Hemiasterlin derivatives and uses thereof

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 Africa (see, Kashman et al. U.S. Pat. No. 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 derivatives were synthesized and their biological activity was also investigated. It was subsequently reported that Hemiasterlin and certain analogs thereof exhibit antimitotic activity and thus are useful for the treatment of certain cancers (see, U.S. Pat. No. 6,153,590 and PCT application WO 99/32509). However, only a rather limited number of Hemiasterlin analogs were prepared, half of which were the natural products themselves, isolated from Cymbastela sp., or were obtained by modifications to the natural products. Thus the number and types of derivatives that could be prepared and evaluated for biological activity were limited.

[0004] Clearly, there remains a need to develop synthetic methodologies to access and examine the therapeutic effect of a variety of novel derivatives of Hemiasterlin, particularly those that are inaccessible by making modifications to the natural product. It would also be of particular interest to develop novel compounds that exhibit a favorable therapeutic profile in vivo (e.g., are safe and effective, while retaining stability in biological media).

SUMMARY OF THE INVENTION

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

[0006] 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 DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

[0007] In recognition of the need to access and further explore the biological activity of novel derivatives of Hemiasterlin, and this class of peptides in general, the present invention provides novel peptide compounds, as described in more detail herein, which demonstrate antitumor activity. Thus, the compounds of the invention, and pharmaceutical compositions thereof, are useful for the treatment of cancer. In certain embodiments, the compounds of the present invention can be used for the treatment of diseases and disorders including, but not limited to prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer, lymphoma, leukemia and multiple myeloma. In certain other embodiments, the inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

[0008] 1) General Description of Compounds of the Invention

[0009] The compounds of the invention include compounds of the general formula (I) as further defined below:

[0010] wherein n is 0, 1, 2, 3 or 4;

[0011] 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;

[0012] R1 and R2 are each independently hydrogen, —(C═O)RC or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein each occurrence of RC is independently hydrogen, OH, ORD, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein RD is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0013] 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;

[0014] 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, heteroalicyclic, aryl or heteroaryl moiety; or R7 may be absent when NR7 is linked to R via a double bond;

[0015] R is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and

[0016] 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(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; and

[0017] pharmaceutically acceptable derivatives thereof.

[0018] In certain embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, are not naturally occurring Hemiasterlins.

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

[0020] In certain embodiments of compounds described directly above and compounds as described in certain classes and subclasses herein, the compounds do not comprise more than four consecutive α-amino acid residues, and/or one or more of the following groups do not occur simultaneously as defined:

[0021] (a) n is 1;

[0022] X1 and X2 are each C(═O);

[0023] R1 and R2 are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at 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 ring; wherein Ar is defined as substituted or unsubstituted phenyl, naphtyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl or pyridyl;

[0024] R3 is hydrogen;

[0025] 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 ring; and R4c is hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and Ar; wherein Ar is as defined directly above;

[0026] R5, R6 and R7 are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and Ar;

[0027] 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

[0028] Q is —ORG, —SRG, —NRGRH, —NHCH(RK)CO2H, or —NRCH(RK)CO2H, wherein RG and RH are each independently hydrogen, aliphatic, alicyclic, heteroaliphatic or heteroalicyclic; RK is aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, or a moiety having the structure —(CH2)tNRK1RK2, wherein t=1-4 and RK1 and RK2 are independently hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic or —C(NH)(NH2);

[0029] (b) n is 1;

[0030] X1 and X2 are each C(═O);

[0031] R1 is an optionally substituted methylene or —CH═ group bonded to the indole moiety thereby forming a tricyclic moiety;

[0032] R2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when R1 is —CH═ as defined above;

[0033] R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein, are linked by a double bond;

[0034] R4 is a moiety having the structure:

[0035] wherein Rw, Ry and Rz are each independently hydrogen, or optionally substituted alkyl or acyl, or Rz is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; Rx is hydrogen or an optional substituent, or is absent when 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;

[0036] R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;

[0037] R6 is hydrogen or an optionally substituted alkyl group;

[0038] R7 is hydrogen or alkyl; and

[0039] —R—X2-Q together represent an optionally substituted alkyl moiety;

[0040] (c) n is 1;

[0041] X1 and X2 are each C(═O);

[0042] 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 tricyclic moiety;

[0043] R2 is hydrogen, an optionally substituted alkyl or acyl group, or is absent when R1 is —CH═ as defined above;

[0044] R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein, are linked by a double bond;

[0045] R4 is a moiety having the structure:

[0046] wherein Rw, Ry and Rz are each independently hydrogen, or optionally substituted alkyl or acyl, or Rz is absent when CR3 and CRyRz, as defined herein, are linked by a double bond; with the limitation that Ry and Rz are not simultaneously hydrogen; Rx is hydrogen or an optional substituent, or is absent when 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;

[0047] R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;

[0048] R6 is hydrogen or an optionally substituted alkyl group;

[0049] R7 is hydrogen or alkyl; and

[0050] —R—X2-Q together represent an optionally substituted alkyl moiety or -Q′-C(O)X, wherein Q′ is an optionally substituted —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH═CH—, —CH2C≡C— or phenylene moiety, wherein X is —OR′, —SR′ or —NR′R″ and each occurrence of R′ and R″ is independently hydrogen or optionally substituted alkyl;

[0051] (d) n is 1;

[0052] X1 is C═O;

[0053] R1 is methyl;

[0054] R2 and R3, taken together, form a piperidine moiety;

[0055] R4 and R5 are each hydrogen,

[0056] R6 is —CH(CH3)CH2CH3;

[0057] R7 is —CH2C(═O)CH2CH(CH3)2, —CH2C(═O)CH2CH2CH3 or CH2C(═O)CH2CH3; and

[0058] —R—X2-Q together represent the moiety having the structure:

[0059] (e) n is 1;

[0060] X1 is C═O;

[0061] R1, R2, and R7 are each methyl;

[0062] R3 and R5 are each hydrogen;

[0063] R4 and R6 are each i-propyl; and

[0064] —R—X2-Q together represent the moiety having the structure:

[0065] wherein Rx is hydrogen or 2-thiazolyl; and/or

[0066] (f) n is 1;

[0067] X1 is C═O;

[0068] R1 and R2 are each independently hydrogen or C1-4alkyl;

[0069] R3 and R5 are each hydrogen;

[0070] R4 and R6 are each i-propyl;

[0071] R7 is methyl; and

[0072] —R—X2-Q together represent a moiety having the structure:

[0073] wherein v is 0, 1 or 2;

[0074] R′ is hydrogen or C1-4alkyl;

[0075] 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, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, di-alkylamino, acylamino, alkoxycarbonylamino or halogen; aralkyloxy or aralkyl both optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino, aminosulfonyl or benzyl; or aralkylamino having 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, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; and

[0076] R′″ is hydrogen, alkyl optionally substituted with one to three substituents selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbonyloxy, carbamoyloxy or halogen; alkenyl; alkynyl; C3-7cycloalkyl; aryl optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; aralkyl with the aryl group optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxyxarbonyl, carbamoyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; or heterocyclylalkyl;

[0077] wherein the groups recited in paragraph (f) above are defined as follows:

[0078] 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;

[0079] alkenyl refers to a hydrocarbon chain as defined for alkyl above having at least one double bond;

[0080] alkynyl refers to a hydrocarbon chain as defined for alkyl above having at least one triple bond;

[0081] C3-7cycloalkyl refers to a saturated, cyclic hydrocarbon group with 3-7 carbon atoms optionally substituted with alkyl, phenyl, amino, hydroxy or halogen;

[0082] C1-4alkylene refers to a biradical linear or branched hydrocarbon chain containing 1-4 carbon atoms;

[0083] Aralkyl, refers to an aryl group attached to an alkylene group;

[0084] 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;

[0085] Amino refers to —NH2 and includes amino groups which are further substituted by lower alkyl groups, or nitrogen protecting groups know in the art;

[0086] Cycloalkylamino refers to cycloalkyl groups as defined above attached to a structure via an amino radical;

[0087] Arylamino is defined as aryl —NH—;

[0088] Aralkylamino is defined as aralkyl —NH—;

[0089] Carbamoyl refers to the group —C(═O)—NH2;

[0090] Carbamoyloxy refers to the group —O—C(═O)—NH—;

[0091] Alkylcarbamoyloxy refers to the group —O—C(═O)—NH-alkyl;

[0092] Alkylcarbonyloxy refers to the group —O—C(═O)-alkyl;

[0093] Aralkyloxy refers to the group —O-aralkyl; and

[0094] Alkylthio refers to the group Alkyl-S—.

[0095] In certain other embodiments of compounds described in (a) above and compounds as described in certain classes and subclasses herein, the following groups do not occur simultaneously as defined:

[0096] 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 —CR4aR4bR4c wherein R4a and R4b are each independently methyl, ethyl, n-propyl or n-butyl; or R4a and R4b, taken together, form a moiety selected from the group consisting of β-cyclopropyl, β-cyclobutyl, β-cyclopentyl, and 13-cyclcohexyl; and R4c is phenyl, naphtyl, anthracyl or pyrrolyl; R5 and R7 are each independently hydrogen or methyl; R6 is a three to six carbon, branched alkyl group; and —R—X2-Q together represent the moiety having the structure:

[0097] 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.

[0098] In certain other embodiments of compounds described in (a) above and compounds as described in certain classes and subclasses herein, the following groups do not occur simultaneously as defined:

[0099] n is 1; X1 and X2 are each C(═O); R1, R3 and R5 are each hydrogen; R2 is methyl; R4 is —CR4aR4bR4c, R6 is tert-butyl; and —R—X2-Q together represent the moiety having the structure:

[0100] wherein R′ is isopropyl; R″ is methyl; and Q is OH; and

[0101] (a) R4a and R4b are each methyl; R4c is methyl or phenyl; and R7 is hydrogen or methyl;

[0102] (b) R4a and R4b are each methyl; R4c is hydrogen; and R7 is methyl; or

[0103] (c) R4a and R4b are each hydrogen; R4c is phenyl; and R7 is methyl.

[0104] In certain other embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed on page 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.

[0105] In certain other embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed on page 10 line 24 through page 17 line 18, page 17 line 26 through page 19 line 3, page 19 line 10 through page 20 line 3, page 20 line 17 through page 21 line 9, page 21 lines 14-29, page 22 lines 1-12, page 22 lines 16-18, page 22 lines 22-27, page 23 line 1 through page 24 line 21, page 24 line 26 through page 25 line 9, and page 28 line 1 through page 32 line 9 of WO 03/008378.

[0106] In certain other embodiments, compounds of formula (I) and compounds described in classes and subclasses herein, do not have the structure of any one or more of the compounds disclosed in Nieman J. et al., “Synthesis and Antitumotic/Cytotoxic Activity of Hemiasterlin Analogues”, Journal of Natural Products, 2003, 66(2):183-199, which is incorporated herein by reference in its entirety.

[0107] 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:

[0108] In certain other embodiments, compounds of formula (I) are defined as follows:

[0109] 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;

[0110] 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

[0111] R1 and R2, taken together, may form a saturated or unsaturated, substituted or unsubstituted cyclic ring of 5 to 8 atoms;

[0112] 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

[0113] R3 and R4, taken together, may form a saturated or unsaturated, substituted or unsubstituted cyclic ring of 3 to 8 atoms;

[0114] the carbon atom bearing R3 and R4 may be of S configuration;

[0115] n is 1;

[0116] R5 is hydrogen or a protecting group; wherein the protecting group may be a nitrogen protecting group;

[0117] 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;

[0118] the carbon atom bearing R6 may be of S configuration;

[0119] 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;

[0120] 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;

[0121] wherein (i) the alkyl moiety may have the structure:

[0122] 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, R8a,

[0123] 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 bearing R8a may be of S configuration;

[0124] (ii) the heteroalkyl moiety may have the structure:

[0125] 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 bearing R8b may be of S configuration;

[0126] (iii) or the heteroalkyl moiety may have the structure:

[0127] 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;

[0128] 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 bearing R8c amay be of S configuration; and

[0129] 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 form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl or heteroalkyl moiety or a substituted or unsubstituted aryl or heteroaryl moiety; and

[0130] pharmaceutically acceptable derivatives thereof.

[0131] 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(R9a)=C(R10a)— and the compound has the structure (Ia):

[0132] wherein R1-R7, X1, X2, Q and n are defined in classes and subclasses herein;

[0133] 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.

[0134] 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.

[0135] Another class of compounds of special interest consists of compounds having the structure of formula (I) in which XI is C═O; n is 1; R1 and R4, taken together, form a cyclic heterocyclic or heteroaryl moiety; R3 is hydrogen or is absent when the carbon atom bearing R3 is linked to N or E via a double bond; and the compound has the structure (Ic):

[0136] wherein R2, R5-R7, R, X2 and Q are defined in classes and subclasses herein;

[0137] each occurrence of G, J, L and M is independently CHRiv, CRivRv, O, S, NRivRv, wherein each occurrence of Riv 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, Riv, Rv or Riv 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 Rvi is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0138] 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

[0139] g, j, 1 and m are each independently 0, 1, 2, 3, 4, 5 or 6, wherein the sum of g, j, l and m is 3-6.

[0140] 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):

[0141] wherein R1, R2, R5-R7, R, X2 and Q are defined in classes and subclasses herein.

[0142] The following structures illustrate several exemplary types of compounds of class (Ia). Additional compounds are described in the Exemplification herein.

[0143] The following structures illustrate several exemplary types of compounds of class (Ib). Additional compounds are described in the Exemplification herein.

[0144] The following structures illustrate several exemplary types of compounds of class (Ic). Additional compounds are described in the Exemplification herein.

[0145] The following structures illustrate several exemplary types of compounds of class (Id). Additional compounds are described in the Exemplification herein.

[0146] Other compounds of the invention will be readily apparent to the reader.

[0147] A number of important subclasses of each of the foregoing classes deserve separate mention; for example, one important subclass of class (Ia) includes those compounds having the structure of formula (Ia) in which X2 is C═O; and the compound has the following structure:

[0148] wherein R1-R7, n and Q are defined in classes and subclasses herein;

[0149] 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

[0150] X1 is CRARB, SO2 or C═O; wherein RA and RB are each independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

[0151] Another important subclass of class (Ia) includes those compounds having the structure of formula (Ia) in which XI is C═O; and the compound has the following structure:

[0152] wherein R1-R7, n and Q are defined in classes and subclasses herein;

[0153] 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

[0154] X2 is CRARB, SO2 or C═O; wherein RA and RB are each independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

[0155] Another important subclass of class (Ia) includes those compounds having the structure of formula (Ia) in which X1 and X2 are each C═O; n is 1; R3 is hydrogen; R4 is a moiety having the structure —CR4aR4bR4c; and the compound has the following structure:

[0156] wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and

[0157] R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl, and R4c is aryl or heteroaryl; and

[0158] 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.

[0159] Another important subclass of class (Ia) includes those compounds having the structure of formula (Ia) 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:

[0160] wherein R1-R7 and n are defined in classes and subclasses herein;

[0161] 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;

[0162] each occurrence of A, B, D or E is independently CHRi, CRiRii, O, S, NRiRii, wherein each occurrence of Ri and Rii is independently absent, hydrogen, —C(═O)Riii, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any two adjacent Ri, Rii or Riii groups, taken together, form a alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety; wherein each occurrence of Riii is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0163] 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

[0164] 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.

[0165] Another important subclass of class (Ia) includes those compounds having the structure of formula (Ia) 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:

[0166] wherein R1, R2, R5-R7, A, B, D, E, a, b, d and e are defined in classes and subclasses herein;

[0167] R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl, and R4c is a substituted or unsubstitued aryl or heteroaryl group;

[0168] 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.

[0169] A number of important subclasses of each of the foregoing subclasses of class (Ia) deserve separate mention; these subclasses include subclasses of the foregoing subclasses of class (la) in which:

[0170] 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;

[0171] ii-a. 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;

[0172] iii-a. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0173] iv-a. R1 is hydrogen and 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0174] v-a. R1 and R2 are each hydrogen;

[0175] vi-a. The carbon atom bearing R3 and R4 is of S configuration;

[0176] 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;

[0177] 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;

[0178] ix-a. 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;

[0179] x-a. R4 is a substituted or unsubstituted 3-indole moiety;

[0180] xi-a. R3 is hydrogen;

[0181] xii-a. R1 and R4, taken together, form a substituted or unsubstituted pyrrolidine group;

[0182] xiii-a. R1 and R4, taken together, form a substituted or unsubstituted piperidine group;

[0183] xiv-a. R1 and R4, taken together, form a substituted or unsubstituted thiazolidine group;

[0184] xv-a. R1 and R4, taken together, form a substituted or unsubstituted morpholine group;

[0185] xvi-a. R1 and R4, taken together, form a substituted or unsubstituted thiomorpholine group;

[0186] xvii-a. R1 and R4, taken together, form a substituted or unsubstituted indole group;

[0187] 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;

[0188] xix-a. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;

[0189] xx-a. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl;

[0190] xxi-a. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, —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;

[0191] xxii-a. R3 and R4 are each independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, —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 linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0192] xxiii-a. R3 and R4 are each ethyl;

[0193] xxiv-a. R3 is phenyl and R4 is lower alkyl;

[0194] xxv-a. R3 is phenyl and R4 is ethyl;

[0195] xxvi-a. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl group;

[0196] xxvii-a. R3 and R4, taken together, form a cyclohexyl group;

[0197] xxviii-a. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

[0198] xxix-a. R5 is hydrogen;

[0199] xxx-a. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0200] xxxi-a. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0201] xxxii-a. R6 is tert-butyl;

[0202] xxxiii-a. The R6-bearing carbon atom is of S configuration;

[0203] xxxiv-a. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0204] xxxv-a. R7 is methyl;

[0205] xxxvi-a. —[C(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:

[0206] 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;

[0207] b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, —C(CH3)2C—CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0208] c) R2 is methyl, ethyl, propyl or i-propyl;

[0209] d) RG1 is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl;

[0210] e) RG1 is hydrogen, methyl or phenyl;

[0211] f) RG1 and the substituents on L, taken together, form a substituted or unsubstituted phenyl group;

[0212] g) RM1 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 RM1 and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety;

[0213] h) RM1 and RM2 are each hydrogen;

[0214] i) g is 1 or 2; and/or

[0215] j) L is CH2, S or O;

[0216] xxxvii-a. —[C(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:

[0217] 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;

[0218] b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, —C(CH3)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0219] c) R2 is methyl, ethyl, propyl or i-propyl;

[0220] d) RL1 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;

[0221] e) RL, and RL2 are each hydrogen;

[0222] f) RL1 and RL2 are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

[0223] g is 1 or 2;

[0224] xxxvi-a. R is —CH(R8a)C(R9a)=C(R10a)—; and

[0225] a) R8a is substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0226] b) R8a is iso-propyl;

[0227] c) The R8a-bearing carbon atom is of S configuration;

[0228] d) R9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0229] e) R9a is hydrogen;

[0230] f) R10a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0231] g) R10a is methyl;

[0232] xxxvii-a. n is 1;

[0233] xxxviii-a. X1 is C═O;

[0234] xxxix-a. X1 is CH2;

[0235] xl-a. X1 is SO2;

[0236] xli-a. X2 is C═O;

[0237] xlii-a. X2 is CH2;

[0238] xliii-a. X2 is SO2;

[0239] xliv-a. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0240] 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; and

[0241] xlv-a. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0242] 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 RQ41 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

[0243] xliv-a. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0244] 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.

