certain embodiments, the compounds are capable of inhibiting the growth of or killing cancer cells. In certain embodiments,
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these compositions optionally further compR1se 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 cytotoX1c 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 eX1st in free form for treatment, or where appropR1ate, as a pharmaceutically acceptable deR1vative thereof. According to the present invention, a pharmaceutically acceptable deR1vative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro drug or other adduct or deR1vative 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 descR1bed herein, or a metabolite or residue thereof.
[0150] 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 toX1city, irR1tation, allergic response and the like, and are commensurate with a reasonable benefit/R1sk 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. descR1be pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ duR1ng the final isolation and puR1fication of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as descR1bed 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

salts. Examples of pharmaceutically acceptable, nontoX1c acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloR1c acid, hydrobromic acid, phosphoR1c acid, sulfuR1c acid and perchloR1c acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaR1c acid, citR1c 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, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, pahnitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, tR1fluoroacetate, 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 appropR1ate, nontoX1c ammonium, quaternary ammonium, and amine cations formed using counterfoils such as halide, hydroX1de, 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 deR1ved 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 toX1city, irR1tation, allergic
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WO 2005/030794 PCT/US2004/030921
response, and the like, commensurate with a reasonable benefit/R1sk ratio, and effective for their intended use, as well as the zwitteR1onic 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, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium SeR1es, and in Edward B. Roche, ed., Bioreversible CarR1ers in Drug Design, AmeR1can Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
[0153] As descR1bed above, the pharmaceutical compositions of the present
invention additionally compR1se a pharmaceutically acceptable carR1er, 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, lubR1cants 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 vaR1ous carR1ers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carR1er medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleteR1ous manner with any other components) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of mateR1als which can serve as phannaceutically acceptable carR1ers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its deR1vatives 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; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffeR1ng agents such as magnesium, hydroX1de and aluminum hydroX1de; alginic acid; pyrogenfree water; isotonic saline; R1nger's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toX1c compatible lubR1cants such as
120

sodium lauryl sulfate and magnesium stearate, as well as coloR1ng agents, releasing agents, coating agents, sweetening, flavoR1ng and perfuming agents, preservatives and antioX1dants 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 descR1bed 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 descR1bed 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 deR1vative 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, ovaR1an cancer, pancreatic cancer, prostate cancer and gastR1c cancer, to name a few.
[0157] As descR1bed in more detail herein, in general, the present invention
provides compounds useful for the treatment of cancer, particularly solid and non-solid tumors. Specifically, certain compounds of the invention have been shown to inhibit the growth of certain tumor cell lines in vitro, as descR1bed 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,
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catheters, artificial implants, pins, electR1cal implants such as pacemakers, and especially for arteR1al 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.
[0159] 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 mateR1als, with the patterns cut on the surface with a laser machine. The stent can be electro-polished to minimize surface irregulaR1ties since these irregulaR1ties can tR1gger an adverse biological response. However, stents may still stimulate foreign body reactions that result in thrombosis or restenosis. To avoid these complications, a vaR1ety of stent coatings and compositions have been proposed in the pR1or art literature both to reduce the incidence of these complications or other complications and restore tissue function by itself or by deliveR1ng 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 P.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, each of these references is incorporated herein by reference in its entirety). 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 vaR1ety 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.:
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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, each of which is incorporated herein by reference in its entirety). 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 mateR1als for the implantable device include biocompatible and nontoX1c mateR1als, 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.
[0160] The invention may be descR1bed therefore, in certain broad aspects as
a method of inhibiting arteR1al restenosis or arteR1al occlusion following vascular trauma compR1sing administeR1ng to a subject in need thereof, a composition compR1sing an inventive compound conjugated to a suitable polymer or polymeR1c mateR1al. In the practice of the method, the subject may be a coronary bypass, vascular surgery, organ transplant or coronary or any other arteR1al 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.
[0161] 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 antiprolifexative 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 defibR1llators); neurologic/neurosurgical devices (e.g., ventR1cular peR1toneal shunts, ventR1cular atR1al shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions);
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gastrointestinal devices (e.g., chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peR1toneal implants for drug delivery, peR1toneal dialysis catheters, implantable meshes for hernias, suspensions or solid implants to prevent surgical adhesions, including meshes); genitouR1nary devices (e.g., uteR1ne implants, including intrauteR1ne devices (IUDs) and devices to prevent endometR1al hyperplasia, fallopian tubal implants, including reversible steR1lization devices, fallopian tubal stents, artificial sphincters and peR1urethral implants for incontinence, ureteR1c 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 neovasculaR1ty, implants for diabetic retinopathy, drug eluting contact lenses for high R1sk corneal 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 saUne-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 vaR1ety of manners, including for example: (a) by directly affiX1ng 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 the 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 compR1sed 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

