U.S. patent application number 14/156522 was filed with the patent office on 2014-05-08 for smac mimetic dimers and trimers useful as anti-cancer agents.
This patent application is currently assigned to JOYANT PHARMACEUTICALS, INC. The applicant listed for this patent is Joyant Pharmaceuticals, Inc.. Invention is credited to Gunnar Hanson, Haizho Sun.
Application Number | 20140127155 14/156522 |
Document ID | / |
Family ID | 39864357 |
Filed Date | 2014-05-08 |
United States Patent
Application |
20140127155 |
Kind Code |
A1 |
Hanson; Gunnar ; et
al. |
May 8, 2014 |
Smac mimetic dimers and trimers useful as anti-cancer agents
Abstract
The invention provides small molecule mimics of the Smac peptide
that are dimer-like or trimer-like compounds having two or three
amide-containing domains connected by a linker. These compounds are
useful to promote apoptosis. The invention includes pharmaceutical
compositions comprising such compounds and methods to use them to
treat conditions including cancer and autoimmune disorders.
Inventors: |
Hanson; Gunnar; (Seattle,
WA) ; Sun; Haizho; (Dallas, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Joyant Pharmaceuticals, Inc. |
San Mateo |
CA |
US |
|
|
Assignee: |
JOYANT PHARMACEUTICALS, INC
Menlo Park
CA
|
Family ID: |
39864357 |
Appl. No.: |
14/156522 |
Filed: |
January 16, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12101733 |
Apr 11, 2008 |
8642554 |
|
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14156522 |
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60952493 |
Jul 27, 2007 |
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60911472 |
Apr 12, 2007 |
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Current U.S.
Class: |
424/85.1 ;
514/19.3; 514/21.9; 514/21.91; 530/323; 530/331; 548/533 |
Current CPC
Class: |
C07K 5/08 20130101; A61P
35/00 20180101; A61K 38/06 20130101; C07D 409/14 20130101; A61K
45/06 20130101; C07D 207/16 20130101; C07K 5/06 20130101; A61P
43/00 20180101; A61P 37/00 20180101; C07D 403/14 20130101; A61K
38/05 20130101; A61P 37/02 20180101; A61P 29/00 20180101 |
Class at
Publication: |
424/85.1 ;
514/19.3; 514/21.9; 514/21.91; 530/331; 548/533; 530/323 |
International
Class: |
A61K 38/06 20060101
A61K038/06; A61K 45/06 20060101 A61K045/06; C07K 5/06 20060101
C07K005/06; A61K 38/05 20060101 A61K038/05; C07K 5/08 20060101
C07K005/08 |
Claims
1. A compound of formula (I): ##STR00289## or a pharmaceutically
acceptable salt or hydrate form thereof, wherein b is 0 or 1; each
Q, Q' and Q'', if present, independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 heteroalkyl; or one or
more of Q, Q' and Q'' may be a bond when L comprises a ring; L
represents an optionally substituted C1-C24 hydrocarbyl linker,
optionally containing from 1-8 heteroatoms selected from N, O and
S, which linker is 1-18 atoms in length when counted along the
shortest path between Q and Q', or Q and Q'', or Q' and Q''; and
each D, D' and D'', if present, is independently selected from the
group consisting of ##STR00290## wherein each R.sub.a and R.sub.b
is independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl,
or a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl; each R.sup.1 is
independently H or optionally substituted C1-C8 alkyl; each Z
independently represents an optionally substituted C1-C6 aminoalkyl
group; each Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted; each W, where present, independently
represents an optionally substituted C1-C6 alkylene or C1-C6
heteroalkylene; each X, where present, independently represents an
optionally substituted C.sub.5-C.sub.20 ring system comprising at
least one aromatic ring and up to four heteroatoms selected from N,
O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring; each n, where present, is
independently 0-3; each m, where present, is independently 0-4; and
each R.sup.6, where present, is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring; with the proviso that, when b is 0, D and D' are not
the same and both of the formula ##STR00291##
2. The compound of claim 1, having the formula (1): ##STR00292## or
a pharmaceutically acceptable salt or hydrate form thereof, wherein
each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl; each Y and Y' independently
represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R,
NRSO.sub.2R or COOR, wherein each R is independently H, C1-C8 alkyl
or C1-C8 heteroalkyl, and wherein two Y or Y' groups can cyclize to
form a 3-6 membered ring that can be saturated, unsaturated or
aromatic, and which ring may include a heteroatom selected from O,
S and N as a ring member and may be optionally substituted; each W
and W' independently represents an optionally substituted C1-C6
alkylene or C1-C6 heteroalkylene; each X and X' independently
represents an optionally substituted C.sub.5-C.sub.20 ring system
comprising at least one aromatic ring and up to four heteroatoms
selected from N, O and S as a ring member, and can represent either
a single 5-15 membered cyclic group or two 5-10 membered cyclic
groups that are both attached to the same atom of W or W', provided
that each X and X' comprises at least one aryl or heteroaryl ring;
each Q and Q' independently represents --O-- or --NR.sup.2--, where
each R.sup.2 is independently H, or optionally substituted C1-C8
alkyl, or optionally substituted C1-C8 heteroalkyl; or one or both
of Q and Q' may be a bond when L comprises a ring; each n and n' is
independently 0-3; each m and m' is independently 0-4; each R.sup.1
and R.sup.1' is independently H or optionally substituted C1-C8
alkyl; each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and L represents an optionally
substituted C1-C24 hydrocarbyl linker, optionally containing from
1-8 heteroatoms selected from N, O and S, which linker is 1-18
atoms in length when counted along the shortest path between Q and
Q'.
3. The compound of claim 1, wherein: each n and n' is 1, and each
of m and m' is 0 or 1, and wherein Y and Y', if present, are the
same; each R.sup.1 and R.sup.1' is H or methyl; and/or each Z and
Z' is a 1-aminoalkyl group represented by the formula
--CH(R.sup.3)NR.sup.4.sub.2, where R.sup.3 and each R.sup.4 is
independently H or C1-C4 alkyl.
4. The compound of claim 2, having the formula (3A): ##STR00293##
or a pharmaceutically acceptable salt or hydrate form thereof,
wherein Ra is H and Rb is R.sup.5; R.sup.5 is H, or C1-C8 alkyl,
C2-C8 alkenyl, C2-C8 alkynyl, or phenyl, each of which may be
optionally substituted; each Y represents C1-C8 alkyl, .dbd.O, OR,
NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl; W represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; X
represents an optionally substituted C.sub.5-C.sub.20 ring system
comprising at least one aromatic ring and up to four heteroatoms
selected from N, O and S as a ring member, and can represent either
a single 5-15 membered cyclic group or two 5-10 membered cyclic
groups that are both attached to the same atom of W, provided that
each X comprises at least one aryl or heteroaryl ring; Q represents
--O-- or --NR.sup.2--, where each R.sup.2 is independently H, or
optionally substituted C1-C8 alkyl, or optionally substituted C1-C8
heteroalkyl; or Q may be a bond when L comprises a ring; m is 0-4;
p is 2-3; Z represents an optionally substituted C1-C6 aminoalkyl
group of the formula --CH(R.sup.3)NR.sup.4.sub.2; R.sup.3 is H, or
an optionally substituted C1-C8 alkyl or optionally substituted
C1-C8 heteroalkyl, and R.sup.3 can cyclize with R.sup.4 on an
adjacent nitrogen atom to form an optionally substituted azacyclic
group having 5-10 ring members, which azacyclic group may be
saturated, unsaturated or aromatic, and may contain 1-2 additional
heteroatoms selected from N, O and S as a ring member; each R.sup.4
is independently H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and the two R.sup.4
groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member; and L represents a C1-C14 alkylene, C1-C14 alkenylene,
C1-C14 alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
6. The compound of claim 4, having the formula (4): ##STR00294## or
a pharmaceutically acceptable salt or hydrate form thereof, wherein
R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or
phenyl, each of which may be optionally substituted; each Y
represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R,
NRSO.sub.2R or COOR, wherein each R is independently H, C1-C8 alkyl
or C1-C8 heteroalkyl; W represents an optionally substituted C1-C6
alkylene or C1-C6 heteroalkylene; X represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W, provided that each X comprises at
least one aryl or heteroaryl ring; Q represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or Q may be a bond when L comprises a ring; m is 0-4;
p is 2 or 3; R.sup.3 is H, or an optionally substituted C1-C8 alkyl
or optionally substituted C1-C8 heteroalkyl, and R.sup.3 can
cyclize with R.sup.4 on an adjacent nitrogen atom to form an
optionally substituted azacyclic group having 5-10 ring members,
which azacyclic group may be saturated, unsaturated or aromatic,
and may contain 1-2 additional heteroatoms selected from N, O and S
as a ring member; each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and L represents a C1-C14 alkylene,
C1-C14 alkenylene, C1-C14 alkynylene, C5-C12 arylene, C5-C21
arylalkylene, C5-C21 arylalkenylene, or C5-C21 arylalkynylene
linker, or a heteroform of one of these, each of which may be
optionally substituted.
6. The compound of claim 4, having the formula (5): ##STR00295## or
a pharmaceutically acceptable salt or hydrate form thereof, R5 is
H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or phenyl, each of
which may be optionally substituted; each Y represents C1-C8 alkyl,
.dbd.O, OR, NR2, OC(O)R, NRC(O)R, NRSO2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl; W represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; X
represents an optionally substituted C5-C20 ring system comprising
at least one aromatic ring and up to four heteroatoms selected from
N, O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring; Q represents --O-- or --NR2-,
where each R2 is independently H, optionally substituted C1-C8
alkyl or optionally substituted C1-C8 heteroalkyl; or Q may be a
bond when L comprises a ring; m is 0-4; R3 is H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and R3 can cyclize with R4 on an adjacent nitrogen
atom to form an optionally substituted azacyclic group having 5-10
ring members, which azacyclic group may be saturated, unsaturated
or aromatic, and may contain 1-2 additional heteroatoms selected
from N, O and S as a ring member; each R4 is independently H, or an
optionally substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and
the two R4 groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member; L represents a C1-C14 alkylene, C1-C14 alkenylene,
C1-C14 alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
7. The compound of claim 2, wherein: each X and X' independently
comprises an optionally substituted phenyl ring; or two phenyl
rings, each of which may be optionally substituted; or a
tetrahydronaphthyl, indanyl or fluorenyl ring system each W and W'
represents --C(O)NR(CHR)p-, where p is 0-2, and each R
independently represents H, C1-C4 alkyl or C1-C4 heteroalkyl; each
Q and Q' is --NR2-, where each R2 is independently H or C1-C4
alkyl; and/or at least one of Q and Q' is a bond.
8. The compound of claim 2, wherein: L comprises at least one
optionally substituted carbocyclic, heterocyclic, aromatic or
heteroaromatic ring that is part of or is fused to the linker which
forms the shortest path between Q and Q'; L comprises at least one
triazole ring; or L comprises a C1-C14 alkylene, C1-C14
heteroalkylene, C2-C14 alkenylene, C2-C14 heteroalkenylene, C2-C14
alkynylene, or a C2-C14 heteroalkynylene group, each of which may
be optionally substituted.
9. The compound of claim 2 wherein: L is a C2-C14 alkynylene or a
C2-C14 heteroalkynylene group or L comprises at least one
optionally substituted carbocyclic, heterocyclic, aromatic or
heteroaromatic ring that is part of or is fused to the linker which
forms the shortest path between Q and Q', said aromatic or
heteroaromatic ring is an optionally substituted 5- or 6-membered
aromatic or heteroaromatic ring, wherein said optionally
substituted 5- or 6-membered aromatic or heteroaromatic ring is
selected from the group consisting of phenyl, pyridyl, pyrazinyl,
triazinyl, pyrazolyl, and thiophenyl, each of which may be
optionally substituted.
10. The compound of claim 2, wherein R3 is selected from methyl,
ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,
sec-butyl, and tert-butyl; and/or each R4 is independently H or
methyl.
11. A compound selected from the group consisting of the compounds
in Tables 3 and 4, or a pharmaceutically acceptable salt
thereof.
12. A pharmaceutical composition comprising a compound of claim 1,
further comprising at least one additional therapeutic agent
selected from the group consisting of TRAIL, etoposide, a TRAIL
receptor antibody, an Hsp90 inhibitor, TNF-.alpha., and
TNF-.beta..
13. A method to treat cancer, inflammation, or an autoimmune
disorder, comprising administering to a subject in need of such
treatment an effective amount of a compound of claim 1.
14. A compound of formula (6): ##STR00296## or a pharmaceutically
acceptable salt or hydrate form thereof, wherein Ra and Rb are
independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; each Y independently represents C1-C8 alkyl, .dbd.O,
OR, NR2, OC(O)R, NRC(O)R, NRSO2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two
Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted; W represents an optionally substituted
C1-C6 alkylene or C1-C6 heteroalkylene; X represents an optionally
substituted C5-C20 ring system comprising at least one aromatic
ring and up to four heteroatoms selected from N, O and S as a ring
member, and can represent either a single 5-15 membered cyclic
group or two 5-10 membered cyclic groups that are both attached to
the same atom of W, provided that each X comprises at least one
aryl or heteroaryl ring; n is 0-3; m is 0-4; R1 is H or optionally
substituted C1-C8 alkyl; U represents --OR8, --OC(O)R8, --OSO2R8,
C.dbd.O, --OC(O)OR8, --COORS, --NR82, azido or halo, where each R8
is independently H, or C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl,
C5-C12 aryl, C5-C21 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted; or C1-C8 alkyl, C2-C8
alkenyl, C2-C8 alkynyl, C5-C12 aryl or C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; and Z is an optionally substituted C1-C6 aminoalkyl
group wherein the amine may be in a protected or unprotected form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser No. 12/101,733,
filed Apr. 11, 2008 (U.S. Pat. No. 8,642,554), which claims
priority from U.S. Provisional Application Ser. No. 60/911,472,
filed 21 Apr. 2007; and U.S. Provisional Application Ser. No.
60/952,493, filed 27 Jul. 2007. The content of each of these
documents is incorporated by reference herein in its entirety.
TECHNICAL FIELD
[0002] The field of the invention is dimer- and trimer-like small
molecule promoters of apoptosis. The compounds of the invention
have a linking group that connects two or three binding domains,
each of which contains two essential amide groups. These compounds
mimic the activity of the protein known as Smac, and are thereby
able to promote the initiation of apoptosis. The compounds are
therefore useful in treating conditions where initiating apoptosis
is desirable, such as in pathological cells or tissues.
BACKGROUND ART
[0003] Apoptosis plays a central role in the development and
homeostasis of all multi-cellular organisms. Abnormal inhibition of
apoptosis is a hallmark of cancer and autoimmune diseases, whereas
excessive activation of cell death is implicated in
neuro-degenerative disorders such as Alzheimer's disease.
Pro-apoptotic chemotherapeutic drugs provide a recent approach to
overcoming the clinical problem of drug resistance; see, e.g. Makin
et al., Cell Tissue Res. (July 2000) 301(1):143-152 ("Apoptosis and
cancer chemotherapy").
[0004] The mechanism of apoptosis is conserved across species and
executed with a cascade of sequential activation of proteases
called caspases. Once activated, these caspases are responsible for
proteolytic cleavage of a broad spectrum of cellular targets that
ultimately lead to cell death. IAPs (inhibitor-of-apoptosis
proteins) regulate apoptosis by inhibiting caspases; and a protein
called Smac (`Smac` stands for second mitochondria-derived
activator of caspases, and is a mitochondrial protein) binds to and
inhibits IAPs, and thereby promotes caspase activation.
[0005] The protein Smac has been shown to inhibit a wide variety of
IAPs, and is believed to be a key regulator of apoptosis in
mammals. See Du, et al., Cell (2000) 102:33-43; Verhagen et al.,
Cell (2000) 102:43-53; and Vucic et al., Biochem. J. (2005)
385(1):11-20. N-terminal Smac-derived peptides and mimetics have
been shown to similarly inhibit IAPs, and promote caspase
activation. IAPs are components of TNFR (tumor necrosis factor
receptor), so IAP inhibitors can divert TNFR signaling from an
NfkB-mediated pro-inflammatory signal, to an anti-inflammatory
apoptotic signal.
[0006] Defective apoptosis regulation can confer resistance to many
current treatment protocols, leading to tumor growth. This may
occur as a result of overexpression of IAPs, which inhibit the
caspases that would otherwise initiate apoptosis. Alternatively,
deregulation can occur as a result of underproduction of the Smac
peptides that act to inhibit IAP activity. Deficiency of Smac can
thus allow IAP to prevent apoptosis from occurring when it should,
and a Smac mimetic like the present compounds can replace the
activity of Smac and thus promote desired apoptosis.
[0007] Debatin, et al., WO 03/086470, describes Smac-peptides as
therapeutic agents useful against cancer and autoimmune diseases;
they are reported to act by sensitizing the cells toward
TRAIL-induced or anticancer drug-induced apoptosis. (TRAIL stands
for TNF related apoptosis-inducing ligand). See also Li, et al.,
Science (3 Sep. 2004) 305:1471-14744. Debatin provides in vivo
evidence that Smac induces the eradication of certain tumors such
as glioblastoma tumor models in animals when administered in
combination with TRAIL. According to Debatin, aggressive cancer
phenotypes, which result from deregulation of signaling pathways,
commonly fail to undergo apoptosis when they otherwise would,
allowing rapid and abnormal tissue growth. Bockbrader, et al.,
disclose efficacy of Smac mimic compounds on breast cancer cell
lines when used in conjunction with TRAIL or etoposide, or when
used in cells that express TRAIL at relatively high levels.
Oncogene (2005) 24:7381-7388.
[0008] Similarly, according to Debatin, defects in apoptosis
regulation play a key role in the pathogenesis of autoimmune
disorders, including lupus erythematodes disseminatus and
rheumatoid arthritis. Accordingly, compounds that mimic the
activity of Smac can treat some of the effects of such
conditions.
[0009] A recent U.S. Patent Application, US 2005/0197403, describes
dimeric compounds with good activity as promoters of apoptosis. The
compounds have two amide-containing groups linked by a linker that
is broadly described. Another U.S. Patent Application, US
2006/0025347, describes small molecule compounds having activity
related to promotion of apoptosis. However, while the latter
reference mentions that dimeric compounds can be used, none of the
compounds it discloses have a dimeric structure, nor is there any
indication of what type of dimers to explore.
[0010] Several recent patent applications, for example, US
2006/0025347, US 2005/0197403, WO 2006/069063, US 2006/0014700, WO
2005/094818, and WO 2005/097791, each of which is incorporated
herein by reference in its entirety, disclose monomeric IAP
inhibitors, but do not describe dimeric structures.
DISCLOSURE OF THE INVENTION
[0011] The present invention relates to novel compounds having
apoptosis promoting effects that, without being bound by theory,
appear to originate in their ability to mimic Smac. These compounds
are believed to bind to two or three separate domains in the
baculovirus inhibitory repeat (BIR) domain within the proteins
referred to as IAP (inhibitor-of-apoptosis) proteins, which
regulate apoptosis by inhibiting caspases. The compounds are dimer-
or trimer-like, in that they possess two or three structurally
similar binding domains. In many embodiments, each binding domain
includes a ring that is substituted by at least one aryl-containing
group --W--X, --W'--X' or --W''--X''. These binding domains are
linked by a linking group, and while similar, the domains need not
be identical. In certain embodiments, the binding domains are the
same, so the molecule is symmetric about its linking group.