[0245] 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:

[0246] wherein R1-R7, n, XI and Q are defined in classes and subclasses herein;

[0247] 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

[0248] 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.

[0249] Another important subclass of class (Ib) includes those compounds having the structure of formula (Ib) in which XI is C═O; R is —C(R8b)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:

[0250] wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and

[0251] R4a and R4bare each independently hydrogen or lower alkyl and R4c is aryl or heteroaryl;

[0252] 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

[0253] 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.

[0254] 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:

[0255] wherein R1-R7, n and Q are defined in classes and subclasses herein;

[0256] p is 1, 2, 3 or 4;

[0257] q is 0-12;

[0258] 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;

[0259] 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

[0260] NR7 and CR8, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.

[0261] 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:

[0262] wherein R1-R7, X1 and Q are defined in classes and subclasses herein;

[0263] p is 1, 2, 3 or 4;

[0264] is 0, 1, 2, 3, 4, 5 or 6;

[0265] 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;

[0266] R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl; and R4c is aryl or heteroaryl;

[0267] 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

[0268] NR7 and CR8b, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.

[0269] 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(R11c)OC(R12c)—; and the compound has the following structure:

[0270] wherein R1-R7, n, X1 and Q are defined in classes and subclasses herein;

[0271] 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

[0272] NR7 and CR8c, CR9c and CR9c, CR9c and CR10c, and CR10c and CR11c are each independently linked by a single or double bond as valency permits.

[0273] 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(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)—; and the compound has the following structure:

[0274] wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;

[0275] R4a and R4b are each independently hydrogen, or lower alkyl or heteroalkyl; and R4c is aryl or heteroaryl;

[0276] 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

[0277] 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.

[0278] 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:

[0279] 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;

[0280] 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;

[0281] iii-b. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0282] iv-b. R1 is hydrogen and 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0283] v-b. R1 and R2 are each hydrogen;

[0284] vi-b. The carbon atom bearing R3 and R4 is of S configuration;

[0285] vii-b. 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;

[0286] viii-b. 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 R4, is substituted or unsubstituted aryl or heteroaryl;

[0287] 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;

[0288] x-b. R4 is a substituted or unsubstituted 3-indole moiety;

[0289] xi-b. R3 is hydrogen;

[0290] xii-b. R1 and R4, taken together, form a substituted or unsubstituted pyrrolidine group;

[0291] xiii-b. R1 and R4, taken together, form a substituted or unsubstituted piperidine group;

[0292] xiv-b. R1 and R4, taken together, form a substituted or unsubstituted thiazolidine group;

[0293] xv-b. R1 and R4, taken together, form a substituted or unsubstituted morpholine group;

[0294] xvi-b. R1 and R4, taken together, form a substituted or unsubstituted thiomorpholine group;

[0295] xvii-b. R1 and R4, taken together, form a substituted or unsubstituted indole group;

[0296] 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;

[0297] xix-b. R3 and R4 are each independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;

[0298] xx-b. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl;

[0299] xxi-b. 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;

[0300] xxii-b. 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 —CRbRcPh; wherein Ra is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rb And Rc are each independently substituted or unsubstituted linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0301] xxiii-b. R3 and R4 are each ethyl;

[0302] xxiv-b. R3 is phenyl and R4 is lower alkyl;

[0303] xxv-b. R3 is phenyl and R4 is ethyl;

[0304] xxvi-b. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl group;

[0305] xxvii-b. R3 and R4, taken together, form a cyclohexyl group;

[0306] xxviii-b. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

[0307] xxix-b. R5 is hydrogen;

[0308] xxx-b. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0309] xxxi-b. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0310] xxxii-b. R6 is tert-butyl;

[0311] xxxiii-b. The R6-bearing carbon atom is of S configuration;

[0312] xxxiv-b. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0313] xxxv-b. R7 is methyl;

[0314] xxxvi-b. —[C(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:

[0315] 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;

[0316] c) 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0317] d) R2 is methyl, ethyl, propyl or i-propyl;

[0318] e) RG1 is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl;

[0319] f) RG1 is hydrogen, methyl or phenyl;

[0320] g) RG1 and the substituents on L, taken together, form a substituted or unsubstituted phenyl group;

[0321] h) RM1 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 RM1 and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety;

[0322] i) RM1 and RM2 are each hydrogen;

[0323] j) g is 1 or 2; and/or

[0324] k) L is CH2, S or O;

[0325] xxxviii-a. —C[(R3)(R4)]nN(R1)(R2) together represent the moiety having the structure:

[0326] 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;

[0327] b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, —C(CH3)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0328] c) R2 is methyl, ethyl, propyl or i-propyl;

[0329] d) RL1 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;

[0330] e) RL1 and RL2 are each hydrogen;

[0331] f) RL1 and RL2 are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

[0332] g is 1 or 2;

[0333] xxxvii-b. R is —C(R8b)C(R9b)N(R10b)CR11b— and

[0334] a) R8b is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0335] b) R8b is iso-propyl;

[0336] c) The R8b-bearing carbon atom is of S configuration;

[0337] d) R9b is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0338] e) R10b is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl;

[0339] f) R10b is hydrogen, methyl or acetyl;

[0340] g) R10b and R11b, taken together, form a substituted or unsubstituted pyrrolidine ring; or

[0341] h) R9b and R11b, taken together, form a substituted or unsubstituted thiazole ring;

[0342] xxxviii-b. R is —C(R8c)C(R9c)C(R10c)CR11cOCR12c— and

[0343] a) R8c is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0344] b) R8c is iso-propyl;

[0345] c) The R8c-bearing carbon atom is of S configuration;

[0346] d) R9c and R10c are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0347] e) CR9c and CR10c are linked via a double bond;

[0348] f) CR9c and CR10c are linked via a double bond and R9c is hydrogen; or

[0349] g) CR9c and CR10c are linked via a double bond and R10c is methyl;

[0350] xxxix-b. n is 1;

[0351] xl-b. X1 is C═O;

[0352] xli-b. XI is CH2;

[0353] xlii-b. XI is SO2;

[0354] xliii-b. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0355] 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(NOR)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 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 which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety;

[0356] xliv-b. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0357] 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 RQ1 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

[0358] xlv-b. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0359] 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.

[0360] An important subclass of class (Ic) includes those compounds having the structure of formula (Ic) in which X2 is C═O; R is —CH(R8a)C(R9a)=C(R10a)—; j is 0; 1 and m are each 1; R3 is hydrogen; G is CRG1; M is CRM1RM2, and the compound has the structure:

[0361] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0362] g is 1, 2, 3 or 4;

[0363] 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;

[0364] L is CRL1RL2, S, O or NRL3, wherein each occurrence of RL1, RL2 and RL3 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0365] each occurrence of RG1, RM1 and RM2 is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0366] wherein any two adjacent RL1, RL2, RL3, RG1, RM1 or RM2 groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety.

[0367] 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, I and m are each 1; R is —CH(R8a)C(R9a)=C(R10a)—; R3 is hydrogen; and the compound has the structure:

[0368] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0369] g is 0, 1, 2 or 3;

[0370] 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;

[0371] RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.

[0372] 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 CHRG1, M is CRM1RM2, and the compound has the structure:

[0373] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0374] g is 1, 2 or 3;

[0375] L is CRL1RL2, S, O or NRL3, wherein each occurrence of RL1, RL2 and RL3 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0376] each occurrence of RG1, RM1 and RM2 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0377] any two adjacent RL1, RL2, RL3, RG1, RM1 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;

[0378] 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

[0379] 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.

[0380] 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)—; i is 0; I and m are each 1; R3 is hydrogen; G is CHRG1, M is CRM1RM2; R10b and R11b, taken together, form a cyclic heteroalkyl group; and the compound has the structure:

[0381] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0382] p is 1, 2, 3 or 4;

[0383] q is 0-12;

[0384] 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;

[0385] 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

[0386] NR7 and CR8b, and CR8b and CR9b are each independently linked by a single or double bond as valency permits.

[0387] 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, I and m are each 1; R is —C(R8b)C(R9b)N(R10b)C(R11bb)—; R3 is hydrogen; and the compound has the structure:

[0388] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0389] g is 0, 1, 2 or 3;

[0390] RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0391] 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

[0392] NR7 and CR8b, CR9b and CR9b, CR9b and NR10b, NR10b and CR11b are each independently linked by a single or double bond as valency permits.

[0393] 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:

[0394] wherein R2, R5-R7 and Q are defined in classes and subclasses herein;

[0395] p is 1, 2, 3 or 4;

[0396] q is 0-12;

[0397] g is 0, 1, 2 or 3; RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0398] each occurrence of S1 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;

[0399] 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.

[0400] 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; l and m are each 1; R3 is hydrogen; G is CHRG1, M is CRM1RM2; and the compound has the following structure:

[0401] wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;

[0402] g is 1, 2 or 3;

[0403] L is CRL1RL2, S, O or NRL3, wherein each occurrence of RL1, RL2 and RL3 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0404] each occurrence of RG1, RM1 and RM2 is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0405] any two adjacent RL1, RL2, RL3, RG1, RM1 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;

[0406] 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

[0407] 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.

[0408] 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)—; G, J and M are each CH2; j, I and m are each 1; R3 is hydrogen; and the compound has the following structure:

[0409] wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;

[0410] g is 0, 1, 2 or 3; RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0411] 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

[0412] 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.

[0413] 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:

[0414] 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;

[0415] ii-c. R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

[0416] iii-c. R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0417] iv-c. 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)2C—CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0418] v-c. R2 is hydrogen;

[0419] vi-c. R2 is hydrogen, methyl or benzyl;

[0420] vii-c. R2 is methyl;

[0421] viii-c. R2 is acyl, wherein the acyl group is a nitrogen proteting group;

[0422] ix-c. R3 is hydrogen;

[0423] x-c. The moiety having the structure

[0424] forms a substituted or unsubstituted pyrrolidine group;

[0425] xi-c. The moiety having the structure

[0426] forms a substituted or unsubstituted piperidine group;

[0427] xii-c. The moiety having the structure

[0428] forms a substituted or unsubstituted thiazolidine group;

[0429] xiii-c. The moiety having the structure

[0430] forms a substituted or unsubstituted morpholine group;

[0431] xiv-c. The moiety having the structure

[0432] forms a substituted or unsubstituted thiomorpholine group;

[0433] xv-c. The moiety having the structure

[0434] forms a substituted or unsubstituted indole group;

[0435] xvi-c. R5 is hydrogen;

[0436] xvii-c. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0437] xviii-c. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0438] xix-c. R6 is tert-butyl;

[0439] xx-c. The R6-bearing carbon atom is of S configuration;

[0440] xxi-c. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0441] xxii-c. R7 is methyl;

[0442] xxiii-c. R is —CH(R8a)C(R9a)=C(R10a)—; and

[0443] a) R8a is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0444] b) R8a is iso-propyl;

[0445] c) The R8a-bearing carbon atom is of S configuration;

[0446] d) R9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0447] e) R9a is hydrogen;

[0448] f) R10a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

[0449] g) R10a is methyl;

[0450] xxiv-c. R is —C(R8b)C(R9b)N(R10b)CR11b— and

[0451] a) R8b is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0452] b) R8b is iso-propyl;

[0453] c) The R8b-bearing carbon atom is of S configuration;

[0454] d) R9b is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0455] e) R10b is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl moiety;

[0456] f) R10b is hydrogen, methyl or acetyl;

[0457] g) R10b and R11b, taken together, form a substituted or unsubstituted pyrrolidine ring; or

[0458] h) R9b and R11b, taken together, form a substituted or unsubstituted thiazole ring;

[0459] xxv-c. R is —C(R8c)C(R9c)C(R10c)CR11cOCR12c— and

[0460] a) R8c is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0461] b) R8c is iso-propyl;

[0462] c) The R8c-bearing carbon atom is of S configuration;

[0463] d) R9c and R10c are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0464] e) CR9c and CR10c are linked via a double bond;

[0465] f) CR9c and CR10c are linked via a double bond and R9c is hydrogen; or

[0466] g) CR9c and CR10c are linked via a double bond and R10c is methyl;

[0467] xxv-c. The moiety having the structure

[0468] represents the moiety having the structure:

[0469] 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;

[0470] b) R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)Et, —CH(CH3)CH2CH2CH3, —CH(CH3)CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —C(CH3)2Et, —CH(CH3)cyclobutyl, —CH(Et)2, —C(CH3)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0471] l) R2 is methyl, ethyl, propyl or i-propyl;

[0472] m) RG1 is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl;

[0473] n) RG1 is hydrogen, methyl or phenyl;

[0474] o) RG1 and the substituents on L, taken together, form a substituted or unsubstituted phenyl group;

[0475] p) RM1 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 RM1 and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety;

[0476] q) RM1 and RM2 are each hydrogen;

[0477] r) g is 1 or 2; and/or

[0478] s) L is CH2, S or O;

[0479] xxvi-c. The moiety having the structure

[0480] represents the moiety having the structure:

[0481] 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;

[0482] h) 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0483] i) R2 is methyl, ethyl, propyl or i-propyl;

[0484] j) RL1 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;

[0485] k) RL1 and RL2 are each hydrogen;

[0486] l) RL1 and RL2 are each substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; and/or

[0487] m) gis 1 or 2;

[0488] xxvii-c. X2 is C═O;

[0489] xxviii-c. X2 is CH2;

[0490] xxix-c. X2 is SO2;

[0491] xxx-c. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0492] 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—, NR K, —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;

[0493] xxxi-c. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0494] 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

[0495] xxxii-c. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0496] 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.

[0497] An important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is —CH(R8a)C(R9a)═C(R10a)—; X2 is C═O; and the compound has the following structure:

[0498] 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

[0499] 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 an alicyclic, heteroalicyclic, alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety.

[0500] Another important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is —C(R8b)C(R9b)N(R10b)C(R11b)—; X2 is C═O; and the compound has the following structure:

[0501] 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;

[0502] 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

[0503] NR7 and CR8b, CR9b and CR9b, CR9b and NR10b, NR10b and CR11b are independently linked by a single or double bond as valency permits.

[0504] Another important subclass of class (Id) includes those compounds having the structure of formula (Id) in which R is —C(R8b)C(R9b)N(R10b)C(R11b)—; X2 is C═O; R10b and R11b, taken together, form a cyclic heteroalkyl group; and the compound has the following structure:

[0505] 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;

[0506] p is 1, 2, 3 or 4;

[0507] q is 0-12;

[0508] 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;

[0509] 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

[0510] NR7 and CR8, and CR8b and CR9b are independently linked by a single or double bond as valency permits.

[0511] 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(R10c)C(R11c)OC(R12c)—; and the compound has the following structure:

[0512] 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;

[0513] R8c, R9c, R10c, R11c and R12, 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

[0514] 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.

[0515] 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:

[0516] 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;

[0517] 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;

[0518] iii-d. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

[0519] iv-d. R1 is hydrogen and 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0520] v-d. R1 and R2 are each hydrogen;

[0521] vi-d. R1 and R2 are independently hydrogen or methyl;

[0522] vii-d. R1 and R2 are each methyl;

[0523] 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;

[0524] 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;

[0525] x-d. R3 and R4 are each independently substituted or unsubstituted lower alkyl, aryl or heteroaryl;

[0526] xi-d. 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;

[0527] xii-d. 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 —CRbRcPh; wherein Ra is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and Rb And Rc are each independently substituted or unsubstituted linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0528] xiii-d. R3 and R4 are each ethyl;

[0529] xiv-d. R3 is phenyl and R4 is lower alkyl;

[0530] xv-d. R3 is phenyl and R4 is ethyl;

[0531] xvi-d. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl group;

[0532] xvii-d. R3 and R4, taken together, form a cyclohexyl group;

[0533] xviii-d. R3 and R4, taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

[0534] xix-d. R5 is hydrogen;

[0535] xx-d. R6 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0536] xxi-d. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

[0537] xxii-d. R6 is tert-butyl;

[0538] xxiii-d. The R6-bearing carbon atom is of S configuration;

[0539] xxiv-d. R7 is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0540] xxv-d. R7 is methyl;

[0541] xxvi-d. R is —CH(R8a)C(R9a)═C(R10a)—; and

[0542] i) R8a is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0543] j). R8a is iso-propyl;

[0544] k) The R8a-bearing carbon atom is of S configuration;

[0545] l) R9a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0546] m) R9a is hydrogen;

[0547] n) R10a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

[0548] o) R10a is methyl;

[0549] xxvii-d. R is —C(R8b)C(R9b)N(R10b)CR11b— and

[0550] p) R8b is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0551] q) R8b is iso-propyl;

[0552] r) The R8b-bearing carbon atom is of S configuration;

[0553] s) R9b is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0554] t) R10b is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl moiety;

[0555] u) R10b is hydrogen, methyl or acetyl;

[0556] v) R10b and R11b, taken together, form a substituted or unsubstituted pyrrolidine ring; or

[0557] w) R9b and R11b, taken together, form a substituted or unsubstituted thiazole ring;

[0558] xxviii-d. R is —C(R8c)C(R9c)C(R10c)CR11cOCR12c— and

[0559] h) R8c is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0560] i) R8c is iso-propyl;

[0561] j) The R8c-bearing carbon atom is of S configuration;

[0562] k) R9c and R10c are each independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

[0563] l) CR9, and CR10, are linked via a double bond;

[0564] m) CR9c and CR10, are linked via a double bond and R9c is hydrogen; or

[0565] n) CR9c and CR10 are linked via a double bond and R10, is methyl;

[0566] xxix-d. X2 is C═O;

[0567] xxx-d. X2 is CH2;

[0568] xxxi-d. X2 is SO2;

[0569] xxxii-d. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0570] wherein each occurrence of r is 0, 1 or 2; 5 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 -ZJRJ; 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;

[0571] xxxiii-d. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, or a moiety selected from the group consisting of:

[0572] 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

[0573] xxxiv-d. Q is ORQ′, SRQ′, NRQ′RQ″, N3, ═N—OH, ═N—OH, or a moiety selected from the group consisting of:

[0574] 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.

