Title of Invention

HEMIASTERLIN DERIVATIVES AND USES THEROF

Abstract The present invention provides compounds having formula (I): (I) and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R1-R7, X1, X2, R, Q, and n are as defined herein.
Full Text HEMIASTERLIN DERIVATIVES AND USES THEREOF
Priority Claim
[0001] The present application claims priority to U.S. Provisional Patent
Application Number 60/366,592, filed March 22, 2002, the entire contents of which
are incorporated herein by reference.
Background of the Invention
[0002] Hemiasterlin (1) was first isolated from the sponge Hemiasterella minor
(class, Demospongiae; order, Hadromedidia; family, Hemiasterllidae) collected in
Sodwana Bay, South Africa (see, Kashman et al. U.S. patent 5,661,175). It was
reported that Hemiasterlin exhibited antitumor activity against several cell lines,
including human lung carcinoma, human colon carcinoma and human melanoma.

[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. Patent No. 6,153,590 and PCT
application WO 99/32509). However, only a rather limited number of Hemiasterlin
analogs were prepared, half of which were the natural products themselves, isolated
from Cymbastela sp., or were obtained by modifications to the natural products. Thus
the number and types of derivatives that could be prepared and evaluated for
biological activity were limited.
[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
fariable therapeutic profile in vivo (e.g., are safe and effective, while retaining
stability in biological media).
Summary of the Invention
[0005] As discussed above, there remains a need to develop novel Hemiasterlin
analogs to evaluate their potential as therapeutic agents for the treatment of cancer.
The present invention provides novel compounds of general formula (I),

and additionally provides methods for the synthesis thereof and methods for
the use thereof in the treatment of cancer, wherein R1-R7, X1, X2, R, Q, and n are as
defined herein. The inventive compounds also find use in the prevention of restenosis
of blood vessels subject to traumas such as angioplasty and stenting.
Detailed Description of Certain Preferred Embodiments of the
Invention
[0006] In recognition of the need to access and further explore the biological
activity of novel derivatives of Hemiasterlin, and this class of peptides in general, the
present invention provides novel peptide compounds, as described in more detail
herein, which demonstrate antitumor activity. Thus, the compounds of the invention,
and pharmaceutical compositions thereof, are useful for the treatment of cancer. In
certain embodiments, the compounds of the present invention can be used for the
treatment of diseases and disorders including, but not limited to prostate, breast,
colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver,
pancreatic or esophageal cancer, lymphoma, leukemia and multiple myeloma. In
certain other embodiments, the inventive compounds also find use in the prevention
of restenosis of blood vessels subject to traumas such as angioplasty and stenting.
[00071 1) General Description of Compounds of the Invention
[0008] The compounds of the invention include compounds of the general
formula (I) as further defined below:

wherein n is 0,1,2, 3 or 4;
X1 and X2 are each independently CRaRb. C(=O), or -SO2-; wherein each
occurrence of RA and RB is independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
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,
aUcyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
each occurrence of R3 and R4 is independently hydrogen, or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or wherein any
two R1, R2, R3 and R4 groups, taken together, may form an alicyclic, heteroalicyclic,
alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or
heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety;
R5, R6, and R7 are each independently hydrogen, -(C=O)RE or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each
occurrence of RE is independently hydrogen, OH, ORf, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any two R5, R6
and R7 groups, taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl),
heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an
aryl or heteroaryl moiety; wherein RF is an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety; or R7 may be absent when NR7 is linked to
R via a double bond;
R is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl
moiety; and
Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein RQ and RQ" are
each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or RQ' and RQ", taken together with the
nitrogen atom to which they are attached, may form an alicyclic, heteroalicyclic,
alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or
heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; and
pharmaceutically acceptable derivatives thereof.
[0009] In certain embodiments, compounds of formula (I) and compounds
described in classes and subclasses herein, are not naturally occurring Hemiasterlins.
[0010] In certain embodiments, compounds of formula (I) and compounds
described in classes and subclasses herein, do not have the following structure:

[0011] In certain embodiments of compounds described directly above and
compounds as described in certain classes and subclasses herein, the compounds do
not comprise more than four consecutive a-amino acid residues, and/or one or more
of the following groups do not occur simultaneously as defined:
(a) n is 1;
X1 and X2 are each C(=O);
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, fury], pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl,
quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl or pyridyl;
R3 is hydrogen;
R4 is -CR4aR4bR4c wherein R4a and R4b are each independently
hydrogen, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-,
Ar-alicyclic-; and, where at least one of R4a and R4b, is aliphatic, ahcyclic,
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;
R5, R6 and R7 are each independently hydrogen, aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic- and Ar;
R is a moiety selected from the group consisting of: a linear, saturated
or unsaturated, substituted or unsubstituted alkyl group containing one to six
carbon atoms; and
Q is -ORG, -SRG, -NRGRH, -NHCH(RK)CO2H, or -NRCH(RK)CO2H,
wherein 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=l-4 and RK1 and RK2 are independently hydrogen, aliphatic, ahcyclic,
heteroaliphatic, heteroalicyclic or-C(NH)(NH2);
(b) n is 1;
X1 and X2 are each C(=O);
R1 is an optionally substituted methylene or -CH= group bonded to the
indole moiety thereby forming a tricyclic moiety;
R2 is hydrogen, an optionally substituted alkyl or acyl group, or is
absent when R1 is -CH= as defined above;
R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein,
are linked by a double bond;
R4 is a moiety having the structure:

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;
R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;
R6 is hydrogen or an optionally substituted alkyl group;
R7 is hydrogen or alkyl; and
-R-X2-Q together represent an optionally substituted alkyl moiety;
(c) n is 1;
X1 and X2 are each C(=O);
R1 is hydrogen, an optionally substituted alkyl or acyl group, or an
optionally substituted methylene or -CH= group bonded to the indole moiety
thereby forming a tricyclic moiety;
R2 is hydrogen, an optionally substituted alkyl or acyl group, or is
absent when R1 is -CH= as defined above;
R3 is hydrogen or is absent when CR3 and CRyRz, as defined herein,
are linked by a double bond;
R4 is a moiety having the structure:
wherein Rw, Ry and are each
independently hydrogen, or optionally substituted alkyl or acyl, or R2 is absent
when CR3 and CRyRz, as defined herein, are linked by a double bond; 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;
R5 is hydrogen, OH or an optionally substituted alkyl or acyl group;
R6 is hydrogen or an optionally substituted alkyl group;
R7 is hydrogen or alkyl; and
-R-X2-Q together represent an optionally substituted alkyl moiety or -
Q'-C(O)X, wherein Q' is an optionally substituted -CH2-, -CH2CH2-, -
CH2CH2CH2-, -CH2CH=CH-, -CH2C=-C- or phenylene moiety, wherein X is
-OR', -SR' or-NR'R" and each occurrence of R' and R" is independently
hydrogen or optionally substituted alkyl;
(d) n is 1;
X1 is C=0;
R1 is methyl;
R2 and R3, taken together, form a piperidine moiety;
R4 and R5 are each hydrogen,
R6 is -CH(CH3)CH2CH3;
R7 is -CH2OC(O)CH2CH(CH3)2, -CH2OC(=O)CH2CH2CH3 or -
CH2OC(=O)CH2CH3; and
-R-X2-Q together represent the moiety having the structure:

(e) n is 1;
X1 is C=O;
R1, R2, and R7 are each methyl;
R3 and R5 are each hydrogen;
R4 and R6 are each i-propyl; and
-R-X2-Q together represent the moiety having the structure:

wherein Rx is hydrogen or 2-thiazolyl; and/or
(f) n is 1;
X1 is C=O;
R1 andR2 are each independently hydrogen or C1-4 alkyl;
R3 and R5 are each hydrogen;
R4 and R6 are each i-propyl;
R7 is methyl; and
-R-X2-Q together represent a moiety having the structure:

wherein v is 0,1 or 2;
R' is hydrogen or C1-4 alkyl;
R" is C1-6alkylamino; hydroxy; C3-7cycloalkylamino optionally
substituted by phenyl or benzyl; arylarnino; 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, rtfluoromethoxy, alkylthio, hydroxy,
alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino,
aminosulfonyl or benzyl; or aralkylamino having C1-4allcylene and the aryl
group optionally substituted with one to three substituents selected from the
group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy,
carbamoyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl,
phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy,
alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or
benzyl; and
R'" is hydrogen, alkyl optionally substituted with one to three
substituents selected from the group consisting of hydroxy, alkoxy, amino,
mono- or di-alkylamino, carboxy, alkoxycarbonyl, . carbamoyl,
alkylcarbonyloxy, carbamoyloxy or halogen; alkenyl; alkynyl; C3-7cycloalkyl;
aryl optionally substituted with one to three substituents selected from the
group consisting of halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy,
cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy,
trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino,
heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; aralkyl with the aryl
group optionally substituted with one to three substituents selected from the
group consisting of halogen, alkoxyxarbonyl, carbamoyl, sulfamoyl,
alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl,
phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy,
alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or
benzyl; or heterocyclylalkyl;
wherein the groups recited in paragraph (f) above are defined as
follows:
alkyl refers to a straight-chain or branched-chain hydrocarbon group
optionally substituted with hydroxy, alkoxy, amino, mono- or di-alkylamino,
acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyloxy, carbamoyl or
halogen;
alkenyl refers to a hydrocarbon chain as defined for alkyl above having
at least one double bond;
alkynyl refers to a hydrocarbon chain as defined for alkyl above having
at least one triple bond;
C3-7cycloalkyl refers to a saturated, cyclic hydrocarbon group with 3-7
carbon atoms optionally substituted with alkyl, phenyl, amino, hydroxy or
halogen;
C1-4alkylene refers to a biradical linear or branched hydrocarbon chain
containing 1-4 carbon atoms;
Aralkyl, refers to an aryl group attached to an alkylene group;
Heterocyclyl refers to saturated, unsaturated or aromatic monovalent
cyclic radical having one to three heteroatoms selected from O, N and S, or
combination thereof, optionally substituted with one or more occurrences of
benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, mono-
or di-alkylamino, acylamino, alkoxycarbonylamino or halogen;
Amino refers to -NH2 and includes amino groups which are further
substituted by lower alkyl groups, or nitrogen protecting groups know in the
art;
Cycloalkylamino refers to cycloalkyl groups as defined above attached
to a structure via an amino radical;
Arylamino is defined as aryl-NH-;
Aralkylamino is defined as aralkyl-NH-;
Carbamoyl refers to the group -C(=O)-NH2;
Carbamoyloxy refers to the group -O-C(=O)-NH-;
Alkylcarbamoyloxy refers to the group -O-C(=O)-NH-alkyl;
Alkylcarbonyloxy refers to the group -O-C(=O)-alkyl;
Aralkyloxy refers to the group -O-aralkyl; and
Alkylthio refers to the group Alkyl-S-.
[0012] In certain other embodiments of compounds described in (a) above and
compounds as described in certain classes and subclasses herein, the following groups
do not occur simultaneously as defined:
n is 1; 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 ß-
cyclopropyl, ß-cyclobutyl, ß-cyclopentyl, and ß-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:

wherein R' is methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl,
or sec-butyl; R" is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-
butyl or sec-butyl; and Q is OH or ORg wherein RG is a linear or branched one
to six carbon alkyl group.
[0013] In certain other embodiments of compounds described in (a) above and
compounds as described in certain classes and subclasses herein, the following groups
do not occur simultaneously as defined:
n is 1; 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:

wherein R' is isopropyl; R" is methyl; and Q is OH; and
(a) R4c and R4b are each methyl; R4c is methyl or phenyl; and R7 is
hydrogen or methyl;
(b) R4a and R4b are each methyl; R4c is hydrogen; and R7 is methyl;
or
(c) R4a and R4b, are each hydrogen; R4c is phenyl; and R7 is methyl.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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:
[0018] In certain other embodiments, compounds of formula (I) are defined as
follows:
X1 and X2 are each independently CHRaRB, SO2 or C=O; wherein RA and RB
are each independently hydrogen or substituted or unsubstituted, linear or branched,
cyclic or acyclic, or saturated or unsaturated lower alkyl;
R1 and R2 are each independently hydrogen, or a linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl or acyl moiety, or
an aryl or heteroaryl moiety; wherein the alkyl, heteroalkyl, and aryl moieties may be
substituted or unsubstituted; or
R1 and R2, taken together, may form a saturated or unsaturated, substituted or
unsubstituted cyclic ring of 5 to 8 atoms;
each occurrence of R3 and R4 is independently hydrogen, or a linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl,
lower -alkyl(aryl), lower -heteroalkyl(aryl) moiety, or an aryl or heteroaryl moiety;
wherein the alkyl, heteroalkyl, -alkyl(aryl), heteroalkyl(aryl), aryl and heteroaryl
moieties may be substituted or unsubstituted; or
R3 and R4, taken together, may form a saturated or unsaturated, substituted or
unsubstituted cyclic ring of 3 to 8 atoms;
the carbon atom bearing R3 and R4 may be of S configuration;
n is 1;
R5 is hydrogen or a protecting group; wherein the protecting group may be a
nitrogen protecting group;
R6 is hydrogen or substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or
unsubstituted aryl or heteroaryl moiety;
the carbon atom bearing R6 may be of S configuration;
R7 is hydrogen, or substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or
unsubstituted aryl or heteroaryl moiety; or R7may be absent when MR7 is linked to R
via a double bond;
R is a substituted or unsubstituted, linear or branched, cyclic or acyclic, or
saturated or unsaturated alkyl moiety; or a heteroaliphatic moiety containing 1-10
carbon atoms, 1 to 4 nitrogen atoms, 0 to 4 oxygen atoms and 0 to 4 sulfur atoms;
whereby the heteroaliphatic moiety may be substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated;
wherein (i) the alkyl moiety may have the structure:
wherein R8a, R9a and R10a are each independently absent, hydrogen, or
substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl or heteroalkyl; or a substituted or unsubstituted aryl or
heteroaryl moiety; wherein any two R7, R8a, 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;
(ii) the heteroalkyl moiety may have the structure:

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;
(iii) or the heteroalkyl moiety may have the structure:

wherein R8c, R9c, R10c, R11c and R12c are each independently absent,
hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic,
or saturated or unsaturated lower alkyl or heteroalkyl; or a substituted or
unsubstituted aryl or heteroaryl moiety, wherein any two R7, R8c, R9c, R10c
R11c and R12c groups may form a substituted or unsubstituted, saturated or
unsaturated cyclic alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or
a substituted or unsubstituted aryl or heteroaryl moiety; wherein NR7 and
CR8c, CR8c and CR9c, CR9c and CR10c, CR11c and CR11c are each independently
linked by a single or double bond as valency permits; and wherein the carbon
atom bearing R8c may be of S configuration; and
Q is ORQ', SRQ', NRQRQ", wherein RQ' and RQ" are each independently
hydrogen or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or
saturated or unsaturated lower alkyl or 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
pharmaceutically acceptable derivatives thereof.
[0019] 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 (1a):

wherein R1-R7, X1, X2, Q and n are defined in classes and subclasses herein;
R8a, R9a and R10a are each independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and wherein any two R7,
R8a, R9a and R10a groups may form a substituted or unsubstituted, saturated or
unsaturated alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),
alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl
moiety.
[0020] Another class of compounds of special interest, herein referred to as class
(1b), 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.
[0021] Another class of compounds of special interest consists of compounds
having the structure of formula (I) in which X1 is C=O; n is 1; R1 and R4, taken
together, form a cyclic heterocyclic or heteroaryl moiety; R3 is hydrogen or is absent
when the carbon atom bearing R3 is linked to N or E via a double bond; and the
compound has the structure (Ic):

wherein R2, R5-R7, R, X2 and Q are defined in classes and subclasses herein;
each occurrence of G, J, L and M is independently CHRIV, CR1VRV, 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 Rvi 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;
N and G, G and J, J and L, L and M, M and CR3, and CR3 and N are each
independently linked by a single or double bond as valency permits; and
g, j, l 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.
[0022] 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)5 alicyclic(heteroaryl) or
heteroalicyclic(heteroaryl) moiety; and the compound has the structure (Id):

wherein R1, R2, R5-R7, R5 X2 and Q are defined in classes and subclasses
herein.
[0023] The following structures illustrate several exemplary types of compounds
of class (1a). Additional compounds are described in the Exemplification herein.

[0024] The following structures illustrate several exemplary types of compounds
of class (1b). Additional compounds are described in the Exemplification herein.
[0025] The following structures illustrate several exemplary types of compounds
of class (Ic). Additional compounds are described in the Exemplification herein.
[0026] The following structures illustrate several exemplary types of compounds
of class (Id). Additional compounds are described in the Exemplification herein.
[0027] Other compounds of the invention will be readily apparent to the reader.
[0028] A number of important subclasses of each of the foregoing classes deserve
separate mention; for example, one important subclass of class (1a) includes those
compounds having the structure of formula (1a) in which X2 is C=O; and the
compound has the following structure:
wherein R1-R7, n and Q are defined in classes and subclasses herein;
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(heteroaryI) moiety, or an aryl or heteroaryl moiety; and
X1 is CRaRB, SO2 or C=O; wherein RA and RB are each independently
hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.
[0029] Another important subclass of class (1a) includes those compounds having
the structure of formula (1a) in which X1 is C=O; and the compound has the following
structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;
R8a, R9a and Rl0a are each independently hydrogen, or an alkyl, heteroalkyl,
aryl or heteroaryl moiety; and wherein any two R7, R8a, R9a and R10a groups may form
a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -
heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety; and
X2 is CRARB, SO2 or C=O; wherein RA and RB are each independently
hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.
[0030] Another important subclass of class (1a) includes those compounds having
the structure of formula (1a) 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:

wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and
R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl,
and R4c is aryl or heteroaryl; and
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.
[0031] Another important subclass of class (1a) includes those compounds having
the structure of formula (1a) in which X1 and X2 are each C=O; Q is an optionally
substituted nitrogen-containing cyclic moiety; and the compound has the following
structure:

wherein R1-R7 and n are defined in classes and subclasses herein;
R8a, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl,
aryl or heteroaryl moiety; and wherein any two R7, R8a, R8a and R10a groups may form
a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or -
heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;
each occurrence of A, B, D or E is independently CHR', CR'R", 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, R" or R1" 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;
N and A, A and B, B and D, D and E, and E and N are each independently
linked by a single or double bond as valency permits; and
a, b, d and e are each independently 0,1,2, 3,4, 5, 6 or 7, wherein the sum of
a, b, d and e is 4-7.
[0032] Another important subclass of class (1a) includes those compounds having
the structure of formula (1a) in which X1 and X2 are each C=O; Q is an optionally
substituted nitrogen-containing cyclic moiety; n is 1; R3 is hydrogen; R4 is a moiety
having the structure -CR4aR4bR4c; and the compound has the following structure:
wherein R1, R2, R5-R7 , A, B, D, E, a, b, d and e are defined in classes and
subclasses herein;
R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl,
and R4c is a substituted or unsubstitued aryl or heteroaryl group;
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.
[0033] A number of important subclasses of each of the foregoing subclasses of
class (1a) deserve separate mention; these subclasses include subclasses of the
foregping subclasses of class (1a) in which:
i-a. R1 and R2 are independently hydrogen or substituted or
unsusbtituted, linear or branched, cyclic or acyclic, saturated or
unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;
ii-a. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl,
heteroalkyl, -alkyl(aryl) or acyl;
iii-a. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
iv-a. R1 is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert-
butyl, i-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -
CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3,
CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C CH, cyclohexyl,
cyclopentyl, cyclobutyl or cyclopropyl;
v-a. R1 and R2 are each hydrogen;
vi-a. The carbon atom bearing R3 and R4 is of S configuration;
vii-a. R3 is hydrogen and R4 is substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl,
heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or
heteroaryl;
viii-a. R3 is hydrogen and R4 is -CR4aR4bR4c; wherein R4a and R4b are
independently hydrogen, or a substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl moiety
and R4c is substituted or unsubstituted aryl or heteroaryl;
ix-a. R3 is hydrogen and R4 is -CR4aR4bPh; wherein R4a and R4b are
independently hydrogen, or a substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl
moiety;
x-a. R4 is a substituted or unsubstituted 3-indole moiety;
xi-a. R3 is hydrogen;
xii-a. R1 and R4, taken together, form a substituted or unsubstituted
pyrrolidine group;
xiii-a. R1 and R4, taken together, form a substituted or unsubstituted
piperidine group;
xiv-a. R1 and R4, taken together, form a substituted or unsubstituted
thiazolidine group;
xv-a. R1 and R4, taken together, form a substituted or unsubstituted
morpholine group;
xvi-a. R1 and R4, taken together, form a substituted or unsubstituted
thiomorpholine group;
xvii-a. R1 and R4, taken together, form a substituted or unsubstituted
indole group;
xviii-a. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or
heteroaryl;
xix-a. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
allcyl, -alkyl(aryl) or substituted or unsubstituted aryl;
xx-a. R3 and R4 are each independently substituted or unsubstituted
lower alkyl, aryl or heteroaryl;
xxi-a. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3,
-CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -
CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, phenyl, -C1-6alkylORa, -C1-6alkylSR8 or -CRaRbRc;
wherein Ra and Rb are independently hydrogen, substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or
heteroaryl;
xxii-a. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, tert-butyl, /-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3,
-CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -
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;
xxiii-a. R3 and R4 are each ethyl;
xxiv-a. R3 is phenyl and R4 is lower alkyl;
xxv-a. R3 is phenyl and R4 is ethyl;
xxvi-a. R3 and R4, taken together, form a substituted or unsubstituted
cycloalkyl group;
xxvii-a. R3 and R4, taken together, form a cyclohexyl group;
xxviii-a. R3 and R4, taken together, form a substituted or unsubstituted
cycloalkyl(aryl) group;
xxix-a. R5 is hydrogen;
xxx-a. R6 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, saturated or unsaturated lower alkyl;
xxxi-a. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -
CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl,
cyclobutyl or cyclopropyl;
xxxii-a. R6 is tert-butyl;
xxxiii-a. The R6 hearing carbon atom is of S configuration;
xxxiv-a. R7 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, saturated or unsaturated lower alkyl;
xxxv-a. R7 is methyl;
xxxvi-a. R is -CH(R8a)C(R9a)=C(R10a)-; and
a) R8a is substituted or unsubstituted, linear or branched, cyclic or
acyclic, saturated or unsaturated lower alkyl;
b) R8a is iso-propyl;
c) The R8a-bearing carbon atom is of S configuration;
d) R8a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower
alkyl;
e) R9a is hydrogen;
f) R10a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower
alkyl;
g) R10a is methyl;
xxxvii-a. n is 1;
xxxviii-a. X1 is C=O;
xxxix-a. X1 is CH2;
xl-a. X1 is SO2;
xli-a. X2 is C=O;
xlii-a. X2 is CH2;
xliii-a. X2 is SO2;
xliv-a. Q is 0RQ', SRQ', NRQ'RQ", N3, =N-OH, or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0,1 or 2; s and t are independently an integer
from 0-8; X is O, S, or NRK; each occurrence of RQ1 and RQ2 is independently
hydrogen, halogen, -CN, -S(O)hR3, -N02, -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 ahphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and wherein each
occurrence of RL and RM is independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and RQ' and RQ" are
independently hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted aryl or
heteroaryl moiety; or RQ' and RQ" , taken together with the nitrogen atom to which
they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl
moiety; and
xlv-a. Q is ORQ', SRQ', NRQ'RQ", N3, =N-OH, or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0,1 or 2; s and t are independently
an integer from 0-8; each occurrence of RQ1 and RQ2 is independently
hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ1 and RQ2, taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted heterocyclic moiety, and RQ' and RQ' are independently
hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ and RQ , taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or
xliv-a. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from the
group consisting of:

wherein each occurrence of r is 0, 1 or 2; and RQ and RQ are
independently hydrogen, or a substituted or unsubstituted, linear or branched,
cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ and RQ , taken together with the nitrogen
atom to which they are attached, form a substituted or unsubstituted
heterocyclic, aryl or heteroaryl moiety.
[0034] An important subclass of class (1b) includes those compounds having the
structure of formula (1b) in which R is -C(R8b)C(R9b)N(R10b)C(R11b)-; and the
compound has the following structure:

wherein R1-R7, n, X1 and Q are defined in classes and subclasses herein;
R8b, R9b, R10b and R11b are each independently absent, hydrogen, -(C=O)RL or
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety,
wherein each occurrence of RL is independently hydrogen, OH, ORM, or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any
two R8b, R9b, R10b and R11b groups, taken together, form a alicyclic or heteroalicyclic
moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and
NR7 and CR8b, CR8b and CR9b, CR8b and NR10b, NR10b and CR11b are each
independently linked by a single or double bond as valency permits.
[00351 Another important subclass of class (1b) includes those compounds having
the structure of formula (lb) in which X, 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:

wherein R1-R2, R5-R7 and Q are defined in classes and subclasses herein; and
R4a and R4b are each independently hydrogen or lower alkyl and R4C is aryl or
heteroaryl;
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 R8b, R10b and R11b groups, taken together, form a alicyclic or heteroalicyclic
moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and
NR7 and CR8b, CR8b and CR9b, CR9b and NR10b, NR10b and CR11b are each
independently linked by a single or double bond as valency permits.
[0036] Another important subclass of class (lb) includes those compounds having
the structure of formula (lb) in which R is-C(R8b)C(R9b)N(R10b)C(R11b)-; R10b and
R11b, taken together, form a substituted or unsubstituted cyclib heteroalkyl or
heteroaryl moiety; and the compound has the following structure:

wherein R1-R7, n and Q are defined in classes and subclasses herein;
p is 1,2, 3 or 4;
q is 0-12;
each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken
together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R^ are each independently absent, hydrogen, -(C=O)Rl or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein
each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein 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 CR8, and CR8b and CR9b are each independently linked by a single or
double bond as valency permits.
[0037] Another important subclass of class (lb) includes those compounds having
the structure of formula (lb) in which n is 1; R is-C(R8b)C(R9b)N(R10b)C(Riib)-; R10b
and R11b, taken together, form a substituted or unsubstituted cyclic heteroalkyl or
heteroaryl moiety; R4 is a moiety having the structure -CR4aR4bR4c; and the
compound has the following structure:

wherein R1-R7, X1 and Q are defined in classes and subclasses herein;
p is 1,2, 3 or 4;
is O, 1,2,3,4, 5 or 6;
each occurrence of Si is independently an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent Si moieties, taken
together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R4a and R4b are each independently hydrogen or lower alkyl or heteroalkyl;
and R4cis aryl or heteroaryl;
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..
[0038] Another important subclass of class (1b) includes those compounds having
the structure of formula (1b) in which R is -C(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)-;
and the compound has the following structure:

wherein R1-R7, n, X1 and Q are defined in classes and subclasses herein;
R8c, R9c, R10c, R11c and R12c are each independently absent, hydrogen, -
(C=O)RL or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl
moiety, wherein each occurrence of RL is independently hydrogen, OH, ORM, or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or
wherein any two R8c, R9c, R10c, R11c and R12c groups, taken together, form a alicyclic
or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein RM is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR8c, CR8c and CR9b, CR9c and CR10c, and CR10c and CR11c are each
independently linked by a single or double bond as valency permits.
[0039] Another important subclass of class (lb) includes those compounds having
the structure of formula (lb) 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:
wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
R4a and R4b are each independently hydrogen, or lower alkyl or heteroalkyl;
and R4c is aryl or heteroaryl;
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, heteroalicychc, aryl or heteroaryl moiety, or
wherein any two R8c, R9b, R10c, R11c and R12c groups, taken together, form a alicyclic
or heteroalicychc moiety, or an aryl or heteroaryl moiety; wherein RM is an aliphatic,
alicyclic, heteroaliphatic, heteroalicychc, aryl or heteroaryl moiety; and
NR7 and CR8c, CRc; and CR9c, CR9c and CR10c, and CR10c and CR11c are each
independently linked by a single or double bond as valency permits.
[0040] A number of important subclasses of each of the foregoing subclasses of
class (1b) deserve separate mention; these subclasses include subclasses of the
foregoing subclasses of class (1b) in which:
i-b. R1 and R2 are independently hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;
ii-b. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl,
heteroalkyl, -alkyl(aryl) or acyl;
iii-b. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
iv-b. R1 is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, 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;
v-b. R1 and R2 are each hydrogen;
vi-b. The carbon atom bearing R3 and R4 is of S configuration;
vii-b. R3 is hydrogen and R4 is substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl,
heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or
heteroaryl;
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 R4c is substituted or unsubstituted aryl or heteroaryl;
ix-b. R3 is hydrogen and R4 is -CR4aR4bPh; wherein R4a and R4b are
independently hydrogen, or a substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl
moiety;
x-b. R4 is a substituted or unsubstituted 3-indole moiety;
xi-b. R3 is hydrogen;
xii-b. R1 and R4, taken together, form a substituted or unsubstituted
pyrrolidine group;
xiii-b. R1 and R4, taken together, form a substituted or unsubstituted
piperidine group;
xiv-b. R1 and R4, taken together, form a substituted or unsubstituted
thiazolidine group;
xv-b. R1 and R4, taken together, form a substituted or unsubstituted
morpholine group;
xvi-b. R1 and R4, taken together, form a substituted or unsubstituted
thiomorpholine group;
xvii-b. R1 and R4, taken together, form a substituted or unsubstituted
indole group;
xviii-b. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or
heteroaryl;
xix-b. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;
xx-b. R3 and R4 are each independently substituted or unsubstituted
lower alkyl, aryl or heteroaryl;
xxi-b. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, 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, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, phenyl, -C1-6alkylORa, -C1-6alkylSR8 or -CRaRbRc;
wherein Ra and Rb are independently hydrogen, substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or
heteroaryl;
xxii-b. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, 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, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, phenyl, -C1-6alkylORa, -C1-6alkylSR8 or -CRbRcPh;
wherein Ra is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and
Rb And Rc are each independently substituted or unsubstituted linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xxiii-b. R3 and R4 are each ethyl;
xxiv-b. R3 is phenyl and R4 is lower alkyl;
xxv-b. R3 is phenyl and R4 is ethyl;
xxvi-b. R3 and R4, taken together, form a substituted or unsubstituted
cycloalkyl group;
xxvii-b. R3 and R4, taken together, form a cyclohexyl group;
xxviii-b. R3 and R4, taken together, form a substituted or unsubstituted
cycloallcyl(aryl) group;
xxix-b. R5 is hydrogen;
xxx-b. R6 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xxxi-b. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -
CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl,
cyclobutyl or cyclopropyl;
xxxii-b. R6,, is tert-butyl;
xxxiii-b. The R6-bearing carbon atom is of S configuration;
xxxiv-b. R7 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xxxv-b. R7 is methyl;
xxxvi-b. R is -C(R8b)C(R9b)N(R10b)CR11b- and
a) R8b is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
b) R8b is iso-propyl;
c) The R8b-bearing carbon atom is of S configuration;
d) R9b, is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;
e) R10b is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or acyl;
f) R10b is hydrogen, methyl or acetyl;
g) R10b and R11b, taken together, form a substituted or
unsubstituted pyrrolidine ring; or
h) R9b, and R11b, taken together, form a substituted or
unsubstituted thiazole ring;
xxxvii-b. R is -C(R8c)C(R9c)C(R10c)CR11cOCR12c- and
a) R8c is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
b) R8c is iso-propyl;
c) The R8c-bearing carbon atom is of S configuration;
d) R9c and R10c are each independently hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated
or unsaturated lower alkyl;
e) CR9c and CR10c are linked via a double bond;
f) CR9c and CR10c are linked via a double bond and R9c is
hydrogen; or
g) CR9c and CR10c are linked via a double bond and R10c is methyl;
xxxviii-b. n is 1;
xxxix-b. X1 is C=O;
xl-b. X1 is CH2;
xli-b. X1 is SO2;
xlii-b. Q is ORQ', SRQ', NRQRQ", N3, =N-OH,or a moiety selected from
the group consisting of:
wherein each occurrence of r is 0, 1 or 2; s and t are independently
an integer from 0-8; X is O, S, or NRK; each occurrence of RQ1 and
RQ2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -COR1,
-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;
xliii-b. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from
the group consisting of:
wherein each occurrence of r is 0, 1 or 2; s and t are independently
an integer from 0-8; each occurrence of RQ1 and RQ2 is independently
hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ1 and RQ2, taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted heterocyclic moiety; and RQ and RQ are independently
hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ and RQ , taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or
xliv-b. Q is ORQ', SRQ', NRQRQ", N3, =N-OH,or a moiety selected from
the group consisting of:
wherein each occurrence of r is 0, 1 or 2; and RQ and RQ are
independently hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety; or RQ and RQ , taken
together with the nitrogen atom to which they are attached, form a
substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.
[0041] An important subclass of class (Ic) includes those compounds having the
structure of formula (Ic) in which X2 is C=O; R is -CH(R8a)C(R9a)=C(R10a)-; j is 0; 1
and m are each 1; R3 is hydrogen; G is CRgi; M is CRM1RM2, and the compound has
the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
gisl,2,3or4;
R9a, 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;
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;
each occurrence of Rgi, Rmi and Rm2 is each independently hydrogen or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
wherein any two adjacent RL1, RL2, RL3, Rgl Rmi or RM2 groups, taken
together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety
containing 3-6 atoms or an aryl or heteroaryl moiety.
[0042] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m
are each 1; R is -CH(R8a)C(R9a)=C(R10a)-; R3 is hydrogen; and the compound has the
structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
g is 0,1,2 or 3;
R8a, R9a and R10a are each independently hydrogen, or an alkyl, heteroalkyl,
aryl or heteroaryl moiety; and wherein any two R7, R9a, 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;
RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0043] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; R is -C(R8b)C(R9b)N(R10b)C(R11b)-;
j is 0; 1 and m are each 1; R3 is hydrogen; G is CHRgu M is CRM1RM2, and the
compound has the structure:
wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
gisl,2or3;
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;
each occurrence of RG1, RM1 and RM2 is independently hydrogen or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
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;
R8b, R9b, R10b and R11b, are each independently absent, hydrogen, -(C=O)Rl or
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety,
wherein each occurrence of RL is independently hydrogen, OH, ORm, or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any
two adjacent R8b R9b, R10b and R11b groups, taken together, form a alicyclic or
heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein RM is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and
NR7 and CR8b, CR8b and CR9b, CR8b and NR10b, NR10b and CR11b are each
independently linked by a single or double bond as valency permits.
[0044] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is CO; 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; R10b and R11b,
taken together, form a cyclic heteroalkyl group; and the compound has the structure:
wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
pis 1,2,3 or 4;
q is 0-12;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken
together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R9b, are each independently absent, hydrogen, -(C=O)Rl or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein
each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein R8b and R9b,,
taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl
moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or
heteroaryl moiety; and
NR7 and CR8b, and CR8b and CR8b are each independently linked by a single
or double bond as valency permits.
[0045] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m
are each 1; R is -C(R8b)C(R9b)N(R10b)C(R11b)-; R3 is hydrogen; and the compound has
the structure:
wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
g is 0,1,2 or 3;
RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
R8b, R9b, R10b and R11b are each independently absent, hydrogen, -(C=O)RL or
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety,
wherein each occurrence of RL is independently hydrogen, OH, ORM, or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any

two adjacent R8b, R8b R10b and R11b groups, taken together, form a alicyclic or
heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein RM is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR8b, CR8b and CR9b, CR8b and NR10b, NR10b and CR11b are each
independently linked by a single or double bond as valency permits.
[0046] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; G, J and M are each CH2; j, 1 and m
are each 1; R is -C(R8b)C(R9b)N(R10b)C(R11b)-; R3 is hydrogen; R10b and R11b, taken
together, form a cyclic heteroalkyl group; and the compound has the structure:

wherein R2, R5-R7 and Q are defined in classes and subclasses herein;
p is 1,2,3 or 4;
q is 0-12;
g is 0,1,2 or 3;
RL1 and RL2 are independently hydrogen or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken
together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R9b, are each independently hydrogen, -(C=O)Rl or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each
occurrence of RL is independently hydrogen, OH, ORM, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein R8b and R9b,
taken together, form a alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl
moiety; wherein Rm is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or
heteroaryl moiety, and
NR7 and CR8b, and CR8b, and CR9b are each independently linked by a single
or double bond as valency permits.
[0047] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; R is -
C(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)-; j is 0; 1 and m are each 1; R3 is hydrogen; G is
CHRG1, M is CRM1RM2; and the compound has the following structure:

wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
g is 1,2 or 3;
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;
each occurrence of RG1, RM1 and RM2 is independently hydrogen or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
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,
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 R9c, R9c, R10c. R11c and R12c groups, taken together, form a alicyclic
or heteroalicyclic moiety, or an aryl or heteroaryl moiety, wherein Rm is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR9c, CR9c and CR9c, CR9c and CR10c, and CR10c and CR11c are each
independently linked by a single or double bond as valency permits.
[0048] Another important subclass of class (Ic) includes those compounds having
the structure of formula (Ic) in which X2 is C=O; R is -
C(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)-; G, J and M are each CH2; j, 1 and m are each 1;
R3 is hydrogen; and the compound has the following structure:

wherein R1, R2, R5-R7 and Q are defined in classes and subclasses herein;
g is 0, 1,2 or 3;
RL1 and RL2, are independently hydrogen or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
R9c, R9c, R10c, R11c and R12C are each independently absent, hydrogen, -
(C=O)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl
moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or
wherein any two R8c, R9c, R10c, R11c and R12c groups, taken together, form a alicyclic
or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR9c, CR8c and CR9c, CR9c and CR10c, and CR10c and CR11c are each
independently linked by a single or double bond as valency permits.
[0049] A number of important subclasses of each of the foregoing subclasses of
class (Ic) deserve separate mention; these subclasses include subclasses of the
foregoing subclasses of class (Ic) in which:
i-c. R2 is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl,
heteroalkyl, -alkyl(aryl) or acyl moiety;
ii-c. R2 is substituted or unsusbtituted, linear or branched, cyclic or
acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl)
or acyl;
iii-c. R2 is substituted or unsusbtituted, linear or branched, cyclic or
acyclic, saturated or unsaturated lower alkyl;
iv-c. R2 is methyl, ethyl, propyl, butyl, pentyl, 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;
v-c. R2 is hydrogen;
vi-c. R2 is hydrogen, methyl or benzyl;
vii-c. R2 is methyl;
viii-c. R2 is acyl, wherein the acyl group is a nitrogen proteting group;
ix-c. R3 is hydrogen;
x-c. R1 and R4, taken together, form a substituted or unsubstituted
pyrrolidine group;
xi-c. R1 and R4, taken together, form a substituted or unsubstituted
piperidine group;
xii-c. R1 and R4, taken together, form a substituted or unsubstituted
thiazolidine group;
xiii-c. R1 and R4, taken together, form a substituted or unsubstituted
morpholine group;
xiv-c. R1 and R4, taken together, form a substituted or unsubstituted
thiomorpholine group;
xv-c. R1 and R4, taken together, form a substituted or unsubstituted
indole group;
xvi-c. R5 is hydrogen;
xvii-c. Rg is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xviii-c. R6 is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, -
CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl,
cyclobutyl or cyclopropyl;
xix-c. R6 is tert-butyl;
xx-c. The R6hearing carbon atom is of S configuration;
xxi-c. R7 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xxii-c. R7 is methyl;
xxiii-c. R is -CH(R8a)C(R9a)=C(R10a)-; and
a) R9a is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
b) R9a is iso-propyl;
c) The R9a-bearing carbon atom is of S configuration;
d) R9a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;
e) R9a is hydrogen;
f) R10a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl; or
g) R10a is methyl;
xxiv-c. R is -C(R8b)C(R9b)N(R10b)CR11b- and
a) R8b is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
b) R8b is iso-propyl;
c) The R8b-bearing carbon atom is of S configuration;
d) R9b is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;
e) R10b is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or acyl moiety;
f) R10b is hydrogen, methyl or acetyl;
g) R10b and R11b, taken together, form a substituted or
unsubstituted pyrrolidine ring; or
h) R8b and R11b, taken together, form a substituted or unsubstituted
thiazole ring;
xxxv-d. R is -C(R8C)C(R9c)C(R10c)CR11cOCR12c- and
a) R9c is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
b) R8c is iso-propyl;
c) The R9c-bearing carbon atom is of S configuration;
d) R9c and R10c are each independently hydrogen of substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated
or unsaturated lower alkyl;
e) CR9c and CR10c are linked via a double bond;
f) CR9c and CR10c are linked via a double bond and R9c is
hydrogen; or
g) CR9c and CR10c are linked via a double bond and R10c is methyl;
xxv-c. -C(R3)(R4)N(R1)(R2) together represent the moiety having the
structure:

a) R2 is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety;
b) R2 is methyl, ethyl or propyl;
c) Rgi is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or substituted or unsubstituted phenyl;
d) RG1 is hydrogen, methyl or phenyl;
e) RG1 and the substituents on L, taken together, form a
substituted or unsubstituted phenyl group;
f) 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 Rmi and the substitutents on L, taken together, form a
substituted or unsubstituted aryl or heteroaryl moiety;
g) g is 1 or 2; or
h) L is CH2, S or O;
xxvi-c. -C(R3)(R4)N(Ri)(R2) together represent the moiety having the
structure:

a) R2 is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety;
b) R2 is methyl;
c) 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;
d) RL1 and RL2 are each hydrogen;
e) RL1 and RL2, are each substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl; or
f) g is for 2;
xxvii-c. X2 is C=O;
xxviii-c. X2 is CH2;
xxix-c. X2 is SO2;
xxx-c. Q is 0RQ', SRQ', NRQRQ", N3, =N-OH,or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0, 1 or 2; s and t are independently
an integer from 0-8; X is O, S, or NRK; each occurrence of RQ1 and
RQ2 is independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2, -CORJ,
-CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ, -CO(NORJ)RJ, aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or
-ZiRJ; wherein h is 1 or 2; and Z\ is independently -O-, -S-, NRK, -
C(O)-, wherein each occurrence of RJ and RK is independently
hydrogen, CORL, COORL, CONRLRM, -NRLRM, -S(O)2RL, or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl
moiety, and wherein each occurrence of RL and RM is independently
hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,
aryl or heteroaryl moiety; and RQ and RQ are independently
hydrogen, or a substituted or unsubstituted, linear or branched, cyclic
or acyclic alkyl or heteroalkyl moiety, or a substituted or unsubstituted
aryl or heteroaryl moiety; or RQ and RQ, taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted heterocyclic, aryl or heteroaryl moiety;
xxxi-c. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from
the group consisting of:

wherein each occurrence of r is G, 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
xxxii-c. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0,1 or 2; 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.
[0050] 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)s X2 is C=O; and the
compound has the following structure:

wherein R3 and R4 are each independently an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together,
form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),
alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, R1, R2, R5-R7 and Q are
defined in classes and subclasses herein; and
R9a, 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.
[0051] Another important subclass of class (Id) includes those compounds having
the structure of formula (Id) in which R is -C(R8b)C(R9b)N(R10b)C(R11b)-; X2 is CO;
and the compound has the following structure:

wherein R3 and R4 are each independently an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together,
form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),
alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; R1, R2, R5-R7 and Q are
defined in classes and subclasses herein;
R8b R9b, R10b and R11b are each independently absent, hydrogen, -(C=O)Rl or
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety,
wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or wherein any
two R8b, R9b, R10b and R11b groups, taken together, form a alicyclic or heteroalicyclic
moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR8b, CRsb and CR9b, CR8b and NR10b, NR10b and CR11b are
independently linked by a single or double bond as valency permits.
[0052] Another important subclass of class (Id) includes those compounds having
the structure of formula (Id) in which R is -C(R8b)C(R9b)N(R10b)C(R11b)-; X2 is C=O;
R10b and R11b, taken together, form a cyclic heteroalkyl group; and the compound has
the following structure:

wherein R3 and R4 are each independently an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together,
form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),
alicyclic(heteroaryl) or heteroahcyclic(heteroaryl) moiety; R1, R2, R5-R7 and Q are
defined in classes and subclasses herein;
p is 1,2, 3 or 4;
q is 0-12;
each occurrence of S1 is independently an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety, or any two adjacent S1 moieties, taken
together, may form an an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;
R8b and R9b are each independently 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 CR8, and CR8b and CR9b, are independently linked by a single or
double bond as valency permits.
[0053] Another important subclass of class (Id) includes those compounds having
the structure of formula (Id) in which X2 is C=O; R is -
C(R8c)C(R9c)C(R10c)C(R11c)OC(R12c)s and the compound has the following structure:

wherein R3 and R4 are each independently an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, when taken together,
form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),
alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety; R1, R2, R5-R7 and Q are
defined in classes and subclasses herein;
R8c, R9c, R10c, R11c and R12c are each independently absent, hydrogen, -
(C '0)Rl or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl
moiety, wherein each occurrence of Rl is independently hydrogen, OH, ORm, or an
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or
wherein any two R9c, R9c, R10c, R11c and R12c groups, taken together, form a alicyclic
or heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein Rm is an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
NR7 and CR9c, CR9c and CR9c, CR9c and CR10c, and CR10c and CR11c are each
independently linked by a single or double bond as valency permits.
[0054] A number of important subclasses of each of the foregoing subclasses of
class (Id) deserve separate mention; these subclasses include subclasses of the
foregoing subclasses of class (Id) in which:
i-d. R1 and R2 are independently hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;
ii-d. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl,
heteroalkyl, -alkyl(aryl) or acyl;
iii-d. R1 is hydrogen and R2 is substituted or unsusbtituted, linear or
branched, cyclic or acyclic, saturated or unsaturated lower alkyl;
iv-d. R1 is hydrogen and R2 is methyl, ethyl, propyl, butyl, pentyl, tert-
butyl, 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;
v-d. R1 and R2 are each hydrogen;
vi-d. R1 and R2 are independently hydrogen or methyl;
vii-d. R1 and R2 are each methyl;
viii-d. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted aryl or
heteroaryl;
ix-d. R3 and R4 are each independently substituted or unsubstituted,
linear or branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;
x-d. R3 and R4 are each independently substituted or unsubstituted
lower alkyl, aryl or heteroaryl;
xi-d. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, tert-butyl, i-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3,
-CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -
CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, phenyl, -Ci^alkylOR8, -C^alkylSR3 or -CRaRbRc;
wherein Ra and Rb are independently hydrogen, substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated or
unsaturated lower alkyl and Rc is substituted or unsubstituted aryl or
heteroaryl;
xii-d. R3 and R4 are each independently methyl, ethyl, propyl, butyl,
pentyl, terf-butyi, /-propyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3,
-CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -
CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, phenyl, -Ci.6alkylOR\ -Ci.6alkylSRa or -CR^Ph;
wherein Ra is hydrogen, substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and
Rb And Rc are each independently substituted or unsubstituted linear or
branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;
xiii-d. R3 and R4 are each ethyl;
xiv-d. R3 is phenyl and R4 is lower alkyl;
xv-d. R3 is phenyl and R4 is ethyl;
xvi-d. R3 and R4, taken together, form a substituted or unsubstituted
cycloalkyl group;
xvii-d. R3 and R4, taken together, form a cyclohexyl group;
xviii-d. R3 and R4, taken together, form a substituted or unsubstituted
cycloalkyl(aryl) group;
xix-d. R5 is hydrogen;
xx-d. R6 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xxi-d. R6 is methyl, ethyl, propyl, butyl, pentyl, terf-butyl, i-propyl, -
CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl,
cyclobutyl or cyclopropyl;
xxii-d. R6 is tert-butyl;
xxiii-d. The Re-bearing carbon atom is of S configuration;
xxiv-d. R7 is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
xxv-d. R7 is methyl;
xxvi-d. R is -CH(R8a)C(R9a)=C(R10a)-; and
i) R9a is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
j) R9a is iso-propyl;
k) The R9a-bearing carbon atom is of S configuration;
1) R9a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;
m) R9a is hydrogen;
n) R10a is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl; or
o) R10a is methyl;
xxvii-d. R is -C(R8b)C(R9b)N(R10b)CR11b- and
p) R8b is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
q) R8b is wo-propyl;
r) The R8b-bearing carbon atom is of S configuration;
s) R9b, is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl;
t) R10b is hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic, or saturated or unsaturated lower
alkyl or acyl moiety;
u) R10b is hydrogen, methyl or acetyl;
v) R10b and R11b, taken together, form a substituted or
unsubstituted pyrrolidine ring; or
w) R9b, and R11b, taken together, form a substituted or
unsubstituted thiazole ring;
xxviii-d. R is -C(R8C)C(R9c)C(R10c)CR11cOCR12c- and
h) R8c is substituted or unsubstituted, linear or branched, cyclic or
acyclic, or saturated or unsaturated lower alkyl;
i) R9c is iso-propyl;
j) The R8C-bearing carbon atom is of S configuration;
k) R9c and R10c are each independently hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic, or saturated
or unsaturated lower alkyl;
1) CR9c and CR10c are linked via a double bond;
m) CR9C and CR10c are linked via a double bond and R9c is
hydrogen; or
n) CR9c and CR10c are linked via a double bond and R10c is methyl;
xxix-d. X2 is C=O;
xxx-d. X2 is CH2;
xxxi-d. X2 is SO2;
xxxii-d. Q is 0RQ', SRQ', NRQRQ", N3, =N-OH,or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0, 1 or 2; s and t are independently
an integer from 0-8; X is O, S, or NRK; each occurrence of RQI and
RQ2 is independently hydrogen, halogen, -CN, -S(O)hR;, -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;
xxxiii-d. Q is 0RQ', SRQ', NRQRQ", N3, =N-OH, or a moiety selected from
the group consisting of:

wherein each occurrence of r is 0,1 or 2; s and t are independently
an integer from 0-8; 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
xxxiv-d. Q is ORQ', SRQ', NRQRQ", N3, =N-OH, =N-OH, or a moiety
selected from the group consisting of:

wherein each occurrence of r is 0, 1 or 2; and RQ and RQ are
independently hydrogen, or a substituted or unsubstituted, linear or
branched, cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted
or unsubstituted aryl or heteroaryl moiety; or RQ and RQ, taken
together with the nitrogen atom to which they are attached, form a
substituted or unsubstituted heterocyclic, aryl or heteroaryl moiety.
[0055] As the reader will appreciate, compounds of particular interest include,
among others, those which share the attributes of one or more of the foregoing
subclasses. Some of those subclasses are illustrated by the following sorts of
compounds:
[0056] I) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof);
wherein R1-R2, 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.
[0057] II) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):

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.
[0058] 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.
[0059] III) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):

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

wherein A, B, D, E, a, b, d, e, Ri-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.
[0061] v) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof);