[0012] In one aspect, the invention provides a compound of formula
(I):
##STR00001##
[0013] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0014] wherein b is 0 or 1;
[0015] each Q, Q' and Q'', if present, independently represents
--O-- or --NR.sup.2--, where each R.sup.2 is independently H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 heteroalkyl; or one or
more of Q, Q' and Q'' may be a bond when L comprises a ring;
[0016] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q', or Q and Q'', or Q' and Q'';
and
[0017] each D, D' and D'', if present, is independently selected
from the group consisting of
##STR00002##
[0018] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0019] each R.sup.1 is independently H or optionally substituted
C1-C8 alkyl;
[0020] each Z independently represents an optionally substituted
C1-C6 aminoalkyl group.
[0021] each Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0022] each W, where present, independently represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0023] each X, where present, independently represents an
optionally substituted C.sub.5-C.sub.20 ring system comprising at
least one aromatic ring and up to four heteroatoms selected from N,
O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring;
[0024] each n, where present, is independently 0-3;
[0025] each m, where present, is independently 0-4; and
[0026] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0027] with the proviso that, when b is 0, D and D' are not both of
the formula
##STR00003##
[0028] In some embodiments, of formula (I), when b is 0, D and D'
are not both of the formula
##STR00004##
[0029] In another aspect, the invention provides a compound of
formula (IA):
##STR00005##
[0030] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0031] wherein b is 0 or 1;
[0032] each Q, Q' and Q'', if present, independently represents
--O-- or --NR.sup.2--, where each R.sup.2 is independently H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 heteroalkyl; or one or
more of Q, Q' and Q'' may be a bond when L comprises a ring;
[0033] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q', or Q and Q'', or Q' and Q'';
and
[0034] each D, D' and D'', if present, is independently selected
from the group consisting of
##STR00006##
[0035] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted;
[0036] each R.sup.1 is independently H or optionally substituted
C1-C8 alkyl;
[0037] each Z independently represents an optionally substituted
C1-C6 aminoalkyl group.
[0038] each Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0039] each W, where present, independently represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0040] each X, where present, independently represents an
optionally substituted C.sub.5-C.sub.20 ring system comprising at
least one aromatic ring and up to four heteroatoms selected from N,
O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring;
[0041] each n, where present, is independently 0-3;
[0042] each m, where present, is independently 0-4; and
[0043] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0044] with the proviso that, when b is 0, D and D' are not both of
the formula
##STR00007##
[0045] In another aspect, the invention provides a compound of
formula (II)
D-U (II)
[0046] or a pharmaceutically acceptable salt or hydrate form
thereof;
[0047] wherein D is selected from the group consisting of
##STR00008##
[0048] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or
optionally substituted phenyl;
[0049] R.sup.1 is independently H or optionally substituted C1-C8
alkyl;
[0050] Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0051] W, where present, independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0052] X, where present, independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W, provided that each X comprises at
least one aryl or heteroaryl ring;
[0053] each n, where present, is independently 0-3;
[0054] each m, where present, is independently 0-4; and
[0055] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0056] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form;
and
[0057] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted.
[0058] In another aspect, the invention provides a compound of
formula (IIA)
D-U (IIA)
[0059] or a pharmaceutically acceptable salt or hydrate form
thereof;
[0060] wherein D is selected from the group consisting of
##STR00009##
[0061] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted;
[0062] R.sup.1 is independently H or optionally substituted C1-C8
alkyl;
[0063] Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0064] W, where present, independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0065] X, where present, independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W, provided that each X comprises at
least one aryl or heteroaryl ring;
[0066] each n, where present, is independently 0-3;
[0067] each m, where present, is independently 0-4; and
[0068] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0069] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form;
and
[0070] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted.
[0071] In another aspect, the invention provides a compound of
formula (I):
##STR00010##
[0072] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0073] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0074] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y or Y' groups can cyclize to form a 3-6 membered ring that can
be saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0075] each W and W' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0076] each X and X' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W or W', provided that each X and X'
comprises at least one aryl or heteroaryl ring;
[0077] each Q and Q' independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, or optionally
substituted C1-C8 alkyl, or optionally substituted C1-C8
heteroalkyl; or one or both of Q and Q' may be a bond when L
comprises a ring;
[0078] each n and n' is independently 0-3;
[0079] each m and m' is independently 0-4;
[0080] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0081] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0082] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q'.
[0083] In another aspect, the invention provides a compound of
formula (1A):
##STR00011##
[0084] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0085] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted;
[0086] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y or Y' groups can cyclize to form a 3-6 membered ring that can
be saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0087] each W and W' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0088] each X and X' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W or W', provided that each X and X'
comprises at least one aryl or heteroaryl ring;
[0089] each Q and Q' independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, or optionally
substituted C1-C8 alkyl, or optionally substituted C1-C8
heteroalkyl; or one or both of Q and Q' may be a bond when L
comprises a ring;
[0090] each n and n' is independently 0-3;
[0091] each m and m' is independently 0-4;
[0092] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0093] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0094] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q'.
[0095] In another aspect, the invention provides a compound of
formula (2):
##STR00012##
[0096] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0097] wherein each R.sub.a, R.sub.a', R.sub.a'', R.sub.b, R.sub.b'
and R.sub.b'' is independently H, or C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl, or a heteroform of one of these, each of which may
be optionally substituted; or is optionally substituted phenyl;
[0098] each Y, Y' and Y'' independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y or Y' groups can cyclize to form a 3-6 membered ring
that can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0099] each W, W' and W'' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0100] each X, X' and X'' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W, W' or W'', provided that each X, X'
and X'' comprises at least one aryl or heteroaryl ring;
[0101] each Q, Q' and Q'' independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or one or more of Q, Q' and Q'' may be a bond when L
comprises a ring;
[0102] each n, n' and n'' is independently 0-3;
[0103] each m, m' and m'' is independently 0-4;
[0104] each R.sup.1, R.sup.1' and R.sup.1'' is independently H or
optionally substituted C1-C8 alkyl;
[0105] each Z, Z' and Z'' is independently an optionally
substituted C1-C6 aminoalkyl group; and
[0106] L represents a C1-C24 hydrocarbyl linker, optionally
containing from 1-8 heteroatoms selected from N, O and S, which
linker is 1-18 atoms in length when counted along the shortest path
between Q and Q', and which linker may be optionally
substituted.
[0107] In another aspect, the invention provides a compound of
formula (3A):
##STR00013##
[0108] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0109] wherein R.sub.a is H and R.sub.b is R.sup.5;
[0110] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0111] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0112] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0113] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0114] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, or optionally substituted C1-C8 alkyl, or
optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L
comprises a ring;
[0115] m is 0-4;
[0116] p is 2-3;
[0117] Z represents an optionally substituted C1-C6 aminoalkyl
group; and
[0118] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0119] In preferred embodiments of formula (3A), Z is a C1-C6
aminoalkyl group of the formula --CH(R.sup.3)NR.sup.4.sub.2, where
R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl.
[0120] In other embodiments, R.sup.3 can cyclize with R.sup.4 on an
adjacent nitrogen atom to form an optionally substituted azacyclic
group having 5-10 ring members, which azacyclic group may be
saturated, unsaturated or aromatic, and may contain 1-2 additional
heteroatoms selected from N, O and S as a ring member.
[0121] In some embodiments of formula (3A), each R.sup.4 is
independently H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and the two R.sup.4
groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member.
[0122] In another aspect, the invention provides a compound of
formula (3):
##STR00014##
[0123] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0124] wherein R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8
alkynyl, each of which may be optionally substituted;
[0125] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0126] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0127] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0128] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, or optionally substituted C1-C8 alkyl, or
optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L
comprises a ring;
[0129] m is 0-4;
[0130] p is 2-3;
[0131] Z represents an optionally substituted C1-C6 aminoalkyl
group; and
[0132] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0133] In yet another aspect, the invention provides a compound of
formula (4):
##STR00015##
[0134] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0135] wherein R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8
alkynyl, or phenyl, each of which may be optionally
substituted;
[0136] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0137] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0138] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0139] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0140] m is 0-4;
[0141] p is 2 or 3;
[0142] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0143] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and
[0144] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0145] In still another aspect, the invention provides a compound
of formula (5):
##STR00016##
[0146] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0147] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0148] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0149] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0150] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0151] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0152] m is 0-4;
[0153] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0154] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and the two
R.sup.4 groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0155] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0156] In another aspect, the invention provides a monomer of
formula (6), and methods of using them for the preparation of
compounds of formula (1)-(5), (7)-(9), (1A) and (3A):
##STR00017##
[0157] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0158] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0159] each Y independently represents C1-C8 alkyl, .dbd.O, OR,
NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two
Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0160] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0161] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0162] n is 0-3;
[0163] m is 0-4;
[0164] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0165] Z is an optionally substituted C1-C6 aminoalkyl group;
and
[0166] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted.
[0167] In another aspect, the invention provides a compound of
formula (7):
##STR00018##
[0168] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0169] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0170] each Y independently represents C1-C8 alkyl, .dbd.O, OR,
NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two
Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0171] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0172] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that X comprises at least one aryl or heteroaryl
ring;
[0173] Q represents --O-- or --NR.sup.2--, where R.sup.2 is H,
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted;
[0174] Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is
H, C1-C4 alkyl or C1-C4 heteroalkyl;
[0175] or one or both of Q and Q' can be a bond where L comprises a
ring;
[0176] n is 0-3;
[0177] m is 0-4;
[0178] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0179] each R.sup.6 is independently H, C1-C8 alkyl, C5-C12 aryl or
C5-C12 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or is a C8-C14 bicyclic or tricyclic
ring system comprising a 5- or 6-membered saturated or partially
unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring,
which ring system may be attached to nitrogen through any available
position on the saturated or aromatic ring;
[0180] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0181] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0182] In another aspect, the invention provides a compound of
formula (8):
##STR00019##
[0183] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0184] wherein each R.sub.a, and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0185] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y or Y' groups on one azacyclic ring can cyclize to form a 3-6
membered ring that can be saturated, unsaturated or aromatic, and
which ring may include a heteroatom selected from O, S and N as a
ring member and may be optionally substituted;
[0186] each W and W' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0187] each X and X' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W or W', provided that each X and X'
comprises at least one aryl or heteroaryl ring;
[0188] Q represents --O-- or --NR.sup.2--, where R.sup.2 is H,
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted;
[0189] Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is
H, C1-C4 alkyl or C1-C4 heteroalkyl;
[0190] or one or both of Q and Q' can be a bond where L comprises a
ring;
[0191] each n and n' is 0-3;
[0192] each m and m' is 0-4;
[0193] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0194] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0195] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0196] In another aspect, the invention provides a compound of
formula (9):
##STR00020##
[0197] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0198] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0199] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0200] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0201] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that X comprises at least one aryl or heteroaryl
ring;
[0202] each Q and Q' independently represents --O-- or
--NR.sup.2--, where R.sup.2 is H, C1-C8 alkyl, C1-C8 alkenyl, or
C1-C8 alkynyl, or a heteroform of one of these, each of which may
be optionally substituted; or one or both of Q and Q' can be a bond
where L comprises a ring;
[0203] each n and n' is 0-3;
[0204] each m and m' is 0-4;
[0205] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0206] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0207] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0208] In another aspect, the invention provides compounds of
formula (10):
##STR00021##
[0209] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0210] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0211] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0212] each R.sup.6 and R.sup.6' is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0213] each Q and Q' independently represents --CH.sub.2--,
--CH(OR)--, --CH(R)--, --CH.sub.2O--, --CH(R)O-- or
--(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl or C1-C4
heteroalkyl; or one or both of Q and Q' can be a bond where L
comprises a ring;
[0214] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0215] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0216] In another aspect, the invention provides compounds of
formula (11):
##STR00022##
[0217] or a pharmaceutically acceptable salt or hydrate form
thereof, wherein p is 2-3;
[0218] wherein R.sub.a and R.sub.b are independently H or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0219] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0220] each R.sup.6 is independently H, C1-C8 alkyl, C5-C12 aryl or
C5-C12 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or is a C8-C14 bicyclic or tricyclic
ring system comprising a 5- or 6-membered saturated or partially
unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring,
which ring system may be attached to nitrogen through any available
position on the saturated or aromatic ring;
[0221] Q represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is
H, C1-C4 alkyl or C1-C4 heteroalkyl; or Q can be a bond when L
comprises a ring;
[0222] Z is an optionally substituted C1-C6 aminoalkyl group;
and
[0223] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0224] In another aspect, the invention provides compounds of
formula (12):
##STR00023##
[0225] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0226] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0227] Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H, or
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted;
[0228] W represents C.dbd.O, C.dbd.S, or an optionally substituted
C2-C6 alkylene or optionally substituted C2-C6 heteroalkylene;
[0229] X represents an optionally substituted C5-C20 ring system
comprising at least one aromatic ring and up to four heteroatoms
selected from N, O and S as a ring member, and can represent either
a single 5-15 membered cyclic group or two 5-10 membered cyclic
groups that are both attached to the same atom of W, provided that
X comprises at least one aryl or heteroaryl ring;
[0230] Q represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O--, or --(CH.sub.2).sub.4NH--, wherein R is
H, or C1-C4 alkyl or C1-C4 heteroalkyl; or Q can be a bond where L
comprises a ring;
[0231] n is 0-3;
[0232] m is 0-4;
[0233] Z represents an optionally substituted C1-C6 aminoalkyl
group; and
[0234] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0235] In another aspect, the invention provides compounds of
formula (13):
##STR00024##
[0236] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0237] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0238] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0239] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, or C1-C8 alkyl or C1-C8 heteroalkyl, each of
which may be optionally substituted;
[0240] each Q and Q' independently represents --O-- or
--NR.sup.2--, where R.sup.2 is H, C1-C8 alkyl, C1-C8 alkenyl, or
C1-C8 alkynyl, or a heteroform of one of these, each of which may
be optionally substituted; or one or both of Q and Q' can be a bond
where L comprises a ring;
[0241] each n and n' is 1-3;
[0242] each m and m' is 0-4;
[0243] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0244] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0245] In one aspect, the invention provides compounds of formula
(13A):
##STR00025##
[0246] or a pharmaceutically acceptable salt or hydrate form
thereof; and including any stereoisomeric forms thereof;
[0247] wherein each Y and Y' independently represents an optionally
substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these; or is .dbd.O, OR, SR, S(O)R, SO.sub.2R,
SO.sub.2NR.sub.2, NR.sub.2, OC(O)R, NRC(O)R, NRCOOR,
NRC(O)NR.sub.2, NRSO.sub.2R, CN, C(O)NR.sub.2, C(O)R, COOR,
NO.sub.2 or halo, wherein each R is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these
each of which may be optionally substituted; or is any other
substituent suitable for an alkyl group;
[0248] and wherein two Y or Y' groups on the same ring can cyclize
to form a 3-6 membered ring that can be saturated, unsaturated or
aromatic, and which ring may include one heteroatom selected from
O, S and N as a ring member and may be optionally substituted;
[0249] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0250] each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H, or C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl,
C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of
one of these, each of which may be optionally substituted; or
[0251] R.sub.a and R.sub.b, or R.sub.a' and R.sub.b' may be taken
together with the carbon atom to which they are attached to form an
optionally substituted 3-7 membered ring, optionally containing one
heteroatom selected from N, O and S as a ring member;
[0252] Q is --O-- or --NR.sup.2--, and Q' is --O-- or
--NR.sup.2'--; wherein Q and Q' are independently selected, and
where each R.sup.2 and R.sup.2' is H, C1-C8 alkyl, C1-C8 alkenyl,
or C1-C8 alkynyl, or a heteroform of one of these, each of which
may be optionally substituted; or one or both of Q and Q' can be a
bond where L comprises a ring;
[0253] each n and n' is independently 1-3;
[0254] each m and m' is independently 0-4;
[0255] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0256] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1 to 18 atoms in length when counted along
the shortest path between Q and Q';
[0257] with the proviso that L does not comprise a disulfide
bond.
[0258] In another aspect, the invention provides a compound of
formula (13B):
##STR00026##
[0259] or a pharmaceutically acceptable salt or hydrate form
thereof; and including any stereoisomeric forms thereof;
[0260] wherein each Y and Y' independently represents an optionally
substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these; or is .dbd.O, OR, SR, S(O)R, SO.sub.2R,
SO.sub.2NR.sub.2, NR.sub.2, OC(O)R, NRC(O)R, NRCOOR,
NRC(O)NR.sub.2, NRSO.sub.2R, CN, C(O)NR.sub.2, C(O)R, COOR,
NO.sub.2 or halo, wherein each R is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
or is any other substituent suitable for an alkyl group;
[0261] and wherein two Y or Y' groups on the same ring can cyclize
to form a 3-6 membered ring that can be saturated, unsaturated or
aromatic, and which ring may include one heteroatom selected from
O, S and N as a ring member and may be optionally substituted;
[0262] each m and m' is independently is 0-4;
[0263] each n and n' is independently 0-3;
[0264] each R.sup.1, R.sup.2, R.sup.1' and R.sup.2 is independently
H or optionally substituted C1-C8 alkyl;
[0265] each R.sub.a, R.sub.a', R.sub.b, R.sub.b', R.sup.3A,
R.sup.3A', R.sup.4A and R.sup.4A' is independently H, or C1-C8
alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl,
C5-C20 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or
[0266] R.sub.a and R.sub.b, R.sub.a' and R.sub.b', R.sup.3A and
R.sup.4A, or R.sup.3A' and R.sup.4A' may be taken together with the
carbon atom to which they are attached to form an optionally
substituted 3-7 membered ring, optionally containing one heteroatom
selected from N, O and S as a ring member;
[0267] each Z and Z' is independently an optionally substituted
C1-C6 aminoalkyl;
[0268] each J and J' independently represents --CH.sub.2--,
--CH(OR')--, --CH(R')--, --(CH.sub.2).sub.rG-, --CH(R')G- or
--CR'.dbd.CR'-- or --C.ident.C--, wherein r is 1-4, each G is
independently O, NR', or S, and wherein each R' is independently H,
or C1-C8 alkyl or C1-C8 heteroalkyl; or one or both of J and J' can
be a bond where K comprises a ring; and
[0269] K represents an optionally substituted C1-C20 hydrocarbyl
linker, optionally containing from 1-6 heteroatoms selected from N,
O and S, which linker is 1 to 14 atoms in length when counted along
the shortest path between J and J';
[0270] with the proviso that K does not comprise a disulfide
bond.