[0575] As the reader will appreciate, compounds of particular interest include, among others, those which share the attributes of one or more of the foregoing subclasses. Some of those subclasses are illustrated by the following sorts of compounds:

[0576] I) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0577] wherein R1-R2, R4a R4b, R9a-R10a and Q are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0578] II) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0579] wherein A, B, D, E, a, b, d, e, R1-R2, R4a, R4b, and R9a-R10a are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0580] It will also be appreciated that for each of the subgroups I-II described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-a. through xliv-a. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0581] III) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0582] wherein R1-R2, R4a, R4b, R9b-R11b and RG are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0583] IV) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0584] wherein A, B, D, E, a, b, d, e, R1-R2, R4a, R4b, and R9b-R11b are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0585] V) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0586] wherein R1-R2, R4a, R4b, R9c-R12c and RG are as defined above and in subclasses herein; and Ar is a substituted or unsubstitued aryl or heteroaryl moiety.

[0587] It will also be appreciated that for each of the subgroups Ill-V described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-b. through xlv-b. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0588] VI) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0589] wherein L, R9a-R10a, RG1, RM1 and RM2 are as defined above and in subclasses herein; g is 1 or 2; Q is ORQ′, wherein RQ′ is hydrogen or lower alkyl; and R2 and R6 are independently substituted or unsubstituted linear or branched lower alkyl.

[0590] VII) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0591] wherein g, R9a-R10a, RL1 and RL2 are as defined above and in subclasses herein; X1 is CH2 or C═O; R2 and R6 are independently substituted or unsubstituted linear or branched lower alkyl; and Q is ORQ′ or NRQ′RQ″ wherein RQ′ is hydrogen or lower alkyl, or RQ′ and RQ″, 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.

[0592] VIII) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0593] wherein A, B, D, E, L, a, b, d, e, p, R9b, RG1, RM1 and RM2 are as defined above and in subclasses herein; g is 1 or 2; and R2 and R6 are independently substituted or unsubstituted linear or branched lower alkyl.

[0594] IX) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0595] wherein p, R9b, RL1, RL2, RQ′ and RQ″ are as defined above and in subclasses herein; and R2 and R6 are independently substituted or unsubstituted linear or branched lower alkyl.

[0596] It will also be appreciated that for each of the subgroups VI-IX described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-c. through xxxii-c. described above and classes, subclasses and species of compounds described above and in the examples herein. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, iso-propyl, sec-butyl or —CH(CH3)CH(CH3)2. In certain embodiments, for compounds of subgroups VI-IX above, R6 is tert-butyl or iso-propyl. In certain embodiments, for compounds of subgroups VI-IX above, R2 is methyl, iso-propyl, sec-butyl or —CH(CH3)CH(CH3)2, and R6 is tert-butyl or iso-propyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is methyl and R6 is tert-butyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is iso-propyl and R6 is tert-butyl. In certain exemplary embodiments, for compounds of subgroups VI-IX above, R2 is sec-butyl and R6 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 tert-butyl.

[0597] X) Compounds of the Formula (and Pharmaceutically Acceptable Derivatives Thereof):

[0598] wherein R1, R9a, R10a and RG 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.

[0599] It will also be appreciated that for subgroup X described above, a variety of other subclasses are of special interest, including, but not limited to those classes i-d. through xxxiv-d. described above and classes, subclasses and species of compounds described above and in the examples herein.

[0600] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. It is to be understood that the invention encompasses every possible isomer such as geometric isomer, optical isomer, stereoisomer and tautomer based on asymmetric carbon, which can occur in the structures of the inventive compounds, and mixtures of such isomers, and is not limited to the specific stereochemistry shown for the compounds disclosed in the present specification. It will be further appreciated that the absolute stereochemistry of some of the compounds recited in the Exemplification herein has not been determined, and that when a stereochemistry was assigned for those compounds it is meant to be tentative and to indicate that a set of diastereomers exists for those compounds and/ot that a diastereomer was isolated in pure form. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.

[0601] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. The invention also encompasses tautomers of specific compounds as described above. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

[0602] Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

[0603] 2) Compounds and Definitions

[0604] 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.

[0605] Compounds of this invention include those specifically set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.

[0606] Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. The phrase, “pharmaceutically acceptable derivative”, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

[0607] Numerous suitable prodrug moieties, and information concerning their selection, synthesis and use are well known in the art. Examples of prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities. Examples of such prodrug moieties include the following:

[0608] Other examples of prodrug moieties of interest include prodrug moieties that can be attached to hydroxyl-containing functionalities. Such prodrug moieties a well-known in the art, and will be readily identified by a person skilled in the relevant art. The present invention encompasses any prodrug form of the compounds described herein.

[0609] Certain compounds of the present invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, 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 described herein, utilize a variety of protecting groups. By the term “protecting group”, as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in “Protective Groups in Organic Synthesis” Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[0610] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the 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 described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example of cancer. The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0611] The term “aliphatic”, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term “alkyl” includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

[0612] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[0613] The term “alicyclic”, as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “alicyclic” is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, —CH2-cyclopropyl, cyclobutyl, —CH2-cyclobutyl, cyclopentyl, —CH2-cyclopentyl-n, cyclohexyl, —CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[0614] 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. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0615] 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. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.

[0616] Some examples of sutstituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO2; —CN; —CF3; —CH2CF3; —CH12; —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 described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0617] In general, the terms “aryl” and “heteroaryl”, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkyl or heteroalkyl moiety and thus also include -(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases “aryl or heteroaryl” and “aryl, heteroaryl, -(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl” are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments of the present invention, “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiements of the present invention, the term “heteroaryl”, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0618] 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; heteroarylthio; F; Cl; Br; I; —OH; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —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 described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0619] 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; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Ry; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)2Rx; —NRx(CO)Rx wherein each occurrence of R, independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0620] The term “heteroaliphatic”, as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have have substituted with an heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched or linear unbranched. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —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 R, independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0621] 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.

[0622] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0623] The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

[0624] The term “heterocycloalkyl” or “heterocycle”, as used herein, refers to a non-aromatic 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certain embodiments, a “substituted heterocycloalkyl or heterocycle” group is utilized and as used herein, refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —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 described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substitutents described above and herein may be substituted or unsubstituted. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples, which are described herein.

[0625] 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 branched groups. Similarly, the terms “alicyclic”, “heteroalicyclic”, “heterocycloalkyl”, “heterocycle”, and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. In addition, the terms “aliphatic(aryl)”, “heteroaliphatic(aryl)”, “aliphatic(heteroaryl)”, “heteroaliphatic(heteroaryl)”, “alicyclic(aryl)”, “heteroalicyclic(aryl)”, “alicyclic(heteroaryl)”, “heteroalicyclic(heteroaryl)”, “-alkyl(aryl)”, “heteroalkyl(aryl)”, “-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.

[0626] 3) Synthetic Methodology

[0627] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[0628] In one aspect, the present invention provides novel peptides having formula (I) as described above and in certain classes and subclasses herein. Examples of synthetic methods for preparing exemplary types of compounds of the invention are provided below, as detailed in Schemes 1-20, and in the Exemplification herein. It will be appreciated that the methods as described herein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting materials are well known to those skilled in the art. Although the following schemes describe certain exemplary compounds, it will be appreciated that the use of alternate starting materials will yield other analogs of the invention. For example, compounds are described below where X1 and X2 are each C═O, R5 is hydrogen, R6 is tert-butyl and R7 is methyl; however, it will be appreciated that alternate starting materials and/or intermediates can be utilized to generate compounds where, for example, X1 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.

[0629] In certain embodiments, the inventive compounds, have the general structure (I′) as shown in Scheme 1, where R, R′ and Q are aliphatic, heteroaliphatic, aryl or heteroaryl moieties. In preferred embodiments, R, R′ and Q are moieties such as those described in classes and subclasses herein. Examples of preferred structures for R, R′ and Q are depicted in Scheme 1.

[0630] In certain embodiments, the inventive compounds belong to class (Ia) and subclasses thereof, as described herein. Scheme 2 depicts the synthesis of exemplary compounds of this class (compounds of general structure 11). As shown in Scheme 2, the dipeptide core can be constructed, for example, from N-Boc-N-methyl-valinal (2) and N-Boc-tert-leucine (4). The N-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 variety of synthetic methods allow access to a variety of analogs, for example, carboxylic esters of general structure 7, carboxylic acid 8 or amides of general structure 11. The reader will appreciate that other synthetic methods known in the art can be used to prepare other derivatives.

[0631] An exemplary synthetic approach for the preparation of intermediate 6 is depicted in Scheme 3. The method afforded (S)-N-Boc-neo-phenylalanine (6) in 20% overall yield.

[0632] In certain other embodiments, the inventive compounds belong to class (Ib) and subclasses thereof, as described herein. Schemes 4-6 depict the synthesis of exemplary types of compounds of this class (for example, Amine Esters, Amine Acids, Amine Amides and N-Acetyl Amine Amides of general structure 18, 20, 23, respectively as seen in Schemes 4; See also Amine Esters, Amine Acids, Amine Amides and N-Acetyl Amine Amides of general structure 25, 26 and 27, respectively in Scheme 5). In certain embodiments, R may be a nitrogen-containing heteroalkyl moiety (see Schemes 4 and 5) or an unsaturated oxygen-containing heteroalkyl moiety (see Scheme 6). Although Schemes 4-6 depict compounds comprising an N-terminal moiety derived from (S)-N-Boc-neo-phenylalanine (6), a person of ordinary skill in the art would appreciate that a wide variety of organic moieties other than those described in Schemes 4-6 may be used to construct the compounds of the invention. Similarly, Schemes 4-6 recite compounds where the C-terminal moiety may be carboxylic esters, carboxylic acids or amides. It is to be understood that the scope of the invention is not limited to these compounds, but rather encompasses derivatives and analogs of these compounds, or compounds obtained from different starting materials.

[0633] In certain other embodiments, the inventive compounds belong to class (1c) and subclasses thereof, as described herein. Schemes 7-10 depict the synthesis of exemplary types of compounds of this class (for example Amine Esters, Amine Acids and Amine Amides of general structure 42, 43 and 45, respectively, as seen in Scheme 7). In certain embodiments, the compounds of the invention comprise a nitrogen-containing heterocyclic N-terminal moiety. For example, the heterocyclic moiety may be a piperidine ring (Schemes 7, 8 and 9) or a thiazolidine ring (Scheme 10). Examples of other suitable moieties are described in the Exemplification herein, or will be apparent to the person of ordinary skill in the art. As dicussed above, R may be a nitrogen-containing heteroalkyl moiety (Scheme 7) or an unsaturated alkyl moiety (Schemes 8, 9 and 10).

[0634] The skilled practitioner will recognize that the synthetic methodology may be applied to pipecolic acid analogs other than those depicted in Scheme 9. For example, the methodology may be used for pipecolic acid analogs having a different substitution pattern on the piperidine ring (e.g., other than 4-methyl) and/or analogs where the piperidine nitrogen atom may be substituted with a group other than methyl (e.g., ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH(CH3)CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH(CH3)2, —CH(CH3)2CH2CH3, —CH(CH3)cyclobutyl, —CH(Et)2, —CH(CH3)2C CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl).

100

[0635] In certain other embodiments, the inventive compounds belong to class (Id) and subclasses thereof, as described herein. One skilled in the art would appreciate that the exemplary heterocyclic starting materials described in Schemes 7-10, that are used in the preparation of compounds of class (Ic) (namely compounds 38, 60 or 65) could be substituted for acyclic α-amino acid moieties to access compounds of class (Id), as illustrated in Scheme 11 below:

101

[0636] For example, reaction of diethylglycine (72) with amine HCl salt 49 gives the N-terminal gem-diethyl ethyl ester 73, or the corresponding carboxylic acid 74, after hydrolysis under suitable conditions (Scheme 12).

102

[0637] In certain other embodiments, there is provided a method for preparing compounds of formula VIA:

103

[0638] wherein L, R9a-R10a, RG1, RM1 and RM2 are as defined above and in subclasses herein; g is 1 or 2; Q is ORQ′, wherein RQ′ is hydrogen, lower alkyl or an oxygen protecting group; and R2 and R6 are independently substituted or unsubstituted linear or branched lower alkyl. In certain embodiments, compounds of formula (VIA) may be prepared according to the methodology depicted in Scheme 13:

104

[0639] Alternatively, or additionally, compounds of formula (VIA) may be prepared according to the methodology depicted in Scheme 14:

105

[0640] In certain embodiments, compound 92 may be prepared according to the methodology depicted in Scheme 15:

106

[0641] In certain other embodiments, compound 92 may be prepared according to the methodology depicted in Scheme 16:

107

[0642] In certain embodiments, compound 95 may be prepared according to the methodology depicted in Scheme 17:

108

[0643] In certain other embodiments, compound 95 may be prepared from intermediate 108 according to the methodology depicted in Scheme 18:

109

[0644] 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, R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. In certain other exemplary embodiments, R6 is tert-butyl.

[0645] In certain embodiments, for the compounds depicted in Schemes 13-18, R10a is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl. In certain exemplary embodiments, R10a is linear or branched lower alkyl. In certain other exemplary embodiments, R10a is methyl.

[0646] In certain embodiments, for the compounds depicted in Schemes 13-18, the moiety having the structure:

110

[0647] has the following structure:

111

[0648] wherein R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl. In certain exemplary embodiments, R2 is substituted or unsusbtituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl. In certain other exemplary embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, 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.

[0649] In certain embodiments, for the compounds depicted in Schemes 13-18, R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH3)CH2CH3, —CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; R10a is methyl; and the moiety having the structure:

112

[0650] has the following structure:

113

[0651] wherein 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)2C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.

[0652] 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.

[0653] It will be appreciated that each of the reactions described in Schemes 2-18 above can be carried out using reagents and conditions as described for the synthesis of various types of exemplary compounds described above, or they may be modified using other available reagents or starting materials. For example, a variety of amide formation conditions, esterification, hydrolysis and aromatic nucleus functionalization conditions are well-known in the art and can be utilized in the method of the invention. See, generally, March, Advanced Organic Chemistry, 5th ed., John Wiley & Sons, 2001; and “Comprehensive Organic Transformations, a guide to functional group preparations”, Richard C. Larock, VCH publishers, 1999; the entire contents of which are incorporated herein by reference.

[0654] As mentioned above, it will be appreciated that the invention is not limited in scope to the compounds recited herein. Synthetic strategies or starting materials other than those described herein may be used to prepare compounds of general structure (I). It will also be appreciated that each of the components/starting materials used in the synthesis of the compounds of the invention can be diversified either before synthesis or alternatively after the construction of the peptide construct. As used herein, the term “diversifying” or “diversify” means reacting an inventive compound, as defined herein, at one or more reactive sites to modify a functional moiety or to add a functional moiety. For example, where an aromatic ring is present in the compound, the aromatic ring can be diversified (prior to or after reaction) to either add functionality (e.g., where hydrogen is present, a halogen or other functionality can be added) or to modify functionality (e.g., where a hydroxyl group is present on the aromatic ring, the aromatic ring can be diversified by reacting with a reagent to protect the hydroxyl group, or to convert it into an aliphatic or heteroaliphatic moiety). Described generally below are a variety of schemes to assist the reader in the synthesis of a variety of analogues, either by diversification of the intermediate components or by diversification of the peptide construct.

[0655] In certain embodiments, the preparation of chemically diverse derivatives may be achieved by diversifying the C-terminal moiety of the compounds. For example, where the C-terminal moiety is a carboxylic acid, examples of chemical transformations suitable to achieve such derivatization include, but are not limited to, reduction to the corresponding aldehyde or alcohol, amidation, Wittig reaction, decarboxylation, esterification, addition of nucleophiles, conversion to ketones, imines, hydrazones, azides, etc. Examples of such transformations are depicted in Schemes 19 and 20. One skilled in the art will recognize that possible chemical transformations suitable to achieve diversification of the compounds of the invention are not limited to those depicted in Schemes 19 and 20. Rather, any suitable synthetic methods known in the art can be used to achieve desired chemical transformations.

114

115

[0656] 4) Research Uses, Formulation and Administration

[0657] According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having a pre-determined biological activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc. In certain exemplary embodiments, the inventive compounds are tested in assays to identify those compounds having cytotoxic or growth inhibitory effect in vitro, or cause tumor regression and/or inhibition of tumor growth in vivo.

[0658] Compounds of this invention which are of particular interest include those which:

[0659] exhibit cytotoxic and/or growth inhibitory effect on cancer cell lines maintained in vitro or in animal studies using a scientifically acceptable cancer cell xenograft model;

[0660] preferably cause tumor regression in vivo;

[0661] exhibit low sensitivity to MDR;

[0662] exhibit low cytotoxicity to non-dividing normal cells; and/or

[0663] exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability).