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.
[0062] It will also be appreciated that for each of the subgroups III-V described
above, a variety of other subclasses are of special interest, including, but not limited
to those classes i-b. through xlii-b. described above and classes, subclasses and
species of compounds described above and in the examples herein.
[0063] VI) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof).'
wherein L, R9a-R10a, Rgi, Rmi and Rm2 are as defined above and in subclasses
herein; g is 1 or 2; Q is ORQ, wherein RQ is hydrogen or lower alkyl; and R2 and R6
are independently substituted or unsubstituted linear or branched lower alkyl.
[0064] VII) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):
wherein g, R9a-R10a, Rli 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.
[0065] VII) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):

wherein A, B, D, E, L, a, b, d, e, p, R9b, Rgi, Rmi 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.
[0066] IX) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):

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.
[0067] It will also be appreciated that for each of the subgroups VI-IX described
above, a variety of other subclasses are of special interest, including, but not limited
to those classes i-c. through xxxii-c. described above and classes, subclasses and
species of compounds described above and in the examples herein. In certain
embodiments, for compounds of subgroups VI-IX above, R2 is methyl, wopropyl,
.sec-butyl or -CH(CH3)CH(CH3)2. In certain embodiments, for compounds of
subgroups VI-IX above, R6 is tert-butyl or iso-piopyl. 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 iyopropyl. 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-provyl 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 R5 is tert-butyl.
[0068] X) Compounds of the formula (and pharmaceutically acceptable
derivatives thereof):
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.
[0069] It will also be appreciated that for subgroup X described above, a variety
of other subclasses are of special interest, including, but not limited to those classes i-
d. through xxxii-d. described above and classes, subclasses and species of compounds
described above and in the examples herein.
[0070] Some of the foregoing compounds can comprise one or more asymmetric
centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or
diastereomers. It is to be understood that the invention encompasses every possible
isomer such as geometric isomer, optical isomer, stereoisomer and tautomer based on
asymmetric carbon, which can occur in the structures of the inventive compounds,
and mixtures of such isomers, and is not limited to the specific stereochemistry shown
for the compounds disclosed in the present specification. It will be further appreciated
that the absolute stereochemistry of some of the compounds recited in the
Exemplification herein has not been determined, and that when a stereochemistry was
assigned for those compounds it is meant to be tentative and to indicate that a set of
diastereomers exists for those compounds and/ot that a diastereomer was isolated in
pure form. Thus, inventive compounds and pharmaceutical compositions thereof may
be in the form of an individual enantiomer, diastereomer or geometric isomer, or may
be in the form of a mixture of stereoisomers. In certain embodiments, the compounds
of the invention are enantiopure compounds. In certain other embodiments, mixtures
of stereoisomers or diastereomers are provided.
[0071] Furthermore, certain compounds, as described herein may have one or
more double bonds that can exist as either the Z or E isomer, unless otherwise
indicated. The invention additionally encompasses the compounds as individual
isomers substantially free of other isomers and alternatively, as mixtures of various
isomers, e.g., racemic mixtures of stereoisomers. The invention also encompasses
tautomers of specific compounds as described above. In addition to the above-
mentioned compounds per se, this invention also encompasses pharmaceutically
acceptable derivatives of these compounds and compositions comprising one or more
compounds of the invention and one or more pharmaceutically acceptable excipients
or additives.
[0072] Compounds of the invention may be prepared by crystallization of
compound of formula (I) under different conditions and may exist as one or a
combination of polymorphs of compound of general formula (I) forming part of this
invention. For example, different polymorphs may be identified and/or prepared using
different solvents, or different mixtures of solvents for recrystallization; by
performing crystallizations at different temperatures; or by using various modes of
cooling, ranging from very fast to very slow cooling during crystallizations.
Polymorphs may also be obtained by heating or melting the compound followed by
gradual or fast cooling. The presence of polymorphs may be determined by solid
probe NMR spectroscopy, 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.
[0073] 2) Compounds and Definitions
[0074] As discussed above, this invention provides novel compounds with a range
of biological properties. Compounds of this invention have biological activities
relevant for the treatment of diseases or other disorders such as proliferative diseases,
including, but not limited to cancer. In certain other embodiments, the inventive
compounds also find use in the prevention of restenosis of blood vessels subject to
traumas such as angioplasty and stenting.
[0075] Compounds of this invention include those specifically set forth above and
described herein, and are illustrated in part by the various classes, subgenera and
species disclosed elsewhere herein.
[0076] Additionally, the present invention provides pharmaceutically acceptable
derivatives of the inventive compounds, and methods of treating a subject using these
compounds, pharmaceutical compositions thereof, or either of these in 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.
[0077] Numerous suitable prodrug moieties, and information concerning their
selection, synthesis and use are well known in the art. Examples of prodrug moieties
of interest include, among others, prodrug moieties that can be attached to primary or
secondary amine-containing functionalities. Examples of such prodrug moieties
include the following:
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.
[0078] 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., 0, 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.
[0079] 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.
[0080] The term "aliphatic", as used herein, includes both saturated and
unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons,
which are optionally substituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to
include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein,
the term "alkyl" includes straight and branched alkyl groups. An analogous
convention applies to other generic terms such as "alkenyl", "alkynyl" and the like.
Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like
encompass both substituted and unsubstituted groups. In certain embodiments, as
used herein, "lower alkyl" is used to indicate those alkyl groups (cyclic, acyclic,
substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
[0081] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in
the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the
alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups
employed in the invention contain 1-8 aliphatic carbon atoms. In still other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention
contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative
aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-
propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl,
isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear
one or more substituents. Alkenyl groups include, but are not limited to, for example,
ethenyl, propenyl, butenyl, l-methyl-2-buten-1-yl, and the like. Representative
alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-
propynyl and the like.
[0082] The term "alicyclic", as used herein, refers to compounds which combine
the properties of aliphatic and cyclic compounds and include but are not limited to
cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds,
which are optionally substituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to
include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties,
which are optionally substituted with one or more functional groups. Illustrative
alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH2-
cyclopropyl, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2-cyclopentyl-n,
cyclohexyl, -CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl
moieties and the like, which again, may bear one or more substituents.
[0083] The term "alkoxy" (or "alkyloxy"), or "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-butyltbio, and the
like.
[0084] The term "alkylamino" refers to a group having the structure -
NHR' wherein R' is alkyl, as defined herein. The term "aminoalkyl" refers to a group
having the structure NH2R'-, wherein R' is alkyl, as defined herein. In certain
embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other
embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention
contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group
contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group
contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not
limited to, methylamino, ethylamino, iso-propylamino and the like.
[0085] Some examples of sutstituents of the above-described aliphatic (and other)
moieties of compounds of the invention include, but are not limited to aliphatic;
alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl;
alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; CI; 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.
[0086] In general, the terms "aryl" and "heteroaryl", as used herein, refer to stable
mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated
moieties having preferably 3-14 carbon atoms, each of which may be substituted or
unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined
herein may be attached via an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,
alkyl or heteroalkyl moiety and thus also include -(aliphatic)aryl, -
(heteroaliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -(alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl moieties. Thus, as
used herein, the phrases "aryl or heteroaryl" and "aryl, heteroaryl, -(aliphatic)aryl, -
(heteroaliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -(alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryr' are
interchangeable. Substituents include, but are not limited to, any of the previously
mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for
other moieties as disclosed herein, resulting in the formation of a stable compound. In
certain embodiments of the present invention, "aryl" refers to a mono- or bicyclic
carbocyclic ring system having one or two aromatic rings including, but not limited
to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain
embodiements of the present invention, the term "heteroaryl", as used herein, refers to
a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is
selected from S, O and N; zero, one or two ring atoms are additional heteroatoms
independently selected from S, O and N; and the remaining ring atoms are carbon, the
radical being joined to the rest of the molecule via any of the ring atoms, such as, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,
isoquinolinyl, and the like.
[0087] It will be appreciated that aryl and heteroaryl groups (including bycyclic
aryl groups) can be unsubstituted or substituted, wherein substitution includes
replacement of one, two or three of the hydrogen atoms thereon independently with
any one or more of the following moieties including, but not limited to: aliphatic;
alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl; alkylheteroaryl;
alkoxy, aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; CI; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -
CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -
OCO2Rx; -OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of
Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, substituents described above and herein may be substituted or
unsubstituted, branched or uribranched, 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.
[0088] The term "cycloalkyl", as used herein, refers specifically to groups having
three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but
are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
the like, which, as in the case of other aliphatic, heteroaliphatic or hetercyclic
moieties, may optionally be substituted with substituents including, but not limited to
aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; CI; 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; -NfR^; -SCO^R -NRx(CO)Rx
wherein each occurrence of Rx independently includes, but is not limited to, aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, substituents 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.
[0089] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in
which one or more carbon atoms in the main chain have have substituted with an
heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains
one or more oxygen sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of
carbon atoms. Heteroaliphatic moieties may be branched or linear unbranched. In
certain embodiments, heteroaliphatic moieties are substituted by independent
replacement of one or more of the hydrogen atoms thereon with one or more moieties
including, but not limited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl;
heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -NO2; -CN; -
CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2QH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -
CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -
NRx(CO)Rx wherein each occurrence of Rx independently includes, but is not limited
to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, alkylaryl, or alkylheteroaryl substituents described above and herein
may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and
wherein any of the aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally applicable substituents
are illustrated by the specific embodiments shown in the Examples that are described
herein.
[0090] The term "heteroalicyclic", as used herein, refers to compounds which
combine the properties of heteroaliphatic and cyclic compounds and include but are
not limited to saturated and unsaturated mono- or polycyclic heterocycles such as
morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally
substituted with one or more functional groups.
[0091] The terms "halo" and "halogen" as used herein refer to an atom selected
from fluorine, chlorine, bromine and iodine.
[0092] The term "haloalkyl" denotes an alkyl group, as defined above, having
one, two, or three halogen atoms attached thereto and is exemplified by such groups
as chloromethyl, bromoethyl, trifluoromethyl, and the like.
[0093] The term "heterocycloalkyl" or "heterocycle", as used herein, refers to a
non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not
limited to a bi- or tri-cyclic group comprising fused six-membered rings having
between one and three heteroatoms independently selected from oxygen, sulfur and
nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-
membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may
be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be 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; CI; Br; I; - OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -
CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -
OCO2Rx; -OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of
Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the
aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl
or heteroaryl substitutents described above and herein may be substituted or
unsubstituted. Additional examples or generally applicable substituents are illustrated
by the specific embodiments shown in the Examples, which are described herein.
[0094] As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl",
"alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass
substituted and unsubstituted, saturated and unsaturated, and linear and 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.
[0095] 3) Synthetic Methodology
[0096] According to the present invention, any available techniques can be used
to make or prepare the inventive compounds or compositions including them. For
example, a variety of solution phase synthetic methods such as those discussed in
detail below may be used. Alternatively or additionally, the inventive compounds
may be prepared using any of a variety combinatorial techniques, parallel synthesis
and/or solid phase synthetic methods known in the art.
[0097] In one aspect, the present invention provides novel peptides having
formula (I) as described above and in certain classes and subclasses herein. Examples
of synthetic methods for preparing exemplary types of compounds of the invention
are provided below, as detailed in Schemes 1-12, 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 1-12 below,
and that any suitable synthetic methods known in the art can be used to prepare the
inventive compounds.
[0098] In certain embodiments, the inventive compounds, have the general
structure (I') as shown in Scheme 1, where R, R' and Q are aliphatic, heteroaliphatic,
aryl or heteroaryl moieties. In preferred embodiments, R, R' and Q are moieties such
as those described in classes and subclasses herein. Examples of preferred structures
for R, R' and Q are depicted in Scheme 1.
Scheme 1
[0099] In certain embodiments, the inventive compounds belong to class (1a) 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.
Scheme 2
[0100] 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.
[0101] In certain other embodiments, the inventive compounds belong to class
(1b) 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 rattier encompasses
derivatives and analogs of these compounds, or compounds obtained from different
starting materials.
[0102] In certain other embodiments, the inventive compounds belong to class
(Ic) 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 Examplification 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).
[0103] 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 a-amino acid moieties to access
compounds of class (Id), as illustrated in Scheme 11 below.
[0104] For example, reaction of diethylglycine (72) with amine HC1 salt 49
gives the ^-terminal gem-diethyl ethyl ester 73, or the corresponding carboxylic acid
74, after hydrolysis under suitable conditions (Scheme 12).
[0105] It will be appreciated that each of the reactions described in Schemes
2-12 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.
[0106] 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.
[0107] 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 12 and 13. 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 1-13. Rather, any suitable synthetic
methods known in the art can be used to achieve desired chemical transformations.
[0108] 4) Research Uses, Formulation and Administration
[0109] 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.
[0110] Compounds of this invention which are of particular interest include
those which:
• exhibit cytotoxic and/or growth inhibitory effect on cancer cell lines
maintained in vitro or in animal studies using a scientifically
acceptable cancer cell xenograft model;
• preferably cause tumor regression in vivo;
• exhibit low sensitivity to MDR;
• exhibit low cytotoxicity to non-dividing normal cells; and/or
• exhibit a favorable therapeutic profile (e.g., safety, efficacy, and
stability).
[0111] 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.
[0112] 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.
[0113] 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.
[0114] In certain embodiments, inventive compounds exhibit stability in
mouse serum.
[0115] 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.
[0116] 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.
[0117] 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%) in suitable cancer cell xenograft models. In certain embodiments, compounds of
the invention have T/C values invention have T/C values invention have T/C values invention have T/C values [0118] 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.
[0119] 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.
[0120] In certain embodiments, compounds of the invention have any one or
more of the following properties:
(i) exhibit growth inhibition IC50 values in cultured human cancer cells in
the range of 0.1 nM -10 nM;
(ii) have a resistance ratio preferably 10, preferably 9, preferably 8,
preferably 7, preferably 6, preferably 5, more preferably 4;
(iii) exhibit little or no cytotoxicity in non-dividing normal cells at
concentrations in the range of up to 1-10 µM;
(iv) exhibit stability in mouse serum;
(v) exhibit mitotic block reversibility ratios of 1 to about 30, preferably of
1 to about 25, preferably of 1 to about 20, preferably of 1 to about 15,
preferably of 1 to about 10, preferably of 1 to about 5, most preferably of
about 1 to about 3;
(vi) cause reduction of tumor size to below 70%, preferably below 65%,
preferably below 60%, preferably below 55%, most preferably below 50%,
of the size at the start of compound administration in suitable cancer cell
xenograft models; and/or
(vii) cause significant inhibition of tumor growth in suitable cancer cell
xenograft model (e.g., T/C value preferably preferably [0121] In certain embodiments, compounds of the invention have the
following properties:
(i) exhibit growth inhibition IC50 values in cultured human cancer cells in
the range of 0.1 nM -10 nM;
(ii) have a resistance ratio preferably 10, preferably 9, preferably 8,
preferably 7, preferably 6, preferably 5, more preferably 4;
(iii) exhibit little or no cytotoxicity in non-dividing normal cells at
concentrations in the range of up to 1-10 µM;
(iv) exhibit stability in mouse serum;
(v) exhibit mitotic block reversibility ratios of 1 to about 30, preferably of
1 to about 25, preferably of 1 to about 20, preferably of 1 to about 15,
preferably of 1 to about 10, preferably of 1 to about 5, most preferably of
about 1 to about 3;
(vi) cause reduction of tumor size to below 70%, preferably below 65%,
preferably below 60%, preferably below 55%, most preferably below 50%,
of the size at the start of compound administration in suitable cancer cell
xenograft models; and
(vii) cause significant inhibition of tumor growth in suitable cancer cell
xenograft model (e.g., T/C value preferably preferably [0122] Examples of compounds exhibiting desired properties include ER-
805913, ER-805736, ER-807102, ER-SO7328, ER-806925, ER-807850, ER-807904,
ER-807974, ER-808368, ER-808662, ER-808824, and salts thereof (See Table
below).
[0123] 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.
[0124] 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).
[0125] Pharmaceutical Compositions
[0126] 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.
[0127] 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.
[0128] 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, palniitate, 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.
[0129] 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.
[0130] 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.
[0131] 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 components) 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.
[0132] Uses and Formulations of Compounds of the Invention
[0133] As described in more detail herein, in general, the present invention
provides compounds useful for the treatment of cancer and proliferative disorders.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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. Patent 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.
[0138] 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.
[0139] 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-larninectomy,
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 (lUDs) 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).
[0140] 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).
[0141] In the case of stents, a wide variety of stents may be developed to
contain and/or release the inventive compounds or compositions provided herein,
including esophageal stents, gastrointestinal stents, vascular stents, biliary stents,
colonic stents, pancreatic stents, ureteric and urethral stents, lacrimal stents,
Eustachian tube stents, fallopian tube stents and tracheal/bronchial stents (See, for
example, U.S. Patent No.: 6,515,016, 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."
[0142] As discussed above, the stent coated with (or otherwise adapted to
release) compositions of the present invention may be used to eliminate a vascular
obstruction and prevent restenosis and/or reduce the rate of restenosis. Within other
aspects of the present invention, stents coated with (or otherwise adapted to release)
compositions of the present invention are provided for expanding the lumen of a body
passageway. Specifically, a stent having a generally tubular structure, and a surface
coated with (or otherwise adapted to release) an inventive compound or composition
may be inserted into the passageway, such that the passageway is expanded. In certain
embodiments, the stent coated with (or otherwise adapted to release) compositions of
the present invention may be used to eliminate a biliary, gastrointestinal, esophageal,
tracheal/bronchial, urethral or vascular obstruction.
[0143] 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).
[0144] 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.
[0145] Within other aspects of the present invention, methods are provided for
expanding the lumen of a body passageway, comprising inserting a stent into the
passageway, the stent having a generally tubular structure, the surface of the structure
being coated with (or otherwise adapted to release) an inventive compound or
composition, such that the passageway is expanded. In certain embodiments, the
lumen of a body passageway is expanded in order to eliminate a biliary,
gastrointestinal, esophageal, tracheal/bronchial, urethral and/or vascular obstruction.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] In certain embodiments, methods are provided for eliminating
tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into a
trachea or bronchi, the stent having a generally tubular structure, the surface of the
structure being coated with (or otherwise adapted to release) an inventive compound
or composition, such that the tracheal/bronchial obstruction is eliminated. Briefly, the
trachea and bronchi are tubes which carry air from the mouth and nose to the lungs.
Blockage of the trachea by cancer, invasion by cancer arising in adjacent organs (e.g.,
cancer of the lung), or collapse of the trachea or bronchi due to chondromalacia
(weakening of the cartilage rings) results in inability to breathe. In certain
embodiments, preinsertion examination, usually an endoscopy, is performed in order
to determine the appropriate position for stent insertion. A catheter or endoscope is
then positioned through the mouth, and a guidewire advanced through the blockage. A
delivery catheter is then passed over the guidewire in order to allow a collapsed stent
to be inserted. The stent is placed under radiologic or endoscopic control in order to
place it precisely across the narrowing. The delivery catheter may then be removed
leaving the stent standing as a scaffold on its own. A post-insertion examination,
usually a bronchoscopy may be utilized to confirm appropriate positioning.
[0151] 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.
[0152] 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.
[0153] 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, intracisternally, 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.
[0154] Liquid dosage forms for oral administration include, but are not limited
to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-
butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com,
germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides
inert diluents, the oral compositions can also include adjuvants such as wetting agents,
emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polyethylene glycols and the like. The solid dosage
forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings
and shells such as enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain opacifying agents and
can also be of a composition that they release the active ingredients) only, or
preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances
and waxes. Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0161] 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.
[0162] 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.
[0163] 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).
[0164] 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
[0165] 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 containers)
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
[0166] 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.
[0167] 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
[0168] 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.
[0169] 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.
[0170] Moreover, the practitioner is directed to the specific guidance and
examples provided in this document relating to various exemplary compounds and
intermediates thereof.
[0171] 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.
[0172] 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.
[0173] 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, WI),
Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well
known to a person of ordinary skill in the art following procedures described in such
references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-17,
John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon
Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic
Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001,
"Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and
Larock 1990, "Comprehensive Organic Transformations: A Guide to Functional
Group Preparations", 2nd ed. VCH Publishers. These schemes are merely illustrative
of some methods by which the compounds of this invention can be synthesized, and
various modifications to these schemes can be made and will be suggested to a person
of ordinary skill in the art having regard to this disclosure.
[0174] 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.
[0175] Certain exemplary compounds of the invention are listed below and are
referred to by compound number as indicated.
[0176] General Reaction Procedures:
[0177] 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.
[0178] Listed below are abbreviations used for some common organic
reagents referred to herein:
[0179] BOCorBOC20: Di-tert-Butyl dicarbonate
[0180] CMC: l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide
metho-j9-
toluenesulfonate
[0181] DCM: Dichloromethane
[0182] DEPC: Diethylphosphoryl cyanide (Diethyl cyanophosphonate)
[0183] DIBAL: Diisobutylaluminum hydride
[0184] DIEA: Diisopropylethylamine
[0185] DMF: N,N-Dimethylfomianiide
[0186] DMSO: Dimethylsulfoxide
[0187] Ether: Diethyl ether
[0188] HBTU: O-(1H'-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium
hexafluorophosphate
[0189] HOAt: 1-Hydroxy-7-azabenzotriazole
[0190] LAH: Lithium aluminum hydride
[0191] MSA: Methane sulfonic acid
[0192] NMM: N-Methyl Morpholine
[0193] TBME: Tert-butyl methyl ether
[0194] TFA: Trifluoroacetic acid
[0195] THF: Tetrahydrofuran
[0196] TMEDA: Tetramethylethylenedxamine
[0197] General Work Up Procedures:
[0198] 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).
[0199] 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.
[0200] General Purification Procedures:
[0201] Chromatographic purification refers either to flash column
chromatography on silica, using a single solvent or mixed solvent as eluent, or HPLC
on a CIS 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.
[0202] Example 1: Preparation of Amine Esters 18. Amine acids 20 and
Amine Amides 23