[0271] In another aspect, the invention provides a compound of
formula (2):
##STR00027##
[0272] or a pharmaceutically acceptable salt or hydrate form
thereof; and including any stereoisomeric forms thereof;
[0273] wherein each Y independently represents an optionally
substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these; or is .dbd.O, OR, SR, S(O)R, SO.sub.2R,
SO.sub.2NR.sub.2, NR.sub.2, OC(O)R, NRC(O)R, NRCOOR,
NRC(O)NR.sub.2, NRSO.sub.2R, CN, C(O)NR.sub.2, C(O)R, COOK,
NO.sub.2 or halo, wherein each R is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
or is any other substituent suitable for an alkyl group;
[0274] m is 0-4;
[0275] n is 0-3;
[0276] each R.sup.1 and R.sup.2 is independently H or optionally
substituted C1-C4 alkyl;
[0277] each R.sub.a, R.sub.b, R.sup.3A and R.sup.4A is
independently H, or C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl,
C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of
one of these, each of which may be optionally substituted;
[0278] Z is a 1-aminoalkyl group represented by the formula
--CH(R.sup.3)NR.sup.4.sub.2;
[0279] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and the two
R.sup.4 groups on one nitrogen can cyclize to form an optionally
substituted 3-8 membered azacyclic ring, which azacyclic ring may
be saturated, unsaturated or aromatic, and may contain 1-2
additional heteroatoms selected from N, O and S as ring
members;
[0280] each R.sup.3 is H, or an optionally substituted C1-C8 alkyl
or C1-C8 heteroalkyl group, and R.sup.3 can cyclize with R.sup.4 on
an adjacent nitrogen atom to form an optionally substituted 3-8
membered azacyclic ring, which azacyclic ring may be saturated,
unsaturated or aromatic, and may contain 1-2 additional heteroatoms
selected from N, O and S as ring members;
[0281] J is selected from the group consisting of --CH.sub.2--,
--CH(R')--, --(CH.sub.2).sub.rG-, and --CH(R')G-, wherein r is 1-4,
each G is independently O or NR', and wherein each R' is
independently H or C1-C4 alkyl; or J can be a bond where K
comprises a ring; and
[0282] K represents a C1-C10 alkylene, C3-C10 cycloalkylene, C2-C10
alkenylene, C2-C10 alkynylene, C5-C12 arylene, or C5-C20
arylalkylene, C5-C20 arylalkenylene or C5-C20 arylalkynylene
linker, or a heteroform of one of these, each of which may be
optionally substituted;
[0283] with the proviso that K does not comprise a disulfide
bond.
[0284] In a further aspect, the invention provides a compound of
formula (13D):
##STR00028##
[0285] or a pharmaceutically acceptable salt or hydrate form
thereof;
[0286] wherein each R.sup.1 and R.sup.2 is independently H or
methyl;
[0287] R.sub.a and R.sup.3A are H;
[0288] each R.sub.b and R.sup.4A is independently H, or C1-C8
alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl,
C5-C20 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted;
[0289] Z is a 1-aminoalkyl group represented by the formula
--CH(R.sup.3)NR.sup.4.sub.2;
[0290] each R.sup.3 and R.sup.4 is independently H or C1-C4
alkyl;
[0291] J is selected from the group consisting of --CH.sub.2--,
--CH(R')--, --(CH.sub.2).sub.rG-, and --CH(R')G-, wherein r is 1-4,
each G is independently O or NR', and wherein each R' is
independently H or C1-C4 alkyl; or J can be a bond where K
comprises a ring; and
[0292] K represents a C1-C10 alkylene, C3-C10 cycloalkylene, C2-C10
alkenylene, C2-C10 alkynylene, C5-C12 arylene, or C5-C20
arylalkylene, C5-C20 arylalkenylene or C5-C20 arylalkynylene
linker, or a heteroform of one of these, each of which may be
optionally substituted;
[0293] with the proviso that K does not comprise a disulfide
bond.
[0294] In another aspect, the invention provides a compound
selected from the group consisting of:
##STR00029##
[0295] or a pharmaceutically acceptable salt or hydrate form
thereof.
[0296] In another aspect, the invention provides compounds of
formula (14):
##STR00030##
[0297] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0298] wherein p is 2 or 3;
[0299] R.sup.5 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or
phenyl, each of which may be optionally substituted;
[0300] Q represents --O-- or --NR.sup.2--, where R.sup.2 is H,
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted; or Q can be a bond where L comprises a ring;
[0301] Z is an optionally substituted C1-C6 aminoalkyl group;
and
[0302] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0303] In another aspect, the invention provides compounds of
formula (15):
##STR00031##
[0304] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0305] wherein R.sub.a and R.sub.b are independently H or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0306] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0307] each R.sup.6 is independently H, C1-C8 alkyl, C5-C12 aryl or
C5-C12 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or is a C8-C14 bicyclic or tricyclic
ring system comprising a 5- or 6-membered saturated or partially
unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring,
which ring system may be attached to nitrogen through any available
position on the saturated or aromatic ring;
[0308] Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H, or
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted;
[0309] Q represents --O-- or --NR.sup.2--, where R.sup.2 is H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl;
[0310] Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is
H, C1-C4 alkyl or C1-C4 heteroalkyl;
[0311] or one or both of Q and Q' can be a bond when L comprises a
ring;
[0312] n is 1-3;
[0313] m is 0-4;
[0314] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0315] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0316] In another aspect, the invention provides compounds of
formula (16):
##STR00032##
[0317] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0318] wherein R.sub.a and R.sub.b are independently H or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0319] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0320] each R.sup.6 is independently H, C1-C8 alkyl, C5-C12 aryl or
C5-C12 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or is a C8-C14 bicyclic or tricyclic
ring system comprising a 5- or 6-membered saturated or partially
unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring,
which ring system may be attached to nitrogen through any available
position on the saturated or aromatic ring;
[0321] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, or C1-C8 alkyl or C1-C8 heteroalkyl, each of
which may be optionally substituted;
[0322] W' represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0323] X' represents an optionally substituted C.sub.5-C.sub.20
ring system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W', provided that X' comprises at least one aryl or heteroaryl
ring;
[0324] Q represents --O-- or --NR.sup.2--, where R.sup.2 is H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl;
[0325] Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--,
--CH.sub.2O--, --CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is
H, C1-C4 alkyl or C1-C4 heteroalkyl;
[0326] or one or both of Q and Q' can be a bond when L comprises a
ring;
[0327] each n and n' is 1-3;
[0328] each m and m' is 0-4;
[0329] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0330] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0331] In another aspect, the invention provides monomers of
formula (17) and methods of using them for the preparation of
compounds of formula (7), (10)-(11) and (15):
##STR00033##
[0332] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0333] wherein R.sub.a and R.sub.b are independently H or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0334] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0335] each R.sup.6 is independently H, C1-C8 alkyl, C5-C12 aryl or
C5-C12 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted; or is a C8-C14 bicyclic or tricyclic
ring system comprising a 5- or 6-membered saturated or partially
unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring,
which ring system may be attached to nitrogen through any available
position on the saturated or aromatic ring;
[0336] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sub.2, azido or halo,
where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted; and
[0337] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[0338] In another aspect, the invention provides a monomer of
formula (18) and methods of using them for the preparation of
compounds of formula (8), (12) and (16):
##STR00034##
[0339] or a pharmaceutically acceptable salt or hydrate form
thereof; and including any stereoisomeric forms thereof;
[0340] wherein R.sup.1 is H or optionally substituted C1-C8
alkyl;
[0341] Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H, or
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted; and wherein two Y groups can cyclize to form a 3-6
membered ring that can be saturated, unsaturated or aromatic, and
which ring may include a heteroatom selected from O, S and N as a
ring member and may be substituted;
[0342] W represents C.dbd.O, C.dbd.S, or an optionally substituted
C2-C6 alkylene or C2-C6 heteroalkylene;
[0343] X represents an optionally substituted C5-C20 ring system
comprising at least one aromatic ring and up to four heteroatoms
selected from N, O and S as a ring member, and can represent either
a single 5-15 membered cyclic group or two 5-10 membered cyclic
groups that are both attached to the same atom of W, provided that
each X comprises at least one aryl or heteroaryl ring;
[0344] n is 0-3;
[0345] m is 0-4;
[0346] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted; with the proviso that U is not
isopropyl; and
[0347] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[0348] In another aspect, the invention provides monomers of
formula (19) and methods of using them for the preparation of
compounds of formula (9) and (13)-(16):
##STR00035##
[0349] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0350] wherein R.sub.a and R.sub.b are independently H or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0351] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0352] Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H, or
C1-C8 alkyl or C1-C8 heteroalkyl, each of which may be optionally
substituted; and wherein two Y groups can cyclize to form a 3-6
membered ring that can be saturated, unsaturated or aromatic, and
which ring may include a heteroatom selected from O, S and N as a
ring member and may be substituted;
[0353] n is 1-3;
[0354] m is 0-4;
[0355] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted; and
[0356] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[0357] In another aspect, the invention provides monomers of
formula (19A) and methods of using them for the preparation of
compounds of formula (13A)-(13D):
##STR00036##
[0358] or a pharmaceutically acceptable salt or hydrate form
thereof; and including any stereoisomeric forms thereof;
[0359] wherein each Y independently represents an optionally
substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these; or is .dbd.O, OR, SR, S(O)R, SO.sub.2R,
SO.sub.2NR.sub.2, NR.sub.2, OC(O)R, NRC(O)R, NRCOOR,
NRC(O)NR.sub.2, NRSO.sub.2R, CN, C(O)NR.sub.2, C(O)R, COOR,
NO.sub.2 or halo, wherein each R is independently H, C1-C8 alkyl,
C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
or is any other substituent suitable for an alkyl group;
[0360] and wherein two Y groups on the same ring can cyclize to
form a 3-6 membered ring that can be saturated, unsaturated or
aromatic, and which ring may include one heteroatom selected from
O, S and N as a ring member and may be optionally substituted;
[0361] m is 0-4;
[0362] n is 0-3;
[0363] each R.sup.1 and R.sup.2 is independently H or optionally
substituted C1-C8 alkyl;
[0364] each R.sub.a, R.sub.b R.sup.3A and R.sup.4A is independently
H, or C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl,
C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted; or
[0365] R.sub.a and R.sub.b, or R.sup.3A and R.sup.4A may be taken
together with the carbon atom to which they are attached to form an
optionally substituted 3-7 membered ring, optionally containing one
heteroatom selected from N, O and S as a ring member;
[0366] V represents a C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8
alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl,
C5-C12 aryl, C5-C12 heteroaryl, C5-C20 arylalkyl or C5-C20
heteroarylalkyl, each of which may be optionally substituted with
--OR.sup.9, --OC(O)R.sup.9, --OSO.sub.2R.sup.9, C.dbd.O,
--OC(O)OR.sup.9, --COOR.sup.8, --NR.sup.9.sub.2, azido or halo,
where each R.sup.9 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; and
[0367] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[0368] The compounds of the invention synergize with TRAIL
(TNF-related apoptosis inducing ligand), with etoposide, with
TRAIL-related substances including a TRAIL receptor antibody or
TNF-.alpha., and with anti-cancer drugs to overcome the
apoptosis-inhibiting activity of caspase inhibiting proteins.
Without being bound by theory, the present compounds are believed
to act by binding to IAP, thus preventing IAP from binding to and
inhibiting caspases. This frees the caspases to initiate apoptosis.
Accordingly, the compounds of the invention can promote apoptosis
in cells that are abnormally resistant to it, which are typically
pathogenic cells.
[0369] For example, compounds of the invention induce apoptosis in
glioblastoma cell culture, typically at picomolar concentrations.
The compounds provide new adjuvant chemotherapeutics for cancers,
particularly those that resist programmed cell death by
over-expressing IAP proteins. The compounds are stable, protease
resistant, and freely membrane permeant. The compounds are not by
themselves cytotoxic, however, they are believed to operate by
overcoming protective mechanisms that some pathogenic cells such as
cancer cells use to prevent apoptosis.
[0370] Accordingly, the invention also provides methods and
compositions for enhancing apoptosis of pathogenic cells using
pro-apoptotic dimer-like or trimer-like small molecules that are
referred to as Smac mimetics. The invention also includes
pharmaceutical compositions comprising at least one compound of any
of formulae (1)-(5) and (7)-(16) admixed with at least one
pharmaceutically acceptable excipient. Also included are
pharmaceutical compositions comprising at least one compound of
formulae (I), (IA), (1A), (3A) and (13A)-(13D) admixed with at
least one pharmaceutically acceptable excipient.
[0371] Compounds of the invention are useful for the treatment or
amelioration of cancer, inflammation, or autoimmune disorders.
Provided herein are methods for the use of a dimeric or trimeric
SMAC mimetic compound for the treatment or amelioration of cancer,
inflammation, or an autoimmune disorder, wherein the dimeric or
trimeric SMAC mimetic compound is a compound as defined in any one
of formulae (I), (IA), (1), (1A), (2)-(5), (7)-(13), (13A), and
(14)-(16). In other embodiments, the invention provides methods for
the use of the compounds of the dimeric and trimeric SMAC mimetics
of the present invention for enhancing or inducing apoptosis. In
another aspect, the invention provides pharmaceutical compositions
comprising a dimeric or trimeric SMAC mimetic compound, useful for
the treatment or amelioration of cancer, inflammation, or an
autoimmune disorder, and at least one pharmaceutically acceptable
excipient, wherein the dimeric or trimeric SMAC mimetic compound is
a compound as defined in any one of formulae (I), (IA), (1), (1A),
(2)-(5), (7)-(13), (13A), and (14)-(16)
[0372] In some embodiments, the pharmaceutical compositions further
include at least one additional cancer therapeutic whose activity
is synergized or potentiated by the Smac mimetic activity of the
compounds of the invention. Examples of such additional cancer
therapeutics include, without limitation, antimetabolites (e.g.
cytarabine, fludaragine, 5-fluoro-2'-deoxyuridine, gemcitabine,
hydroxyurea and methotrexate), DNA active agents (e.g. bleomycin,
chlorambucil, cisplatin and cyclophosphamide), intercalating agents
(e.g. adriamycin and mitoxantrone), protein synthesis inhibitors
(e.g. L-asparaginase, cycloheximide and puromycin); topoisomerase
inhibitors of Type I class (e.g. camptothecin, topotecan and
irinotecan) and Type II class (e.g. etoposide, teniposide
anthraquinones, anthracyclines and podophyllotoxin), microtubule
inhibitors (e.g. docetaxel, paclitaxel, colcemid, colchicines,
vinblastine and vincristine), kinase inhibitors (e.g. flavopiridol,
staurosporin and hydroxystaurosporine), drugs that affect Hsp90
(e.g. geldanomycin and geldanomycin derivatives, radicicol, purine
derivatives and antibodies or antibody fragments that selectively
bind to Hsp90), and/or radiation therapy. In some embodiments, the
additional cancer therapeutic agent is TRAIL, etoposide, a TRAIL
receptor antibody, a Hsp90 inhibitor, TNF-.alpha. or
TNF-.beta..
[0373] The general method for enhancing or inducing apoptosis
comprises the step of contacting a cell with an effective amount of
a Smac mimetic compound, optionally followed by the step of
detecting, directly, indirectly or inferentially, a resultant
increase in apoptosis of the target cells. It may also include a
step of identifying or diagnosing a subject in need of such
treatment, particularly a subject having one of the conditions
described herein as being treated or alleviated by a Smac
mimetic.
[0374] In preferred embodiments, the cells are in situ in an
individual diagnosed as in need of an apoptosis promoting
treatment, and the contacting step is effected by administering to
the individual a pharmaceutical composition including a
therapeutically effective amount of the Smac mimetic, wherein the
individual may be subject to concurrent or antecedent radiation or
chemotherapy for treatment of a neoproliferative pathology. In
particular embodiments, the pathogenic cells are of a tumor, such
as glioblastoma, astrocytoma, breast cancer, prostate cancer, lung
cancer, pancreatic cancer, gastric cancer, colon cancer, ovarian
cancer, renal cancer, hepatoma, melanoma, lymphoma, or sarcoma.
[0375] In additional embodiments, the target cells are
pro-inflammatory cells or cells of tissue subject to pathogenic
inflammation and/or autoimmunity. A wide variety of diseases
involve such pathogenic inflammation, including rheumatoid
arthritis, diabetes, asthma, lupus, myasthenia gravis, Graves
disease, inflammatory bowel disease (e.g. Crohn's disease,
ulcerative colitis and related conditions), pelvic inflammatory
diseases, chronic obstructive pulmonary disease (COPD), chronic
bronchitis, pneumoconiosis, pulmonary emphysema, interstitial lung
fibrosis, allergic rhinitis (hay fever), inflammatory
cardiovascular diseases (e.g. congestive heart failure and
ischemia/reperfusion injuries), atherosclerosis (including coronary
artery disease), stroke, neurodegenerative diseases, such as
Alzheimer's disease, multiple sclerosis and amyotrophic lateral
sclerosis (ALS), neuroinflammatory diseases, organ transplant
rejection, autoimmune hematological disorders, psoriasis,
sclerodoma, chronic active hepatitis, primary biliary cirrhosis,
glomerulonephritis, uveitis and keratoconjunctivitis.
[0376] The subject compositions encompass pharmaceutical
compositions containing a therapeutically effective amount of an
active, dimer-like or trimer-like Smac mimetic as described above
in dosage form, and a pharmaceutically acceptable carrier. In some
embodiments, such compositions also contain an additional
therapeutic agent, such as an anti-neoproliferative
chemotherapeutic agent, in addition to the Smac mimetic.
MODES OF CARRYING OUT THE INVENTION
[0377] The present invention may be understood more readily by
reference to the following detailed description of the preferred
embodiments of the invention and the Examples included herein. It
is to be understood that the terminology used herein is for the
purpose of describing specific embodiments only and is not intended
to be limiting. It is further to be understood that unless
specifically defined herein, the terminology used herein is to be
given its traditional meaning as known in the relevant art.
[0378] As used herein, the singular form "a", "an", and "the"
include plural references unless indicated otherwise. For example,
"a" dimer includes one of more dimers.
[0379] As used herein, a "therapeutically effective amount" is an
amount required to produce a desired therapeutic effect in a
tissue, system, animal, or human, that is being sought, e.g., by a
researcher or clinician. Furthermore, the term "therapeutically
effective amount" means any amount which, as compared to a
corresponding subject who has not received such amount, results in
improved treatment, healing, prevention, or amelioration of a
disease, disorder, or side effect, or a decrease in the rate of
advancement of a disease or disorder. The term also includes within
its scope amounts effective to enhance normal physiological
function.
[0380] As used herein, "subject" refers to a human or animal
subject. In certain preferred embodiments, the subject is
human.
[0381] As used herein, "hydrocarbyl residue" refers to a residue
which contains only carbon and hydrogen, unless otherwise provided.
The residue may be aliphatic or aromatic, straight-chain, cyclic,
branched, saturated or unsaturated, or any combination of these.
The hydrocarbyl residue, when so stated, however, may contain
heteroatoms in addition to or instead of the carbon and hydrogen
members of the hydrocarbyl group itself. Thus, when specifically
noted as containing or optionally containing heteroatoms, the
hydrocarbyl group may contain one or more heteroatoms as indicated
within the "backbone" of the hydrocarbyl residue, and when
optionally substituted, the hydrocarbyl residue may also have one
or more carbonyl groups, amino groups, hydroxyl groups and other
suitable substituents as further described herein in place of one
or more hydrogens of the parent hydrocarbyl residue.