[0664] As detailed in the exemplification herein, in assays to determine the ability of compounds to inhibit the growth of tumor cell lines in vitro, certain inventive compounds exhibited IC50 values≦10 μM. In other embodiments, compounds of the invention exhibit IC50 values≦5 μM. In other embodiments, compounds of the invention exhibit IC50 values≦1 μM. In other embodiments, compounds of the invention exhibit IC50 values≦750 nM. In other embodiments, compounds of the invention exhibit IC50 values≦500 nM. In other embodiments, compounds of the invention exhibit IC50 values≦250 nM. In other embodiments, compounds of the invention exhibit IC50 values≦100 nM. In other embodiments, compounds of the invention exhibit IC50 values≦50 nM. In other embodiments, compounds of the invention exhibit IC50 values≦25 nM. In other embodiments, compounds of the invention exhibit IC50 values≦10 nM. In other embodiments, compounds of the invention exhibit IC50 values≦7.5 nM. In other embodiments, compounds of the invention exhibit IC50 values≦5 nM. In other embodiments, compounds of the invention exhibit IC50 values≦2.5 nM. In other embodiments, compounds of the invention exhibit IC50 values≦1 nM. In other embodiments, compounds of the invention exhibit IC50 values≦0.75 nM. In other embodiments, compounds of the invention exhibit IC50 values≦0.5 nM. In other embodiments, compounds of the invention exhibit IC50 values≦0.25 nM. In other embodiments, compounds of the invention exhibit IC50 values≦0.1 nM. In certain embodiments, compounds of the invention exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM-10 nM.

[0665] In certain other embodiments, compounds of the invention exhibit low sensitivity to MDR. In certain exemplary embodiments, compounds of the invention have a ratio [cell growth inhibition in MDR-positive cells]/[cell growth inhibition in MDR-negative cells] (i.e., resistance ratio)≦10. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦9. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦8. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦7. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦6. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦5. In certain exemplary embodiments, compounds of the invention have a resistance ratio ≦4.

[0666] In certain other embodiments, compounds of the invention exhibit low cytotoxicity to non-dividing normal cells. In certain exemplary embodiments, inventive compounds exhibit little or no cytotoxicity in non-dividing normal cells at concentrations ≧1000 fold the concentration at which they inhibit cancer cell growth. In certain exemplary embodiments, inventive compounds exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μM.

[0667] In certain embodiments, inventive compounds exhibit stability in mouse serum.

[0668] In certain embodiments, inventive compounds exhibit a low mitotic block reversibility ratio. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 30. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 25. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 20. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 15. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 10. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 5. In certain embodiments, inventive compounds exhibit mitotic block reversibility ratios of 1 to about 3.

[0669] 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.

[0670] In certain exemplary embodiments, compounds of the invention cause inhibition of tumor growth in vivo. In certain exemplary embodiments, compounds of the invention cause significant inhibition of tumor growth in suitable cancer cell xenograft models. In certain exemplary embodiments, compounds of the invention cause significant inhibition of tumor growth in suitable multidrug resistant cancer cell xenograft models. In certain exemplary embodiments, compounds of the invention cause inhibition of tumor growth in treated animals by >50% compared to that of control aninals (i.e., “treated” tumor size <50% “control” tumor size; or T/C value <50%) in suitable cancer cell xenograft models. In certain embodiments, compounds of the invention have T/C values <70%. In certain embodiments, compounds of the invention have T/C values <65%. In certain embodiments, compounds of the invention have T/C values <60%. In certain embodiments, compounds of the invention have T/C values <55%.

[0671] In certain embodiments, compounds of the invention inhibit the growth of human cancer cells in vitro, exhibit low sensitivity to MDR (e.g., low resistance ratio), exhibit low cytotoxicity to non-dividing normal cells, exhibit stability in mouse serum, have a low mitotic block reversibility ratio, cause tumor regression in vivo, and/or cause inhibition of tumor growth in vivo.

[0672] In certain embodiments, compounds of the invention inhibit the growth of human cancer cells in vitro, exhibit low sensitivity to MDR (e.g., low resistance ratio), exhibit low cytotoxicity to non-dividing normal cells, exhibit stability in mouse serum, have a low mitotic block reversibility ratio, cause tumor regression in vivo, and cause inhibition of tumor growth in vivo.

[0673] In certain embodiments, compounds of the invention have any one or more of the following properties:

[0674] (i) exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM-10 nM;

[0675] (ii) have a resistance ratio preferably ≦10, preferably ≦9, preferably ≦8, preferably ≦7, preferably ≦6, preferably ≦5, more preferably ≦4;

[0676] (iii) exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μM;

[0677] (iv) exhibit stability in mouse serum;

[0678] (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;

[0679] (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

[0680] (vii) cause significant inhibition of tumor growth in suitable cancer cell xenograft model (e.g., T/C value preferably ≦70%, preferably ≦65%, preferably ≦60%, preferably ≦55%, most preferably ≦50%).

[0681] In certain embodiments, compounds of the invention have the following properties:

[0682] (i) exhibit growth inhibition IC50 values in cultured human cancer cells in the range of 0.1 nM-10 nM;

[0683] (ii) have a resistance ratio preferably ≦10, preferably ≦9, preferably ≦8, preferably ≦7, preferably ≦6, preferably ≦5, more preferably ≦4;

[0684] (iii) exhibit little or no cytotoxicity in non-dividing normal cells at concentrations in the range of up to 1-10 μM;

[0685] (iv) exhibit stability in mouse serum;

[0686] (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;

[0687] (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

[0688] (vii) cause significant inhibition of tumor growth in suitable cancer cell xenograft model (e.g., T/C value preferably ≦70%, preferably ≦65%, preferably ≦60%, preferably ≦55%, most preferably ≦50%).

[0689] 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).

[0690] As discussed above, compounds of the invention exhibit activity for the inhibition of tumor cell growth. As such, the inventive compounds as useful for the treatment of a variety of disorders, including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few. In certain embodiments, the inventive compounds are useful for the treatment of solid and non-solid tumors. In still other embodiments of interest, the inventive compounds are particularly useful for the treatment of breast cancer, prostate cancer, colon cancer, lung cancer, leukemia and lymphoma.

[0691] In certain embodiment, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the inventive compounds as useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).

[0692] Pharmaceutical Compositions

[0693] As discussed above this invention provides novel compounds that have biological properties useful for the treatment of cancer. In certain embodiments, certain of the compounds as described herein act as inhibitors of tumor growth and thus are useful in the treatment of cancer and in the inhibition of tumor growth and in the killing of cancer cells. In certain embodiments, the inventive compounds are useful for the treatment of solid tumors or non-solid tumors. In still other embodiments of interest, the inventive compounds are useful for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few. The inventive compounds also find use in the prevention of restenosis of blood vessels subject to traumas such as angioplasty and stenting.

[0694] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, the compounds are capable of inhibiting the growth of or killing cancer cells. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be a cytotoxic agent or anticancer agent approved for the treatment of cancer, as discussed in more detail herein, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of an immune disorder or cancer. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a prodrug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0695] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with little or no undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, trifluoroacetate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0696] Additionally, as used herein, the term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moeity advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0697] Furthermore, the term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0698] As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0699] Uses and Formulations of Compounds of the Invention

[0700] As described in more detail herein, in general, the present invention provides compounds useful for the treatment of cancer and proliferative disorders.

[0701] As discussed above, certain of the compounds as described herein act as inhibitors of tumor growth and thus are useful in the treatment of cancer and in the inhibition of tumor growth and in the killing of cancer cells. The invention further provides a method for inhibiting tumor growth and/or tumor metastasis. The method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the inventive compounds are useful for the treatment of solid tumors or non-solid tumors. In still other embodiments of interest, the inventive compounds are useful for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, to name a few.

[0702] As described 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 described in more detail herein, and are useful for the treatment of cancer, including solid and non-solid tumors.

[0703] 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, catheters, artificial implants, pins, electrical implants such as pacemakers, and especially for arterial or venous stents, including balloon-expandable stents. In certain embodiments inventive compounds may be bound to an implantable medical device, or alternatively, may be passively adsorbed to the surface of the implantable device. In certain other embodiments, the inventive compounds may be formulated to be contained within, or, adapted to release by a surgical or medical device or implant, such as, for example, stents, sutures, indwelling catheters, prosthesis, and the like.

[0704] In certain exemplary embodiments, the inventive compounds may be used as coating for stents. A stent is typically an open tubular structure that has a pattern (or patterns) of apertures extending from the outer surface of the stent to the lumen. It is commonplace to make stents of biocompatible metallic materials, with the patterns cut on the surface with a laser machine. The stent can be electro-polished to minimize surface irregularities since these irregularities can trigger an adverse biological response. However, stents may still stimulate foreign body reactions that result in thrombosis or restenosis. To avoid these complications, a variety of stent coatings and compositions have been proposed in the prior art literature both to reduce the incidence of these complications or other complications and restore tissue function by itself or by delivering therapeutic compound to the lumen. For example, drugs having antiproliferative and anti-inflammatory activities have been evaluated as stent coatings, and have shown promise in preventing retenosis (See, for example, Presbitero P. et al., “Drug eluting stents do they make the difference?”, Minerva Cardioangiol, 2002, 50(5):431-442; Ruygrok 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 variety of compositions and methods related to stent coating and/or local stent drug delivery for preventing restenosis are known in the art (see, for example, U.S. Pat. Nos. 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 materials for the implantable device include biocompatible and nontoxic materials, and may be chosen from the metals such as nickel-titanium alloys, steel, or biocompatible polymers, hydrogels, polyurethanes, polyethylenes, ethylenevinyl acetate copolymers, etc. In certain embodiments, the inventive compound, is coated onto a stent for insertion into an artery or vein following balloon angioplasty.

[0705] The invention may be described therefore, in certain broad aspects as a method of inhibiting arterial restenosis or arterial occlusion following vascular trauma comprising administering to a subject in need thereof, a composition comprising an inventive compound conjugated to a suitable polymer or polymeric material. In the practice of the method, the subject may be a coronary bypass, vascular surgery, organ transplant or coronary or any other arterial angioplasty patient, for example, and the composition may be administered directly, intravenously, or even coated on a stent to be implanted at the sight of vascular trauma.

[0706] In another aspect, the invention encompasses implants and surgical or medical devices, including stents and grafts, coated with or otherwise constructed to contain and/or release any of the inventive compounds disclosed herein. In certain embodiments, the compounds have antiproliferative activity. In certain other embodiments, the compounds inhibit smooth muscle cell proliferation. Representative examples of the inventive implants and surgical or medical devices include cardiovascular devices (e.g., implantable venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemaker wires, implantable defibrillators); neurologic/neurosurgical devices (e.g., ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions); gastrointestinal devices (e.g., chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, implantable meshes for hernias, suspensions or solid implants to prevent surgical adhesions, including meshes); genitourinary devices (e.g., uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy); phthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk 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 saline-containing breast implants in the subpectoral or subglandular approaches or post-mastectomy, or chin implants), and orthopedic implants (e.g., cemented orthopedic prostheses).

[0707] Implants and other surgical or medical devices may be coated with (or otherwise adapted to release) compositions of the present invention in a variety of manners, including for example: (a) by directly affixing to the implant or device an inventive compound or composition (e.g., by either spraying the implant or device with a polymer/drug film, or by dipping 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 comprised of or coated with an inventive compound or composition; (e) constructing the implant or device itself with an inventive compound or composition; or (f) by otherwise adapting the implant or device to release the inventive compound. In certain embodiments, the composition should firmly adhere to the implant or device during storage and at the time of insertion. The inventive compound or composition should also preferably not degrade during storage, prior to insertion, or when warmed to body temperature after insertion inside the body (if this is required). In addition, it should preferably coat the implant or device smoothly and evenly, with a uniform distribution of inventive compound, while not changing the stent contour. Within preferred embodiments of the invention, the inventive implant or device should provide a uniform, predictable, prolonged release of the inventive compound or composition into the tissue surrounding the implant or device once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stent thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated).

[0708] In the case of stents, a wide variety of stents may be developed to contain and/or release the inventive compounds or compositions provided herein, including esophageal stents, gastrointestinal stents, vascular stents, biliary stents, colonic stents, pancreatic stents, ureteric and urethral stents, lacrimal stents, Eustachian tube stents, fallopian tube stents and tracheal/bronchial stents (See, for example, U.S. Pat. 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 described in U.S. Pat. No. 4,768,523, entitled “Hydrogel Adhesive”; U.S. Pat. No. 4,776,337, entitled “Expandable Intraluminal Graft, and Method and Apparatus for Implanting and Expandable Intraluminal Graft”; U.S. Pat. No. 5,041,126 entitled “Endovascular Stent and Delivery System”; U.S. Pat. No. 5,052,998 entitled “Indwelling Stent and Method of Use”; U.S. Pat. No. 5,064,435 entitled “Self-Expanding Prosthesis Having Stable Axial Length”; U.S. Pat. No. 5,089,606, entitled “Water-insoluble Polysaccharide Hydrogel Foam for Medical Applications”; U.S. Pat. No. 5,147,370, entitled “Nitinol Stent for Hollow Body Conduits”; U.S. Pat. No. 5,176,626, entitled “Indwelling Stent”; U.S. Pat. No. 5,213,580, entitled “Biodegradable Polymeric Endoluminal Sealing Process”; and U.S. Pat. No. 5,328,471, entitled “Method and Apparatus for Treatment of Focal Disease in Hollow Tubular Organs and Other Tissue Lumens.”

[0709] As discussed above, the stent coated with (or otherwise adapted to release) compositions of the present invention may be used to eliminate a vascular obstruction and prevent restenosis and/or reduce the rate of restenosis. Within other aspects of the present invention, stents coated with (or otherwise adapted to release) compositions of the present invention are provided for expanding the lumen of a body passageway. Specifically, a stent having a generally tubular structure, and a surface coated with (or otherwise adapted to release) an inventive compound or composition may be inserted into the passageway, such that the passageway is expanded. In certain embodiments, the stent coated with (or otherwise adapted to release) compositions of the present invention may be used to eliminate a biliary, gastrointestinal, esophageal, trachealibronchial, urethral or vascular obstruction.

[0710] In another aspect of the invention, methods for the treatment of cancer are provided comprising administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof. In certain embodiments, the inventive compounds are useful for the treatment of solid and non-solid tumors. It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of cancer. Thus, the expression “effective amount” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells, or refers to a sufficient amount to reduce the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular anticancer agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound 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).

[0711] In certain other embodiments, methods are provided for using the inventive implants and other surgical or medical devices coated with (or otherwise adapted to release) compounds and compositions of the present invention. In certain embodiments, methods are provided for preventing restenosis, comprising inserting a stent into an obstructed blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the obstruction is eliminated and the inventive compound or composition is delivered in amounts effective to prevent restenosis and/or reduce the rate of restenosis. In other embodiments, methods are provided for preventing restenosis, comprising inserting a stent into an obstructed blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the obstruction is eliminated and the inventive compound or composition is delivered in amounts effective to inhibit smooth muscle cell proliferation.

[0712] Within other aspects of the present invention, methods are provided for expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the passageway is expanded. In certain embodiments, the lumen of a body passageway is expanded in order to eliminate a biliary, gastrointestinal, esophageal, trachealibronchial, urethral and/or vascular obstruction.

[0713] In certain embodiments, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary 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 biliary obstruction is eliminated. Briefly, tumor overgrowth of the common bile duct results in progressive cholestatic jaundice which is incompatible with life. Generally, the biliary system which drains bile from the liver into the duodenum is most often obstructed by (1) a tumor composed of bile duct cells (cholangiocarcinoma), (2) a tumor which invades the bile duct (e.g., pancreatic carcinoma), or (3) a tumor which exerts extrinsic pressure and compresses the bile duct (e.g., enlarged lymph nodes). Both primary biliary tumors, as well as other tumors which cause compression of the biliary tree may be treated utilizing stents Implants and other surgical or medical devices may be coated with (or otherwise adapted to release) compositions of the present invention. One example of primary biliary tumors are adenocarcinomas (which are also called Klatskin tumors when found at the bifurcation of the common hepatic duct). These tumors are also referred to as biliary carcinomas, choledocholangiocarcinomas, or adenocarcinomas of the biliary system. Benign tumors which affect the bile duct (e.g., adenoma of the biliary system), and, in rare cases, squamous cell carcinomas of the bile duct and adenocarcinomas of the gallbladder, may also cause compression of the biliary tree and therefore, result in biliary obstruction. Compression of the biliary tree is most commonly due to tumors of the liver and pancreas which compress and therefore obstruct the ducts. Most of the tumors from the pancreas arise from cells of the pancreatic ducts. This is a highly fatal form of cancer (5% of all cancer deaths; 26,000 new cases per year in the U.S.) with an average of 6 months survival and a 1 year survival rate of only 10%. When these tumors are located in the head of the pancreas they frequently cause biliary obstruction, and this detracts significantly from the quality of life of the patient. While all types of pancreatic tumors are generally referred to as “carcinoma of the pancreas” there are histologic subtypes including: adenocarcinoma, adenosquamous carcinoma, cystadenocarcinoma, and acinar cell carcinoma. Hepatic tumors, as discussed above, may also cause compression of the biliary tree, and therefore cause obstruction of the biliary ducts.

[0714] In certain embodiments, a biliary stent is first inserted into a biliary passageway in one of several ways: from the top end by inserting a needle through the abdominal wall and through the liver (a percutaneous transhepatic cholangiogram or “PTC”); from the bottom end by cannulating the bile duct through an endoscope inserted through the mouth, stomach, and duodenum (an endoscopic retrograde cholangiogram or “ERCP”); or by direct incision during a surgical procedure. In certain embodiments, a preinsertion examination, PTC, ERCP, or direct visualization at the time of surgery is performed to determine the appropriate position for stent insertion. A guidewire is then advanced through the lesion, and over this a delivery catheter is passed to allow the stent to be inserted in its collapsed form. If the diagnostic exam was a PTC, the guidewire and delivery catheter is inserted via the abdominal wall, while if the original exam was an ERCP the stent may be placed via the mouth. The stent is then positioned under radiologic, endoscopic, or direct visual control taking particular care to place it precisely across the narrowing in the bile duct. The delivery catheter is then removed leaving the stent standing as a scaffolding which holds the bile duct open. A further cholangiogram may be performed to document that the stent is appropriately positioned.