[0203] Preparation of Compound 13

[0204] To a solution of Compound 12 (205mg) in DMF (3.8ml), at room
temperature, was added (S)-N-Boc-neo-phenylalanine (6) (140mg), NMM (0.30ml),
HOAt (0.124g), and CMC (1.16g). The reaction mixture was shaken at room
temperature for 24hr. Aqueous workup followed by chromatographic purification
gave Compound 13 (153mg, 61%).
[0205] Preparation of Compound 14

[0206] To a solution of compound 13 (153mg) in methanol (20ml), at 0°C,
was added sodium borohydride (3.18g) portionwise with shaking over a 3 day period.
The reaction mixture temperature was maintained between 0° - 5°C. On occasion
where the reaction mixture turned into a solidified mass, THF was added to aid
agitation. The reaction mixture was allowed to warm to room temperature then re-
cooled to 0°C and worked up in the usual manner to give compound 14 (140mg,
96%).
[0207] Preparation of Compound 15

[0208] To a solution of compound 14 (50mg) in THF (3ml), at room
temperature, was added Dess Martin periodinane (204mg) in one portion. The
resultant suspension was stirred vigorously for 4.5hr. An aqueous work up gave
crude compound 15 (50mg) which was used immediately in the next stage without
purification.
[0209] General Procedure for the Preparation of Amine Esters 18

[0210] To a solution of compound 15 (1 equivalent) in a suitable volume of
1,2-dichloroethane, at room temperature, was added 4A molecular sieves (crashed
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.
[0211] General Procedure for the Preparation of Amine Acids 20

[0212] To a solution of the N-Boc Amine Ester 17 in a suitable mixture of
THF and methanol, was added 1M 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 iV-terminal free amine 20.

[0214] 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 ^-terminal free amine 23.

[0217] To a solution of aldehyde 13 (50mg) in 1,2-dichloroethane (2ml), at
room temperature, was added 4A molecular sieves (crushed and dried) (50mg).
Glycine methyl ester hydrochloride (120mg) was added with vigorous stirring
followed by sodium triacetoxyborohydride (205mg). The reaction mixture was stirred
at 40°C) for two hours. Aqueous work up followed by chromatographic purification
gave compound 24 (31mg, 46%).

[0219] To a solution of compound 24 (5.5mg) in DMF (0.4ml), at room
temperature, was added pyridine (0.006ml) followed by acetic anhydride (0.004ml).
The reaction mixture was shaken for three hours at room temperature then
concentrated in vacuo to dryness. The residue was dissolved in saturated HC1 in
methanol (1ml) and stood at room temperature for 15 minutes. The reaction mixture
was concentrated in vacuo to give compound 25 (4mg, 90%).

[0221] 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 HC1 gave the hydrochloride salt of compound 26 (1.95mg, 61%).
[0222] General Procedure for the Preparation of N-Acetyl Amine Amides 27

[0223] 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.

[0226] To a solution of compound 3b (1.94 g) in dry DCM (20 mL), at 0°C
under an inert atmosphere, was added alM 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%).
[0227] Preparation of Compound 29

[0228] 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 HC1 in ethanol (2
mL). The reaction mixture was stood at room temperature for 10 min then
concentrated in vacuo to dryness to give compound 29 (114 mg).

[0230] 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),
HO At (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 HC1 in ethanol (5 mL) and stood at room
temperature for 10 min. Concentration in vacuo gave compound 30 (37mg).

[0232] 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 HC1 in ethanol (5 mL) and stood at room
temperature for 10 min. Concentration in vacuo gave compound 31 as its HC1 salt.

[0234] A solution of compound 31 (4 mg) in ethanol (2 mL) was treated with
1 M lithium hydroxide (0.5ml). The reaction mixture was stirred at room temperature
for 1.5 hr. Aqueous work up followed by chromatographic purification gave
compound 32 (2.9mg, 76%).

[0236] 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%).
[0239] 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%).

[0241] 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.
[0242] Preparation of compound 41

[0243] 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.

[0245] 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.