[0382] As used herein, the terms "alkyl," "alkenyl" and "alkynyl"
include straight-chain, branched-chain and cyclic monovalent
hydrocarbyl radicals, and combinations of these, which contain only
C and H when they are unsubstituted. Examples include methyl,
ethyl, isobutyl, tert-butyl, cyclohexyl, cyclopentylethyl,
2-propenyl, 3-butynyl, and the like. The total number of carbon
atoms in each such group is sometimes described herein, e.g., when
the group can contain up to ten carbon atoms it may be described as
1-10C or as C1-C10 or as C.sub.1-10. When heteroatoms (typically N,
O and S) are allowed to replace carbon atoms of an alkyl, alkenyl
or alkynyl group, as in heteroalkyl groups, for example, the
numbers describing the group, though still written as e.g. C1-C6,
represent the sum of the number of carbon atoms in the group plus
the number of such heteroatoms that are included as replacements
for carbon atoms in the ring or chain being described.
[0383] Typically, the alkyl, alkenyl and alkynyl substituents of
the invention contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl).
Preferably they contain 1-8C (alkyl) or 2-8C (alkenyl or alkynyl).
Sometimes they contain 1-4C (alkyl) or 2-4C (alkenyl or alkynyl). A
single group can include more than one type of multiple bond, or
more than one multiple bond; such groups are included within the
definition of the term "alkenyl" when they contain at least one
carbon-carbon double bond, and they are included within the term
"alkynyl" when they contain at least one carbon-carbon triple
bond.
[0384] Alkyl, alkenyl and alkynyl groups are often substituted to
the extent that such substitution makes sense chemically. Typical
substituents include, but are not limited to, halo, .dbd.O,
.dbd.N--CN, .dbd.N--OR, .dbd.NR, OR, NR.sub.2, SR, SO.sub.2R,
SO.sub.2NR.sub.2, NRSO.sub.2R, NRCONR.sub.2, NRCOOR, NRCOR, CN,
COOR, CONR.sub.2, OOCR, COR, and NO.sub.2, wherein each R is
independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8
heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl,
C2-C8 heteroalkynyl, C5-C12 aryl, or C5-C12 heteroaryl, and each R
is optionally substituted with one or more groups selected from
halo, .dbd.O, .dbd.N--CN, .dbd.N--OR', .dbd.NR', OR', NR'.sub.2,
SR', SO.sub.2R', SO.sub.2NR'.sub.2, NR'SO.sub.2R', NR'CONR'.sub.2,
NR'COOR', NR'COR', CN, COOR', CONR'.sub.2, OOCR', COR' and
NO.sub.2, wherein each R' is independently H, C1-C8 alkyl, C2-C8
heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C5-C12 aryl or C5-C12
heteroaryl. Alkyl, alkenyl and alkynyl groups can also be
substituted by C1-C8 acyl, C2-C8 heteroacyl, C5-C12 aryl or C5-C12
heteroaryl, each of which can be substituted by the substituents
that are appropriate for the particular group.
[0385] "Heteroalkyl", "heteroalkenyl", and "heteroalkynyl" and the
like are defined similarly to the corresponding hydrocarbyl (alkyl,
alkenyl and alkynyl) groups, but the `hetero` terms refer to groups
that contain one or more heteroatoms selected from O, S and N and
combinations thereof, within the backbone residue; thus at least
one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group
is replaced by one of the specified heteroatoms to form a
heteroalkyl, heteroalkenyl, or heteroalkynyl group. Preferably,
each heteroalkyl, heteroalkenyl and heteroalkynyl group contains
only 1-2 heteroatoms as part of the skeleton of backbone of the
heteroalkyl group, i.e., not including substituents that may be
present.
[0386] The typical and preferred sizes for heteroforms of alkyl,
alkenyl and alkynyl groups are generally the same as for the
corresponding hydrocarbyl groups, and the substituents that may be
present on the heteroforms are the same as those described above
for the hydrocarbyl groups. Where such groups contain N, the
nitrogen atom may be present as NH or it may be optionally
substituted if the heteroalkyl or similar group is described as
optionally substituted. Where such groups contain S, the sulfur
atom may optionally be oxidized to SO or SO.sub.2 unless otherwise
indicated. For reasons of chemical stability, it is also understood
that, unless otherwise specified, such groups do not include more
than two contiguous heteroatoms as part of the heteroalkyl chain,
although an oxo group may be present on N or S as in a nitro or
sulfonyl group. Thus --C(O)NH.sub.2 can be a C2 heteroalkyl group
substituted with .dbd.O; and --SO.sub.2NH-- can be a C2
heteroalkylene, where S replaces one carbon, N replaces one carbon,
and S is substituted with two .dbd.O groups.
[0387] While "alkyl" as used herein includes cycloalkyl and
cycloalkylalkyl groups, the term "cycloalkyl" may be used herein to
specifically describe a carbocyclic non-aromatic group that is
connected via a ring carbon atom, and "cycloalkylalkyl" may be used
to describe a carbocyclic non-aromatic group that is connected to
the base molecule through an alkyl linker. Similarly,
"heterocyclyl" may be used to describe a non-aromatic cyclic group
that contains at least one heteroatom as a ring member and that is
connected to the molecule via a ring atom of the cyclic group,
which may be C or N; and "heterocyclylalkyl" may be used to
describe such a group that is connected to another molecule through
an alkyl linker. The sizes and substituents that are suitable for
the cycloalkyl, cycloalkylalkyl, heterocyclyl, and
heterocyclylalkyl groups are the same as those described above for
alkyl groups. The size of a cycloalkylalkyl or heterocyclylalkyl
group describes the total number of carbon atoms or of carbon atoms
plus heteroatoms that replace carbon atoms of an alkyl, alkenyl,
alkynyl, cycloalkyl, or alkylenyl portion. As used herein, these
terms also include rings that contain a double bond or two, as long
as the ring is not aromatic. As used herein, cycloalkyl may also
include bridged carbocyclic ring systems, such as the adamantyl
ring system.
[0388] As used herein, "acyl" encompasses groups comprising an
alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one
of the two available valence positions of a carbonyl carbon atom,
e.g., --C(.dbd.O)R where R is an alkyl, alkenyl, alkynyl, aryl, or
arylalkyl group, and heteroacyl refers to the corresponding groups
wherein at least one carbon other than the carbonyl carbon has been
replaced by a heteroatom chosen from N, O and S. Thus heteroacyl
includes, for example, --C(.dbd.O)OR and --C(.dbd.O)NR.sub.2 as
well as --C(.dbd.O)-heteroaryl.
[0389] Acyl and heteroacyl groups are bonded to any group or
molecule to which they are attached through the open valence of the
carbonyl carbon atom. Typically, they are C1-C8 acyl groups, which
include formyl, acetyl, pivaloyl, and benzoyl, and C2-C8 heteroacyl
groups, which include methoxyacetyl, ethoxycarbonyl, and
4-pyridinoyl. The hydrocarbyl groups, aryl groups, and heteroforms
of such groups that comprise an acyl or heteroacyl group can be
substituted with the substituents described herein as generally
suitable substituents for each of the corresponding component of
the acyl or heteroacyl group.
[0390] "Aromatic" moiety or "aryl" moiety refers to a monocyclic or
fused bicyclic moiety having the well-known characteristics of
aromaticity; examples include phenyl and naphthyl. Similarly,
"heteroaromatic" and "heteroaryl" refer to such monocyclic or fused
bicyclic ring systems which contain as ring members one or more
heteroatoms selected from O, S and N. The inclusion of a heteroatom
permits aromaticity in 5-membered rings as well as 6-membered
rings.
[0391] Typical heteroaromatic systems include monocyclic C5-C6
aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
triazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl,
thiadiazolyl, oxadiazolyl, and tetrazolyl rings, and the fused
bicyclic moieties formed by fusing one of these monocyclic groups
with a phenyl ring or with any of the heteroaromatic monocyclic
groups to form a C8-C12 bicyclic group such as indolyl,
benzimidazolyl, indazolyl, benzotriazolyl, isoquinolinyl,
quinolinyl, benzothiazolyl, benzofuranyl, benzothienyl,
benzisoxazolyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl,
cinnolinyl, and the like. Any monocyclic or fused ring bicyclic
system which has the characteristics of aromaticity in terms of
electron distribution throughout the ring system is included in
this definition. It also includes bicyclic groups where at least
the ring which is directly attached to the remainder of the
molecule has the characteristics of aromaticity, even though it may
be fused to a nonaromatic ring, such as tetrahydronaphthyl,
indanyl, fluorenyl, and the like. Typically, the ring systems
contain 5-12 ring member atoms. Preferably the monocyclic
heteroaryl groups contain 5-6 ring members, and the bicyclic
heteroaryls contain 8-12 ring members.
[0392] Aryl and heteroaryl moieties may be optionally substituted
with a variety of substituents including C1-C8 alkyl, C2-C8
alkenyl, C2-C8 alkynyl, C5-C12 aryl, C1-C8 acyl, and heteroforms of
these, each of which can itself be further substituted; other
substituents for aryl and heteroaryl moieties include halo, OR,
NR.sub.2, SR, SO.sub.2R, SO.sub.2NR.sub.2, NRSO.sub.2R,
NRCONR.sub.2, NRCOOR, NRCOR, CN, COOR, CONR.sub.2, OOCR, --C(O)R,
and NO.sub.2, wherein each R is independently H, C1-C8 alkyl, C2-C8
heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl,
C2-C8 heteroalkynyl, C5-C12 aryl, C5-C12 heteroaryl, C5-C21
arylalkyl, or C5-C21 heteroarylalkyl, and each R is optionally
substituted as described above for alkyl groups.
[0393] Preferred optional substituents when present on an aryl or
heteroaryl ring include optionally halogenated alkyl (C1-C4),
optionally halogenated alkoxy (C1-C4), halo, --NH.sub.2, --OH,
--CN, --NO.sub.2, and NR.sub.2, where each R is independently H or
C1-4 alkyl.
[0394] The substituent groups on an aryl or heteroaryl group may of
course be further substituted with the groups described herein as
suitable for each type of group that comprises the substituent.
Thus, for example, an arylalkyl substituent may be optionally
substituted on the aryl portion with substituents described herein
as typical for aryl groups, and it may be further substituted on
the alkyl portion with substituents described herein as typical or
suitable for alkyl groups.
[0395] Similarly, "arylalkyl" and "heteroarylalkyl" refer to
aromatic and heteroaromatic ring systems which are bonded to their
attachment point through a linking group such as an alkylene,
including substituted or unsubstituted, saturated or unsaturated,
cyclic or acyclic linkers. Typically the linker is C1-C8 alkyl or a
hetero form thereof. These linkers may also include a carbonyl
group, thus making them able to provide substituents as an acyl or
heteroacyl moiety.
[0396] An aryl or heteroaryl ring in an arylalkyl or
heteroarylalkyl group may be optionally substituted with the same
substituents described above for aryl groups. Preferably, an
arylalkyl group includes a phenyl ring optionally substituted with
the groups defined above for aryl groups and a C1-C8 alkylene that
is unsubstituted or is substituted with one or two C1-C4 alkyl
groups or heteroalkyl groups, where the alkyl or heteroalkyl groups
can optionally cyclize to form a ring such as cyclopropane,
dioxolane, or oxacyclopentane.
[0397] Similarly, a heteroarylalkyl group preferably includes a
C5-C6 monocyclic heteroaryl group that is optionally substituted
with the groups described above as substituents typical on aryl
groups and a C1-C8 alkylene that is unsubstituted or is substituted
with one or two C1-C4 alkyl groups or heteroalkyl groups, or it
includes an optionally substituted phenyl ring or C5-C6 monocyclic
heteroaryl and a C1-C8 heteroalkylene that is unsubstituted or is
substituted with one or two C1-C4 alkyl or heteroalkyl groups,
where the alkyl or heteroalkyl groups can optionally cyclize to
form a ring such as cyclopropane, dioxolane, or
oxacyclopentane.
[0398] Where an arylalkyl or heteroarylalkyl group is described as
optionally substituted, the substituents may be on either the alkyl
or heteroalkyl portion or on the aryl or heteroaryl portion of the
group. The substituents optionally present on the alkyl or
heteroalkyl portion are the same as those described above for alkyl
groups generally; the substituents optionally present on the aryl
or heteroaryl portion are the same as those described above for
aryl groups generally.
[0399] "Arylalkyl" groups as used herein are hydrocarbyl groups if
they are unsubstituted, and are described by the total number of
carbon atoms in the ring and alkylene or similar linker. Thus a
benzyl group is a C7-arylalkyl group, and phenylethyl is a
C8-arylalkyl.
[0400] "Heteroarylalkyl" as described above refers to a moiety
comprising an aryl group that is attached through a linking group,
and differs from "arylalkyl" in that at least one ring atom of the
aryl moiety or one atom in the linking group is a heteroatom
selected from N, O and S. The heteroarylalkyl groups are described
herein according to the total number of atoms in the ring and
linker combined, and they include aryl groups linked through a
heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl
linker such as an alkylene; and heteroaryl groups linked through a
heteroalkyl linker. Thus, for example, C7-heteroarylalkyl would
include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.
[0401] "Alkylene" as used herein refers to a divalent hydrocarbyl
group; because it is divalent, it can link two other groups
together. Typically it refers to --(CH.sub.2).sub.n-- where n is
1-14 and preferably n is 1-8, though where specified, an alkylene
can also be substituted by other groups, and can be of other
lengths, and the open valences need not be at opposite ends of a
chain. Thus --CH(Me)- and --C(Me).sub.2- may also be referred to as
alkylenes, as can a cyclic group such as cyclopropan-1,1-diyl.
However, for clarity, a three-atom linker that is an alkylene
group, for example, refers to a divalent group in which the
available valences for attachment to other groups are separated by
three atoms such as --(CH.sub.2).sub.3--, i.e., the specified
length represents the number of atoms linking the attachment points
rather than the total number of atoms in the hydrocarbyl group:
--C(Me).sub.2- would thus be a one-atom linker, since the available
valences are separated by only one atom. Where an alkylene group is
substituted, the substituents include those typically present on
alkyl groups as described herein, thus --C(.dbd.O)-- is an example
of a one-carbon substituted alkylene. Where it is described as
unsaturated, the alkylene group may contain one or more double or
triple bonds, and may be referred to as alkenylene group if it
contains at least one carbon-carbon double bond, or as an
alkynylene group if it contains at least one carbon-carbon triple
bond.
[0402] "Heteroalkylene" as used herein is defined similarly to the
corresponding alkylene groups, but the `hetero` terms refer to
groups that contain one or more heteroatoms selected from O, S and
N and combinations thereof, within the backbone residue; thus at
least one carbon atom of a corresponding alkylene group is replaced
by one of the specified heteroatoms to form a heteroalkylene group.
Thus, --C(.dbd.O)NH-- is an example of a two-carbon substituted
heteroalkylene, where N replaces one carbon, and C is substituted
with a .dbd.O group.
[0403] "Arylene" as used herein refers to divalent or trivalent
aromatic or heteroaromatic ring systems that are bonded to their
attachment points through a bond.
[0404] "Arylalkylene" as used herein refers to divalent or
trivalent aromatic and heteroaromatic ring systems which are bonded
to their attachment points through alkylene linking groups,
including substituted or unsubstituted, saturated or unsaturated,
cyclic and acyclic linkers. In some embodiments, the alkylene
linking group is unsaturated, and may be referred to as
arylalkenylene group if it contains at least one carbon-carbon
double bond, or as an arylalkynylene group if it contains at least
one carbon-carbon triple bond. Typically the alkylene linker is
C1-C8 alkylene or a heteroform thereof. These linkers may also
include a carbonyl group, thus making them able to provide
substituents such as an acyl or heteroacyl moiety. For example,
--(CH.sub.2).sub.2C(O)--Ar--C(O)(CH.sub.2).sub.2-- and
--CH.sub.2--Ar--CH.sub.2-- are examples of arylalkylene groups.
[0405] "Heteroarylalkylene" as used herein is defined similarly to
the corresponding arylalkylene group, but contains one or more
heteroatoms, selected from O, S and N and combinations thereof,
within the alkylene residue or the aromatic ring; thus at least one
carbon atom of a corresponding alkylene group or one carbon atom of
the aromatic ring is replaced by one of the specified heteroatoms
to form a heteroarylalkylene group. For example,
--(CH.sub.2).sub.2NHC(O)--Ar--C(O)NH((CH.sub.2).sub.2-- and
--CH.sub.2-pyridyl-CH.sub.2-- are examples of heteroarylalkylene
groups.
[0406] In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or
arylalkyl group or any heteroform of one of these groups that is
contained in a substituent may itself be optionally substituted by
additional substituents. The nature of these substituents is
similar to those recited with regard to the primary substituents
themselves if the substituents are not otherwise described. Thus,
where an embodiment of, for example, R.sup.7 is alkyl, this alkyl
may optionally be substituted by the remaining substituents listed
as embodiments for R.sup.7 where this makes chemical sense, and
where this does not undermine the size limit provided for the alkyl
per se; e.g., alkyl substituted by alkyl or by alkenyl would simply
extend the upper limit of carbon atoms for these embodiments, and
is not intended to be included. However, alkyl substituted by halo,
aryl, heteroaryl, amino, hydroxy, alkoxy (C1-C4 alkyl), .dbd.O,
.dbd.S, and the like would be included within the scope of the
invention, and the atoms of these substituent groups are not
counted in the number used to describe the alkyl, alkenyl, etc.
group that is being described.
[0407] Where no number of substituents is specified, each such
alkyl, alkenyl, alkynyl, acyl, or aryl group may be optionally
substituted with a number of substituents according to its
available valences and in accord with known principles of chemical
stability; in particular, any of these groups may be optionally
substituted with fluorine atoms at any or all of the available
valences on carbon atoms, for example.
[0408] "Heteroform" as used herein refers to a derivative of a
group such as an alkyl, aryl, or acyl, wherein at least one carbon
atom of the designated carbocyclic group has been replaced by a
heteroatom selected from N, O and S. Thus the heteroforms of alkyl,
alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl,
heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl, and
heteroarylalkyl, respectively. It is understood that, unless
otherwise specified, no more than two N, O or S atoms are
ordinarily connected sequentially, except where an oxo group is
attached to N or S to form a nitro or sulfonyl group.
[0409] "Optionally substituted" as used herein indicates that the
particular group or groups being described may have no non-hydrogen
substituents, or the group or groups may have one or more
non-hydrogen substituents. If not otherwise specified, the total
number of such substituents that may be present is equal to the
number of H atoms present on the unsubstituted form of the group
being described. Where an optional substituent is attached via a
double bond, such as a carbonyl oxygen (.dbd.O), the group takes up
two available valences, so the total number of substituents that
may be included is reduced according to the number of available
valences.
[0410] "Halo", as used herein includes fluoro, chloro, bromo and
iodo. Fluoro and chloro are often preferred.
[0411] "Amino" as used herein refers to NH.sub.2, but where an
amino is described as "substituted" or "optionally substituted",
the term includes NR'R'' wherein each R' and R'' is independently
H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group
or a heteroform of one of these groups, and each of the alkyl,
alkenyl, alkynyl, acyl, aryl, or arylalkyl groups or heteroforms of
one of these groups is optionally substituted with the substituents
described herein as suitable for the corresponding type of group.