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to the implant or device duR1ng storage and at the time of insertion. The inventive compound or composition should also preferably not degrade duR1ng storage, pR1or 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 distR1bution 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).
[0163] In the case of stents, a wide vaR1ety 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, ureteR1c and urethral stents, lacR1mal stents, Eustachian tube stents, fallopian tube stents and tracheal/bronchial stents (See, for example, U.S. Patent No.: 6,515,016, the entire contents of which are incorporated herein by reference). Stents may be readily obtained from commercial sources, or constructed in accordance with well-known techniques. Representative examples of stents include those descR1bed 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 AX1al Length"; U.S. Pat. No. 5,089,606, entitled "Water-insoluble PolysacchaR1de 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 PolymeR1c 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."
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[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 ^vith (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 compR1sing administeR1ng a therapeutically effective amount of a compound of formula (I), as descR1bed 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 seveR1ty 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 appropR1ate 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 vaR1ety of factors including the disorder being treated and the seveR1ty of the disorder; the activity of the specific compound

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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, which is incorporated herein by reference in its entirety).
[0166] 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, hi certain embodiments, methods are provided for preventing restenosis, compR1sing 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, compR1sing 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.
[0167] Within other aspects of the present invention, methods are provided
for expanding the lumen of a body passageway, compR1sing 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, hi certain embodiments, the
lumen of a body passageway is expanded in order to eliminate a biliary,
gastrointestinal, esophageal, tracheal/bronchial, wethral and/or vascular obstruction.
[0168] hi certain embodiments, methods are provided for eliminating biliary
obstructions, compR1sing inserting a biliary stent into a biliary passageway, the stent
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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. BR1efly, 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 extR1nsic pressure and compresses the bile
duct (e.g., enlarged lymph nodes). Both pR1mary 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 pR1mary
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 aR1se 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 binary stent is first inserted into a biliary
passageway in one of several ways: from the top end by inserting a needle through
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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 duR1ng a surgical procedure. In certain embodiments, a preinsertion examination, PTC, ERCP, or direct visualization at the time of surgery is performed to determine the appropR1ate 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 oR1ginal 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 appropR1ately positioned.
[0170] In certain embodiments, methods are provided for eliminating
esophageal obstructions, compR1sing inserting an 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. BR1efly, 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 aR1sing 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 baR1um swallow or endoscopy is performed in order to determine the appropR1ate 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 baR1um swallow x-ray, may be utilized to confirm appropR1ate positioning.
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[0171] In certain embodiments, methods are provided for eliminating
colonic obstructions, compR1sing 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. BR1efly, the colon is the hollow tube which transports digested food and waste mateR1als from the small intestines to the anus. Cancer of the rectum and/or colon or invasion by cancer aR1sing 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 baR1um enema or colonoscopy is performed in order to determine the appropR1ate 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 post-insertion examination, usually a baR1um enema x-ray, may be utilized to confirm appropR1ate positioning.
[0172] In certain embodiments, methods are provided for eliminating
tracheal/bronchial obstructions, compR1sing 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. BR1efly, 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 aR1sing in adjacent organs (e.g., cancer of the lung), or collapse of the trachea or bronchi due to chondromalacia (weakening of the cartilage R1ngs) results in inability to breathe. In certain embodiments, preinsertion examination, usually an endoscopy, is performed in order to determine the appropR1ate 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
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examination, usually a bronchoscopy may be utilized to confirm appropR1ate positioning.
[0173] In certain embodiments, methods are provided for eliminating
urethral obstructions, compR1sing 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. BR1efly, the urethra is the tube which drains the bladder through the penis. ExtR1nsic 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 uR1nation, hi certain embodiments, a preinsertion examination, usually an endoscopy or urethrogram is first performed in order to determine the appropR1ate position for stent insertion, which is above the external uR1nary 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 post-insertion examination, usually endoscopy or retrograde urethrogram, may be utilized to confirm appropR1ate position.
[0174} hi certain embodiments, methods are provided for eliminating
vascular obstructions, compR1sing 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. BR1efly, stents may be placed in a wide array of blood vessels, both arteR1es 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 arteR1es, the supeR1or 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
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percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropR1ate blood vessel by steeR1ng 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 appropR1ate positioning.
[0175] Furthermore, after formulation with an appropR1ate pharmaceutically
acceptable carR1er in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intrapeR1toneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the seveR1ty 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 mg/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 eliX1rs. 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, corn, 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, flavoR1ng, and perfuming agents.
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[0177] Injectable preparations, for example, steR1le injectable aqueous or
oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The steR1le injectable preparation may also be a steR1le injectable solution, suspension or emulsion in a nontoX1c 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, R1nger's solution, U.S.P. and isotonic sodium chloR1de solution. In addition, steR1le, 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 diglyceR1des. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0178] The injectable formulations can be steR1lized, for example, by
filtration through a bacteR1al-retaining filter, or by incorporating steR1lizing agents in the form of steR1le solid compositions which can be dissolved or dispersed in steR1le water or other steR1le injectable medium pR1or 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 intramusculax injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous mateR1al 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 matR1ces 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(anhydR1des). 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
suppositoR1es which can be prepared by miX1ng the compounds of this invention
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with suitable non-irR1tating excipients or carR1ers 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, m such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carR1er 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) lubR1cants 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 compR1se buffeR1ng 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 enteR1c 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 ingredient(s) 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 polymeR1c 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.
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[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 enteR1c 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 compR1se, as in normal practice, additional substances other than inert diluents, e.g., tableting lubR1cants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also compR1se buffeR1ng agents. They may optionally contain opacifying agents and can also be of a. composition that they release the active ingredient(s) 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 polymeR1c 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 steR1le conditions with a pharmaceutically acceptable carR1er and any needed
preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and
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 matR1x 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, pR1or 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
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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, y-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocR1ne 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 drags (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), puR1ne antagonists and pyR1midine antagonists (6-MercaptopuR1ne, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, VincR1stine, Vinorelbine, Paclitaxel), podophyllotoX1ns (Etoposide, IR1notecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (TamoX1fen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference. 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/druglistframe -See Appendix A).
[0186] In certain embodiments, the pharmaceutical compositions of the
present invention further compR1se 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