[0247] To a solution of the TV-terminal N-heterocyclic Amine Esters (42) in a
suitable mixture of THF and methanol, was added 1 M lithium hydroxide solution
(10-50 equivalents). When the TV-terminal N-heterocyclic Amine Esters 42 was
hydrolyzed to a satisfactory degree, the reaction mixture was given an aqueous work
up. The TV-terminal N-heterocyclic Amine acid 43 was purified chromatographically,
except in cases where it was deemed unnecessary.

[0249] To a solution of the TV-terminal N-heterocyclic Amine acid 43 in DMF,
at room temperature, was added NMM (20 equivalents). A suitably chosen amine
hydrochloride (44) (20 equivalents) was added followed by DEPC (20 equivalents).
When the TV-terminal N-heterocyclic Amine acid 43 was consumed to a satisfactory
degree the TV-terminal N-heterocyclic Amine Amide 45 was isolated either by direct
chromatographic purification of the reaction mixture, or by an aqueous work up
followed by chromatographic purification.


[0253] Procedure a.
[0254] 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%).

[0256] 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.

[0258] 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 x 25 mL) and brine (25 mL), and dried over Na2SO4, filtered, and evaporated
to give an oil. Purification by Flash Chromatography on SiO2 (FC) gave pure
compound 3b (0.7863 g, 68%).

[0260] 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 HC1 (2.4 mL, 13.2 mmol) was added.
Evaporation gave the HC1 salt, compound 48 (0.618 g, 100%).

[0262] 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 H20 (2 x 25 mL), aq. pH 7.2
phosphate buffer (25 mL), H20 (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%).
[0263] Preparation of compound 49:

[0264] Compound 5b (0.1159 g, 0.2809 mmol) was dissolved in CH2C12 (3.0
mL) and triethylsilane (0.050 niL, 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 HC1 was added (0.3 mL, 1.65 mmol). Evaporation gave
the HC1 salt, compound 49 (0.0662 g, 100%).
[0265] Step 2: Preparation of Compound 51:

[0267] 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%).

[0269] Compound 50 (0.0989 g, 0.2086 mmol) was dissolved in 1:1
H2O/MeOH (14 mL) at room temp. LiOH (0.0537 g, 2.2422 mmol) was added. The
suspension was stirred at room temp. 19 h. The solution was acidified with 5.5 N HC1
(0.50 mL), and 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 HC1 (ca. 1 mL, 5.5
mmol) and evaporated to give the HC1 salt of compound 51 (0.0667 g, 72%).

[0271] 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 H20 (1.0 mL), and purified by RP HPLC to give the TFA
salt of compound 52. This was dissolved in CH3CN (ca. 3 mL) and treated with 5.5 N
HCl (0.10 mL, 0.55 mmol) and evaporated to give the HCl salt of compound 52
(0.0078 g, 100%).

[0274] 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 Boc20 (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.

[0276] A solution of compound 54 (926.5 mg, 5.0 mmol) in Et20 (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 Mcyclohexane solution of sec-butyllithiurn (4.6 mL, 6.0 mmol) over
a 30 minute period. The reaction solution was then wanned 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 NHCl (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).

[0278] To a solution of compound 55 (292 mg, 1.2 mmol) in CH2Cl2 (2.4mL)
at 0°C was added TFA (2.4 mL). After 15 minutes, the reaction solution was warmed
to r.t. and stirred for 3 hours. The reaction mixture was then concentrated in vacuo to
provide compound 59a (309 mg) quantitatively as a light yellow oil.
[0281] To a solution of compound 55 (780 mg, 3.2 mmol) in DMF (6.4 mL)
was added K2CO3 (663 mg, 4.8 mmol) followed by Mel (300 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.

[0283] 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 363.6mg (79%) of racemic
compound 57 as a colorless oil.
[0284] Step 3: Preparation of compound 58
[0285] To a solution of compound 57 (360 mg, 1.4 mmol) in a 2:1 mixture of
H20 (2.75mL) and EtOH (5.50 mL) was added KOH pellets (786 mg, 14 mmol) and
the reaction solution was stirred at room temperature until complete by TLC. The
reaction mixture was then diluted with H2O and extracted several times with ether.
The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to
provide compound 58 (341 mg) quantitatively as a white solid.
[0286] Step 4: Preparation of compound 59b
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 wanned 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..







[0288] 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 H20 (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.
(61a and 61b)
[0290] To a solution of compound 60a and 60b (11.0 mg, 0.07 mmol) in
CH2Cl2 (350 µL) was added HBTU (40mg, 0.11 mmol) and DIEA (37 µL, 0.21
mmol). After 5 minutes, amine 49 (22.0 mg, 0.07mmol) was added. The reaction
mixture was stirred for 30 minutes, filtered, and concentrated. Purification of the
residue by silica gel chromatography (2% EtOH in CH2Cl2) yielded 15.1 mg (96 %)
of each diastereomer 61a and 61b as colorless oils.

[0292] To a solution of diastereomer 61a (9.0 mg, 0.02 mmol) in a 2:1
mixture of H20 (80 µL) and EtOH (160 µL) was added LiOHH20 (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.

[0295] 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 1NHCl 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%)

[0297] To a solution of crude 64 (47 mg, 0.2 mmol) in THF (1 mL) was added
aq. 37% formaldehyde solution (49ul, 0.6 mmol) followed by 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(67mg,>100%).

[0299] To a mixture of 65 (29 mg, 0.115 mmol), amine HCl salt 49 (15 mg,
0.043 mmol), CMC (55 mg, 0.129 mmol), and HOAt (3 mg, 0.022 mmol) was added
DMF (0.5 mL) followed by NMM (6ml, 0.055 mmol). The mixture was stirred at r.t.
for 24 h. The reaction was quenched by adding water (0.5 mL) and methanol (0.5
mL). The products 66a (32%), and 66b (75%) were obtained after separation by RP
HPLC (0-100% B in 30 min. A: 5% MeCN+0.15% TFA in H20; B: 0.15% TFA in
MeCN) and lyophilization.
[0300] Preparation of compounds 67b

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

[0303] 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%).

[0305] 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 M in hexanes, 2.0 mmol).
The solution was stirred at r.t. for 1 h. Evaporation gave crude product 70 (0.58
mmol).

[0307] 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).

[0309] A solution of compound 71 (118 mg, 0.46 mmol) in cone. HCl (1 mL)
was stirred at room temp, for 24 h. Product 72 was obtained after evaporation of
volatiles.

[0311] 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 HO At (14 mg, 0.103 mmol)
was added DMF (1.5 mL) followed by NMM (6ml, 0.128 mmol). The mixture was
stirred at room temp, for 24 h. The reaction was quenched by adding water (0.5 mL)
and methanol (0.5 mL). Product 73 (27 mg, 34%) was obtained after separation by RP
HPLC (0-100% B in 30 min. A: 5% MeCN+0.15% TFA in H20; B: 0.15% TFA in
MeCN) and lyophilization.

[0313] 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.

[0316] To a solution of compound 75 (123 mg) in dry DCM (1 mL), at 0°C
under an inert atmosphere, was added a 1M solution of DEBAL (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 0ºC. 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%).

[0318] 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 urn PTFE syringe filter and concentrated in vacuo to give
crude compound 77 (4 mg).

[0320] 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%).

[0322] Preparation of compound 79

[0323] 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%).

[0325] To a solution of compound 79 (5 mg) in THF (0.5 mL) was added
sodium bicarbonate (3.6 mg) and Dess Martin periodinane (7.2 mg). The reaction
mixture was stirred at room temperature for 3hr then concentrated in vacuo to give
crude compound 80.

[0327] 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).

[0330] To a solution of compound 28 (335 mg) in THF (10 mL), at 0°C under
an inert atmosphere, was added sodium hydride (65% dispersion in mineral oil; 144
mg) portionwise. The reaction mixture was stirred at 0°C for 30 min then treated with
methyl iodide (0.405 mL). The reaction mixture was allowed to warm to room
temperature and stirred at room temperature for 3 hr. An aqueous work up followed
by chromatographic purification gave compound 84 (254mg, 72%).

[0332] 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 (145mg).
[0333] Preparation of compound 86

[0334] To a solution of compound 85 (145 mg) in DMF (3 mL), at room
temperature, was added (S)-N-Boc-tert-leucine (4S3 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 (49mg).

[0336] 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%).
[0337] Example 12: Preparation of compound 91
[0339] To a solution of compound 28 (344mg) 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%).

[0341] Compound 88 (140mg) was dissolved in DCM (1 mL) and treated with
TFA (1 mL). The reaction mixture was stood at room temperature for 30 min then
concentrated in vacuo to dryness. The residue was dissolved in saturated HCl in
methanol (1 mL) and stood at room temperature and then concentrated in vacuo to
give compound 89 (109 mg).

[0343] To a solution of compound 89 (109 mg) in DMF (2 mL), at room
temperature, was added (S)-N-Boc-tert-leucine (347 mg), NMM (0.165 mL), HO At
(68 mg), and CMC (635 mg). The reaction mixture was stirred at room temperature
for 16 hr. Aqueous workup followed by chromatographic purification gave an
intermediate Boc compound (173 mg, 87%). The intermediate Boc compound (51
mg) was dissolved in methanol (1 mL) and treated with saturated HCl in methanol (3
mL) and stood at room temperature for 30 min. Concentration in vacuo gave
compound 90 (43mg).

[0345] 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%).

[0347] 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).

N2O-demethyllaydroxylamine (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 (IN, 500 mL), water (250
mL), NaHCO3 (sat. 250 mL) and brine (250 mL). The organic solution was dried over
MgSO4 (-120 g). The solution was filtered through a silica gel bed (-200 g) and
concentrated. Crude amide ER-807641 was used without any further purification.

[0352] To a stirred solution of amide ER-807641 (207 g, 755 mmol, leq.) 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%).

[0355] To a stirred solution of aldehyde ER-808993 (138 g, 641 mmol, leq.)
in dry THF ( 1.4 L) at 25 °C was added Ph3P=CMeCO2Et (256 g, 705.1 mmol, 1.1

eq.). The solution was stirred at r.t for 18 h. Reaction was not completed after that
time. The solution was heated to reflux for 5 h, after which TLC showed no aldehyde
remaining. The solution was cooled to room temp and heptane (1.5 L) was added.
Precipitation of by-product Ph3P=0 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).
[0356] Part B:
[0357] To a stirred solution of crude ER-808994 in EtOAc (800 mL) was
added MSA (80 mL). The mixture was stirred at r.t. for 45 min. (until complete by
TLC). The amino-ester MSA salt was extracted from organic solution with water (2 x
300 mL). The aqueous layer was neutralized to pH 7-8 with sat. NaHCO3 (300 mL).
The resultant solution was extracted with EtOAc (2 x 400 mL), washed with brine
(300 mL), dried over MgSO4, and filtered. The EtOAc solution of the free arnino-
ester was bubbled with HCl (gas), and the HCl salt of ER-808995 precipitated and
was collected by filtration under N2.

[0359] To a stirred solution of ER-808995 (61.2 g, 259.6 mmol, leq.), N-Boc-
tBu-Gly-OH (90.1 g, 389.4 mmol, 1.5 eq) and DIEA (158 mL, 906.6 mmol, 3.5 eq) in
dry DCM (612 mL) at 25 °C was added HBTU (147.7 g, 389.4 mmol, 1.5 eq.). The
solution was stirred at room temp for 4 h After concentration, the solid residue was
suspended in TBME (250 mL). The mixture was filtered through a silica gel bed
(~120 g), and the filtrate was washed with a solution of aq. HCl (IN, 200 mL), water
(200 mL) and NaHCO3 (sat, 200 mL). The organic layer was dried over 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 x 250 mL),

followed by neutralization with a solution NaOH (ca.50%, 300 mL) to pH~8-9. The
free amine was extracted with TBME (2 x 30 mL). The combined organic solution
was washed with water (200 mL) and brine (200 mL). After drying over MgSO4 and
filtration, HCl (g) was bubbled to obtain the hydrochloride salt of ER-803921 as a
white solid collected by filtration at ca. 5°C.

[0361] A stirred suspension of D-pipecolic acid (100.0 g, 0.77 mol, leq.) and
Pd(OH)2 (20% wt. Pd, 10 g) in a mixture MeOH/acetone (2:1 v/v, 1.5 L) was
submitted to hydrogenation (H2 60 psi) for 24 h. Reaction was monitored by TLC
(ethanol) and deemed complete when no D-pipecolic acid was observed. The mixture
was filtered through a Celite (~50 g) bed. The clear filtrate was concentrated to ca.
100 mL and TBME (50 mL) was added. ER-808998 was filtered as a white
crystalline solid in 88% yield.