[0715] In certain embodiments, methods are provided for eliminating esophageal obstructions, comprising 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. Briefly, the esophagus is the hollow tube which transports food and liquids from the mouth to the stomach. Cancer of the esophagus or invasion by cancer arising in adjacent organs (e.g., cancer of the stomach or lung) results in the inability to swallow food or saliva. In certain embodiments, a preinsertion examination, usually a barium swallow or endoscopy is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope may then be positioned through the mouth, and a guidewire is advanced through the blockage. A stent delivery catheter is passed over the guidewire under radiologic or endoscopic control, and a stent is placed precisely across the narrowing in the esophagus. A post-insertion examination, usually a barium swallow x-ray, may be utilized to confirm appropriate positioning.

[0716] In certain embodiments, methods are provided for eliminating colonic obstructions, comprising inserting a colonic stent into a colon, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the colonic obstruction is eliminated. Briefly, the colon is the hollow tube which transports digested food and waste materials from the small intestines to the anus. Cancer of the rectum and/or colon or invasion by cancer arising in adjacent organs (e.g., cancer of the uterus, ovary, bladder) results in the inability to eliminate feces from the bowel. In certain embodiments, a preinsertion examination, usually a barium enema or colonoscopy is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope may then be positioned through the anus, and a guidewire is advanced through the blockage. A stent delivery catheter is passed over the guidewire under radiologic or endoscopic control, and a stent is placed precisely across the narrowing in the colon or rectum. A post-insertion examination, usually a barium enema x-ray, may be utilized to confirm appropriate positioning.

[0717] In certain embodiments, methods are provided for eliminating trachealibronchial obstructions, comprising inserting a tracheal/bronchial stent into a trachea or bronchi, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the trachealibronchial obstruction is eliminated. Briefly, the trachea and bronchi are tubes which carry air from the mouth and nose to the lungs. Blockage of the trachea by cancer, invasion by cancer arising in adjacent organs (e.g., cancer of the lung), or collapse of the trachea or bronchi due to chondromalacia (weakening of the cartilage rings) results in inability to breathe. In certain embodiments, preinsertion examination, usually an endoscopy, is performed in order to determine the appropriate position for stent insertion. A catheter or endoscope is then positioned through the mouth, and a guidewire advanced through the blockage. A delivery catheter is then passed over the guidewire in order to allow a collapsed stent to be inserted. The stent is placed under radiologic or endoscopic control in order to place it precisely across the narrowing. The delivery catheter may then be removed leaving the stent standing as a scaffold on its own. A post-insertion examination, usually a bronchoscopy may be utilized to confirm appropriate positioning.

[0718] In certain embodiments, methods are provided for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the urethral obstruction is eliminated. Briefly, the urethra is the tube which drains the bladder through the penis. Extrinsic narrowing of the urethra as it passes through the prostate, due to hypertrophy of the prostate, occurs in virtually every man over the age of 60 and causes progressive difficulty with urination. In certain embodiments, a preinsertion examination, usually an endoscopy or urethrogram is first performed in order to determine the appropriate position for stent insertion, which is above the external urinary sphincter at the lower end, and close to flush with the bladder neck at the upper end. An endoscope or catheter is then positioned through the penile opening and a guidewire advanced into the bladder. A delivery catheter is then passed over the guidewire in order to allow stent insertion. The delivery catheter is then removed, and the stent expanded into place. A post-insertion examination, usually endoscopy or retrograde urethrogram, may be utilized to confirm appropriate position.

[0719] In certain embodiments, methods are provided for eliminating vascular obstructions, comprising inserting a vascular stent into a blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with (or otherwise adapted to release) an inventive compound or composition, such that the vascular obstruction is eliminated. Briefly, stents may be placed in a wide array of blood vessels, both arteries and veins, to prevent recurrent stenosis at the site of failed angioplasties, to treat narrowings that would likely fail if treated with angioplasty, and to treat post-surgical narrowings (e.g., dialysis graft stenosis). Suitable sites include, but ar enot limited to, the iliac, renal, and coronary arteries, the superior vena cava, and in dialysis grafts. In certain embodiments, angiography is first performed in order to localize the site for placement of the stent. This is typically accomplished by injecting radiopaque contrast through a catheter inserted into an artery or vein as an x-ray is taken. A catheter may then be inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering it through the vascular system under fluoroscopic guidance. A stent may then be positioned across the vascular stenosis. A post-insertion angiogram may also be utilized in order to confirm appropriate positioning.

[0720] Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.

[0721] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, 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, flavoring, and perfuming agents.

[0722] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0723] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0724] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0725] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0726] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0727] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active 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 polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0728] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active 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 polymeric substances and waxes.

[0729] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0730] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination 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), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, 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).

[0731] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative). For purposes of the invention, the term “Palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).

Treatment Kits

[0732] In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the 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 oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Equivalents

[0733] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.

[0734] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

Exemplification

[0735] The practitioner has a well-established literature of peptide chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention.

[0736] The various references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest.

[0737] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof. For example, synthetic guidance may be found in J. Org. Chem., 2001, 66:7355-7364.

[0738] 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. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

[0739] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[0740] It will be appreciated as described below, that a variety of inventive compounds can be synthesized according to the methods described herein. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1-17, John Wiley and Sons, New York, N.Y., 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, N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wiley and Sons, New York, N.Y.; and Larock 1990, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd ed. VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.

[0741] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.

[0742] Certain exemplary compounds of the invention are listed below and are referred to by compound number as indicated.

1CompoundStructureER-803840 (HEMIASTERLIN)

116

ER-803887

117

ER-803888

118

ER-803889

119

ER-803890

120

ER-803921

121

ER-803995

122

ER-803996

123

ER-803997 Higher Rf diastereomer

124

ER-803998 Lower Rf diastereomer

125

ER-803999

126

ER-804000

127

ER-804001

128

ER-804002

129

ER-804332

130

ER-804333

131

ER-804334

132

ER-804635

133

ER-804636

134

ER-804762

135

ER-805206

136

ER-805230

137

ER-805231

138

ER-805257

139

ER-805258

140

ER-805268

141

ER-805316

142

ER-805324

143

ER-805532

144

ER-805590

145

ER-805594

146

ER-805599

147

ER-805697

148

ER-805701

149

ER-805711

150

ER-805713

151

ER-805734

152

ER-805735

153

ER-805736

154

ER-805738

155

ER-805847

156

ER-805865

157

ER-805876

158

ER-805913

159

ER-805914

160

ER-805925

161

ER-805938

162

ER-805968

163

ER-805974

164

ER-806004

165

ER-806005

166

ER-806021

167

ER-806022

168

ER-806023

169

ER-806031

170

ER-806032

171

ER-806073

172

ER-806085

173

ER-806086

174

ER-806105

175

ER-806110

176

ER-806119

177

ER-806135

178

ER-806147

179

ER-806180

180

ER-806223

181

ER-806318

182

ER-806356

183

ER-806371

184

ER-806395

185

ER-806396

186

ER-806397

187

ER-806398

188

ER-806399

189

ER-806400

190

ER-806409

191

ER-806418

192

ER-806713

193

ER-806717

194

ER-806718

195

ER-806735

196

ER-806748

197

ER-806749

198

ER-806791

199

ER-806792

200

ER-806793

201

ER-806794

202

ER-806822

203

ER-806823

204

ER-806824

205

ER-806825

206

ER-806830

207

ER-806831

208

ER-806853

209

ER-806854

210

ER-806861

211

ER-806862

212

ER-806863

213

ER-806864

214

ER-806865

215

ER-806866

216

ER-806867

217

ER-806868

218

ER-806869

219

ER-806870

220

ER-806871

221

ER-806879

222

ER-806880

223

ER-806881

224

ER-806882

225

ER-806920

226

ER-806921

227

ER-806922

228

ER-806923

229

ER-806924

230

ER-806925

231

ER-807000

232

ER-807001

233

ER-807002

234

ER-807077 single diastereomer

235

ER-807078 single diastereomer

236

ER-807079

237

ER-807080

238

ER-807081 single diastereomer

239

ER-807096

240

ER-807101

241

ER-807102

242

ER-807133

243

ER-807134

244

ER-807135

245

ER-807145

246

ER-807146

247

ER-807147

248

ER-807148

249

ER-807160

250

ER-807161

251

ER-807180

252

ER-807192

253

ER-807193

254

ER-807194

255

ER-807195

256

ER-807209

257

ER-807210

258

ER-807212

259

ER-807213

260

ER-807214

261

ER-807215

262

ER-807217

263

ER-807218

264

ER-807219

265

ER-807222

266

ER-807226

267

ER-807228

268

ER-807229

269

ER-807230

270

ER-807231

271

ER-807232

272

ER-807237

273

ER-807238

274

ER-807246

275

ER-807247

276

ER-807248

277

ER-807249

278

ER-807303

279

ER-807324

280

ER-807328

281

ER-807329

282

ER-807332

283

ER-807334

284

ER-807339

285

ER-807341

286

ER-807342

287

ER-807343

288

ER-807344

289

ER-807345

290

ER-807346

291

ER-807347

292

ER-807352

293

ER-807353

294

ER-807354

295

ER-807355

296

ER-807360

297

ER-807361

298

R-807362

299

ER-807364

300

ER-807365

301

ER-807366

302

ER-807370

303

ER-807371

304

ER-807374

305

ER-807375

306

ER-807393

307

ER-807413

308

ER-807414

309

ER-807417

310

ER-807418

311

ER-807419

312

ER-807420

313

ER-807421

314

ER-807431

315

ER-807461

316

ER-807470 single diastereomer

317

ER-807471 single diastereomer

318

ER-807480 single diastereomer

319

ER-807481 single diastereomer

320

ER-807482 single diastereomer

321

ER-807483 single diastereomer

322

ER-807484

323

ER-807487

324

ER-807494

325

ER-807495

326

ER-807499

327

ER-807500

328

ER-807501

329

ER-807502

330

ER-807503

331

ER-807504

332

ER-807529

333

ER-807530

334

ER-807533

335

ER-807534

336

ER-807535

337

ER-807540

338

ER-807541

339

ER-807542

340

ER-807575

341

ER-807576

342

ER-807577

343

ER-807602

344

ER-807603

345

ER-807619

346

ER-807620

347

ER-807621

348

ER-807622

349

ER-807625

350

ER-807626

351

ER-807739

352

ER-807740

353

ER-807742

354

ER-807743

355

ER-807744

356

ER-807745

357

ER-807760

358

ER-807761

359

ER-807796 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

360

ER-807797 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

361

ER-807798

362

ER-807799 Mixture of two diastereomers

363

ER-807800

364

ER-807801

365

ER-807802

366

ER-807803

367

ER-807804

368

ER-807805

369

ER-807806

370

ER-807807

371

ER-807808

372

ER-807809

373

ER-807810

374

ER-807811

375

ER-807812

376

ER-807820 single diastereomer

377

ER-807821 single diastereomer

378

ER-807829

379

ER-807830

380

ER-807831

381

ER-807832

382

ER-807833

383

ER-807839

384

ER-807840

385

ER-807842

386

ER-807844

387

ER-807846

388

ER-807850

389

ER-807860

390

ER-807861

391

ER-807863 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

392

ER-807864 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

393

ER-807874

394

ER-807875

395

ER-807877 Cis-substituents on the piperidine ring. Two diastereomers (4:1).

396

ER-807880

397

ER-807881

398

ER-807882

399

ER-807883

400

ER-807884

401

ER-807885

402

ER-807886

403

ER-807888

404

ER-807889

405

ER-807890

406

ER-807891

407

ER-807899

408

ER-807900

409

ER-807902

410

ER-807904

411

ER-807905

412

ER-807906

413

ER-807907

414

ER-807908

415

ER-807909

416

ER-807911

417

ER-807944

418

ER-807945

419

ER-807947

420

ER-807948

421

ER-807949

422

ER-807950

423

ER-807951

424

ER-807953

425

ER-807954

426

ER-807959 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

427

ER-807960 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

428

ER-807961

429

ER-807963

430

ER-807973

431

ER-807974

432

ER-807975

433

ER-807981

434

ER-807982

435

ER-807983

436

ER-807986

437

ER-807987

438

ER-807988

439

ER-807989

440

ER-807990

441

ER-807991

442

ER-807992

443

ER-807994

444

ER-807995

445

ER-807996

446

ER-807997

447

ER-807998

448

ER-807999

449

ER-808000

450

ER-808001

451

ER-808002

452

ER-808007

453

ER-808008

454

ER-808010

455

ER-808011

456

ER-808012

457

ER-808013

458

ER-808029

459

ER-808030

460

ER-808031

461

ER-808032

462

ER-808033

463

ER-808034

464

ER-808035

465

ER-808037

466

ER-808038

467

ER-808057

468

ER-808058

469

ER-808059

470

ER-808060

471

ER-808061

472

ER-808062

473

ER-808063

474

ER-808065 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer.

475

ER-808066 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

476

ER-808067 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

477

ER-808068 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

478

ER-808071 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

479

ER-808072 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

480

ER-808073 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

481

ER-808074 Trans-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

482

ER-808075

483

ER-808076

484

ER-808077

485

ER-808108

486

ER-808109

487

ER-808110

488

ER-808111

489

ER-808112

490

ER-808113

491

ER-808114

492

ER-808115

493

ER-808116

494

ER-808117

495

ER-808118

496

ER-808119

497

ER-808120

498

ER-808121

499

ER-808122

500

ER-808123

501

ER-808124

502

ER-808125

503

ER-808126 Absolute stereochemistry is unknown. Single diastereomer

504

ER-808131

505

ER-808139

506

ER-808140

507

ER-808141

508

ER-808142

509

ER-808143

510

ER-808144

511

ER-808145

512

ER-808146

513

ER-808147

514

ER-808148

515

ER-808149

516

ER-808150

517

ER-808161

518

ER-808166

519

ER-808167

520

ER-808168

521

ER-808169

522

ER-808170

523

ER-808171

524

ER-808172

525

ER-808173

526

ER-808174

527

ER-808175

528

ER-808176

529

ER-808177

530

ER-808178

531

ER-808179

532

ER-808180

533

ER-808181

534

ER-808182

535

ER-808183

536

ER-808189

537

ER-808190

538

ER-808191

539

ER-808192

540

ER-808193

541

ER-808194

542

ER-808195

543

ER-808196

544

ER-808197

545

ER-808198

546

ER-808199

547

ER-808200

548

ER-808201

549

ER-808202

550

ER-808203

551

ER-808204 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

552

ER-808205 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

553

ER-808206

554

ER-808207

555

ER-808208

556

ER-808209

557

ER-808210

558

ER-808211

559

ER-808212

560

ER-808213

561

ER-808214

562

ER-808215

563

ER-808216

564

ER-808217

565

ER-808218

566

ER-808219

567

ER-808220

568

ER-808221

569

ER-808222

570

ER-808223

571

ER-808224

572

ER-808225

573

ER-808226

574

ER-808248

575

ER-808249

576

ER-808251

577

ER-808253

578

ER-808292

579

ER-808293

580

ER-808294

581

ER-808295

582

ER-808296

583

ER-808297

584

ER-808298

585

ER-808299

586

ER-808300

587

ER-808301-

588

ER-808302

589

ER-808303

590

ER-808304

591

ER-808305

592

ER-808306

593

ER-808307

594

ER-808308

595

ER-808309

596

ER-808323

597

ER-808324

598

ER-808325

599

ER-808326

600

ER-808328

601

ER-808329

602

ER-808330

603

ER-808331

604

ER-808332

605

ER-808333

606

ER-808334

607

ER-808335

608

ER-808336

609

ER-808337

610

ER-808338

611

ER-808339

612

ER-808340

613

ER-808341

614

ER-808342

615

ER-808343

616

ER-808344

617

ER-808345

618

ER-808357 single diastereomer

619

ER-808358 single diastereomer

620

ER-808359 single diastereomer

621

ER-808366 single diastereomer

622

ER-808367

623

ER-808368

624

ER-808383

625

ER-808384

626

ER-808389

627

ER-808390

628

ER-808391

629

ER-808392

630

ER-808393

631

ER-808394

632

ER-808395

633

ER-808396

634

ER-808397

635

ER-808398

636

ER-808399

637

ER-808400

638

ER-808401

639

ER-808402

640

ER-808403

641

ER-808404

642

ER-808433

643

ER-808434

644

ER-808435

645

ER-808436

646

ER-808437

647

ER-808447 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

648

ER-808448 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

649

ER-808449 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

650

ER-808450 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

651

ER-808451 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

652

ER-808452 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

653

ER-808453 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

654

ER-808454 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

655

ER-808475 Single diastereomer

656

ER-808476 Single diastereomer

657

ER-808477 Single diastereomer

658

ER-808478 Single diastereomer

659

ER-808479

660

ER-808480

661

ER-808481

662

ER-808482

663

ER-808483

664

ER-808484

665

ER-808485

666

ER-808486

667

ER-808487

668

ER-808488

669

ER-808489

670

ER-808490

671

ER-808491 Single diastereomer

672

ER-808492 Single diastereomer

673

ER-808493 Single diastereomer

674

ER-808494 Single diastereomer

675

ER-808495

676

ER-808552

677

ER-808553

678

ER-808563

679

ER-808564

680

ER-808565

681

ER-808566

682

ER-808567

683

ER-808568

684

ER-808609

685

ER-808610

686

ER-808656 Single diastereomer

687

ER-808662 Single diastereomer

688

ER-808674

689

ER-808676

690

ER-808677

691

ER-808678

692

ER-808679

693

ER-808680

694

ER-808681

695

ER-808682

696

ER-808683

697

ER-808684

698

ER-808685

699

ER-808686

700

ER-808687

701

ER-808688

702

ER-808689

703

ER-808690

704

ER-808693

705

ER-808694

706

ER-808695

707

ER-808696

708

ER-808697

709

ER-808698

710

ER-808699

711

ER-808700

712

ER-808706 Single diastereomer

713

ER-808707 Single diastereomer

714

ER-808708 Single diastereomer

715

ER-80870 Single diastereomer

716

ER-808710 Single diastereomer

717

ER-808731

718

ER-808732

719

ER-808774 Single diastereomer

720

ER-808775 Single diastereomer

721

ER-808777 Single diastereomer

722

ER-808779 Single diastereomer

723

ER-808780 Single diastereomer

724

ER-808815 Single diastereomer

725

ER-808816 Single diastereomer

726

ER-808817 Single diastereomer

727

ER-808818 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

728

ER-808819 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

729

ER-808820 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

730

ER-808821 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

731

ER-808822 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

732

ER-808823 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

733

ER-808824

734

ER-808825

735

ER-808826 Single diastereomer

736

ER-808827 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

737

ER-808828 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

738

ER-808829 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

739

ER-808830 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

740

ER-808831 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

741

ER-808832 Cis-substituents on the piperidine ring, but absolute stereochemistry is unknown. Single diastereomer