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 shR1nking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).
TREATMENT KITS
[0187] 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 compR1ses one or more containers filled with one or more of the ingredients of the pharmaceutical 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 oR1ented 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 containers) can be a notice in the form prescR1bed 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
[0188J 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, vaR1ous modifications of the invention and many further embodiments thereof, in addition to those shown and descR1bed 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. It should further be appreciated that the contents of those
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cited references are incorporated herein by reference to help illustrate the state of the art.
[0189] The following examples contain important additional information,
exemplification and guidance that can be adapted to the practice of this invention in its vaR1ous embodiments and the equivalents thereof.
EXEMPLIFICATION
[0190] 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 mateR1als and methods useful for the synthesis of the compounds of this invention.
[0191] The vaR1ous references cited herein provide helpful background
information on prepaR1ng compounds similar to the inventive compounds descR1bed herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest.
[0192] Moreover, the practitioner is directed to the specific guidance and
examples provided in this document relating to vaR1ous exemplary compounds and intermediates thereof. For example, synthetic guidance may be found in J. Org. Chem., 2001,66:7355-7364.
[0193] 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 be appreciated, however, that these examples do not limit the invention. VaR1ations of the invention, now known or further developed, are considered to fall within the scope of the present invention as descR1bed herein and as hereinafter claimed.
[0194] 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 vaR1ety 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 vaR1ety combinatoR1al techniques, parallel synthesis and/or solid phase synthetic methods known in the art.
[0195] It will be appreciated as descR1bed below, that a vaR1ety of inventive
compounds can be synthesized according to the methods descR1bed herein. The
138

starting mateR1als and reagents used in prepaR1ng these compounds are either available from commercial suppliers such as AldR1ch 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 descR1bed 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 vaR1ous 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 mateR1als, intermediates, and compounds of this
invention may be isolated and puR1fied using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characteR1zed 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
(HEML4STERLIN)
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14o


141



142
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143

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144



145
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146


147

148
WO 2005/030794 PCT/US2004/030921



149



150
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151


152
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153


154
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161

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163

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167

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169

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WO 2005/030794 PCT/US2004/030921




WO 2005/030794 PCT/US2004/030921


ER-807905 QJ
Me O Y Me °y-N\/
Kj H o j^ \~~J
ER-807906 ^v
ER-807907 V
Me O >K Me CV'O
CX H O A. ^
______ .
Me O S/ Me °V^>Me
______ J
Me O "Nr^ Me CO2Me
ER-8079H r j i r f PJH
ER-807944 M^C~~~T
Me O ^ Me (VN^
I oVAro
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177

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179

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WO 2005/030794 PCT/US2004/030921




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WO 2005/030794 PCT/US2004/030921




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WO 2005/030794 PCT/US2004/030921




WO 2005/030794 PCT/US2004/030921




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WO 2005/030794 PCT/US2004/030921




WO 2005/030794 PCT/US2004/030921




WO 2005/030794 PCT/US2004/030921



209

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211

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213

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215

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217

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219

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221

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223

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225

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227

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229

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231

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233

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235

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237

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239

WO 2005/030794 PCT/US2004/030921

[0198] General Reaction Procedures:
[0199] Unless mentioned specifically, reaction mixtures were stirred using a
magnetically dR1ven 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

[0201] BOCorBOC20: Di-tert-Butyl dicarbonate
[0202] CMC: l-Cyclohexyl-3-(2-morphoIinoethyl)carbodiimide
metho-p- toluenesulfonate
[0203] DCM: Dichloromethane
[0204] DEPC: Diethylphosphoryl cyanide (Diethyl
cyanophosphonate)
[0205] DIBAL: Diisobutylaluminum hydR1de
[0206] DIEA: Diisopropylethylamine
[0207] DMF: TVI^-Dimethylformamide
[0208] DMSO: DimethylsulfoX1de
[0209] Ether: Diethyl ether
[0210] HBTU: O-(l-if-benzotR1azol-l-yl)-^^V^-
tetramethyluronium hexafluorophosphate
[0211] HOAt: l-Hydroxy-7-azabenzotR1azole
[0212] LAH: Lithium aluminum hydR1de
[0213] MSA: Methane sulfonic acid
[0214] NMM: N-Methyl Morpholine
[0215] TBME: Tert-butyl methyl ether
[0216] TFA: TR1fluoroacetic 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 chloR1de. 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 appropR1ately with water followed by a saturated solution of bR1ne. On
occasions where the product containing extract was deemed to contain residual
oX1dants, the extract was washed with a 10% solution of sodium thiosulphate in
saturated aqueous sodium bicarbonate solution, pR1or to the aforementioned washing
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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, pR1or 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 citR1c acid solution, pR1or 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 dR1ed over anhydrous magnesium sulphate, then filtered. The crude products were then isolated by removal of solvents) by rotary evaporation under reduced pressure, at an appropR1ate temperature (generally less than 45°C).
[0221] On occasions where tR1phenylphosphine oX1de 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 tR1phenylphosphine oX1de was removed
by filtration and the filtrate processed in the usual manner.
[0222] General PuR1fication Procedures:
[0223] Chromatographic puR1fication refers either to flash column