[0363] To a stirred solution of dipeptide ER-803921 (5.0 g, 16.8 mmol, 1 eq.),
N-iPr-pipecolic acid ER-808998 (3.7 g, 21.8 mmols, 1.3 eq.) and HBTU (8.3 g, 21.8
mmols, 1.3 eq.) in 50 mL DCM was added DIEA (7.3 mL, 41.9 mmols, 2.5 eq.)
dropwise at 25°C. The mixture was stirred for 18 h (overnight) at which time reaction
was deemed complete by TLC (heptane/EtOAc 1:1). The mixture was concentrated
under vacuum and TBME (50 mL) was added. The residual "thick" oil was separated
from the ethereal solution by filtration through a Celite pad. The filtrate was washed
with aq HCl (1M, 3 x 25 mL). The combined aqueous phases were neutralized with
NH4OH to pH 8-9 in the presence of EtOAc (25 mL). The aqueous layer was

separated and back-extracted with TBME (25 mL). The combined organic phase was
washed with brine and dried over MgSO4, filtered, and concentrated to give
tripeptide-amino-ester ER-807961 in 93% yield.

To a stirred solution of ester ER-807961 (5.0 g, 16.8 mmol) in 5:1 THF/H20 (50 mL)
was added LiOH (3.50 g, 83.8 mmol), and the mixture was stirred at room
temperature for 20 h. The reaction was monitored by TLC (ethanol) and deemed
complete when no ER-807961 was observed. The suspension was acidified with
H2SO4 (-0.50 mL) to pH 7. The mixture was extracted with EtOAc (3 x 25 mL). The
combined organic solution was washed with 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.

[0367] 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.

[0369] To a solution of 2Z (650 mg, 3.5lmmol) in DMF (8.8 mL) was added
K2CO3 (728mg 5.27mmol) and p-nitrobenzylbromide (1.1g, 5.27mmol). The reaction
mixture was allowed to stir overnight. The reaction solution was diluted with water
and extracted several times with diethyl ether. The ether extracts were combined,
washed with water and brine. The solution was dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture of diasteomers was then separated by flash
chromatography eluting with 8% EtOAc in hexanes to give each diastereomer as a
pale yellow oil. Compound 3Z (360mg) was obtained in 32% yield with an Rf =
0.590 (SiO4) using 30% EtOAc in hexanes. Compound 4Z (652mg) was obtained in
58% yield with an Rf = 0.482 (SiO2) using 30% EtOAc in hexanes.

[0371] To a solution of compound 3Z (320mg, 1.0 mmol) in MeOH (10 mL)
was added Pd(OH)2 (50mg). Gaseous H2 (balloon pressure) was charged in and the
reaction mixture was allowed to stir under an H2 atmosphere for 3 hours. The
reaction solution was then filtered through a bed of celite, and concentrated to provide
compound ER-809439 (185mg) as a white solid, quantitatively. Compound ER-
809439, Rf = (SiO2, 0.292, 100% EtOH).
[0372] Preparation of compound ER-809447
[0373] A procedure similar to that used for the preparation of compound ER-
809439 was used. Compound ER-809447, Rf = (SiO2,0.292,100% EtOH).

[0375] Compound 49 (9.6mg, 0.031mmol), N-sec-butylpipecolic ER-809439
(5.2mg, 0.028 mmol), HBTU (12.9mg, 0.034 mmol), were combined. DMF
(0.28mL) was added, followed by DIEA (14.9mL, 0.084mmol). The solution was
stirred at room temperature under nitrogen for 20 h. The solution was purified
directly by RP HPLC to give the TFA salt of compound ER-808357 (13.6mg, 82%).

[0377] The TFA salt of compound ER-088357 (10.4 mg, 0.018 mmol) was
dissolved in 1:2 H20/EtOH (0.072 mL/0.144 mL) at room temperature. LiOH (7.5 g,
0.18mmol) was added. The suspension was stirred at room temperature for 19 hours.
The solution was purified directly by RP HPLC to give the TFA salt of compound
ER-808367 (10.1 mg, quantitative).
[0378] Example 16: Preparation of compound ER-808368

[0385] 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).

[0387] A procedure similar to that used for the preparation of compouiid ER-
808357 was used.

[0389] A procedure similar to that used for the preparation of compound ER-
808367 was used.
[0390] 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.

[0393] Compound 48 (325.5mg, 1.38mmol), L-N-BOC-valine (300.0mg, 1.38
mmol), HBTU (628.3rag, 1.66 mmol), were combined. CH2Cl2 (7mL) was added,
followed by DIEA (0.72mL, 4.14mmol). The solution was stirred at room
temperature under nitrogen for 1 hour. The solution was concentrated in vacuo, and
the crude was purified by flash chromatography (SiC^) eluting with 4% ElOAc in
hexanes. This provided compound 6Z (476.8mg) as a colorless oil in 86.7% yield.

[0395] Compound 6Z (450mg, 1.13mmol) was dissolved directly in 4N
HCl/dioxane (2.8mL). The reaction was stirred for overnight and then concentrated in
vacuo to give compound 7Z (374.8mg) as a white solid, quantitatively.
[0396] Preparation of compound ER-808815
[0399] A procedure similar to that used for the preparation of compound ER-
808367 was used.
[0400] Example 19: Biological Assays:
[0401] 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.
[0402] In vitro potency was determined in the MDA-MB-435 cell growth
inhibition assay, and active compounds (IC50 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.
[0403] 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
promyelocyte 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.
[0404] Mitotic block reversibility assay was performed as described (See,
Patent US 6,214,865 Bl, by B. Littelfield et al, 4/10/01; which is incorporated herein
be reference in its entirety).
[0405] 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).
[0406] Determination of activity in vitro utilizing the MDR assay. This is a
modification of the standard cell growth inhibition assays described above. Two
cultured himan cancer cell lines were used: human uterine sarcoma MDR negative
MES-SA cells (ATCC accession number CRL-1976) and human uterine sarcoma
MDR-positive MES-SA/Dx5 cells (ATCC accession number CRL-1977). Cells were
plated in a 96-well microtiter plates at a density of 7500 cells / well. The cells were
incubated in the presence or absence of test compounds for 96 hours. Cell growth was
assessed using modifications (Amin et al, Cancer Res., 47: 6040-6045, 1987) of a
methylene blue-based microculture assay (Finlay et al, Anal. Biochem., 139: 272-
277, 1984). Absorbances at 620 and 405 nm were measured on a Titertek Multiscan
MCC/340 plate reader and absorbances at 405 nm were subtracted from absorbances
at 620 nm. The ratio of the concentrations of the compounds inhibiting the growth of
cells by 50% was calculated and used to estimate the sensitivity of the compounds to
MDR (multidrug-resistance, or P-glycoprotein-mediated drug efflux). In some cases, .
a different pair of cell lines was used: MDR-negative murine leukemia cells P388/S,
and MDR-positive murine leukemia cells P388/VMDRC.04. Cells were plated in a
96-well microtiter plates at a density of 4000 cells / well. The cells were incubated in
the presence or absence of test compounds for 72 hours. Cell growth was assessed
using a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide-based assay
(Mosmann et al, J. Immunol. Methods, 65: 55-63,1983) modified as follows. After 3
days of incubation with test compounds, sterile-filtered 3-(4,5-dimethylthiazol-2- yl)-
2,5-diphenyl tetrazolium bromide was added to 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.
[0407] 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.
[0408] 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.
[0409] 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-299S,
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.
WE CLAIM :
1. A compound having the structure (I):

or pharmaceutically acceptable salt thereof; >
wherein n is 1;
X1 and X2 are each C(=O); v

wherein g, j, 1 and m are each 1; each occurrence of G, J, L and M is
independently CHRiv or CRiv Rv , wherein each occurrence of Riv and Rv is
independently hydrogen, or an aliphatic, alicyclic, or aryl moiety;
R2 is hydrogen, or optionally substituted alkyl or arylalkyl; where the alkyl
moiety is linear or branched, cyclic or acyclic;
R3 is hydrogen;
R5, R6 and R7 are each independently hydrogen or substituted or unsubstituted,
linear or branched, cyclic or acyclic alkyl;
R is -CH(R8a)C(R9a)=C(R10a)-; where R9a is substituted or unsubstituted, linear or
branched, cyclic or acyclic C1-6alkyl; R9a is hydrogen and R10a is hydrogen or
substituted or unsubstituted, linear or branched, cyclic or acyclic C1-6alkyl; and
Q is ORQ', wherein RQ' is hydrogen or substituted or unsubstituted, linear or
branched, cyclic or acyclic alkyl.
2. The compound as claimed in claim 1 wherein R2 is substituted or unsubstituted,
linear or branched, cyclic or acyclic C1-6 alkyl.
3. The compound as claimed in claim 1 having the following stereochemistry:

4. The compound as claimed in claim 3 wherein R5 and R9a are each hydrogen, and
R6, R7, R8a and R10a are each independently alkyl, whereby the alkyl moiety may
be substituted or unsubstituted, linear or branched, cyclic or acyclic.
5. The compound as claimed in claim 3 wherein R6 is tert-butyl, R7 and R10a are
each methyl and R9a is iso-propyl.
6. The compound as claimed in claim 1 wherein G, J and M are each CH2; j, 1 and m
are each 1; and the moiety -X1-(CR3R4)nNR1R2 has the following structure:

wherein RL1 and RL2, are each independently hydrogen or an aliphatic,
alicyclic, or aryl moiety.

7. The compound as claimed in claim 6 wherein R2 is hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic C1-6alkyl; RL1 and RL2, are each
independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or
acyclic C1-6alkyl or substituted or unsubstituted aryl.
8. The compound as claimed in claim 1 wherein R2 is methyl, R5 is hydrogen, R6 is
tert-butyl, R7 is methyl, R9a is iso-propyl, and the moiety -X1-(CR3R4)nNR1R2 has
the following structure:
wherein RL1 and RL2, are each independently hydrogen or substituted or
unsubstituted, linear or branched, cyclic or acyclic C1-6alkyl.
9. The compound as claimed in claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
10. The compound as claimed in claim 1 having the structure:

wherein Q is OH or OEt;
or pharmaceutically acceptable salt thereof.
11. The compound as claimed in claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
12. The compound as claimed in claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
13. The compound as claimed in claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound as claimed in claim 1, and
a pharmaceutically acceptable carrier or diluent.
15. The compound as claimed in claim 1 wherein R9a is methyl, ethyl, propyl, iso-
propyl, or sec-butyl.
16. The compound as claimed in claim 1 wherein R5 is hydrogen.
17. The compound as claimed in claim 1 wherein R6 is tert-butyl or iso-propyl.
18. The compound as claimed in claim 1 wherein R7 is hydrogen, methyl or ethyl.
19. The compound as claimed in claim 1 wherein R10a is methyl.
20. The pharmaceutical composition as claimed in claim 88 comprising an
additional therapeutic agent.
21. The compound as claimed in claim 1 wherein R2 is methyl or iso-propyl, R5 is
hydrogen, R6 is tert-butyl, R7 is methyl, R9a is iso-propyl, and the moiety -X1-
(CR3R4)nNR1R2 has the following structure:

wherein Riv is hydrogen or substituted or unsubstituted, linear or branched, cyclic
or acyclic C1-6alkyl.

The present invention provides compounds having
formula (I): (I) and additionally provides methods for the synthesis
thereof and methods for the use thereof in the treatment of cancer,
wherein R1-R7, X1, X2, R, Q, and n are as defined herein.

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1275-KOLNP-2004-FORM 27.pdf

1275-KOLNP-2004-FORM-27-1.pdf

1275-KOLNP-2004-FORM-27.pdf

1275-kolnp-2004-granted-abstract.pdf

1275-kolnp-2004-granted-assignment.pdf

1275-kolnp-2004-granted-claims.pdf

1275-kolnp-2004-granted-correspondence.pdf

1275-kolnp-2004-granted-description (complete).pdf

1275-kolnp-2004-granted-examination report.pdf

1275-kolnp-2004-granted-form 1.pdf

1275-kolnp-2004-granted-form 3.pdf

1275-kolnp-2004-granted-form 5.pdf

1275-kolnp-2004-granted-form 6.pdf

1275-kolnp-2004-granted-gpa.pdf

1275-kolnp-2004-granted-pa.pdf

1275-kolnp-2004-granted-reply to examination report.pdf

1275-kolnp-2004-granted-specification.pdf


Patent Number 233870
Indian Patent Application Number 1275/KOLNP/2004
PG Journal Number N/A
Publication Date 17-Apr-2009
Grant Date 16-Apr-2009
Date of Filing 01-Sep-2004
Name of Patentee EISAI R&D MANAGEMENT COMPANY LTD.
Applicant Address 6-10 KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 KOWALCZYK JAMES J 22 RAILROAD STREET #405, ANDOVER, MA 01810
2 YANG HU 33 STIRLING STREET, ANDOVER, MA 01810
3 SCHILLER SHAWN 614 HILLDATE AVENUE, HAVERHILL, MA 01832
4 SELETSKY BORIS M 8 DELPHI CIRCLE, ANDOVER, MA 01810
5 SPYVEE MARK 75 LAURA LANE, HAMPSTEAD, NH 03841
6 KUZNETSOV GALINA 28 WOOD STREET, LEXINGTON, MA 02421
PCT International Classification Number C07D 295/185
PCT International Application Number PCT/US2003/08888
PCT International Filing date 2003-03-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/366,592 2002-03-22 U.S.A.