742

ER-808861

743

ER-808862

744

ER-808863

745

ER-808864

746

ER-808865

747

ER-808866

748

ER-808867

749

ER-808868

750

ER-808869

751

ER-808870

752

ER-808871

753

ER-808872

754

ER-808873

755

ER-808874

756

ER-808875

757

ER-808876

758

ER-808877

759

ER-808878

760

ER-808879

761

ER-808880

762

ER-808881

763

ER-808882

764

ER-808883

765

ER-808884

766

ER-808885

767

ER-808886

768

ER-808887

769

ER-808888

770

ER-808889

771

ER-808890

772

ER-808891

773

ER-808892

774

ER-808893

775

ER-808894

776

ER-808895

777

ER-808896

778

ER-808897

779

ER-808898

780

ER-808899

781

ER-808900

782

ER-808901

783

ER-808902

784

ER-808903

785

ER-808904

786

ER-808905

787

ER-808906

788

ER-808907

789

ER-808908

790

ER-808909

791

ER-808910

792

ER-808911

793

ER-808912

794

ER-808913

795

ER-808914

796

ER-808915

797

ER-808916

798

ER-808917

799

ER-808918

800

ER-808919

801

ER-808920

802

ER-808921

803

ER-808922

804

ER-808923

805

ER-808987

806

ER-808988

807

ER-808990

808

ER-809040 Single diastereomer

809

ER-809041

810

ER-809043

811

ER-809044

812

ER-809045 Single diastereomer

813

ER-809046

814

ER-809054

815

ER-809055

816

ER-809056

817

ER-809057

818

ER-809058

819

ER-809059

820

ER-809060

821

ER-809061

822

ER-809062

823

ER-809063

824

ER-809064

825

ER-809065

826

ER-809066

827

ER-809067

828

ER-809068

829

ER-809069

830

ER-809070

831

ER-809071

832

ER-809072

833

ER-809073

834

ER-809074

835

ER-809075

836

ER-809076

837

ER-809077

838

ER-809078

839

ER-809079

840

ER-809080

841

ER-809081

842

ER-809082

843

ER-809083

844

ER-809084

845

ER-809085

846

ER-809086

847

ER-809087

848

ER-809088

849

ER-809089

850

ER-809090

851

ER-809091

852

ER-809092

853

ER-809093

854

ER-809094

855

ER-809095

856

ER-809096

857

ER-809097

858

ER-809098

859

ER-809099

860

ER-809100

861

ER-809101

862

ER-809102

863

ER-809103

864

ER-809104

865

ER-809105

866

ER-809106

867

ER-809107

868

ER-809108

869

ER-809109

870

ER-809110

871

ER-809111

872

ER-809112

873

ER-809113

874

ER-809114

875

ER-809115

876

ER-809116

877

ER-809117

878

ER-809118

879

ER-809119

880

ER-809120

881

ER-809121

882

ER-809122

883

ER-809123

884

ER-809124

885

ER-809125

886

ER-809126

887

ER-809127

888

ER-809128

889

ER-809129

890

ER-809130

891

ER-809131

892

ER-809132

893

ER-809133

894

ER-809134

895

ER-809135

896

ER-809136

897

ER-809137

898

ER-809138

899

ER-809139

900

ER-809140

901

ER-809141

902

ER-809142

903

ER-809143

904

ER-809144

905

ER-809145

906

ER-809146

907

ER-809147

908

ER-809148

909

ER-809149

910

ER-809150

911

ER-809151

912

ER-809152

913

ER-809153

914

ER-809154

915

ER-809155

916

ER-809156

917

ER-809157

918

ER-809158

919

ER-809159

920

ER-809160

921

ER-809161

922

ER-809162

923

ER-809163

924

ER-809164

925

ER-809165

926

ER-809166

927

ER-809167

928

ER-809240

929

ER-809241

930

ER-809242

931

ER-809243

932

ER-809244

933

ER-809245

934

ER-809246

935

ER-809247

936

ER-809268

937

ER-809269

938

ER-809282

939

ER-809283

940

ER-809284

941

ER-809285

942

ER-809300

943

ER-809301

944

ER-809302

945

ER-809303

946

ER-809304

947

ER-809305

948

ER-809306

949

ER-809308

950

ER-809309

951

ER-809310

952

ER-809311

953

ER-809312

954

ER-809313

955

ER-809314

956

ER-809315

957

ER-809316

958

ER-809317

959

ER-809318

960

ER-809319

961

ER-809320

962

ER-809321

963

ER-809322

964

ER-809323

965

ER-809324

966

ER-809325

967

ER-809326

968

ER-809638

969

ER-809640

970

ER-809641 Single diastereomer

971

ER-809642 Single diastereomer

972

ER-809643 Single diastereomer

973

ER-809644 Single diastereomer

974

ER-809645

975

ER-809646

976

ER-809647 Single diastereomer

977

ER-809648 Single diastereomer

978

ER-809649 Single diastereomer

979

ER-809650 Single diastereomer

980

981

982

983

984

985

986

987

988

989

990

991

992

[0743] General Reaction Procedures:

[0744] Unless mentioned specifically, reaction mixtures were stirred using a magnetically driven stirrer bar. An inert atmosphere refers to either dry argon or dry nitrogen. Reactions were monitored either by thin layer chromatography (TLC), by proton nuclear magnetic resonance or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.

[0745] Listed below are abbreviations used for some common organic reagents referred to herein:

[0746] BOC or BOC2O: Di-tert-Butyl dicarbonate

[0747] CMC: 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate

[0748] DCM: Dichloromethane

[0749] DEPC: Diethylphosphoryl cyanide (Diethyl cyanophosphonate)

[0750] DIBAL: Diisobutylaluminum hydride

[0751] DIEA: Diisopropylethylamine

[0752] DMF: N,N-Dimethylformamide

[0753] DMSO: Dimethylsulfoxide

[0754] Ether: Diethyl ether

[0755] HBTU: O-(1-H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate

[0756] HOAt: 1-Hydroxy-7-azabenzotriazole

[0757] LAH: Lithium aluminum hydride

[0758] MSA: Methane sulfonic acid

[0759] NMM: N-Methyl Morpholine

[0760] TBME: Tert-butyl methyl ether

[0761] TFA: Trifluoroacetic acid

[0762] THF: Tetrahydrofuran

[0763] TMEDA: Tetramethylethylenediamine

[0764] General Work Up Procedures:

[0765] Unless mentioned specifically, reaction mixtures were cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride. Desired products were extracted by partitioning between water and a suitable water-immiscible solvent (eg. ethyl acetate, dichloromethane, diethyl ether). The desired product containing extracts were washed appropriately with water followed by a saturated solution of brine. On occasions where the product containing extract was deemed to contain residual oxidants, the extract was washed with a 10% solution of sodium thiosulphate in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure. On occasions where the product containing extract was deemed to contain residual acids, the extract was washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character). On occasions where the product containing extract was deemed to contain residual bases, the extract was washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character). Post washing, the desired product containing extracts were dried over anhydrous magnesium sulphate, then filtered. The crude products were then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45° C.).

[0766] On occasions where triphenylphosphine oxide was a major byproduct of the reaction, the reaction mixture was added directly to a large volume of well-stirred hexane. The resultant precipitate of triphenylphosphine oxide was removed by filtration and the filtrate processed in the usual manner.

[0767] General Purification Procedures:

[0768] Chromatographic purification refers either to flash column chromatography on silica, using a single solvent or mixed solvent as eluent, or HPLC on a C18 column. Suitably purified desired product containing elutes were combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45° C.) to constant mass. Final compounds were prepared for biological testing by either a) dissolved in 50% aqueous acetonitrile, filtered and transferred to vials, then freeze-dried under high vacuum; or b) dissolved in methanol, filtered and transferred to vials, then concentrated to dryness using a Centrifugal vacuum evaporator.

Example 1

Preparation of Amine Esters 18, Amine Acids 20 and Amine Amides 23

[0769]

993

[0770] Preparation of Compound 13

994

[0771] To a solution of Compound 12 (205 mg) in DMF (3.8 ml), at room temperature, was added (S)-N-Boc-neo-phenylalanine (6) (140 mg), NMM (0.30 ml), HOAt (0.124 g), and CMC (1.16 g). The reaction mixture was shaken at room temperature for 24 hr. Aqueous workup followed by chromatographic purification gave Compound 13 (153 mg, 61%).

[0772] Preparation of Compound 14

995

[0773] To a solution of compound 13 (153 mg) in methanol (20 ml), at 0° C., was added sodium borohydride (3.18 g) portionwise with shaking over a 3 day period. The reaction mixture temperature was maintained between 0°-5° C. On occasion where the reaction mixture turned into a solidified mass, THF was added to aid agitation. The reaction mixture was allowed to warm to room temperature then re-cooled to 0° C. and worked up in the usual manner to give compound 14 (140 mg, 96%).

[0774] Preparation of Compound 15

996

[0775] To a solution of compound 14 (50 mg) in THF (3 ml), at room temperature, was added Dess Martin periodinane (204 mg) in one portion. The resultant suspension was stirred vigorously for 4.5 hr. An aqueous work up gave crude compound 15 (50 mg) which was used immediately in the next stage without purification.

[0776] General Procedure for the Preparation of Amine Esters 18

997

[0777] To a solution of compound 15 (1 equivalent) in a suitable volume of 1,2-dichloroethane, at room temperature, was added 4A molecular sieves (crushed and dried) (equal mass to that of the amine hydrochloride). A suitably chosen amine hydrochloride (16) (10 equivalents) was added with vigorous stirring followed by sodium triacetoxyborohydride (1.5 equivalents). The reaction mixture was stirred at an appropriate temperature (20′-50° C.) until compound 15 was consumed to a satisfactory degree. Aqueous work up followed by chromatographic purification gave the corresponding N-Boc Amine Ester 17. Deprotection of the N-Boc moiety under suitable conditions would give the corresponding N-terminal free amine 18.

[0778] General Procedure for the Preparation of Amine Acids 20

998

[0779] To a solution of the N-Boc Amine Ester 17 in a suitable mixture of THF and methanol, was added IM lithium hydroxide 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 purified chromatographically. Deprotection of the N-Boc moiety under suitable conditions would give the corresponding N-terminal free amine 20.

[0780] General Procedure for the Preparation of Amine Amides 23

999

[0781] To a solution of the N-Boc Amine Acid 19 in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (21) (20 equivalents) was added followed by DEPC (20 equivalents). When the N-Boc Amine Acid 19 was consumed to a satisfactory degree the N-Boc Amine Amide 22 was isolated either by direct chromatographic purification of the reaction mixture, or by an aqueous work up followed by chromatographic purification. Deprotection of the N-Boc moiety under suitable conditions would give the corresponding N-terminal free amine 23.

Example 2

Preparation of N-Acetyl Amine Amides 27

[0782]

1000

[0783] Preparation of Compound 24

1001

[0784] To a solution of aldehyde 13 (50 mg) in 1,2-dichloroethane (2 ml), at room temperature, was added 4A molecular sieves (crushed and dried) (50 mg). Glycine methyl ester hydrochloride (120 mg) was added with vigorous stirring followed by sodium triacetoxyborohydride (205 mg). The reaction mixture was stirred at 40° C.) for two hours. Aqueous work up followed by chromatographic purification gave compound 24 (31 mg, 46%).

[0785] Preparation of Compound 25

1002

[0786] To a solution of compound 24 (5.5 mg) in DMF (0.4 ml), at room temperature, was added pyridine (0.006 ml) followed by acetic anhydride (0.004 ml). The reaction mixture was shaken for three hours at room temperature then concentrated in vacuo to dryness. The residue was dissolved in saturated HCl in methanol (1 ml) and stood at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to give compound 25 (4 mg, 90%).

[0787] Preparation of compound 26

1003

[0788] To a solution of compound 25 (3.35 mg) in methanol (0.2 mL), was added 1 M lithium hydroxide solution (0.118 mL). The reaction mixture was stirred at room temperature for 5 hr. Chromatographic purification followed by treatment with methanolic HCl gave the hydrochloride salt of compound 26 (1.95 mg, 61%).

[0789] General Procedure for the Preparation of N-Acetyl Amine Amides 27

1004

[0790] To a solution of compound 26 (1 equivalent) in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (21) (20 equivalents) was added followed by DEPC (20 equivalents). When compound 26 was consumed to a satisfactory degree the N-Acetyl Amine Amide (27) was isolated by direct chromatographic purification of the reaction mixture.

Example 3

Preparation of Compound 33

[0791]

1005

[0792] Preparation of Compound 28

1006

[0793] To a solution of compound 3b (1.94 g) in dry DCM (20 mL), at 0° C. under an inert atmosphere, was added a 1 M solution of DIBAL (32 mL) dropwise. The reaction mixture was stirred at 0° C. for 2.5 hr then methanol (4.4 mL) was added dropwise followed by a saturated solution of ammonium chloride (8.8 mL). DCM (200 mL) was added and the reaction mixture stirred vigorously at room temperature for 30 min. Filtration followed by concentrated in vacuo gave crude compound 28 (1.08 g, 65%).

[0794] Preparation of Compound 29

1007

[0795] To a solution of compound 28 (207 mg) in THF (5 mL), at 0° C. under an inert atmosphere, was added sodium hydride (60% dispersion in mineral oil; 160 mg) portionwise. The reaction mixture was stirred at 0° C. for 45 min then treated with ethyl bromoacetate (0.47 mL). The reaction mixture was allowed to warm to room temperature. An aqueous work up followed by chromatographic purification gave an intermediate Boc compound (185 mg, 67%). The intermediate Boc compound (139 mg) was dissolved in ethanol (2 mL) and treated with saturated HCl in ethanol (2 mL). The reaction mixture was stood at room temperature for 10 min then concentrated in vacuo to dryness to give compound 29 (114 mg).

[0796] Preparation of Compound 30

1008

[0797] To a solution of compound 29 (114 mg) in DMF (1.8 mL), at room temperature, was added (S)-N-Boc-tert-leucine (4) (283 mg), NMM (0.135 mL), HOAt (56 mg), and CMC (518 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (42 mg, 22%). The intermediate Boc compound (42 mg) was dissolved in saturated HCl in ethanol (5 mL) and stood at room temperature for 10 min. Concentration in vacuo gave compound 30 (37 mg).

[0798] Preparation of Compound 31

1009

[0799] To a solution of compound 30 (24 mg) in DMF (0.26 mL), at room temperature, was added (S)-N-Boc-neo-phenylalanine (6) (38 mg), NMM (0.014 mL), HOAt (8.3 mg), and CMC (52 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (38 mg, 64%). The intermediate Boc compound (38 mg) was dissolved in saturated HCl in ethanol (5 mL) and stood at room temperature for 10 min. Concentration in vacuo gave compound 31 as its HCl salt.

[0800] Preparation of Compound 32

1010

[0801] A solution of compound 31 (4 mg) in ethanol (2 mL) was treated with 1 M lithium hydroxide (0.5 ml). The reaction mixture was stirred at room temperature for 1.5 hr. Aqueous work up followed by chromatographic purification gave compound 32 (2.9 mg, 76%).

[0802] Preparation of Compound 33

1011

[0803] To a solution of compound 32 (1.9 mg) in DMF (70 μl), at room temperature, was added NMM (3.8 μl), pyrrolidine (2.8 μl), and DEPC (5.2 μl). The reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was purified chromatographically to give compound 33 (1.2 mg, 58%).

Example 4

Preparation of Amine Esters 42, Amine Acids 43 and Amine Amides 45

[0804]

1012

[0805] Preparation of Compound 39

1013

[0806] To a solution of compound 12 (1.25 g) in DMF (21 mL), at room temperature, was added (R)-N-methylpipecoline hydrochloride (38) (0.38 g), NMM (1.4 mL), HOAt (0.575 g), and CMC (5.37 g). The reaction mixture was shaken at room temperature for 24 hr. Aqueous workup gave compound 39 (0.511 g, 63%).

[0807] Preparation of Compound 40

1014

[0808] To a solution of compound 39 (0.8 g) in methanol (8 mL), at 0° C., was added sodium borohydride (7.9 g) portionwise over a 3 day period. The reaction mixture temperature was maintained between 0°-5° C. On occasion where the reaction mixture turned into a solidified mass, THF was added to aid stirring. The reaction mixture was allowed to warm to room temperature then re-cooled to 0° C. and quenched with saturated sodium bicarbonate solution. Aqueous workup gave compound 40.

[0809] Preparation of Compound 41

1015

[0810] To a solution of compound 40 (50 mg) in THF (3 mL), at room temperature, was added Dess Martin periodinane (225 mg) in one portion. The resultant suspension was stirred vigorously for 4 hr. An aqueous work up gave crude compound 41 (55 mg) which was used immediately in the next stage without purification.

[0811] General Procedure for the Preparation of N-Terminal N-Heterocyclic Amine Esters 42

1016

[0812] To a solution of compound 41 (300 mg) in 1,2-dichloroethane (10 mL), at room temperature, was added 4 A molecular sieves (crushed and dried) (1.5 g). The amino acid ester hydrochloride (16) (10 equivalents) was added and the reaction mixture stirred vigorously for ˜10 min. Sodium triacetoxyborohydride (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 N-terminal N-heterocyclic Amine Esters 42 was purified chromatographically, except in cases where it was deemed unnecessary.

[0813] General Procedure for the Preparation of N-Terminal N-Heterocyclic Amine Acids 43

1017

[0814] To a solution of the N-terminal N-heterocyclic Amine Esters (42) in a suitable mixture of THF and methanol, was added 1 M lithium hydroxide solution (10-50 equivalents). When the N-terminal N-heterocyclic Amine Esters 42 was hydrolyzed to a satisfactory degree, the reaction mixture was given an aqueous work up. The N-terminal N-heterocyclic Amine acid 43 was purified chromatographically, except in cases where it was deemed unnecessary.