[0225] Preparation of Compound 13

242
chromatography on silica, using a single solvent or mixed solvent as eluent, or
HPLC on a C18 column. Suitably puR1fied desired product containing elutes were
combined and concentrated under reduced pressure at an appropR1ate temperature
(generally less than 45 °C) to constant mass. Final compounds were prepared for
biological testing by either a) dissolved in 50% aqueous acetonitR1le, filtered and
transferred to vials, then freeze-dR1ed under high vacuum; or b) dissolved in
methanol, filtered and transferred to vials, then concentrated to dryness using a
CentR1fugal vacuum evaporator.
[0224] Example 1: Preparation of Amine Esters 18, Amine acids 20 and


[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 (6.30ml),
HO At (0.124g), and CMC (1.16g). The reaction mixture was shaken at room
temperature for 24hr. Aqueous workup followed by chromatographic puR1fication
gave Compound 13 (153mg, 61%).
[0227] Preparation of Compound 14

[0228] To a solution of compound 13 (153mg) in methanol (20ml), at 0°C,
was added sodium borohydR1de (3.18g) portionwise with shaking over a 3 day
peR1od. 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 peR1odinane (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
puR1fication.
[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 dR1ed) (equal mass to that of the amine hydrochloR1de). A suitably chosen amine
hydrochloR1de (16) (10 equivalents) was added with vigorous stirR1ng followed by
sodium tR1acetoxyborohydR1de (1.5 equivalents). The reaction mixture was stirred at
an appropR1ate temperature (20°-50°C) until compound 15 was consumed to a
satisfactory degree. Aqueous work up followed by chromatographic puR1fication
gave the corresponding N-Boc Amine Ester 17. Deprotection of the N-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 JV-Boc Amine Ester 17 in a suitable mixture of
THF and methanol, was added \M lithium hydroX1de solution (10-50 equivalents). When the N-Boc Amine Ester 17 was hydrolyzed to a satisfactory degree, the reaction mixture was given an aqueous work up. The N-Boc Amine Acid 19 was puR1fied chromatographically. Deprotection of the N-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


[0236] To a solution of the .N-Boc Amine Acid 19 in DMF, at room
temperature, was added NMM (20 equivalents). A suitably chosen amine
hydrochloR1de (21) (20 equivalents) was added followed by DEPC (20 equivalents).
When the N-Boc Amine Acid 19 was consumed to a satisfactory degree the N-Boc
Amine Amide 22 was isolated either by direct chromatographic puR1fication of the
reaction mixture, or by an aqueous work up followed by chromatographic
puR1fication. Deprotection of the N-Boc moiety under suitable conditions would
give the corresponding //-terminal free amine 23.
[0237] Example 2: Preparation of N-Acetvl Amine Amides 27

[0238] Preparation of Compound 24

[0239] To a solution of aldehyde 13 (50mg) in 1,2-dichloroethane (2ml), at
room temperature, was added 4A molecular sieves (crushed and dR1ed) (50mg).
Glycine methyl ester hydrochloR1de (120mg) was added with vigorous stirR1ng
followed by sodium tR1acetoxyborohydR1de (205mg). The reaction mixture was
stirred at 40°C) for two hours. Aqueous work up followed by chromatographic
puR1fication gave compound 24 (31mg, 46%).
[0240] Preparation of compound 25
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WO 2005/030794 PCT/US2004/030921

[0241] To a solution of compound 24 (5.5mg) in DMF (0.4ml), at room
temperature, was added pyR1dine (0.006ml) followed by acetic anhydR1de (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 HC1 in
methanol (lml) 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 hydroX1de solution (0.118 mL). The reaction mixture was stirred
at room temperature for 5 hr. Chromatographic puR1fication followed by treatment
with methanolic HC1 gave the hydrochloR1de salt of compound 26 (1.95mg, 61%).
[0244] General Procedure for the Preparation of JV-Acetyl Amine Amides 27

[0245] To a solution of compound 26 (1 equivalent) in DMF, at room
temperature, was added NMM (20 equivalents). A suitably chosen amine
hydrochloR1de (21) (20 equivalents) was added followed by DEPC (20 equivalents).
When compound 26 was consumed to a satisfactory degree the N-Acetyl Amine
Amide (27) was isolated by direct chromatographic puR1fication of the reaction
mixture. 246

[0246] Example 3: Preparation of compound 33

[0247] Preparation of Compound 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 chloR1de (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

[0250] To a solution of compound 28 (207 mg) in THF (5 mL), at 0°C under
an inert atmosphere, was added sodium hydR1de (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 puR1fication gave an intermediate Boc compound (185 mg, 67%). The intermediate Boc compound (139 mg) was dissolved in ethanol (2 mL) and treated with saturated HC1 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).
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WO 2005/030794 PCT/US2004/030921
[0251J Preparation of compound 30