The term also includes forms wherein R' and R'' are linked together
to form a 3-8 membered ring which may be saturated, unsaturated or
aromatic and which contains 1-3 heteroatoms independently selected
from N, O and S as ring members, and which is optionally
substituted with the substituents described as suitable for alkyl
groups or, if NR'R'' is an aromatic group, it is optionally
substituted with the substituents described as typical for
heteroaryl groups.
[0412] As used herein, an `azacyclic` group refers to a
heterocyclic group containing at least one nitrogen as a ring atom,
wherein the group is attached to the base molecule through a
nitrogen atom of the azacyclic ring. Typically these azacyclic
groups are 3-8 membered monocyclic rings or 8-12 membered bicyclic
fused ring systems. An azacyclic group having more than four ring
members can optionally include one additional heteroatom selected
from N, O and S, and an azacyclic group having more than six ring
members can optionally include one or two additional heteroatoms
selected from N, O and S. Typically, an azacyclic group is
non-aromatic, and such azacyclic groups can optionally be
substituted with substituents that are suitable for alkyl groups.
Typical examples of azacyclic groups include pyrrolidine,
pyrrolidinone, piperidine, morpholine, thiomorpholine, and
piperazine. In certain embodiments, an azacyclic group can be
aromatic, provided that at least one ring nitrogen atom is in a
five membered ring so the nitrogen can serve as the point of
attachment to the base molecule. Examples of aromatic systems that
can be azacyclic groups include pyrrole, imidazole, pyrazole,
triazole or indole.
[0413] The invention provides dimer-like and trimer-like compounds
of formulae (I) and (IA) that possess two or three structurally
similar binding domains. In many embodiments, each binding domain
includes a monocyclic or fused bicyclic ring system that is
substituted by at least one aryl-containing group, --W--X. These
binding domains are linked by a linking group, and while similar,
the domains need not be identical. In certain embodiments of
formula (I), each binding domain is the same, so the molecule is
symmetric about its linking group.
[0414] The apoptosis-promoting compounds of formula (I) where b is
0 are sometimes described herein as `dimers`. These `dimers`
include both symmetric dimers formed containing two identical
monomers of, e.g., formula (6), or formula (17), or formula (18),
or formula (19), as well as unsymmetrical dimers. The unsymmetrical
dimers may contain two non-identical monomers of a single class
(e.g., both are compounds of formula (6)), or they may contain
monomers selected from different classes, e.g., a monomer of
formula (6) with a monomer of formula (17) or (18) or (19).
[0415] In other embodiments, the apoptosis-promoting compounds of
formula (I) are sometimes described herein as `trimers`, when b is
1. These `trimers` include both symmetric trimers formed containing
three identical monomers of, e.g., formula (6), or formula (17), or
formula (18), or formula (19), as well as unsymmetrical trimers.
The unsymmetrical trimers may contain three non-identical monomers
of a single class (e.g., all are compounds of formula (6)), or they
may contain monomers selected from one or two or three different
classes, e.g., one or two monomers of formula (6) with one or more
monomers of formula (17) or (18) or (19).
[0416] In compounds of formula (I), two or three amide-containing
binding domains, D, D' and D'', are linked together by a linkage
depicted as Q-L-Q', when b is 0, or Q-L(-Q'')-Q'', when b is 1:
##STR00037##
[0417] As further described herein for specific embodiments, this
linkage can comprise numerous alternatives that can include a chain
that may be substituted and may be saturated or unsaturated; it may
also include a combination of cyclic and acyclic features. In
frequent embodiments, L represents an optionally substituted C1-C24
hydrocarbyl linker, optionally containing from 1-8 heteroatoms
selected from N, O and S, which linker is 1-18 atoms in length when
counted along the shortest path between Q and Q', or Q and Q'', or
Q' and Q''.
[0418] In compounds of formula (I), each Q, Q' and Q'', where
present, independently represents --O-- or --NR.sup.2--, where each
R.sup.2 is independently H, optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl; or --CH.sub.2--,
--CH(OR)--, --CH(R)--, --CH.sub.2O--, --CH(R)O-- or
--(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl or C1-C4
heteroalkyl; or one or more of Q, Q' and Q'' may be a bond when L
comprises a ring.
[0419] Each amide-containing binding domain, D, D' and D'', where
present, is independently selected from the group consisting of
##STR00038##
[0420] wherein each R.sub.a, R.sub.b, R.sup.1, Z, Y, W, X, n, m,
and R.sup.6 are as further defined herein;
[0421] with the proviso that, when b is 0, D and D' are not both of
the formula
##STR00039##
[0422] In some embodiments, of formula (I), when b is 0, D and D'
are not both of the formula
##STR00040##
[0423] In compounds of formula (I) where b is 0, the amide binding
domains D and D' may be the same or different. In certain
embodiments, they are different, meaning that their backbone
structures are different. In other embodiments of formula (I), the
amide binding domains D and D' are the same, meaning that their
backbone structures are the same, although they may be
differentially substituted. In further embodiments, amide binding
domains D and D' may be identical, comprising identical backbone
structures, and bearing identical substituents.
[0424] In preferred embodiments of formulae (1), when b is 0, both
D and D' are of the formula
##STR00041##
[0425] In compounds of formula (I) where b is 1, the amide binding
domains D, D' and D'' may be the same or different. In certain
embodiments, they are different, meaning that the backbone
structures of one or more of D, D' and D'' are different. In other
embodiments of formula (I) where b is 1, the amide binding domains
D, D' and D'' are the same, meaning that their backbone structures
are the same, although they may be differentially substituted. In
further embodiments, amide binding domains D, D' and D'' may
comprise identical backbone structures, bearing identical
substituents.
[0426] In some embodiments of formula (I), each R.sub.a and R.sub.b
is independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl,
or a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl. Each R.sup.1 is
independently H or optionally substituted C1-C8 alkyl, and each n,
where present, is independently 0-3. In preferred embodiments, each
R.sup.1 is H and n is 1.
[0427] Each Z in compounds of formula (I) independently represents
an optionally substituted C1-C6 aminoalkyl group. In frequent
embodiments, each Z represents a 1-aminoalkyl substituent. In
certain preferred embodiments, Z represents a group of the formula
--CH(R.sup.3)NR.sup.4.sub.2, where R.sup.3 and R.sup.4 are as
further described herein. In more preferred embodiments, each of
R.sup.3 and R.sup.4 is independently selected from H and C1-C4
alkyl. In particularly preferred embodiments, one R.sup.4 is H and
the other is methyl.
[0428] Where present, each Y in compounds of formula (I)
independently represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two Y groups can
cyclize to form a 3-6 membered ring that can be saturated,
unsaturated or aromatic, and which ring may include a heteroatom
selected from O, S and N as a ring member and may be optionally
substituted. Each m, where present, is independently 0-4; in many
embodiments, m is 0 or 1, and each Y, where present, is the
same.
[0429] In compounds of formula (I), each W, where present,
independently represents an optionally substituted C1-C6 alkylene
or C1-C6 heteroalkylene. In certain preferred embodiments, W
comprises an amide moiety. Each X, where present, independently
represents an optionally substituted C.sub.5-C.sub.20 ring system
comprising at least one aromatic ring and up to four heteroatoms
selected from N, O and S as a ring member, and can represent either
a single 5-15 membered cyclic group or two 5-10 membered cyclic
groups that are both attached to the same atom of W, provided that
each X comprises at least one aryl or heteroaryl ring. In specific
embodiments, X represents a phenyl ring, or two phenyl rings
attached to the same atom of W, or a tetrahydronaphthyl or indanyl
ring system, each of which may be optionally substituted.
[0430] In compounds of formula (I), each R.sup.6, where present, is
independently H, C1-C8 alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or is a C8-C14 bicyclic or tricyclic ring system
comprising a 5- or 6-membered saturated or partially unsaturated
ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring, which ring
system may be attached to nitrogen through any available position
on the saturated or aromatic ring. In certain embodiments, each
R.sup.6 independently represents H, methyl, or optionally
substituted benzyl, phenethyl, diphenylmethyl, pyridylmethyl, or
pyridylethyl. In specific embodiments, one R.sup.6 is H, and the
other represents an optionally substituted tetrahydronaphthyl,
indanyl or fluorenyl ring system attached to nitrogen through an
open valence on the saturated ring.
[0431] The same groups described herein for formula (I) are also
suitable for formula (IA).
[0432] In compounds of formula (1), two amide-containing domains
are linked together by a linkage depicted as -Q-L-Q'-. This linkage
can comprise numerous alternatives that can include a chain that
may be optionally substituted and/or unsaturated; it may also
include a combination of cyclic and acyclic features.
[0433] In many embodiments of formula (1), L represents a C1-C24
hydrocarbyl linker, optionally containing from 1-8 heteroatoms
selected from N, O and S. In compounds of formula (1), L represents
a linker between Q and Q' that is 1-18 atoms in length when counted
along the shortest path (by atom count) between Q and Q'. L may be
optionally substituted as described herein with substituents that
are suitable for its structure.
[0434] In some embodiments, L is an optionally substituted and/or
unsaturated C1-C14 alkylene or C1-C14 heteroalkylene. For example,
L may represent a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene linker, or a heteroform of one of these, each of which
may be optionally substituted. In frequent embodiments, L is
substituted with one or more carbonyl substituents (.dbd.O), to
form a linker comprising one or more acyl groups.
[0435] In certain embodiments, L is symmetric about its central
atom (if the chain connecting the two available valences is an odd
number of atoms in length) or its central bond (if the chain
connecting the two available valences is an even number of atoms in
length). In some embodiments, L is 2-8 atoms in length, counting
along the shortest path between Q and Q'. In certain embodiments, L
can also include one or more heteroatoms selected from N, O and S,
but does not include a disulfide linkage.
[0436] In compounds of formula (1), L can be substituted by
substituents including rings, and it can comprise one or more rings
as part of the linkage that connects Q and Q' together. Where L
comprises at least one ring that is part of or is fused to the
shortest path (by atom count) connecting Q and Q', Q and/or Q' in
formula (1) can be a bond as well as any of the other structures
described herein for Q and Q'. Where L comprises a ring, the
ring(s) may be cycloalkyl, heterocyclyl, aryl, or heteroaryl, and
may be further substituted. Such rings may be alternatively
referred to herein as carbocyclic, heterocyclic, aromatic or
heteroaromatic, each of which may be optionally substituted.
[0437] Such rings can be connected to Q and/or Q' (or, where Q
and/or Q' represents a bond, the rings can be connected by the bond
Q or Q' directly to the carbon to which Q or Q' is attached), at
any ring position, and it may be attached either directly or
through an optionally substituted intervening alkylene or
heteroalkylene group, provided the shortest path (by atom counting)
between Q and Q' is 1-18 atoms in length, and preferably 2-8 atoms
in length. For example, L could be a 1,3-disubstituted aryl or
heteroaryl linker, or a buten-1,4-diyl linker.
[0438] Frequently, the ring which is part of L is substituted by
carboxy groups which form the point of attachment to Q or Q', such
that an ester or amide linkage is formed by the bond between Q/Q'
and L.
[0439] In preferred embodiments, L comprises an optionally
substituted 5- or 6-membered aromatic or heteroaromatic ring. In
specific embodiments, L comprises at least one optionally
substituted phenyl, pyrazole or triazole ring.
[0440] In some embodiments, L comprises an optionally substituted
phenyl or pyridyl ring that may be 1,2-disubstituted, or
1,3-disubstituted, or 1,4-disubstituted, by the groups Q and Q',
which may be directly attached to the ring or may be separated from
the ring by one or more atoms that are included in L. In other
embodiments, L comprises an optionally substituted pyrazinyl,
triazinyl, pyrazolyl, or thiophenyl ring, each of which may be
optionally substituted. In further embodiments, L comprises at
least one optionally substituted triazole ring that is part of the
linker between Q and Q'.
[0441] Rings which comprise part of the linker, L, may be
optionally substituted to the extent such substitution makes
chemical sense. Preferred optional substituents when present on a
ring which comprises part of L include alkyl (C1-C4), alkoxy
(C1-C4), --CF.sub.3, --OCF.sub.3, halo, --OH, --NO.sub.2, --CN, or
NR.sub.2, where each R is independently H or C1-C4 alkyl.
[0442] In certain embodiments of formula (1), L comprises an
optionally substituted arylene or arylalkylene group, or a
heteroform of one of these, to which Q and Q' are attached. For
example, L can be --CH.sub.2--Ar--CH.sub.2--, --C(O)--Ar--C(O)--,
--SO.sub.2--Ar--SO.sub.2--, --C(O)--Ar-- or --Ar--, where Ar
represents an optionally substituted 5- or 6-membered aromatic or
heteroaromatic ring. In some embodiments, L comprises a phenyl ring
that may be 1,2-disubstituted, or 1,3-disubstituted, or
1,4-disubstituted by the groups Q and Q', which may be directly
attached to the ring or may be separated from the ring by one or
more atoms that are included in L. In other embodiments, L
comprises an optionally substituted 5- or 6-membered heteroaryl
ring, which may contain from 1-4 heteroatoms selected from N, O and
S as a ring member. In further embodiments, L comprises an
optionally substituted C3-C10 cycloalkylene ring.
[0443] In certain embodiments, L comprises one or more triazole
rings which may be directly attached to the azacyclic core through
the bond Q and/or Q' or which may be attached through an alkylene
or heteroalkylene linker. In specific embodiments, L comprises two
triazole rings each attached directly to an azacyclic core through
the bonds Q and Q', wherein the two triazole rings are separated by
an optionally substituted, saturated or unsaturated alkylene or
heteroalkylene group, or by an arylene moiety.
[0444] In certain embodiments of formula (1), -Q-L-Q'- represents a
structure selected from the following group:
##STR00042##
[0445] wherein each q is independently 0-8, and each aromatic,
heteroaromatic and heterocyclic ring is optionally substituted. In
certain embodiments, the ring that comprises part of L is
substituted with one or more substituents selected from the group
consisting of --OH, --OMe, halo, NO.sub.2 or NH.sub.2.
[0446] In particular embodiments, -Q-L-Q'- represents a
structure
##STR00043##
[0447] wherein R is --OH, --OMe, halo, NO.sub.2 or NH.sub.2. In
certain preferred embodiments, R is OH, OMe or NH.sub.2
[0448] In other preferred embodiments, -Q-L-Q'- represents a
structure
##STR00044##
[0449] In other embodiments, -Q-L-Q'- represents a structure
selected from the following group:
##STR00045##
[0450] In still further embodiments, -Q-L-Q'- represents a
structure selected from the following group:
##STR00046##
[0451] wherein each q is independently 0-8, and each aryl or
heteroaryl ring and alkylene group is optionally substituted.
[0452] In other embodiments, L comprises an optionally substituted
C1-C14 alkylene or C1-C14 heteroalkylene which may be saturated or
unsaturated. For example, L can be --(CH.sub.2).sub.q-- where q is
1-8, and may be optionally substituted with groups suitable for an
alkyl group. In certain embodiments, the alkylene chain is
substituted with one or two carbonyl oxygens (.dbd.O). When L is
unsaturated, it is sometimes a C1-C14 alkenylene or C1-C14
alkynylene linker. For example, L can be 1,4-but-2-enylene
(--CH.sub.2--CH.dbd.CH--CH.sub.2--); 1,10-deca-4,6-diynylene
(--(CH.sub.2).sub.3C.ident.C--C.ident.C(CH.sub.2).sub.3--;
1,7-hepta-1,3-diynylene (--C.ident.C--C.ident.C(CH.sub.2).sub.3--;
or an optionally substituted version of one of these. L can also
include one or more heteroatoms, for example, it can be
--CH.sub.2--O--CH.sub.2-- or
--(CH.sub.2).sub.2NHC(O)ArC(O)NH(CH.sub.2).sub.2-- or a substituted
version of one of these.
[0453] In some embodiments, -Q-L-Q'- represents a structure
selected from the following group:
##STR00047##
[0454] wherein each q is independently 0-8, and each alkylene group
may be optionally substituted.
[0455] The same groups described here for L in compounds of formula
(1) are also suitable for L in compounds of formulae (I), (IA),
(1A), (2)-(5), (7)-(16), (3A) and (13A).
[0456] In compounds of formula (1), each Q and Q' may independently
represent --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, or a C1-C4 alkyl. In some embodiments, Q and Q'
are the same. In specific embodiments, each Q and Q' is --NH--. In
other embodiments, each Q and Q' may independently represent a bond
when L comprises a ring. In specific embodiments, each Q and Q'
independently represents a bond when L comprises at least one
triazole ring.
[0457] The same groups described here for Q and Q' in compounds of
formula (1) are also suitable for Q, Q', and Q'', if present, in
compounds of formulas (2)-(5), (9) and (13), and for Q in compounds
of formulas (7)-(8) and (14)-(16).
[0458] In compounds of formula (1), n and n' can independently be
0-3, and in some embodiments n and n' are the same. In certain
embodiments, n and n' are each selected from 1 and 2 and can be the
same or different; in specific embodiments, n and n' are both
1.
[0459] In compounds of formula (1), each of (Y).sub.m and
(Y').sub.m' represents one or more substituents optionally present
on the nitrogen-containing ring, and each of m and m' is 0-4. In
compounds of formula (1), each of the nitrogen-containing rings may
be differently substituted. Each Y and Y' is independently selected
from the substituents described herein as suitable for alkyl
groups. For example, each Y and Y' may independently represent
C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or
COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8
heteroalkyl. In certain embodiments, two Y or Y'' groups on a
single nitrogen-containing ring groups may cyclize to form a
saturated, unsaturated or aromatic ring having 3-6 ring members and
optionally containing one heteroatom (N, O or S) as a ring member,
and such ring embodiments may be optionally substituted with
suitable substituents as described herein.
[0460] In certain embodiments of formula (1), m and m' are the
same. In many embodiments, each of m and m' is either 0 or 1.
Specific embodiments include m=m'=1 and m=m'=0. In some embodiments
where m and m' are 1, each of Y and Y' are the same.
[0461] The groups described herein for Y and Y' in compounds of
formula (1) are also suitable for Y, Y', and Y'', where present, in
compounds of formulas (1A), (3A), (2)-(9), (12)-(13), (15)-(16),
and (18)-(19). In such compounds, each of m, m' and m'', where
present, are 0-4.
[0462] In compounds of formula (1), each R.sub.a, R.sub.a', R.sub.b
and R.sub.b' is independently H, C1-C8 alkyl, C2-C8 alkenyl, or
C2-C8 alkynyl, or a heteroform of one of these, each of which may
be optionally substituted; or is optionally substituted phenyl. In
some embodiments, one of R.sub.a and R.sub.b is H, and the other is
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and one of R.sub.a' and
R.sub.b' is H, and the other is C1-C4 alkyl, C2-C4 alkenyl, or
C2-C4 alkynyl. In other embodiments, one of R.sub.a' and R.sub.b'
is H, and the other is cyclohexyl or optionally substituted
phenyl.
[0463] For compounds of formula (1), each R.sup.1 and R.sup.1' is
independently H or optionally substituted C1-C8 alkyl; in preferred
embodiments, R.sup.1 and R.sup.1' are H.