[0815] General Procedure for the Preparation of N-Terminal N-Heterocyclic Amine Amides 45

1018

[0816] To a solution of the N-terminal N-heterocyclic Amine acid 43 in DMF, at room temperature, was added NMM (20 equivalents). A suitably chosen amine hydrochloride (44) (20 equivalents) was added followed by DEPC (20 equivalents). When the N-terminal N-heterocyclic Amine acid 43 was consumed to a satisfactory degree the N-terminal N-heterocyclic Amine Amide 45 was isolated either by direct chromatographic purification of the reaction mixture, or by an aqueous work up followed by chromatographic purification.

Example 5

Preparation of Compounds 51 and 52

[0817]

1019

[0818] Step 1: Preparation of Compound 49:

1020

[0819] Preparation of Compound 47:

1021

[0820] Procedure a.

[0821] 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%).

[0822] Preparation of Compound 2:

1022

[0823] Compound 47 (0.9447 g, 3.8509 mmol) was dissolved in toluene (15 mL), and the solution was cooled to −78° C. under nitrogen. DIBAL (6.0 mL, 6.00 mmol, 1.0 M in hexanes) was added via syringe over 5 min. The solution was stirred for 1 h, and was quenched with MeOH (1.0 mL) at −78° C. The bath was removed and 5.0 mL of saturated potassium sodium tartrate solution was added. The mixture was stirred for ca. 1 h, and was filtered through Celite. The filtrate was washed with H2O and brine, and dried over Na2SO4, filtered, and evaporated to give compound 2 (0.8413 g, 101%) sufficiently pure for the next step.

[0824] Preparation of Compound 3b:

1023

[0825] Compound 2 (0.8413 g, 3.8509 mmol) was dissolved in CH2Cl2 (5.0 mL) and (carbethoxyethylidene)triphenylphosphorane (1.8212 g, 5.0254 mmol) was added. The solution was stirred at room temp under nitrogen overnight. The solution was evaporated, and the residue was diluted with EtOAc (70 mL) and washed with H2O (2×25 mL) and brine (25 mL), and dried over Na2SO4, filtered, and evaporated to give an oil. Purification by Flash Chromatography on SiO2 (FC) gave pure compound 3b (0.7863 g, 68%).

[0826] Preparation of Compound 48:

1024

[0827] Compound 3b (0.7863 g, 2.6262 mmol) was dissolved in CH2Cl2 (1.0 mL) and triethylsilane (0.460 mL, 2.880 mmol) was added. Trifluoroacetic acid (TFA) (2.5 mL) was added at room temp. After 30 min (complete reaction as judged by HPLC), the solution was evaporated to give a solid (1.1307 g). This solid was dissolved in CH3CN (ca. 10 mL) and 5.5 N HCl (2.4 mL, 13.2 mmol) was added. Evaporation gave the HCl salt, compound 48 (0.618 g, 100%).

[0828] Preparation of Compound 5b:

1025

[0829] 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 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 (2×25 mL), aq. pH 7.2 phosphate buffer (25 mL), H2O (25 mL), and brine (25 mL), and dried over MgSO4, filtered, and evaporated to give a solid which was purified by FC to give compound 5b (0.4239 g, 62%).

[0830] Preparation of Compound 49:

1026

[0831] Compound 5b (0.1159 g, 0.2809 mmol) was dissolved in CH2Cl2 (3.0 mL) and triethylsilane (0.050 mL, 0.3130 mmol) was added. Trifluoroacetic acid (TFA) (2.5 mL) was added at room temp. After 30 min (complete reaction as judged by HPLC), the solution was evaporated to give a solid. This solid was dissolved in CH3CN (ca. 5 mL) and 5.5 N HCl was added (0.3 mL, 1.65 mmol). Evaporation gave the HCl salt, compound 49 (0.0662 g, 100%).

[0832] Step 2: Preparation of Compound 51:

[0833] Preparation of Compound 50:

1027

[0834] Compound 49 (0.0774 g, 0.2219 mmol), (R)—N-methylpipecolic (0.0705 g, 0.3925 mmol), CMC (0.1752 g, 0.4136 mmol), HOAt (0.0344 g, 0.2527 mmol), and NMM (0.063 mL, 0.5730 mmol) were combined, and DMF (2.0 mL) was added. The solution was stirred at room temp under nitrogen for 20 h. The solution was purified directly by RP HPLC to give compound 50 (0.0989 g, 81%).

[0835] Preparation of Compound 51:

1028

[0836] Compound 50 (0.0989 g, 0.2086 mmol) was dissolved in 1:1H2O/MeOH (14 mL) at room temp. LiOH (0.0537 g, 2.2422 mmol) was added. The suspension was stirred at room temp. 19 h. The solution was acidified with 5.5 N HCl (0.50 mL), and purified by RP HPLC to give the TFA salt of 11 (0.0978 g, 90%). This was dissolved in CH3CN (ca. 5 mL) and treated with 5.5 N HCl (ca. 1 mL, 5.5 mmol) and evaporated to give the HCl salt of compound 51 (0.0667 g, 72%).

[0837] Step 2: Preparation of Compound 52:

1029

[0838] Compound 51 (0.0062 g, 0.0139 mmol), L-proline methyl ester hydrochloride (0.0263 g, 0.1588 mmol) were dissolved in DMF (1.0 mL) at room temp. under nitrogen. DEPC (0.017 mL, 0.1120 mmol) was added via syringe. NMM (0.025 mL, 0.2274 mmol) was added via syringe. The solution was stirred overnight, quenched with H2O (1.0 mL), and purified by RP HPLC to give the TFA salt of compound 52. This was dissolved in CH3CN (ca. 3 mL) and treated with 5.5 N HCl (0.10 mL, 0.55 mmol) and evaporated to give the HCl salt of compound 52 (0.0078 g, 1100%).

Example 6

Preparation of Compound 62a

[0839]

1030

[0840] Preparation of Compound 54

1031

[0841] To a solution of 4-methylpiperidine (53) (600 μL, 5.0 mmol) in MeOH (20 mL) was added Et3N (770 μL, 5.5 mmol) followed by Boc2O (1.2 g, 5.5 mmol) at 0° C. After 15 minutes, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction solution was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 54 (926.5 mg) quantitatively as a colorless oil.

[0842] Preparation of Compound 55

1032

[0843] 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 μL, 5.0 mmol) followed by slow addition of a 1.3 M cyclohexane solution of sec-butyllithium (4.6 mL, 6.0 mmol) over a 30 minute period. The reaction solution was then warmed to −20° C. and maintained at that temperature for 30 minutes, after which the solution was re-cooled to −78° C. and purged with gaseous carbon dioxide for 15 minutes. The reaction solution was then slowly warmed to 0° C. and poured into a biphasic mixture of 1 N HCl (100 mL) and EtOAc (50 mL). The reaction solution was then extracted several times with EtOAc. The EtOAc extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 55 (1.07 g) in 89% yield as a colorless oil (a mixture of two cis enantiomers).

[0844] Preparation of Compound 59a

1033

[0845] To a solution of compound 55 (292 mg, 1.2 mmol) in CH2Cl2 (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 59a (309 mg) quantitatively as a light yellow oil.

[0846] Preparation of Compound 59b

1034

[0847] Step 1: Preparation of Compound 56

1035

[0848] 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 MeI (300 μL, 4.8 mmol). The reaction solution was allowed to stir overnight. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (4% EtOAc in hexanes) yielded 535 mg (65%) of compound 56 as a colorless oil.

[0849] Step 2: Preparation of Compound 57

1036

[0850] 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 μL). The solution was allowed to stir overnight. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (4% EtOAc in hexanes) yielded 363.6 mg (79%) of racemic compound 57 as a colorless oil.

[0851] Step 3: Preparation of Compound 58

1037

[0852] To a solution of compound 57 (360 mg, 1.4 mmol) in a 2:1 mixture of H2O (2.75 mL) and EtOH (5.50 mL) was added KOH pellets (786 mg, 14 mmol) and the reaction solution was stirred at room temperature until complete by TLC. The reaction mixture was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 58 (341 mg) quantitatively as a white solid.

[0853] Step 4: Preparation of Compound 59b

[0854] To a solution of compound 58 (292 mg, 1.2 mmol) in CH2Cl2 (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.

[0855] Preparation of Compounds 60a and 60b

1038

[0856] 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 μL). 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.

[0857] Preparation of Compounds 61a and 61b

1039

[0858] To a solution of compound 60a and 60b (11.0 mg, 0.07 mmol) in CH2Cl2 (350 μL) was added HBTU (40 mg, 0.11 mmol) and DIEA (37 μL, 0.21 mmol). After 5 minutes, amine 49 (22.0 mg, 0.07 mmol) was added. The reaction mixture was stirred for 30 minutes, filtered, and concentrated. Purification of the residue by silica gel chromatography (2% EtOH in CH2Cl2) yielded 15.1 mg (96%) of each diastereomer 61a and 61b as colorless oils.

[0859] Preparation of Compound 62a

1040

[0860] To a solution of diastereomer 61a (9.0 mg, 0.02 mmol) in a 2:1 mixture of H2O (80 μL) and EtOH (160 mL) was added LiOH.H2O (840 mg, 0.20 mmols). The reaction solution was allowed to stir overnight. The reaction mixture was then acidified with 1 N HCl until the pH=6.00. The solution was then extracted several times with CH2Cl2. The CH2Cl2 extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 62a (8.4 mg) quantitatively as a white solid.

Example 7

Preparation of Compound 67b

[0861]

1041

[0862] Preparation of Compound 64

1042

[0863] 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 stirring for 16 h. After cooling to r.t., it was acidified to pH 5 with 1 N HCl and extracted with ethyl acetate three times. The organic phase was concentrated to give a yellow solid as the crude product 64 (469 mg, 99%)

[0864] Preparation of Compound 65

1043

[0865] To a solution of crude 64 (47 mg, 0.2 mmol) in THF (1 mL) was added aq. 37% formaldehyde solution (49 μl, 0.6 mmol) followed by NaBH4 (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 dried and concentrated to give crude product 65 (67 mg, >100%).

[0866] Preparation of Compounds 66a and 66b

1044

[0867] To a mixture of 65 (29 mg, 0.115 mmol), amine HCl salt 49 (15 mg, 0.043 mmol), CMC (55 mg, 0.129 mmol), and HOAt (3 mg, 0.022 mmol) was added DMF (0.5 mL) followed by NMM (6 ml, 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.

[0868] Preparation of Compounds 67b

1045

[0869] 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 N HCl. Product 67b (2.79 mg, 74%) was obtained after RP HPLC purification and lyophilization.

Example 8

Preparation of Compound 74

[0870]

1046

[0871] Preparation of Compound 69

1047

[0872] To a solution of diethylglycine (68) (131 mg, 1.0 mmol) in 1 N NaOH (1.5 mL) was added a solution of di-t-butyl-dicarbonate (436 mg, 2.0 mmol) in dioxane (1.0 mL). The mixture was stirred for 16 h. It was acidified to pH 3 with 1 N HCl and extracted with ethyl acetate three times. The organic phases were combined, dried, and concentrated to yield crude product 69 (135 mg, 58%).

[0873] Preparation of Compound 70

1048

[0874] To a solution of crude 69 (135 mg, 0.58 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added trimethylsilyldiazomethane (2 Min hexanes, 2.0 mmol). The solution was stirred at r.t. for 1 h. Evaporation gave crude product 70 (0.58 mmol).

[0875] Preparation of Compound 71

1049

[0876] To a mixture of sodium hydride (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 μl, 3 mmol). The mixture was stirred at room temperature for 24 h. Water was added to quench the reaction. The product 71 (118 mg, 78% 2 steps) was extracted with ethyl acetate and purified by flash column chromatography (silica, ethyl acetate/hexanes).

[0877] Preparation of Compound 72

1050

[0878] A solution of compound 71 (118 mg, 0.46 mmol) in conc. HCl (1 mL) was stirred at room temp. for 24 h. Product 72 was obtained after evaporation of volatiles.

[0879] Preparation of Compound 73

1051

[0880] To a mixture of compound 72 (30 mg, 0.166 mmol), amine 49 HCl salt (39 mg, 0.166 mmol), CMC (141 mg, 0.332 mmol), and HOAt (14 mg, 0.103 mmol) was added DMF (1.5 mL) followed by NMM (6 ml, 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.

[0881] Preparation of Compound 74

1052

[0882] To a solution of compound 73 (18 mg) in methanol (0.5 mL) was added aq. LiOH (1 M, 0.5 mL). The mixture was stirred for 16 h and then acidified by 1 N HCl. Product 74 (12.3 mg, 73%) was obtained after RP HPLC purification and lyophilization.

Example 9

Preparation of Compound 78

[0883]

1053

[0884] Preparation of Compound 76

1054

[0885] To a solution of compound 75 (123 mg) in dry DCM (1 mL), at 0° C. under an inert atmosphere, was added a 1 M solution of DIBAL (1.6 mL) dropwise. The reaction mixture was stirred at 0° C. for 2 hr then allowed to warm to 10° C. then re-cooled to 0° C. Methanol (0.22 mL) was added dropwise followed by a saturated solution of ammonium chloride (0.44 mL). DCM (20 mL) was added and the reaction mixture stirred vigorously at room temperature for 30 min. Filtration followed by concentrated in vacuo gave compound 76 (73 mg, 65%).

[0886] Preparation of Compound 77

1055

[0887] To a solution of compound 76 (3 mg) in acetonitrile (0.6 mL) was added Dess Martin periodinane (3.1 mg). The reaction mixture was stirred at room temperature for 1 hr then diluted with diethyl ether (2 mL). The resultant suspension was filtered through a 0.25 μm PTFE syringe filter and concentrated in vacuo to give crude compound 77 (4 mg).

[0888] Preparation of Compound 78

1056

[0889] To a solution of compound 77 (3 mg) in DCM (0.5 mL), at room temperature, was added ethyl carbethoxymethylidene triphenylphosphorane (21 mg). The reaction mixture was stirred at room temperature for 16 hr then concentrated in vacuo to dryness. Chromatographic purification gave compound 78 (1.48 mg, 44%).

Example 10

Preparation of Compound 81

[0890]

1057

[0891] Preparation of Compound 79

1058

[0892] To a solution of compound 7b (10 mg) in dry DCM (0.5 mL), at 0° C. under an inert atmosphere, was added a 1 M solution of DIBAL (0.085 mL) dropwise. The reaction mixture was stirred at 0° C. for 1.5 hr then methanol (0.012 mL) was added dropwise followed by a saturated solution of ammonium chloride (0.024 mL). DCM (5 mL) was added and the reaction mixture stirred vigorously at room temperature for 20 min. Filtration followed by concentrated in vacuo gave crude compound 79 (9 mg, 95%).

[0893] Preparation of Compound 80

1059

[0894] To a solution of compound 79 (5 mg) in THF (0.5 mL) was added sodium bicarbonate (3.6 mg) and Dess Martin periodinane (7.2 mg). The reaction mixture was stirred at room temperature for 3 hr then concentrated in vacuo to give crude compound 80.

[0895] Preparation of Compound 81

1060

[0896] To a solution of compound 80 (4.8 mg) in ethanol (0.5 mL), at room temperature, was added hydroxylamine hydrochloride (4 mg) and sodium acetate (6 mg). The reaction mixture was stirred at 40° C. for 1.5 hr then concentrated to dryness. The residue was dissolved in DCM (0.2 mL) and treated with TFA (0.2 mL) and stood at room temperature for 10 min. Concentration in vacuo to dryness followed by chromatographic purification gave compound 81 (2.04 mg).

Example 11

Preparation of Compound 87

[0897]

1061

[0898] Preparation of Compound 84

1062

[0899] To a solution of compound 28 (335 mg) in THF (10 mL), at 0° C. under an inert atmosphere, was added sodium hydride (65% dispersion in mineral oil; 144 mg) portionwise. The reaction mixture was stirred at 0° C. for 30 min then treated with methyl iodide (0.405 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 hr. An aqueous work up followed by chromatographic purification gave compound 84 (254 mg, 72%).

[0900] Preparation of Compound 85

1063

[0901] Compound 84 (189 mg) was treated with saturated HCl 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 (145 mg).

[0902] Preparation of Compound 86

1064

[0903] To a solution of compound 85 (145 mg) in DMF (3 mL), at room temperature, was added (S)-N-Boc-tert-leucine (483 mg), NMM (0.230 mL), HOAt (95 mg), and CMC (884 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (249 mg, 93%). The intermediate Boc compound (60 mg) was dissolved in methanol (1 mL) and treated with saturated HCl in methanol (3 mL) and stood at room temperature for 30 min. Concentration in vacuo gave compound 86 (49 mg).

[0904] Preparation of Compound 87

1065

[0905] 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 μl), HOAt (21 mg), and CMC (130 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (41 mg, 47%). The intermediate Boc compound (5.5 mg) was dissolved in DCM (1 mL) and treated with TFA (1 mL). The reaction mixture was stood at room temperature for 30 min then concentrated in vacuo to dryness. The residue was dissolved in saturated HCl in methanol (1 mL) and stood at room temperature and then concentrated in vacuo to give compound 87 (4.39 mg, 89%).

Example 12

Preparation of Compound 91

[0906]

1066

[0907] Preparation of Compound 88

1067

[0908] To a solution of compound 28 (344 mg) in 0.5 M Hunnig's base in DCM (8 mL), at 0° C. under an inert atmosphere, was added methane sulphonyl chloride (0.207 mL) dropwise. The reaction mixture was stirred at 0° C. for 1.5 hr then subjected to an aqueous work up followed by chromatographic purification to give an intermediate mesylate (444 mg). The intermediate mesylate was dissolved in DMSO (2 mL) and treated with sodium azide (258 mg). The reaction mixture was heated at 40° C. for 6 hr. An aqueous work up gave compound 88 (306 mg, 82%).

[0909] Preparation of Compound 89

1068

[0910] Compound 88 (140 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 HCl in methanol (1 mL) and stood at room temperature and then concentrated in vacuo to give compound 89 (109 mg).

[0911] Preparation of Compound 90

1069

[0912] 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), HOAt (68 mg), and CMC (635 mg). The reaction mixture was stirred at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (173 mg, 87%). The intermediate Boc compound (51 mg) was dissolved in methanol (1 mL) and treated with saturated HCl in methanol (3 mL) and stood at room temperature for 30 min. Concentration in vacuo gave compound 90 (43 mg).