[0252J To a solution of compound 29 (114 mg) in DMF (1.8 mL), at room
temperature, was added (S)-^-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 puR1fication
gave an intermediate Boc compound (42 mg, 22%). The intermediate Boc
compound (42 mg) was dissolved in saturated HC1 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 puR1fication
gave an intermediate Boc compound (38 mg, 64%). The intermediate Boc
compound (38 mg) was dissolved in saturated HC1 in ethanol (5 mL) and stood at
room temperature for 10 min. Concentration in vacuo gave compound 31 as its HC1
salt.
[0255] Preparation of compound 32

248

[0256] A solution of compound 31 (4 mg) in ethanol (2 mL) was treated
with 1 M lithium hydroX1de (0.5ml). The reaction mixture was stirred at room
temperature for 1.5 hr. Aqueous work up followed by chromatographic puR1fication
gave compound 32 (2.9mg, 76%).
[0257] Preparation of compound 33

[0258] To a solution of compound 32 (1.9 mg) in DMF (70 ul), at room
temperature, was added NMM (3.8 ul), pyrrolidine (2.8 ul), and DEPC (5.2 ul).
The reaction mixture was stirred at room temperature for 16 hr. The reaction
mixture was puR1fied chromatographically to give compound 33 (1.2 mg, 58%).
[0259] Example 4: Preparation of Amine Esters 42, Amine Acids 43 and
Amine Amides 45
i

[0260] Preparation of compound 39

[0261] To a solution of compound 12 (1.25 g) in DMF (21 mL), at room
temperature, was added (i?)-JV-methylpipecoline hydrochloR1de (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
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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 borohydR1de (7.9 g) portionwise over a 3 day peR1od. 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 stirR1ng.
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 peR1odinane (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
puR1fication.
[0266] General Procedure for the Preparation of //-terminal N-heterocvclic
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 dR1ed) (1.5 g). The amino acid ester hydrochloR1de (16) (10 equivalents) was added and the reaction mixture stirred vigorously for -10 min. Sodium tR1acetoxyborohydR1de
2 50

(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 puR1fied chromatographically, except in cases where it was deemed unnecessary.
[0268] General Procedure for the Preparation of TV-terminal N-heterocvclic
Amine Acids 43
[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 hydroX1de 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 puR1fied
chromatographically, except in cases where it was deemed unnecessary.
[0270] General Procedure for the Preparation of TV-terminal N-heterocvclic
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 hydrochloR1de (44) (20 equivalents) was added followed by DEPC (20 equivalents). When the TV-terminal N-heterocj'clic Amine acid 43 was consumed to a satisfactory degree the TV-terminal N-heterocyclic Amine Amide 45 was isolated either by direct chromatographic puR1fication of the reaction mixture, or by an aqueous work up followed by chromatographic puR1fication.
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WO 2005/030794 PCT/US2004/030921
[0272] Example 5: Preparation of compounds 51 and 52

10273] Step 1: Preparation of Compound 49:

[0274] Preparation of compound 47:
[0275] Procedure a.
[0276] Compound 46 (1.0405 g, 4.4984 mmol) was dissolved in DMF (8.0
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:
[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 syR1nge 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

washed with H2O and bR1ne, and dR1ed over Na2SO4, filtered, and evaporated to give
compound 2 (0.8413 g, 101%) sufficiently pure for the next step.
[0279] Preparation of compound 3b:

[02801 Compound 2 (0.8413 g, 3.8509 mmol) was dissolved in CH2C12 (5.0
mL) and (carbethoxyethylidene)tR1phenylphosphorane (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 bR1ne (25 mL), and dR1ed over Na2SC«4, filtered,
and evaporated to give an oil. PuR1fication by Flash Chromatography on SiC>2 (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 tR1ethylsilane (0.460 mL, 2.880 mmol) was added. TR1fluoroacetic 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 HC1 (2.4 mL, 13.2 mmol) was added. Evaporation gave the HC1 salt, compound 48 (0.618 g, 100%). Preparation of compowid 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
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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 bR1ne (25 mL), and dR1ed
over MgSO4, filtered, and evaporated to give a solid which was puR1fied 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 tR1ethylsilane (0.050 mL, 0.3130 mmol) was added. TR1fluoroacetic 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 HC1 was added (0.3 mL, 1.65 mmol).
Evaporation gave the HC1 salt, compound 49 (0.0662 g, 100%).
[0286] Step 2: Preparation of Compound 51:
[0287] Preparation of compound 50:

[0288J Compound 49 (0.0774 g, 0.2219 mmol), CR)-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 puR1fied directly by RP HPLC to give compound 50 (0.0989 g, 81%).
[0289] Preparation of compound 51:
254


[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
HC1 (0.50 mL), and puR1fied 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 HC1 (ca. 1
mL, 5.5 mmol) and evaporated to give the HC1 salt of compound 51 (0.0667 g,
72%).
[0291] Step 2: Preparation of Compound 52:

[0292] Compound 51 (0.0062 g, 0.0139 mmol), L-proline methyl ester
hydrochloR1de (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 syR1nge.
NMM (0.025 mL, 0.2274 mmol) was added via syR1nge. The solution was stirred
overnight, quenched with H2O (1.0 mL), and puR1fied 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 HC1 (0.10 mL, 0.55 mmol) and evaporated to give the HC1 salt of compound 52
(0.0078 g, 100%).
[0293] Example 6: Preparation of compound 62a

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

[0295] To a solution of 4-methylpipeR1dine (53) (600 pL, 5.0 mmol) in
MeOH (20 mL) was added Et3N (770 uL, 5.5 mmol) followed by Boc2O (1.2 g, 5.5
mmol) at 0°C. After 15 minutes, the reaction mixture was wanned 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,
dR1ed over MgiSOit, filtered, and concentrated to provide compound 54 (926.5 mg)
quantitatively as a colorless oil.
[0296] Preparation of compound 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 uL, 5.0 mmol) followed by
slow addition of a 1.3 M cyclohexane solution of jec-butyllithium (4.6 mL, 6.0
mmol) over a 30 minute peR1od. The reaction solution was then warmed to -20°C
and maintained at that temperature for 30 minutes, after which the solution was re-
cooled to -78°C and purged with gaseous carbon dioX1de for 15 minutes. The
reaction solution was then slowly wanned to 0°C and poured into a biphasic mixture
of 1 NBCl (100 mL) and EtOAc (50 mL). The reaction solution was then extracted
several times with EtOAc. The EtOAc extracts were combined, dR1ed over Mg2SC>4,
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

[0299] To a solution of compound 55 (292 mg, 1.2 mmol) in CH2C12
(2.4mL) 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 59a (309 mg) quantitatively as a light
yellow oil.
[0300] Preparation of compound 59b

[0301] Step 1: Preparation of compound 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 uL, 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, dR1ed over Mg2SC>4, filtered, and concentrated in vacuo. PuR1fication 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

[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 uL). 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, dR1ed over Mg2SO4, filtered, and concentrated in vacuo. PuR1fication of the residue by silica gel
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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

[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, dR1ed 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

[0309J 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 uL). 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


[0311] To a solution of compound 60a and 60b (11.0 mg, 0.07 mmol) in
CH2C12 (350 uL) was added HBTU (40mg, 0.11 mmol) and DDBA (37 uL, 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. PuR1fication 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.
[0312J 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 uL) and EtOH (160 uL) was added LiOHH2O (840 mg, 0.20
mmols). The reaction solution was allowed to stir overnight The reaction mixture
was then acidified with 1 AT HC1 until the pH = 6.00. The solution was then
extracted several times with CH2CI2. The CH2CI2 extracts were combined, dR1ed
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 PCTAJS2004/030921
(64)
[0316] To a suspension of L-penicillamine (63) (300 mg, 2.0 mmol) in
methanol (10 mL) was added benzaldehyde (233 mg, 2.2 mmol) followed by sodium
bicarbonate (336 mg, 4.0 mmol). The mixture was heated to reflux with stirR1ng for
16 h. After cooling to r.t, it was acidified to pH 5 with 1 N HC1 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 (49ul, 0.6 mmol) followed by NaBRj (38 mg,
0.6 mmol). The mixture was stirred at r.t for 24 h. After acidifying to pH 5 and
extracting with ethyl acetate, the organic phase was dR1ed and concentrated to give
crude product 65 (67 mg, >100%).
[0319] Preparation of compounds 66a and 66b

[0320] To a mixture of 65 (29 mg, 0.115 mmol), amine HC1 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


To a solution of 66b (4 mg, 0.0073 mmol) in methanol (0.5 mL) was added aq.
LiOH (1 M, 0.5 mL). The mixture was stirred for 16 h and acidified with 1 7/HC1.
Product 67b (2.79 mg, 74%) was obtained after RP HPLC puR1fication and
lyophilization.
[0322] Example 8: Preparation of compound 74

[0323] Preparation of compound 69

[0324] To a solution of diethylglycine (68) (131 mg, 1.0 mmol) in 1 JV
NaOH (1.5 mL) was added a solution of di-?-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 N HC1 and extracted with ethyl acetate three times. The organic phases were
combined, dR1ed, 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 tR1methylsilyldiazomethane (2 M 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 hydR1de (160 mg 60%, 4 mmol) in DMF (1
mL) was added a solution of compound 70 (0.58 mmol) in DMF (1 mL) followed by
methyl iodide (188 ul, 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 puR1fied by flash column chromatography
(silica, ethyl acetate/hexanes).
[0329] Preparation of compound 72

[0330] A solution of compound 71 (118 mg, 0.46 mmol) in cone. HC1 (1
mL) was stirred at room temp, for 24 h. Product 72 was obtained after evaporation
ofvolatiles.
[0331] Preparation of compound 73

[0332] To a mixture of compound 72 (30 mg, 0.166 mmol), amine 49 HC1
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

[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 NHCl. Product 74 (12.3 mg, 73%) was obtained after RP HPLC puR1fication
and lyophilization.
[0335] Example 9: Preparation of compound 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 1 .A/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 chloR1de (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
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WO 2005/030794 PCT/US2OO4/O30921