[0464] Each of Z and Z' in compounds of formula (1) is
independently an optionally substituted C1-C6 aminoalkyl group.
This can be a C1-C6 alkyl group that is substituted with at least
one amine group and is optionally substituted with one or more
other groups suitable as substituents for an alkyl group. In some
embodiments, Z and Z' can be a 1-aminoalkyl group such as a
1-aminomethyl or 1-aminoethyl or 1-aminopropyl, where the amine
group is substituted with one or two optionally substituted C1-C8
alkyl groups, and may also be substituted with a C1-C8 acyl or
heteroacyl group. In a typical embodiment, each of Z and Z' is
1-aminopropyl, or 1-aminoethyl, or aminomethyl, or
1-methylaminopropyl, or 1-methylaminoethyl, or methylaminomethyl.
Alternatively, Z or Z' can be 1-ethylaminomethyl or
1-ethylaminoethyl. In certain embodiments, Z and Z' are the same.
Where Z or Z' has a chiral center adjacent to the carbonyl to which
it is connected, the chiral center may have either the (R) or the
(S) configuration. For specific embodiments, it is sometimes
preferably in the (S) absolute configuration. In specific
embodiments, Z is a group of the formula
--CH(R.sup.3)NR.sup.4.sub.2, as further described herein.
[0465] The same groups described for Z and Z' in compounds of
formula (1) are suitable for Z, Z' and Z'', where present, in
compounds of formulae (1A), (2)-(3) and (6)-(17).
[0466] In compounds of formula (1), each W and W' independently
represents an optionally substituted C1-C6 alkylene or C1-C6
heteroalkylene linker to which X or X' is attached. Each of W and
W' in formula (1) is independently selected, so they can be the
same or different. In some embodiments, W and W' are the same; in
many embodiments, each of W and W' is substituted with .dbd.O. In
certain embodiments, each of W and W' may be represented as
--C(O)NR(CHR)p-, where each p is 0-2, and each R is independently
H, or C1-C4 alkyl or C1-C4 heteroalkyl.
[0467] Each of X and X' in compounds of formula (1) represents a
C5-C20 ring system comprising at least one aryl or heteroaryl group
and up to four heteroatoms selected from N, O and S as a ring
member, and can be a single 5-15 membered cyclic group or it can be
two 5-10 membered cyclic groups that are both attached to a single
atom of W or W'. Each of these cyclic groups can be a single ring,
a fused ring system, or linked rings such as a biaryl group.
Optionally, each X and X' can be substituted and can include up to
four heteroatoms selected from O, N and S. Thus, by way of example,
each X and X' can comprise an aryl or heteroaryl ring, which can be
monocyclic or bicyclic, provided at least one ring of a bicyclic
group is aromatic, or it can represent two 5-10 membered cyclic
group provided that at least one of them comprises an aryl or
heteroaryl ring.
[0468] In specific embodiments, each X and X' independently
comprises an optionally substituted phenyl ring; or two phenyl
rings on one atom of W or W', which can be substituted on one or
both phenyl rings; or each X and X' can independently comprise a
fused ring system having two aromatic rings or having a saturated
5-6 membered ring fused to a 5-6 membered aryl ring, each of which
can be substituted on either or both rings. X and X' are
independently selected, and may be the same or different. In
specific embodiments, X and X' are sometimes the same.
[0469] When X and/or X' comprises a 5 or 6 membered saturated ring
fused to a 5 or 6 membered aryl ring, in some embodiments, X is
attached to W through an atom in the saturated ring. In specific
embodiments, each X and X' is independently a tetrahydronaphthyl,
indanyl or fluorenyl ring system linked to nitrogen of W or W'
through an open valence on the saturated ring of the
tetrahydronaphthyl, indanyl or fluorenyl ring system. In certain
embodiments, X comprises one or two aryl rings, preferably one or
two phenyl rings; and each aryl ring is attached to W through a
terminal carbon atom of W. For example, in some embodiments, --W--X
comprises an arylalkyl group, such as benzyl, 1-phenylethyl, or
diphenylmethyl.
[0470] The aryl or heteroaryl ring in any of these embodiments may
be optionally substituted. Preferred substituents when present on
an aryl or heteroaryl ring that is part of X or X' include C1-C4
alkyl, C1-4 heteroalkyl, C1-C4 alkenyl, C1-4 heteroalkenyl, C1-C4
alkynyl, C1-4 heteroalkynyl, OR, NR.sub.2, SR, S(O)R, SO.sub.2R,
C(O)R, C5-12 aryl, C5-12 heteroaryl, C5-12 arylalkyl, C5-12
heteroarylalkyl, and halo, where each R is independently H, or
C1-C4 alkyl, C1-C4 heteroalkyl, C5-C12 aryl, C5-C12 heteroaryl,
C5-C12 arylalkyl, or C5-C12 heteroarylalkyl, each of which may be
further substituted with groups suitable for its structure; and
wherein any alkyl or arylalkyl substituent may be optionally
fluorinated on the alkyl portion. More preferred substituents when
present on an aryl or heteroaryl ring that is part of X include
C1-4 alkyl, C1-4 alkoxy, CF.sub.3, OCF.sub.3, halo, NO.sub.2, CN,
and NR.sub.2, where each R is independently H or C1-4 alkyl.
[0471] In particular embodiments of the compounds of the invention,
--W--X and W'--X' represent a group of the form
--C(O)NR(CHR).sub.pX or --C(O)NR(CHR).sub.pX', where each p is 0-2,
and each R is independently H or a C1-C8 alkyl group. In certain
embodiments, p is 0 or 1, and each R may be H or methyl. In some
embodiments, --W--X and W'--X' are the same, though they can be
different. In preferred embodiments, each X and X' independently
comprises one or two phenyl groups, or a tetrahydronaphthyl,
indanyl or fluorenyl ring system linked to nitrogen of W through an
open valence on the saturated ring of the tetrahydronaphthyl,
indanyl or fluorenyl ring system.
[0472] In preferred embodiments of the compounds of the invention,
--W--X and W'--X' represent a group of the form --C(O)NH(CHR)Ph',
where R is H or Me, and Ph' is optionally substituted phenyl. In
other preferred embodiments, --W--X and W'--X' represent a group of
the form --C(O)NHCH(Ph').sub.2, where Ph' is optionally substituted
phenyl. In further preferred embodiments, --W--X and W'--X'
represent a group of the form --C(O)NH--Ar', where Ar' represents a
tetrahydronaphthyl ring system, preferably bonded to the amide
nitrogen through one of the atoms in the saturated ring.
[0473] The same groups described for W, W', X and X' in compounds
of formula (1) are suitable for W, W', W'', X, X' and X'', where
present, in compounds of formulae (1A), (2)-(9), (12), (16) and
(18).
[0474] The same groups described here for compounds of formula (1)
are also suitable for compounds of formulae (I), (IA), (1A),
(2)-(5), (7)-(16), (3A) and (13A).
[0475] In compounds of formula (2), three amide-containing domains
are linked together by a linkage depicted as Q-L(-Q'')-Q', wherein
L is defined as above for compounds of formula (1). In many
embodiments, L comprises a C5-C12 arylene or C5-C21 arylalkylene
group, or a heteroform of one of these, each of which may be
optionally substituted. In preferred embodiments, L comprises a
tri-substituted 5- or 6-membered aryl or heteroaryl ring. In
specific embodiments, Q-L(-Q'')-Q' represents a structure selected
from the following group:
##STR00048##
[0476] wherein each q is independently 0-8, and each phenyl ring is
optionally substituted with 1-2 groups selected from C1-C4 alkyl,
C1-C4 alkoxy, CF.sub.3 and halo.
[0477] In compounds of formula (2), each Q, Q' and Q'' may
independently represent --O-- or NR.sup.2--, where each R.sup.2 is
independently H or a C1-C8 alkyl, or C1-C8 heteroalkyl, which may
be optionally substituted. In some embodiments, each of Q, Q' and
Q'' may independently be a bond when L comprises a ring. In certain
embodiments, Q, Q' and Q'' are the same. In specific embodiments,
each of Q, Q' and Q'' is --NH--. In other specific embodiments,
each of Q, Q' and Q'' represents a bond. In specific embodiments,
each of Q, Q'' and Q' is a bond when L comprises one or more
triazole rings.
[0478] In compounds of formula (2), n, n' and n'' can independently
be 0-3, and in some embodiments n, n' and n'' are the same. In
specific embodiments, each of n, n' and n'' is 1.
[0479] In compounds of formula (2), (Y).sub.m, (Y').sub.m' and
(Y'').sub.m'', where present, are defined as described above for
compounds of formula (1). Each of m, m' and m'', where present, may
be 0-4. In some embodiments of formula (2), each of m, m' and m''
is the same. In certain embodiments, each of m, m' and m'' is 0.
Where any of m, m' or m'' is other than zero, each Y, Y' and Y''
present is independently selected from the substituents suitable
for alkyl groups as described above.
[0480] In compounds of formula (2), each R.sub.a, R.sub.a',
R.sub.a'', R.sub.b, R.sub.b', and R.sub.b'' is independently H or
C1-C8 alkyl, which may be optionally substituted. In some
embodiments, R.sub.a, R.sub.a' and R.sub.a'' are H and R.sub.b,
R.sub.b' and R.sub.b'' are C1-C8 alkyl. Each R.sup.1, R.sup.1' and
R.sup.1'' is independently selected from H and C1-C8 alkyl; in
preferred embodiments, each R.sup.1, R.sup.1' and R.sup.1'' is
H.
[0481] Each of Z, Z' and Z'' in compounds of formula (2) is
independently an optionally substituted (C1-C6) aminoalkyl group,
as described for formula (1). In some embodiments, Z, Z' and Z''
can be a 1-aminoalkyl group such as the groups described above for
formula (1). In a typical embodiment, each of Z, Z' and Z'' is
1-aminopropyl, or 1-aminoethyl, or aminomethyl, or
1-methylaminopropyl, or 1-methylaminoethyl, or methylaminomethyl.
Alternatively, each Z, Z' and Z'' can be 1-ethylaminomethyl or
1-ethylaminoethyl. In certain embodiments, Z, Z' and Z'' are the
same. Where Z, Z' or Z'' has a chiral center adjacent to the
carbonyl to which it is connected, the chiral center may have
either the (R) or the (S) configuration. For specific embodiments,
it is sometimes preferably in the (S) configuration.
[0482] In compounds of formula (2), each W, W' and W''
independently represents an optionally substituted C1-C6 alkylene
or C1-C6 heteroalkylene linker to which X, X' or X'' is attached.
In some embodiments, W, W' and W'' are the same; in many
embodiments, each of W, W' and W'' is substituted with C.dbd.O. In
certain embodiments, each of W, W' and W'' may be represented as
--C(O)NR(CHR).sub.p--, where each p is 0-2, and each R is
independently H, or C1-C4 alkyl or C1-C4 heteroalkyl.
[0483] Each of X, X' and X'' in compounds of formula (2) represents
an optionally substituted C5-C20 ring system comprising at least
one aryl or heteroaryl group having up to four heteroatoms selected
from O, N and S as a ring member, as described for groups X and X'
in formula (1). In preferred embodiments, each of X, X' and X''
comprises an optionally substituted phenyl ring; or two phenyl
rings, each of which may be optionally substituted, on one atom of
W, W' or W''; or each of X, X' and X'' comprises a
tetrahydronaphthyl, indanyl or fluorenyl group, each of which can
be optionally substituted on either or both rings.
[0484] When X, X' or X'' comprises a 5 or 6 membered saturated ring
fused to a 5 or 6 membered aryl ring, in some embodiments, each X,
X' or X'' is attached to W, W' or W'' through an atom in the
saturated ring. The aryl or heteroaryl ring in any of these
embodiments may be optionally substituted, with groups described as
preferred substituents when present on an aryl ring that is part of
X or X' for compounds for formula (1). In some embodiments,
substituents on an aryl or heteroaryl ring that is part of X, X' or
X'' include methyl, methoxy, trifluoromethyl and halo. X, X' and
X'' in formula (2) can be the same or different; in some
embodiments they are the same.
[0485] In some embodiments of formula (2), each of --W--X, --W'--X'
and --W''--X'' represents a group of the form --C(O)NR(CHR).sub.pX,
where p is 0-2, X represents one or two phenyl groups,
tetrahydronaphthyl, indanyl or fluorenyl, each of which may be
optionally substituted, and R is independently H or a C1-C8 alkyl
group. In certain embodiments, q is 0 or 1, and each R may be H or
methyl. In specific embodiments, each of --W--X, W'--X' and
--W''--X'' is the same and represents a group of the form
--C(O)NR(CHR).sub.pX, where p is 0, X is tetrahydronaphthyl and
each R is H.
[0486] Compounds of formula (3A) contain two or three amino
acid-derived binding domains that have the same formula, but may
differ in stereochemistry. For compounds of formula (3A), p is 2 or
3, and m, Q, L, W, X, Y and Z are as described for compounds
formula (1) and/or (2). In compounds of formula (3A), R.sub.a is H,
and R.sub.b is R.sup.5, where R.sup.5 is H, or C1-C8 alkyl, C2-C8
alkenyl, C2-C8 alkynyl, or phenyl, each of which may be optionally
substituted. In preferred embodiments of formula (3A), p is 2. In
many embodiments, L in compounds of formula (3A) represents a
C1-C14 alkylene, C1-C14 alkenylene, or C1-C14 alkynylene linker, or
a heteroform of one of these, each of which may be optionally
substituted. In other embodiments of formula (3A), L represents a
C5-C12 arylene, C5-C21 arylalkylene, C5-C21 arylalkenylene, or
C5-C21 alkynylene linker, or a heteroform of one of these, each of
which may be optionally substituted.
[0487] Compounds of formula (3) contain two or three amino
acid-derived binding domains that have the same formula, but may
differ in stereochemistry. For compounds of formula (3), p is 2 or
3, and m, Q, L, W, X, Y and Z are as described for compounds
formula (1) and/or (2). In preferred embodiments of formulae (3), p
is 2. In many embodiments, L in compounds of formulae (3)-(5)
represents a C1-C14 alkylene, C1-C14 alkenylene, or C1-C14
alkynylene linker, or a heteroform of one of these, each of which
may be optionally substituted. In other embodiments of formulae
(3)-(5), L represents a C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 alkynylene linker, or a heteroform of one
of these, each of which may be optionally substituted.
[0488] Compounds of formula (4) contain two or three amino
acid-derived binding domains that have the same formula and
stereochemistry. For compounds of formula (4), p is 2 or 3, and m,
Q, L, W, X, and Y are as described for compounds formula (1) and/or
(2). In preferred embodiments of formula (4), p is 2.
[0489] Compounds of formula (5) contain two amino acid-derived
binding domains that have the same formula and opposite
stereochemistry. For compounds of formula (5), m, Q, L, W, X, and Y
are as described for compounds formula (1) and/or (2).
[0490] For compounds of formula (3)-(5), R.sup.5 is H, or C1-C8
alkyl, C1-C8 alkenyl, C1-C8 alkynyl, or phenyl, each of which may
be optionally substituted. In certain embodiments, R.sup.5 is
selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, propyn-3-yl, cyclohexyl,
or phenyl.
[0491] For compounds of formula (3)-(5), m is 0-4. Frequently, m is
0 or 1, and where m is 1, Y is often .dbd.O, C1-C4 alkyl or C1-C4
alkoxy. In preferred embodiments, Q is --NH-- or a bond.
[0492] In many embodiments of formulas (3)-(5), W is an amide
linker. In certain embodiments, --W--X represents
--C(O)NR(CHR).sub.pX, where p is 0, 1 or 2 and each R is H or a
C1-C4 alkyl group. In specific embodiments, --X represents an
optionally substituted phenyl ring, or two phenyl rings attached to
the same atom of W, each of which may be optionally substituted, or
is a tetrahydronaphthyl, indanyl group or fluorenyl group linked to
a nitrogen atom of W through an open valence on the saturated ring
of the tetrahydronaphthyl, indanyl or fluorenyl ring system.
[0493] R.sup.3 in formula (4) or (5) can be H or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl
group, and can optionally cyclize with a group R.sup.4 if an
R.sup.4 is other than H. In certain preferred embodiments, R.sup.3
is H or a C1-C4 alkyl group such as methyl, ethyl or propyl.
[0494] Each R.sup.4 in formula (4) or (5) is independently H or an
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl. If two R.sup.4 groups other than H are present on one
nitrogen atom, they can optionally cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic ring may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S, as
further described herein. In certain preferred embodiments, each
R.sup.4 is independently H or a C1-C4 alkyl group, such as methyl,
ethyl or propyl.
[0495] In another aspect, the invention relates to monomers of
formula (II), useful for the preparation of the dimers and trimers
of the invention. A suitable monomer is a molecule that can be
readily covalently linked to a second or third monomer molecule
which may be identical or different, to form a dimer, trimer,
dimer-like or trimer-like Smac mimetic compound as described above.
Accordingly, compounds encompassed in the present invention include
dimer, trimer, dimer-like and trimer-like molecules and monomeric
intermediates useful for the synthesis of such dimeric and trimeric
compounds. Also provided are methods of synthesizing such dimer,
trimer, dimer-like and trimer-like molecules from monomeric
intermediates.
[0496] The invention provides monomers of formula (II)
D-U (II)
[0497] wherein D is selected from the group consisting of
##STR00049##
[0498] wherein each R.sub.a, R.sub.b, R.sup.1, Y, W, X, n, m, and
R.sup.6 are as further defined herein for compounds of formula (I),
and Z is an optionally substituted C1-C6 aminoalkyl group wherein
the amine may be in a protected or unprotected form.
[0499] U in compounds of formula (II) preferably comprises at least
one functional group that can be used to connect the monomer
directly to another monomer, or that is capable of undergoing
reaction with another molecule that will be used to connect two or
more monomers, each having a group U present that can be linked
together using conventional transformations. Monomers of formula
(II) may be linked together directly or by reaction with an
additional component that forms part of the linker, L.
[0500] Thus, U represents at least one functional group capable of
undergoing chemical reaction with another molecule. For example, U
can represent a functional group such as --OR.sup.8,
--OC(O)R.sup.8, --OSO.sub.2R.sup.8, C.dbd.O, --OC(O)OR.sup.8,
--COOR.sup.8, --NR.sup.8.sub.2, azido or halo, or the like, where
each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8 alkenyl,
C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a heteroform of
one of these, each of which may be optionally substituted.
Alternatively, U can be an optionally substituted C1-C8 alkyl,
C2-C8 alkenyl, C2-C8 alkynyl group, C5-C20 aryl or C5-C20 arylalkyl
group, or a heteroform of one of these.
[0501] In some embodiments, U represents a C1-C8 alkyl or C5-C12
aryl group substituted with halo, azide, --COOH, --NH.sub.2, --OH,
or --OSO.sub.2R, where R is C1-C4 alkyl, CF.sub.3, or optionally
substituted phenyl; in other embodiments, U comprises a terminal
alkene or a terminal alkyne. In certain preferred embodiments, U is
--NH.sub.2, azide, --CH.sub.2C.ident.CH,
--NH(CH.sub.2).sub.rC.ident.CH or NHC(O)(CH.sub.2).sub.rC.ident.CH,
where r is 1-2, --CH(R)OCH.sub.2C.ident.CH, where R is H or methyl,
or U is (CH.sub.2).sub.tAr, where t is 0 or 1 and Ar represents a
phenyl ring substituted with halo, --OH or --OTf.