[0913] Preparation of Compound 91

1070

[0914] 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 μl), HOAt (17 mg), and CMC (108 mg). The reaction mixture was shaken at room temperature for 16 hr. Aqueous workup followed by chromatographic purification gave an intermediate Boc compound (88 mg). The intermediate Boc compound (88 mg) was dissolved in saturated HCl in methanol (5 mL) and stood at room temperature for 30 min and then concentrated in vacuo to give compound 91 (70 mg, 89%).

Example 13

General Procedure for the Preparation of C-Terminal Acid Compounds:

[0915]

1071

1072

[0916] 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 hydroxide (10-50 equivalents). The reaction mixture was stirred or shaken or stood at room temperature until the starting ester had been satisfactorily hydrolyzed. The usual workup followed by chromatographic purification gave the desired C-terminal acid compound (e.g., compound 82).

Example 14

Preparation of Compound ER-807974

[0917]

1073

[0918] Preparation of Compound ER-807641

1074

[0919] 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 HCl (1N, 500 mL), water (250 mL), NaHCO3 (sat. 250 mL) and brine (250 mL). The organic solution was dried over MgSO4 (Q120 g). The solution was filtered through a silica gel bed (Q200 g) and concentrated. Crude amide ER-807641 was used without any further purification.

[0920] Preparation of Compound ER-808993

1075

[0921] To a stirred solution of amide ER-807641 (207 g, 755 mmol, 1 eq.) in dry THF (2070 mL) at −78° C. was added a solution of LiAlH4 (1.0M/THF, 754 mL, 755 mmol, 1.0 eq.). The solution was stirred at −78° C. for 1 h. Reaction was quenched at −78° C. by addition of reaction solution to a suspension of Na2SO4.10H2O (243 g) in TBME (1.5 L). The slurry was allowed to warm up to −15° C. and was then filtered through a Celite pad. The filtrate was concentrated, and the crude aldehyde ER-808993 was obtained as a clear oil and used without further purification.: 157.9 g (97%).

[0922] Preparation of Compound ER-808995-01

1076

[0923] Part A:

[0924] To a stirred solution of aldehyde ER-808993 (138 g, 641 mmol, 1 eq.) 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).

[0925] Part B:

[0926] 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 (2×300 mL). The aqueous layer was neutralized to pH 7-8 with sat. NaHCO3 (300 mL). The resultant solution was extracted with EtOAc (2×400 mL), washed with brine (300 mL), dried over MgSO4, and filtered. The EtOAc solution of the free amino-ester was bubbled with HCl (gas), and the HCl salt of ER-808995 precipitated and was collected by filtration under N2.

[0927] Preparation of Compound ER-803921-01

1077

[0928] To a stirred solution of ER-808995 (61.2 g, 259.6 mmol, 1 eq.), N-Boc-tBu-Gly-OH (90.1 g, 389.4 mmol, 1.5 eq) and DIEA (158 mL, 906.6 mmol, 3.5 eq) in dry DCM (612 mL) at 25° C. was added HBTU (147.7 g, 389.4 mmol, 1.5 eq.). The solution was stirred at room temp for 4 h After concentration, the solid residue was suspended in TBME (250 mL). The mixture was filtered through a silica gel bed (˜120 g), and the filtrate was washed with a solution of aq. HCl (1N, 200 mL), water (200 mL) and NaHCO3 (sat, 200 mL). The organic layer was dried over MgSO4, filtered and concentrated. The N-Boc-amino-ester ER-808996 was isolated as an oil. This intermediate was re-dissolved in EtOAc (120 mL) and MSA (75 mL) was added. The solution was stirred at room temp for 1 h, at which time the reaction was deemed complete by TLC. The amino-ester MSA salt was extracted with water (2×250 mL), followed by neutralization with a solution NaOH (ca.50%, 300 mL) to pH˜8-9. The free amine was extracted with TBME (2×30 mL). The combined organic solution was washed with water (200 mL) and brine (200 mL). After drying over MgSO4 and filtration, HCl (g) was bubbled to obtain the hydrochloride salt of ER-803921 as a white solid collected by filtration at ca. 5° C.

[0929] Preparation of Compound ER-808998

1078

[0930] A stirred suspension of D-pipecolic acid (100.0 g, 0.77 mol, 1 eq.) 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.

[0931] Preparation of Compound ER-807961

1079

[0932] To a stirred solution of dipeptide ER-803921 (5.0 g, 16.8 mmol, 1 eq.), N-iPr-pipecolic acid ER-808998 (3.7 g, 21.8 mmols, 1.3 eq.) and HBTU (8.3 g, 21.8 mmols, 1.3 eq.) in 50 mL DCM was added DIEA (7.3 mL, 41.9 mmols, 2.5 eq.) dropwise at 25° C. The mixture was stirred for 18 h (overnight) at which time reaction was deemed complete by TLC (heptane/EtOAc 1:1). The mixture was concentrated under vacuum and TBME (50 mL) was added. The residual “thick” oil was separated from the ethereal solution by filtration through a Celite pad. The filtrate was washed with aq HCl (1M, 3×25 mL). The combined aqueous phases were neutralized with NH4OH to pH 8-9 in the presence of EtOAc (25 mL). The aqueous layer was separated and back-extracted with TBME (25 mL). The combined organic phase was washed with brine and dried over MgSO4, filtered, and concentrated to give tripeptide-amino-ester ER-807961 in 93% yield.

[0933] Preparation of Compound ER-807974

1080

[0934] To a stirred solution of ester ER-807961 (5.0 g, 16.8 mmol) in 5:1 THF/H2O (50 mL) was added LiOH (3.50 g, 83.8 mmol), and the mixture was stirred at room temperature for 20 h. The reaction was monitored by TLC (ethanol) and deemed complete when no ER-807961 was observed. The suspension was acidified with H2SO4 (˜0.50 mL) to pH 7. The mixture was extracted with EtOAc (3×25 mL). The combined organic solution was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was triturated with TBME: 1.8 g (83%) of thick oil free-base ER-807974 was obtained.

Example 15

Preparation of Compound ER-808367

[0935]

1081

[0936] Preparation of Compound 2Z

1082

[0937] To a suspension of D-pipecolic acid 1Z (750 mg, 5.81 mmol) in MeOH (23.2 mL) and 2-butanone (11.6 mL) was added Pd(OH)2 (175 mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to give a crude white solid. The crude product was subjected to flash chromatography (SiO2) eluting with 100% EtOH. This provided compound 2Z (721 mg, white solid) as a mixture of diastereomers in 67% yield.

[0938] Preparation of Compounds 3Z and 4Z

1083

[0939] To a solution of 2Z (650 mg, 3.51 mmol) in DMF (8.8 mL) was added K2CO3 (728 mg 5.27 mmol) and p-nitrobenzylbromide (1.1 g, 5.27 mmol). The reaction mixture was allowed to stir overnight. The reaction solution was diluted with water and extracted several times with diethyl ether. The ether extracts were combined, washed with water and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture of diasteomers was then separated by flash chromatography eluting with 8% EtOAc in hexanes to give each diastereomer as a pale yellow oil. Compound 3Z (360 mg) was obtained in 32% yield with an Rf=0.590 (SiO2) using 30% EtOAc in hexanes. Compound 4Z (652 mg) was obtained in 58% yield with an Rf=0.482 (SiO2) using 30% EtOAc in hexanes.

[0940] Preparation of Compound ER-809439

1084

[0941] To a solution of compound 3Z (320 mg, 1.0 mmol) in MeOH (10 mL) was added Pd(OH)2 (50 mg). 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 (185 mg) as a white solid, quantitatively. Compound ER-809439, Rf=(SiO2, 0.292, 100% EtOH).

[0942] Preparation of Compound ER-809447

[0943] A procedure similar to that used for the preparation of compound ER-809439 was used. Compound ER-809447, Rf=(SiO2, 0.292, 100% EtOH).

[0944] Preparation of compound ER-808357

1085

[0945] Compound 49 (9.6 mg, 0.031 mmol), N-sec-butylpipecolic ER-809439 (5.2 mg, 0.028 mmol), HBTU (12.9 mg, 0.034 mmol), were combined. DMF (0.28 mL) was added, followed by DIEA (14.9 mL, 0.084 mmol). The solution was stirred at room temperature under nitrogen for 20 h. The solution was purified directly by RP HPLC to give the TFA salt of compound ER-808357 (13.6 mg, 82%).

[0946] Preparation of Compound ER-808367

1086

[0947] The TFA salt of compound ER-088357 (10.4 mg, 0.018 mmol) was dissolved in 1:2H2O/EtOH (0.072 mL/0.144 mL) at room temperature. LiOH (7.5 g, 0.18 mmol) was added. The suspension was stirred at room temperature for 19 hours. The solution was purified directly by RP HPLC to give the TFA salt of compound ER-808367 (10.1 mg, quantitative).

Example 16

Preparation of Compound ER-808368

[0948]

1087

[0949] Preparation of Compound ER-808358

1088

[0950] A procedure similar to that used for the preparation of compound ER-808357 was used.

[0951] Preparation of Compound ER-808368

1089

[0952] A procedure similar to that used for the preparation of compound ER-808367 was used.

Example 17

Preparation of Compound ER-808662

[0953]

1090

[0954] Preparation of Compound 5Z

1091

[0955] 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 (SiO2) 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).

[0956] Preparation of Compound ER-808656

1092

[0957] A procedure similar to that used for the preparation of compound ER-808357 was used.

[0958] Preparation of Compound ER-808662

1093

[0959] A procedure similar to that used for the preparation of compound ER-808367 was used.

[0960] 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.

Example 18

Preparation of Compound ER-808824

[0961]

1094

[0962] Preparation of Compound 6Z

1095

[0963] Compound 48 (325.5 mg, 1.38 mmol), L-N-BOC-valine (300.0 mg, 1.38 mmol), HBTU (628.3 mg, 1.66 mmol), were combined. CH2Cl2 (7 mL) was added, followed by DIEA (0.72 mL, 4.14 mmol). The solution was stirred at room temperature under nitrogen for 1 hour. The solution was concentrated in vacuo, and the crude was purified by flash chromatography (SiO2) eluting with 4% EtOAc in hexanes. This provided compound 6Z (476.8 mg) as a colorless oil in 86.7% yield.

[0964] Preparation of Compound 7Z

1096

[0965] Compound 6Z (450 mg, 1.13 mmol) was dissolved directly in 4N HCl/dioxane (2.8 mL). The reaction was stirred for overnight and then concentrated in vacuo to give compound 7Z (374.8 mg) as a white solid, quantitatively.

[0966] Preparation of Compound ER-808815

1097

[0967] A procedure similar to that used for the preparation of compound ER-808357 was used.

[0968] Preparation of compound ER-808824

1098

[0969] A procedure similar to that used for the preparation of compound ER-808367 was used.

Example 19

Biological Assays

[0970] In certain embodiments, compounds of the invention were tested for in vitro and in vivo activity. Screening methods included standard in vitro cell growth inhibition assays using a panel of human cancer cell lines, a U937 (ATCC accession number CRL 1593) mitotic block reversibility assay, mouse serum stability assay, MDR assay, and cytotoxicity assay. In certain other emdodiments, compounds of the invention were evaluated in tumor xenograft in vivo growth inhibition assays.

[0971] In vitro potency was determined in the MDA-MB-435 cell growth inhibition assay, and active compounds (IC50<20 rtM) were evaluated in the reversibility, MDR, and mouse serum stability assays. In addition, the active compounds were tested in the IMR-90 cytotoxicity assay and in additional cell growth inhibition assays in a panel of human cancer cell lines, both solid and non-solid tumors.

[0972] 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. The human cell lines used in this cell growth inhibition assay, include, but are not limited to, the following solid tumor cell lines and non-solid tumor cell lines: DLD-1 colon cancer cells (ATCC accession number CCL-221), DU 145 prostate cancer cells (ATCC accession number HTB-81), H460 non small cell lung cancer, HCT-15 colon cancer cells (ATCC accession number CCL-225), HEL erythroleukemia cells, HL-60 promyelocytic leukemia cells (ATCC accession number CCL-240), K562 leukemia (ATCC accession number CCL-243), LOX melanoma, MDA-MB-435 breast cancer cells, U937 lymphoma cells (ATCC accession number CRL 1593), PANC-1 pancreatic cancer (ATCC accession number CRL -1469), HCC-2998 colon cancer (NCI-Frederick Cancer DCTD Tumor/Cell Line Repository), HCT 116 colon cancer (ATCC accession number CCL-247), HT-29 colon cancer (ATCC accession number HTB-38), LoVo colon cancer (ATCC accession number CCL-229), SW-480 colon cancer (ATCC accession number CCL-228), SW-620 colon cancer (ATCC accession number CCL-227) and COLO-205 colon cancer (ATCC accession number CCL-222). For monolayer cultures, growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340 plate reader and absorbances at 405 nm were subtracted from absorbances at 620 nm. For suspension cultures, growth was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-based assay (Mosmann et al, J. Immunol. Methods, 65: 55-63, 1983) modified as follows. After 4 days of incubation with test compounds, sterile-filtered 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide was added to each well (final concentration, 0.5 mg/ml), and plates were incubated at 37° C. for 4 h. Acid-isopropanol (0.1 N HCl in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dis-solved by gentle mixing. Absorbances at 540 nm were measured on a Titertek Multiscan MCC/340 plate reader.

[0973] Mitotic block reversibility assay was performed as described (See, Patent U.S. Pat. No. 6,214,865 BI, by B. Littelfield et al, Apr. 10, 2001; which is incorporated herein be reference in its entirety).

[0974] Briefly, U937 (ATCC accession number CRP 1593) were exposed to various concentration of compounds for 12 hours. The compounds were washed away and the cells were allowed to recover for an additional 10 hours. The cells were collected by centrifugation and fixed overnight in 70% ethanol. The cells were washed in PBS, incubated with RNase A and stained with propidium iodide. Single channel flow cytometry was performed on a Becton Dickinson FACScan; the collection and analysis of data were performed using Becton Dickinson CELLQuest software. Doublet events were eliminated from analyses by proper gating on FL2-W/FL2-A primary plots before histogram analysis of DNA content (measured as FL2-A).

[0975] Determination of activity in vitro utilizing the MDR assay. This is a modification of the standard cell growth inhibition assays described above. Two cultured himan cancer cell lines were used: human uterine sarcoma MDR negative MES-SA cells (ATCC accession number CRL-1976) and human uterine sarcoma MDR-positive MES-SA/Dx5 cells (ATCC accession number CRL-1977). Cells were plated in a 96-well microtiter plates at a density of 7500 cells/well. The cells were incubated in the presence or absence of test compounds for 96 hours. Cell growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340 plate reader and absorbances at 405 nm were subtracted from absorbances at 620 nm. The ratio of the concentrations of the compounds inhibiting the growth of cells by 50% was calculated and used to estimate the sensitivity of the compounds to MDR (multidrug-resistance, or P-glycoprotein-mediated drug efflux). In some cases, a different pair of cell lines was used: MDR-negative murine leukemia cells P388/S, and MDR-positive murine leukemia cells P388NVMDRC.04. Cells were plated in a 96-well microtiter plates at a density of 4000 cells/well. The cells were incubated in the presence or absence of test compounds for 72 hours. Cell growth was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-based assay (Mosmann et al, J. Immunol. Methods, 65: 55-63, 1983) modified as follows. After 3 days of incubation with test compounds, sterile-filtered 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide was added to each well (final concentration, 0.5 mg/ml), and plates were incubated at 37° C. for 4 h. Acid-isopropanol (0.1 N HCl in isopropanol, 150 mL) was then added to each well, and the resultant formazan crystals were dis-solved by gentle mixing. Absorbances at 540 rn were measured on a Titertek Multiscan MCC/340 plate reader.

[0976] Stability to esterase degradation was determined in the mouse serum stability assays. The enzymatic activity of mouse serum can result in inactivation of compounds in vivo despite their promising in vitro activity. A modification of the standard cell growth inhibition assays described above was used to determine stability of the test compounds to esterase degradation. Human breast carcinoma cell line MDA-MB-435 or human prostate carcinoma cell line DU 145 were used. The cells were plated in a 96-well microtiter plates at a density of 7500 cells/well. Prior to adding the test compounds to cells in the cell growth inhibition assay, the test compounds were incubated in 100% mouse serum or normal growth medium for 6 hours at 37° C. After that, the test compounds were added to the 96-well microtiter plates containing the cells. The cells were incubated in the presence or absence of test compounds for 96 hours. Cell growth was assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan MCC/340. Ability of test compounds to inhibit cell growth after compounds' exposure to mouse serum esterases was assessed.

[0977] Cytotoxicity assay. To determine toxicity of compounds against normal, non-dividing cells, quiescent IMR-90 normal human fibroblasts (ATCC accession number CCL-186) were used. IMR-90 cells were plated in a 96-well microtiter plate format and grown to confluency (for 72 hours). After the 72-hour growth, the cells were washed and the medium was replaced from normal medium containing 10% fetal bovine serum to medium containing low concentration of serum (0.1%). Cells were made quiescent by incubation in 0.1% serum-containing growth medium for additional 72 hours. Cells were incubated with the test compounds for 24 hours. Cellular ATP levels were measured using a ViaLight HS kit (LumiTech Ltd). A cytotoxic compound carbonyl cyanide was used in all assays as a positive control for cytotoxicity.

[0978] Determination of antitumor activity in vivo in mice. In vivo tumor xenograft studies were performed in immunocompromised (nude) mice. Mice (female Ncr athymic) were implanted subcutaneously with human tumor xenografts (including breast MDA-MB-435, colon COLO-205, HCT-15, HCT-116, HCC-2998, HT-29, SW-620, DLD-1, LoVo, melanoma LOX, lung H522, pancreatic PANC-1). After the xenografts reached an average size of 75-200 mm3 or 400-600 mm3, the animals were weighed and randomly divided into groups of 8-10 on the first day of compound administration. Test compounds were administered intravenously or intraperitoneally. Tumor and body weight measurements were done twice weekly.

	Number	Date	Country
Parent	PCT/US03/08888	Mar 2003	US
Child	10667864	Sep 2003	US

Hemiasterlin derivatives and uses thereof

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