{0339] To a solution of compound 76 (3 mg) in acetonitR1le (0.6 mL) was
added Dess Martin peR1odinane (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 \im PTFE syR1nge 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 tR1phenylphosphorane (21 mg).
The reaction mixture was stirred at room temperature for 16 hr then concentrated in
vacuo to dryness. Chromatographic puR1fication gave compound 78 (1.48 mg,
44%).
[0342] Example 10: Preparation of compound 81

[0343] Preparation of compound 79

264

[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 chloR1de
(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%).
[0345J Preparation of compound 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 peR1odinane (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 hydrochloR1de (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 puR1fication gave compound 81 (2.04 mg).
[0349] Example 11: Preparation of compound 87
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WO 2005/030794 PCT/US2004/030921

(0350J Preparation of compound 84

[0351] To a solution of compound 28 (335 mg) in THF (10 mL), at 0°C
under an inert atmosphere, was added sodium hydR1de (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 puR1fication gave compound 84 (254mg, 72%).
[0352] Preparation of compound 85

[0353] Compound 84 (189 mg) was treated with saturated HC1 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), HO At (95 mg), and CMC (884 mg). The reaction mixture was shaken at room temperature
266

for 16 hr. Aqueous workup followed by chromatographic puR1fication gave an
intermediate Boc compound (249 mg, 93%). The intermediate Boc compound (60
mg) was dissolved in methanol (1 mL) and treated with saturated HC1 in methanol
(3 mL) and stood at room temperature for 30 min. Concentration in vacuo gave
compound 86 (49mg).
[0356] Preparation of compound 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 \i\),
HOAt (21 mg), and CMC (130 mg). The reaction mixture was shaken at room
temperature for 16 hr. Aqueous workup followed by chromatographic puR1fication
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 HC1 in methanol (1 mL)
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

[0359] Preparation of compound 88

[0360] To a solution of compound 28 (344mg) in 0.5 MHunnig's base in
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WO 2005/030794 PCT/US2004/030921
DCM (8 mL), at 0°C under an inert atmosphere, was added methane sulphonyl
chloR1de (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 puR1fication 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

[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 HC1
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 puR1fication gave an
intermediate Boc compound (173 mg, 87%). The intermediate Boc compound (51
mg) was dissolved in methanol (1 mL) and treated with saturated HC1 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


[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 ul), HO At (17 mg), and CMC (108 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic puR1fication gave an intermediate Boc compound (88 mg). The intermediate Boc compound (88 mg) was dissolved in saturated HC1 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:

[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 M lithium hydroX1de (10-50 equivalents). The
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WO 2005/030794 PCT/US2004/030921
reaction mixture was stirred or shaken or stood at room temperature until the starting
ester had been satisfactoR1ly hydrolyzed. The usual workup followed by
chromatographic puR1fication 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

[0371] To a stirred solution of N-Boc-N-Me-L-Valine (200 g, 0.86 mols),
N,O-demethylhydroxylamine (92.8 g, 0.95 mols, 1.1 eq) and DIEA (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 (Hept/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 HC1 (IN, 500 mL),
water (250 mL), NaHCO3 (sat. 250 mL) and bR1ne (250 mL). The organic solution
was dR1ed over MgSC>4 (~120 g). The solution was filtered through a silica gel bed
(~200 g) and concentrated. Crude amide ER-807641 was used without any further
puR1fication.
[0372] Preparation of compound ER-808993

[0373] To a stirred solution of arnide ER-807641 (207 g, 755 mmol, leq.) in

270

dry THF (2070 mL) at -78 °C was added a solution of LiAIR, (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
puR1fication.: 157.9 g (97%).
[0374] Preparation of compound 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
bR1ne (300 mL), dR1ed over MgSC>4, and filtered. The EtOAc solution of the free
amino-ester was bubbled with HC1 (gas), and the HC1 salt of ER-808995
precipitated and was collected by filtration under N2.
[0379] Preparation of compound ER-803921-01
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WO 2005/030794 PCT/US2004/030921

[0380J To a stirred solution of ER-808995 (61.2 g, 255.6 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. HC1 (IN, 200
mL), water (200 mL) and NaHCC>3 (sat, 200 mL). The organic layer was dR1ed over
MgSO/}, 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 ammo-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 bR1ne (200 mL). After drying
over MgSC>4 and filtration, HC1 (g) was bubbled to obtain the hydrochloR1de salt of
ER-803921 as a white solid collected by filtration at ca. 5°C.
[0381] Preparation of compound ER-808998

[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

(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 HC1 ( 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 bR1ne and dR1ed over MgSCU, filtered, and
concentrated to give tR1peptide-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 THF7H2O (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
H2SO4 (-0.50 mL) to pH 7. The mixture was extracted with EtOAc (3 x 25 mL).
The combined organic solution was washed with bR1ne (20 mL), dR1ed over MgSOit,
filtered, and concentrated. The residue was tR1turated with TBME: 1.8 g (83%) of
thick oil free-base ER-807974 was obtained.
[0386] Example 15: Preparation of compound ER-808367
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WO 2005/030794 PCT/US2004/030921