[0502] Such monomers may undergo chemical reaction using conditions
well known in the art to connect a monomer containing such a
functional group U to another molecule. The following examples are
included for illustrative purposes only and are not intended to
represent or limit the scope of the subject matter claimed herein.
A person of skill in the art would understand that a wide variety
of chemical reactions would be suitable to provide the compounds of
the invention.
[0503] In some embodiments, monomers undergoing dimerization or
trimerization contain different functional groups, U. In other
embodiments, the functional groups, U, in monomers undergoing
dimerization or trimerization are the same.
[0504] Where the functional groups, U, are different, they
sometimes represent a monomer in which U comprises a primary or
secondary amine and a monomer containing a carboxylic acid or acyl
halide, which undergo an acylation or amide coupling reaction to
form an amide-linked dimer. In other embodiments, an azide
containing monomer can undergo cycloaddition with a monomer in
which U comprises an alkyne to form a dimer wherein the linker
comprises at triazole ring.
[0505] In certain embodiments, the functional groups, U, are the
same. For example, two amine containing monomers of formula (II)
may undergo reaction with a diacid, which may be optionally
activated as a diacyl halide, mixed anhydride, activated ester, a
bis-sulfonyl halide, or the like, to provide a dimer wherein L
comprises a bis-amide or bis-sulfonamide linkage. In other
embodiments, three amine containing monomers may react with a
triacid, triacyl halide or tris-sulfonyl halide, to give trimeric
compounds. In still other embodiments, two monomers containing a
terminal alkyne can undergo copper catalyzed cross-coupling
reaction to give a linker comprising a bis-acetylene moiety, or two
terminal alkene containing monomers may undergo dimerization via an
olefin metathesis reaction. In further embodiments, two azide
containing monomers can undergo reaction with a bis-acetylene
containing molecule to form a dimer wherein the linker comprises
two triazole rings. In additional embodiments, two monomers
containing a terminal alkyne can react with a third molecule
containing a bis-azide to form a dimer wherein the linker comprises
two triazole rings.
[0506] Compounds of formulae (6) and (17)-(19) and (19A) represent
specific embodiments of monomers of formula (II) which are useful
for the preparation of dimer, trimer, dimer-like or trimer-like
compounds.
[0507] U in compounds of formula (6) represents at least one
functional group such as --OR.sup.8, --OC(O)R.sup.8,
--OSO.sub.2R.sup.8, C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8,
--NR.sup.8.sub.2, azido or halo, or the like, where each R.sup.8 is
independently H, or C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl,
C5-C12 aryl, C5-C21 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted; or C1-C8 alkyl, C2-C8
alkenyl, C2-C8 alkynyl, C5-C12 aryl or C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted. In other embodiments, U can be an optionally
substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl group, C5-C20
aryl or C5-C20 arylalkyl group, or a heteroform of one of these. In
preferred embodiments, U is --NH.sub.2, azide, or
--NH(CH.sub.2).sub.rC.ident.CH or NHC(O)(CH.sub.2).sub.rC.ident.CH,
where r is 1-2.
[0508] Monomers of formula (6) may be linked together directly or
by reaction with an additional component that forms part of the
linker, L. In frequent embodiments, the linker comprises one or
more carboxylate groups such that an ester or amide linkage is
formed by the bond Q-L and/or Q'-L.
[0509] In compounds of formula (6), n, m, R.sub.a, R.sub.b,
R.sup.1, W, X, Y and Z are as described for compounds of any of
formulae (1)-(5) and (3A). In many embodiments of formula (6), Z
represents a protected amine. One of skill in the art would
appreciate that appropriate amine protecting groups may vary
depending on the functionality present in the particular monomer.
Suitably protected amines may include, for example, carbamates
(e.g. tert-butoxycarbonyl, benzyloxycarbonyl,
fluorenylmethyloxycarbonyl, allyloxycarbonyl or
(trialkylsilyl)ethoxy-carbonyl), carboxamides (e.g. formyl, acyl or
trifluoroacetyl), sulfonamides, phthalimides, Schiff base
derivatives, and the like.
[0510] Two monomers may be brought together by reaction with a
third molecule containing at least two reactive centers, such as
the reaction of two amine containing monomers with
carbonyldiimidazole to form a urea-containing linkage; the reaction
of two amine containing monomers with a diacid or diacyl halide to
form a bis-amide containing linkage; the reaction of two amine
containing monomers with a bis-sulfonyl halide to form a
bis-sulfonamide linkage; or the reaction of two azido containing
monomers with a bis-acetylene compound to form a dimer wherein Q
and Q' represent a bond and L comprises two triazole rings.
[0511] Alternatively, three monomers may be brought together by
reaction with a fourth molecule containing at least three reactive
centers to form a trimer or trimer-like molecule. For example,
reaction of three amine containing monomers with, e.g.
1,3,5-tricarboxybenzene, or an activated form thereof, can be used
to form a trimeric molecule wherein each binding domain is attached
to the 1,3,5-tricarboxybenzene linker through an amide bond.
[0512] When an unsymmetrical dimer of formula (1) is desired, two
monomers having complementary functional groups can be combined.
For example, cycloaddition of a monomer containing an azide to an
alkyne-containing monomer may be used to provide dimers wherein the
linking group comprises a triazole ring.
[0513] For compounds of formula (7)-(19), each of m, m', n, n'
R.sub.a, R.sub.a', R.sub.b, R.sub.b, R.sup.1, R.sup.1', W, W', X,
X' Y, Z, and Z', where present, are as described for compounds of
formulae (1)-(5). In many embodiments, where present, n is 1 and m
is 0 or 1. Where m is 1, Y is frequently .dbd.O. In preferred
embodiments, R.sup.1 and R.sup.1' are H.
[0514] For compounds of formula (19A), each of m, m', n, n'
R.sub.a, R.sub.a', R.sub.b, R.sub.b, R.sup.1, R.sup.1', W, W', X,
X' Y, Z, and Z', where present, are as described for compounds of
formulae (1)-(5). In many embodiments, where present, n is 1 and m
is 0 or 1. Where m is 1, Y is frequently .dbd.O. In preferred
embodiments, R.sup.1 and R.sup.1' are H.
[0515] In certain embodiments of formula (7)-(9), (12) and (16),
--W-- and/or --W'--, where present, represent a group of the form
--C(O)NR(CHR).sub.p--, where each p is 0-2, and each R is
independently H, or C1-C4 alkyl or C1-C4 heteroalkyl. In certain
embodiments, p is 0 or 1, and each R may be H or methyl. In some
embodiments, --W--X and --W'--X' are the same. In preferred
embodiments, each X and X' is independently one or two phenyl
groups, each of which may be optionally substituted, or is a
tetrahydronaphthyl, indanyl or fluorenyl ring system linked to
nitrogen of W or W' through an open valence on the saturated ring
of the tetrahydronaphthyl, indanyl or fluorenyl ring system.
[0516] For compounds of formula (7), (10)-(11), (15) and (17),
where present, each R.sup.6 and/or R.sup.6' is independently H,
C1-C8 alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of
one of these, each of which may be optionally substituted; or is a
C8-C14 bicyclic or tricyclic ring system comprising a 5- or
6-membered saturated or partially unsaturated ring fused to a C5-C6
aryl or C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring. In preferred embodiments, one of R.sup.6 and
R.sup.6' is H, and the other is a tetrahydronaphthyl, indanyl or
fluorenyl ring system attached to the nitrogen atom through an open
valence on the saturated ring.
[0517] For compounds of formula (7)-(16), L represents a C1-C14
alkylene, C5-C20 arylene or C5-C20 arylalkylene linker, or a
heteroform of one of these, each of which may be optionally
substituted, and wherein the alkylene portion may be saturated or
unsaturated. L may be optionally substituted with substituents
suitable for its nature, and may include a combination of cyclic
and acyclic features. In some embodiments, L comprises at least one
ring that is part of or is fused to the linker that forms the
shortest path between any two Q and/or Q'. Such rings may be
saturated, unsaturated or aromatic, and may contain from 1-3
heteroatoms selected from the group consisting of N, O and S. In
certain embodiments, L is symmetric about its central atom (if the
chain connecting the two available valences is an odd number of
atoms in length) or its central bond (if the chain connecting the
two available valences is an even number of atoms in length).
Frequently, L is 3-6 atoms in length, counting along the shortest
path between Q and Q'. L can also include one or more heteroatoms
selected from N, O and S, but does not include a disulfide linkage.
The same groups are suitable for compounds of formula (13A).
[0518] For compounds of formula (7) and (8), Q represents --O-- or
--NR.sup.2--, where R.sup.2 is independently H, or optionally
substituted C1-C8 or optionally substituted C1-C8 heteroalkyl; and
Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl
or C1-C4 heteroalkyl. In certain embodiments, Q and/or Q' can
independently be a bond when L comprises a ring.
[0519] In some embodiments of formulas (7) and (8), Q is a bond
where L comprises a triazole ring. In other embodiments, Q is
--NH--, and L represents an optionally substituted C1-C8 alkylene
linker, which may be saturated or unsaturated. In certain
embodiments, Q' is --CH.sub.2-- and L represents an optionally
substituted C2-C8 alkylene linker, which may be saturated or
unsaturated. In further embodiments, Q' is a bond where L comprises
an aryl ring.
[0520] In certain embodiments of formula (7) and (8), L represents
an optionally substituted C2-C8 alkynylene linker. For example, L
can be an optionally substituted bis-acetylenic linker, such as
--(CH.sub.2).sub.q--C.ident.C--C.ident.C--(CH.sub.2).sub.q-- or
--C.ident.C--C.ident.C--(CH.sub.2).sub.qC(O)-- where q is 0-5, or
an arylalkynyl linker, such as -Ph-C.ident.C--(CH.sub.2).sub.q--
where q is 0-5. In other embodiments, L comprises a triazole
ring.
[0521] For compounds of formula (9), each of Q and Q' independently
represents --O-- or --NR.sup.2--, where R.sup.2 is independently H,
or optionally substituted C1-C8 or optionally substituted C1-C8
heteroalkyl; or one or both of Q and Q' can be a bond where L
comprises a ring. In certain embodiments, Q represents a bond where
L comprises a triazole ring.
[0522] In compounds of formula (10), each of Q and Q' independently
represents --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl
or C1-C4 heteroalkyl. In certain embodiments, Q and/or Q' can
independently be a bond when L comprises a ring. In some
embodiments Q and Q' are --CH.sub.2-- and L is a C5-C12 arylene or
C5-C20 arylalkylene linker, or a heteroform of one of these, each
of which may be optionally substituted.
[0523] In certain embodiments of formula (10), Q and/or Q'
represent --CH.sub.2-- and L represents an optionally substituted
C1-C8 alkylene or C1-C8 heteroalkylene linker, which may be
saturated or unsaturated. In other embodiments, Q and/or Q'
represent a bond when L comprises an aryl ring. In further
embodiments, Q and/or Q' represent --(CH.sub.2).sub.4NH-- and L
comprises one or more amide groups.
[0524] For compounds of formula (10), each R.sup.6 and/or R.sup.6'
is independently H, C1-C8 alkyl, C5-C12 aryl or C5-C12 arylalkyl,
or a heteroform of one of these, each of which may be optionally
substituted; or is a C8-C14 bicyclic or tricyclic ring system
comprising a 5- or 6-membered saturated or partially unsaturated
ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring, which ring
system may be attached to nitrogen through any available position
on the saturated or aromatic ring. In preferred embodiments, one of
R.sup.6 and R.sup.6' is H, and the other is a tetrahydronaphthyl,
indanyl or fluorenyl ring system attached to the nitrogen atom
through an open valence on the saturated ring.
[0525] For compounds of formula (11), p is 2 or 3, and Q, L and
R.sup.6 are as described for compounds of formula (10). In some
embodiments, p is 3 and L comprises a tri-substituted phenyl
ring.
[0526] For compounds of formula (12), Q is represents --CH.sub.2--,
--CH(OR)--, --CH(R)--, --CH.sub.2O--, --CH(R)O-- or
--(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl or C1-C4
heteroalkyl. In certain embodiments, Q can independently be a bond
when L comprises a ring. In preferred embodiments, Q is
--(CH.sub.2).sub.4NH-- and L comprises a tri-substituted phenyl
ring.
[0527] For compounds of formula (13), each of Q and Q'
independently represents --O-- or --NR.sup.2--, where R.sup.2 is
independently H, or optionally substituted C1-C8 alkyl, C1-C8
heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl or
C2-C8 heteroalkynyl; or one or both of Q and Q' can be a bond where
L comprises a ring. In certain embodiments, Q and Q' are the same.
In preferred embodiments, each of Q and Q' represents --NH-- or
--N(Me)- where L comprises one or more triazole rings. The same
groups are suitable for compounds of formula (13A).
[0528] For compounds of formula (14), p is 2 or 3. In certain
embodiments, R.sup.5 is C1-C8 alkyl or C1-C8 heteroalkyl. In
preferred embodiments, R.sup.5 is tert-butyl. In some embodiments
of formula (14), L is an optionally substituted and/or unsaturated
C1-C14 alkylene or C5-C20 arylalkylene linker, or a heteroform of
one of these. In certain embodiments, L comprises one or more
triazole rings. In some embodiments, Q is --NR.sup.2--, wherein
R.sup.2 is H or methyl.
[0529] In compounds of formula (13A), two amide-containing binding
domains are linked together by a linkage depicted as Q-L-Q'. As
further described herein for specific embodiments, this linkage can
comprise numerous alternatives that can include a chain that may be
substituted and may be saturated or unsaturated; it may also
include a combination of cyclic and acyclic features.
[0530] In some embodiments of formula (13A), L represents an
optionally substituted C1-C24 hydrocarbyl linker, optionally
containing from 1-8 heteroatoms selected from N, O and S, which
linker is 1-18 atoms in length when counted along the shortest path
between Q and Q'.
[0531] In certain embodiments, L is a C1-C12 alkylene, C3-C12
cycloalkylene, C2-C12 alkenylene, or C2-C12 alkynylene linker, or a
heteroform of one of these, each of which may be optionally
substituted. In frequent embodiments, L is an optionally
substituted acyclic C1-C12 alkylene, which may be saturated or
unsaturated (i.e., an alkenylene or alkynylene).
[0532] In certain embodiments, such alkylene linker is preferably
unsaturated, and may be an alkynylene linker. In some embodiments,
L is symmetric, and frequently L is 6-10 atoms in length, counting
along the shortest path (by atom count) between Q and Q'. In
certain embodiments, L can also include one or more heteroatoms
selected from N, O and S, but does not include a disulfide
linkage.
[0533] L can be substituted by substituents including rings, and it
can comprise one or more rings as part of the linkage that connects
Q and Q' together. Where L comprises at least one ring that is part
of or is fused to the shortest path (by atom count) connecting Q
and Q', Q and/or Q' in formula (13A) can be a bond as well as any
of the other structures described herein for Q and Q'.
[0534] Where L comprises a ring, the ring(s) may be carbocyclic,
heterocyclic, aromatic or heteroaromatic, each of which may be
optionally substituted. Such rings can be connected to Q and/or Q'
(or, where Q and/or Q' represent a bond, the rings can be connected
by the bond Q or Q' directly to the carbon to which Q/Q' are
attached), at any ring position, and may be attached either
directly or through an intervening alkylene or heteroalkylene
group, provided the shortest path (by atom counting) between Q and
Q' consists of 1-18 atoms, and preferably 1-14 atoms or 1-10
atoms.
[0535] Rings which comprise part of the linker, L, may be
optionally substituted to the extent such substitution makes
chemical sense. Preferred optional substituents when present on a
ring which comprises part of L include alkyl (C1-C4), alkoxy
(C1-C4), --CF.sub.3, --OCF.sub.3, halo, --OH, --NO.sub.2, --CN, or
NR.sub.2, where R is H or C1-C4 alkyl.
[0536] Alternatively, L can be a saturated or unsaturated
arylalkylene linker, comprised of an aryl ring and an alkylene
group, or an aryl ring and two alkylene groups combined, each of
which may be optionally substituted. For example, it can be
--CH.sub.2--Ar--, --(CH.sub.2).sub.2--Ar--(CH.sub.2).sub.2--,
--C(O)--Ar--C(O)--, or --CH.sub.2--Ar--C.ident.C--, where Ar
represents a 5- or 6-membered aromatic or heteroaromatic ring. L
can also include one or more heteroatoms, for example, it can be
--CH.sub.2--Ar--O-- or --NH--Ar--CH.sub.2-- or a substituted
version of one of these.
[0537] In compounds of formula (13A), Q is --O-- or --NR.sup.2--,
and Q' is --O-- or --NR.sup.2'--, where Q and Q' are independently
selected, and each R.sup.2 and R.sup.2' is independently H, or
C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl, or a heteroform of
one of these, each of which may be optionally substituted; or one
or both of Q and Q' can be a bond where L comprises a ring;
[0538] In preferred embodiments, Q and Q' are --NR.sup.2-- and
--NR.sup.2'--, respectively, where each R.sup.2 and R.sup.2' is
independently H, or C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl,
or a heteroform of one of these, each of which may be optionally
substituted.
[0539] In compounds of formula (13A), each R.sup.1 and R.sup.1' is
independently H or optionally substituted C1-C8 alkyl, preferably
C1-C4 alkyl. In certain embodiments, each R.sup.1 and R.sup.1' is
independently H or methyl.
[0540] In formula (13A), each R.sub.a, R.sub.b, R.sub.a' and
R.sub.b' is independently H, or C1-C8 alkyl, C3-C7 cycloalkyl,
C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted. In certain embodiments, the two R-groups on one carbon
atom, i.e., R.sub.a and R.sub.b, or R.sub.a' and R.sub.b' may be
taken together with the carbon atom to which they are attached to
form an optionally substituted 3-7 membered ring, optionally
containing one heteroatom selected from N, O and S as a ring
member.
[0541] Each Z and Z' in compounds of formula (13A) independently
represents an optionally substituted C1-C6 aminoalkyl group. In
frequent embodiments, each Z and Z' represents a 1-aminoalkyl
substituent. In some embodiments, Z and Z' may comprise an
optionally protected amino group Amino groups in Z and Z' may be
suitably protected as, for example, carbamates (e.g.
tert-butoxycarbonyl, benzlyoxycarbonyl,
fluorenylmethyloxy-carbonyl, allyloxycarbonyl or
(trialkylsilyl)ethoxycarbonyl), carboxamides (e.g. formyl, acyl or
trifluoroacetyl), sulfonamides, phthalimides, Schiff base
derivatives, and the like.
[0542] In preferred embodiments, each Z and Z' represents a
1-aminoalkyl substituent of the formula
--CH(R.sup.3)NR.sup.4.sub.2, wherein R.sup.3 and R.sup.4 are as
further described herein.