[0387J Preparation of compound 2Z

[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 (S1O2) eluting with 100% EtOH.
This provided compound 2Z (721 mg, white solid) as a mixture of diastereomers in
67% yield.
10389] Preparation of compounds 3Z and 4Z

[0390] To a solution of 2Z (650 mg, 3.51mmol) in DMF (8.8 mL) was added
K2CO3 (728mg 5.27mmol) and /?-rurrobenzylbromide (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 bR1ne. The solution was dR1ed over MgSO4, filtered, and concentrated in vacuo. The crude mixture of diasteomers was then
274

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.
[0391J Preparation of compound ER-809439

[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).
[0395] Preparation of compound ER-808357

[0396] Compound 49 (9.6mg, 0.031mmol), 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 puR1fied directly by RP HPLC to give the TFA salt of compound ER-808357 (13.6mg, 82%).
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WO 2005/030794 PCTAJS2004/030921
[0397] Preparation of compound 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
g5 0.18mmol) was added. The suspension was stirred at room temperature for 19
hours. The solution was puR1fied 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

[0400] Preparation of compound ER-808358

[0401] A procedure similar to that used for the preparation of compound ER-
808357 was used.
[0402] Preparation of compound ER-808368

[0403] A procedure similar to that used for the preparation of compound ER-
808367 was used.

276

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



[0405] Preparation of compound 5Z

[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 Et3N (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 (SiC>2)
eluting with 100% EtOH. This provided compound 5Z (377.9 mg, white solid) as a
single diastereomer in 24.5% yield. Rf = (SiO2,0.280,100% EtOH).
[0407] Preparation of compound ER-808656

[0408] A procedure similar to that used for the preparation of compound ER-
808357 was used.
[0409] Preparation of compound ER-808662

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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. CH2C12 (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 puR1fied by flash chromatography (S1O2) eluting with 4% EtOAc in
hexanes. This provided compound 6Z (476.8mg) as a colorless oil in 86.7% yield.
[0415] Preparation of compound 7Z

[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

(0417] Preparation of compound ER-808815

[0418] A procedure similar to that used for the preparation of compound ER-
808357 was used.
[0419] Preparation of compound ER-808824

[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 cytotoX1city assay, hi 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 [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

WO 2005/030794 PC17US2004/030921
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-FredeR1ck 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, steR1le-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 HC1 in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dis-solved by gentle miX1ng. Absorbances at 540 nm were measured on a Titertek Multiscan MCC/340 plate reader.
[0425] Mitotic block reversibility assay was performed as descR1bed (See,
Patent US 6,214,865 Bl, by B. Littelfield et al, 4/10/01; which is incorporated herein be reference in its entirety).
280

[0426J BR1efly, U937 (ATCC accession number CRP 1593) were exposed to
vaR1ous 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 centR1fugation 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 pR1mary 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 descR1bed above. Two cultured himan cancer cell lines were used: human uteR1ne sarcoma MDR negative MES-SA cells (ATCC accession number CRL-1976) and human uteR1ne 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 muR1ne leukemia cells P388/S, and MDR-positive muR1ne 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, steR1le-filtered 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide was added to
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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 HC1 in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dis-solved by gentle miX1ng. 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 descR1bed 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. PR1or 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] CvtotoX1city assay. To determine toX1city 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

kit (LumiTech Ltd). A cytotoX1c compound carbonyl cyanide was used in all assays as a positive control for cytotoX1city.
[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 intrapeR1toneally. Tumor and body weight measurements were done twice weekly.
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WO 2005/030794 PCT/US2004/030921
CLAIMS
What is claimed is:
1. A comnound havine the structure flD:

and pharmaceutically acceptable deR1vatives thereof;
wherein n is 0,1,2,3 or 4;
X1 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;
R1 and R2 are each independently hydrogen, -(C=O)Rc or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein each occurrence of Re 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 R1, 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;
R5, R6 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, R$ 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,
284

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Patent Number 238640
Indian Patent Application Number 835/KOLNP/2006
PG Journal Number 08/2010
Publication Date 19-Feb-2010
Grant Date 15-Feb-2010
Date of Filing 05-Apr-2006
Name of Patentee EISAI R & D MANAGEMENT COMPANY LTD.
Applicant Address 6-10 KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO 112-8088
Inventors:
# Inventor's Name Inventor's Address
1 KOWALCZYK, JAMES, J 22 RAILROAD STREET #405, ANDOVER, MA 01810
2 SCHILLER, SHWAN 614 HILLDALE AVENUE, HAVERHILL, MA 01832
3 SELETSKY, BORIS, M 8 DELPHI CIRCLE, ANDOVER, MA 01810
4 SPYVEE, MARK 75 LAURA LANE, HAMPSTEAD, NH 03841
5 YANG, HU 33 0STIRLING STREET, ANDOVER, MA 01810
6 CAMPAGNA, SILVIO, A 621 OLD CANDIA ROAD, CANDIA, NH 03034
7 FANG, FRANCIS, G 16 GREYBRICH ROAD, ANDOVER, MA 01810
8 KUZNETSOV, GALINA 28 WOOD STREET, LEXINGTON, MA 02421,
PCT International Classification Number A61K31/395
PCT International Application Number PCT/US2004/030921
PCT International Filing date 2004-09-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/667,864 2003-09-22 U.S.A.