[0543] In some such embodiments, each R.sup.4 is independently H,
or an optionally substituted C1-C8 alkyl or optionally substituted
C1-C8 heteroalkyl group, and the two R.sup.6 groups on one nitrogen
can cyclize to form an optionally substituted 3-8 membered
azacyclic ring, which azacyclic ring may be saturated, unsaturated
or aromatic, and may contain 1-2 additional heteroatoms selected
from N, O and S as ring members.
[0544] Each R.sup.3 is H, or an optionally substituted C1-C8 alkyl
or optionally substituted C1-C8 heteroalkyl group, and R.sup.3 can
cyclize with R.sup.4 on an adjacent nitrogen atom to form an
optionally substituted 3-8 membered azacyclic ring, which azacyclic
ring may be saturated, unsaturated or aromatic, and may contain 1-2
additional heteroatoms selected from N, O and S as ring members. In
preferred embodiments, each R.sup.3 and R.sup.4 is independently H
or C1-C4 alkyl.
[0545] In compounds of formula (13A), where present, each Y and Y'
independently represents an optionally substituted C1-C8 alkyl,
C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or
is .dbd.O, --OR, --SR, --S(O)R, --SO.sub.2R, --SO.sub.2NR.sub.2,
--NR.sub.2, --OC(O)R, --NRC(O)R, --NRCOOR, --NRC(O)NR.sub.2,
--NRSO.sub.2R, --CN, --C(O)NR.sub.2, --C(O)R, --COOR, --NO.sub.2 or
halo, wherein each R is independently H, C1-C8 alkyl, C5-C12 aryl
or C5-C20 arylalkyl, or a heteroform of one of these; or is any
other substituent suitable for an alkyl group; and wherein two Y or
Y' groups on the same ring can cyclize to form a 3-6 membered ring
that can be saturated, unsaturated or aromatic, and which ring may
include one heteroatom selected from O, S and N as a ring member
and may be substituted.
[0546] Each m and m' in compounds of formula (13A) is independently
0-4, and each n and n' is independently 0-3. In frequent
embodiments, each of n and n' is 1, and each m and m' is 0 or 1,
and Y and Y', if present, are the same.
[0547] In a particularly preferred embodiment of formula (13A), Q
and Q' are --NR.sup.2-- and --NR.sup.2'--, respectively, and L
represents an optionally substituted C1-C24 hydrocarbyl linker of
the formula --C(R.sup.3AR.sup.4A)-J-K-J'-C(R.sup.3A'R.sup.4A')--,
optionally containing from 1-8 heteroatoms selected from N, O and
S, wherein R.sup.3A, R.sup.4A, R.sup.3A', R.sup.4A', J, J' and K
are as further described herein for compounds of formula
(13B)-(13D).
[0548] In certain embodiments, the compounds of the invention have
the formula (13B). In compounds of formula (13B), each of Y, Y', m,
m', n, n', R.sub.a, R.sub.a', R.sub.b, R.sub.b', R.sup.1, R.sup.1',
Z and Z' are as described for formula (13A). In compounds of
formula (13B), Q and Q' in formula (13A) are --NR.sup.2-- and
--NR.sup.2'--, respectively, and L represents a linker having the
formula --C(R.sup.3AR.sup.4A)-J-K-J'-C(R.sup.3A'R.sup.4A')--, as
described herein.
[0549] In compounds of formula (13B), the linkage described as
J-K-J' can comprise numerous alternatives that can include a chain
that may be substituted and may be saturated or unsaturated; it may
also include a combination of cyclic and acyclic features.
[0550] In compounds of formula (13B), K represents an optionally
substituted C1-C20 hydrocarbyl linker, optionally containing from
1-6 heteroatoms selected from N, O and S, which linker is 1-14
atoms in length when counted along the shortest path between J and
F. In some embodiments, K is symmetric, and frequently L is 6-10
atoms in length, counting along the shortest path (by atom count)
between J and F. In certain embodiments, K can also include one or
more heteroatoms selected from N, O and S, but does not include a
disulfide linkage.
[0551] In some embodiments of formula (13B), K represents a C1-C10
alkylene, C3-C10 cycloalkylene, C2-C10 alkenylene, C2-C10
alkynylene, C5-C12 arylene, C5-C20 arylalkylene, C5-C20
arylalkenylene or C5-C20 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted; with the
proviso that K does not comprise a disulfide bond.
[0552] For example, K can be --(CH.sub.2).sub.k-- where k is 1-8,
and may be optionally substituted with groups suitable for an alkyl
group. Some saturated embodiments of K include 1,3-propylene,
1,4-butylene, 1,5-pentylene and 1,6-hexylene, or 1,4-cyclohexylene,
each of which can be substituted. In certain embodiments, the
alkylene chain is substituted with one or two carbonyl oxygens
(.dbd.O).
[0553] When K is unsaturated, it is sometimes a C2-C10 alkenylene
or C2-C10 alkynylene linker. Some unsaturated embodiments of K
include 1,4-but-2-enylene (--CH.sub.2--CH.dbd.CH--CH.sub.2--),
1,4-buta-1,3-dienylene (--CH.dbd.CH--CH.dbd.CH);
1,4-buta-1,3-diynylene (--C.ident.C--C.ident.C--); or an optionally
substituted version of one of these. K can also include one or more
heteroatoms selected from N, O and S. When K is substituted, it is
frequently substituted with one or two .dbd.O, halo, C1-C4 alkyl,
--OR or --NR.sub.2, where R is H or C1-C4 alkyl.
[0554] K can be substituted by substituents including rings, and it
can comprise one or more rings as part of the linkage that connects
J and J' together. Where K comprises at least one ring that is part
of or is fused to the shortest path (by atom count) connecting J
and J', J and/or J' in formula (13B) can be a bond as well as any
of the other structures described herein for J and F.
[0555] Where K comprises a ring, the ring(s) may be carbocyclic,
heterocyclic, aromatic or heteroaromatic, each of which may be
optionally substituted. Such rings can be connected to J and/or J'
(or, where J and/or J' represent a bond, the rings can be connected
by the bond J or J' directly to the carbon to which they are
attached), at any ring position, and may be attached either
directly or through an intervening alkylene or heteroalkylene
group, provided the shortest path (by atom counting) between J and
J' consists of 1-14 atoms, and preferably 1-10 atoms or 1-8
atoms.
[0556] In certain embodiments, K comprises at least one
carbocyclic, heterocyclic, aromatic or heteroaromatic ring that is
part of or is fused to the linker which forms the shortest path
between J and J'. In specific embodiments, K comprises at least one
optionally substituted phenyl or triazole ring.
[0557] In some embodiments, K comprises a phenyl or pyridyl ring
that may be 1,2-disubstituted, or 1,3-disubstituted, or
1,4-disubstituted, by the groups J and J', which may be directly
attached to the ring or may be separated from the ring by one or
more atoms that are included in K.
[0558] In compounds of formula (13B), each of J and J'
independently represents --CH.sub.2--, --CH(OR')--, --CH(R')--,
--(CH.sub.2).sub.rG-, --CH(R')G-, or --CR'.dbd.CR'-- or
--C.ident.C--, wherein r is 1-4, each G is independently O, NR', or
S, and wherein each R' is independently H, or C1-C8 alkyl or C1-C8
heteroalkyl; or one or both of J and J' can be a bond where K
comprises a ring.
[0559] In preferred embodiments, each J and J' is independently
selected from the group consisting of --CH.sub.2--, --CH(R')--,
--(CH.sub.2).sub.rG-, and --CH(R')G-, wherein r is 1-4, each G is
independently O or NR', and wherein each R' is independently H or
C1-C4 alkyl.
[0560] In particularly preferred embodiments, each of J and J' is
independently --CH.sub.2--, --CH.sub.2O-- or --CH.sub.2N(R')--,
where R' is H or methyl.
[0561] In compounds of formula (13B), each R.sup.1 and R.sup.1' is
independently H or optionally substituted C1-C8 alkyl, preferably
C1-C4 alkyl. In certain embodiments, each R.sup.1 and R.sup.1' is
independently H or methyl.
[0562] In formula (13B), each R.sub.a, R.sub.b, R.sub.a' and
R.sub.b' is independently H, or C1-C8 alkyl, C3-C7 cycloalkyl,
C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted. In certain embodiments, the two R-groups on one carbon
atom, i.e., R.sub.a and R.sub.b, or R.sub.a' and R.sub.b' may be
taken together with the carbon atom to which they are attached to
form an optionally substituted 3-7 membered ring, optionally
containing one heteroatom selected from N, O and S as a ring
member.
[0563] In compounds of formula (13B), each R.sup.2 and R.sup.2' is
independently H or optionally substituted C1-C8 alkyl, preferably
C1-C4 alkyl. In preferred embodiments, each R.sup.2 and R.sup.2' is
independently H or methyl.
[0564] Each R.sup.3A, R.sup.4A, R.sup.3A' and R.sup.4A' in formula
(13B) is independently H, or C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8
alkenyl, C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted. In certain embodiments, the two R-groups on one carbon
atom, i.e., R.sup.3A and R.sup.4A, or R.sup.3A' and R.sup.4A' may
be taken together with the carbon atom to which they are attached
to form an optionally substituted 3-7 membered ring, optionally
containing one heteroatom selected from N, O and S as a ring
member.
[0565] Each Z and Z' in compounds of formula (13B) independently
represents an optionally substituted C1-C6 aminoalkyl group. In
frequent embodiments, each Z and Z' represents a 1-aminoalkyl
substituent. In certain embodiments, each Z and Z' represents a
group of the formula --CH(R.sup.3)NR.sup.4.sub.2, wherein R.sup.3
and R.sup.4 are as described for preferred embodiments of formula
(13A).
[0566] In some such embodiments, each R.sup.4 is independently H,
or an optionally substituted C.sub.1-C.sub.8 alkyl or optionally
substituted C.sub.1-C.sub.8 heteroalkyl group, and the two R.sup.4
groups on one nitrogen can cyclize to form an optionally
substituted 3-8 membered azacyclic ring, which azacyclic ring may
be saturated, unsaturated or aromatic, and may contain 1-2
additional heteroatoms selected from N, O and S as ring
members.
[0567] Each R.sup.3 is H, or an optionally substituted
C.sub.1-C.sub.8 alkyl or optionally substituted C.sub.1-C.sub.8
heteroalkyl group, and R.sup.3 can cyclize with R.sup.4 on an
adjacent nitrogen atom to form an optionally substituted 3-8
membered azacyclic ring, which azacyclic ring may be saturated,
unsaturated or aromatic, and may contain 1-2 additional heteroatoms
selected from N, O and S as ring members. In preferred embodiments,
each R.sup.3 and R.sup.4 is independently H or C1-C4 alkyl.
[0568] In specific embodiments, each R.sup.3 and R.sup.4 is
independently H or C1-C4 alkyl. In preferred embodiments, each
R.sup.4 is independently H or methyl, and R.sup.3 is selected from
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,
sec-butyl, and tert-butyl.
[0569] In compounds of formula (13B), where present, each Y and Y'
is defined as for formula (13A), each m and m' is independently
0-4, and each n and n' is independently 0-3. In frequent
embodiments, each of n and n' is 1, each m and m' is 0 or 1, and Y
and Y', if present, are the same.
[0570] In other embodiments, the compounds of the invention have
the formula (13C), wherein each Y, m, n, R.sub.a, R.sub.b, R.sup.1,
R.sup.2, R.sup.3A, R.sup.4A, J, K and Z is as defined for compounds
of formula (13B).
[0571] In preferred embodiments of formula (13C), each of R.sup.1
and R.sup.2 is independently H or methyl, n is 1, and m is 0 or 1.
In particularly preferred embodiments, R.sub.a and R.sup.3A are H,
and each of R.sub.b and R.sup.4A is independently H, or C1-C8
alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl,
C5-C20 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted.
[0572] In compounds of formula (13C), Z is a 1-aminoalkyl group
represented by the formula --CH(R.sup.3)NR.sup.4.sub.2, wherein
R.sup.3 and R.sup.4 are defined as above. In specific embodiments,
each R.sup.3 and R.sup.4 is independently H or C1-C4 alkyl. In
preferred embodiments, each R.sup.4 is independently H or methyl,
and R.sup.3 is selected from methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
[0573] In compounds of formula (13C), J is selected from the group
consisting of --CH.sub.2--, --CH(R')--, --(CH.sub.2).sub.rG-, and
--CH(R')G-, wherein r is 1-4, each G is independently O or NR', and
wherein each R' is independently H or C1-C4 alkyl; or J can be a
bond where K comprises a ring.
[0574] In preferred embodiments, J is --CH.sub.2--, --CH.sub.2O--
or --CH.sub.2N(R')--, where R' is H or methyl.
[0575] In compounds of formula (13C), K represents a C1-C10
alkylene, C3-C10 cycloalkylene, C2-C10 alkenylene, C2-C10
alkynylene, C5-C12 arylene, C5-C20 arylalkylene, C5-C20
arylalkenylene or C5-C20 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0576] In specific embodiments of formula (13C), K comprises a
C1-C6 alkylene, C1-C6 alkenylene, or C1-C6 alkynylene linker. In
other embodiments, K is a C5-C12 arylene or a saturated or
unsaturated C5-C20 arylalkylene linker. In specific embodiments, K
comprises an optionally substituted phenyl or triazole ring.
[0577] In some embodiments, the compounds of the invention have the
formula (13D), wherein each Z, J and K is as defined for compounds
of formula (13B) and (13C).
[0578] In compounds of formula (13D), each R.sup.1 and R.sup.2 is
independently H or methyl. In preferred embodiments, each of
R.sup.1 and R.sup.2 is H.
[0579] In compounds of formula (13D), each of R.sub.a and R.sup.3A
is H, and each R.sub.b and R.sup.4A is independently H, or C1-C8
alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl,
C5-C20 arylalkyl, or a heteroform of one of these, each of which
may be optionally substituted. In a preferred embodiment, each of
R.sub.b and R.sup.4A is independently a C1-C8 alkyl or C3-C7
cycloalkyl group.
[0580] In another aspect, the invention provides monomeric
compounds of formulae (19) and (19A), and methods of using them to
prepare compounds of formulae (13) and (13B)-(13D). In compounds of
formulae (19A), each of Y, m, n, R.sub.a, R.sub.b, R.sup.1,
R.sup.2, R.sup.3A, R.sup.4A and Z is defined as for formula
(13B).
[0581] In certain embodiments of formula (19A), Z is often a
protected amine, as further described herein. One of skill in the
art would appreciate that appropriate amine protecting groups may
vary depending on the functionality present in the particular
monomer. Suitably protected amines may include, for example,
carbamates (e.g. tert-butoxycarbonyl, benzlyoxycarbonyl,
fluorenylmethyloxycarbonyl, allyloxycarbonyl or
(trialkylsilyl)ethoxycarbonyl), carboxamides (e.g. formyl, acyl or
trifluoroacetyl), sulfonamides, phthalimides, Schiff base
derivatives, and the like.
[0582] In compounds of formula (19A), V represents a C1-C8 alkyl,
C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8
alkynyl, C2-C8 heteroalkynyl, C5-C12 aryl, C5-C12 heteroaryl,
C5-C20 arylalkyl or C5-C20 heteroarylalkyl, each of which may be
optionally substituted with --OR.sup.9, --OC(O)R.sup.9,
--OSO.sub.2R.sup.9, C.dbd.O, --OC(O)OR.sup.9, --COOR.sup.8,
--NR.sup.9.sub.2, azido or halo, where each R.sup.9 is
independently H, or C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl,
C5-C12 aryl, C5-C21 arylalkyl, or a heteroform of one of these,
each of which may be optionally substituted.
[0583] Preferred substituents when present on V include hydroxyl,
optionally substituted amino, azido, alkylsulfonate, arylsulfonate,
halo, acyl, carbonyl, and carboxyl. In specific embodiments, V is
--CH.sub.2OH, --CH.sub.2OMs, --CH.sub.2NH.sub.2, --CH.sub.2N.sub.3,
or --CH.sub.2OCH.sub.2C.ident.CH.
[0584] For compounds of formulae (15) and (16), Q represents --O--
or --NR.sup.2--, where R.sup.2 is independently H, or optionally
substituted C1-C8 or optionally substituted C1-C8 heteroalkyl; and
Q' represents --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl
or C1-C4 heteroalkyl. In certain embodiments of formulae (15) and
(16), Q and/or Q' can independently be a bond when L comprises a
ring. In frequent embodiments, Q represents --NR.sup.2--, where
R.sup.2 is H or methyl. In certain embodiments, Q' is a bond where
L comprises a C5-C12 arylene or C5-C12 heteroarylene ring. In other
embodiments, Q' is --CH.sub.2-- and L comprises an optionally
substituted C2-C8 alkylene or heteroalkylene group, which may be
saturated or unsaturated.
[0585] For compounds of formula (17), R.sub.a, R.sub.b, R.sup.1 and
Z are as described for compounds of formulae (1)-(5), and R.sup.6
is as defined for compounds of formulas (10) and (11). In many
embodiments, Z represents a protected C1-C6 aminoalkyl group.
[0586] For compounds of formula (18), R.sup.1, m, n, W, X, Y and Z
are as defined for compounds of formulae (1)-(5). Frequently, Z
represents a protected C1-C6 aminoalkyl group.
[0587] For compounds of formula (17) and (18), U represents C1-C8
alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, or C5-C21
arylalkyl, or a heteroform of one of these, each of which may be
optionally substituted. In some embodiments, U comprises a terminal
alkene or terminal alkyne. In preferred embodiments of formula (17)
or (18), U is --CH.sub.2C.ident.CH, --CH(R)OCH.sub.2C.ident.CH,
where R is H or methyl, or U is (CH.sub.2).sub.tAr, where t is 0 or
1 and Ar represents a phenyl ring substituted with halo, --OH or
--OTf.
[0588] For compounds of formula (19), R.sub.a, R.sub.b, R.sup.1, m,
n, Y and Z are as defined for compounds of formulae (1)-(5), and U
is as defined for compounds of formula (6). In preferred
embodiments, U is --NH.sub.2 or --NH(CH.sub.2).sub.rC.ident.CH
where r is 1-2. In frequent embodiments, Z represents a protected
C1-C6 aminoalkyl group.
[0589] For compounds of formula (19A), R.sub.a, R.sub.b, R.sup.1,
m, n, Y and Z are as defined for formula (19), and R.sup.2,
R.sup.3, and R.sup.4 are defined as for formula (13B). V in formula
(19A) represents a C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl,
C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C5-C12
aryl, C5-C12 heteroaryl, C5-C20 arylalkyl or C5-C20
heteroarylalkyl, each of which may be optionally substituted with
--OR.sup.9, --OC(O)R.sup.9, --OSO.sub.2R.sup.9, C.dbd.O,
--OC(O)OR.sup.9, --COOR.sup.8, --NR.sup.9.sub.2, azido or halo,
where each R.sup.9 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted.
[0590] In some embodiments, two or three monomers of formula (6),
formula (17), formula (18), formula (19) or formula (19A), which
may be the same or different, are reacted to produce dimeric or
trimeric Smac inhibitors.
[0591] For example, two monomers of formula (17) may be reacted to
give a dimer of formula (10) or formula (11), wherein p is 2. For
example, two monomers of formula (17) in which U comprises a
terminal acetylene moiety may be coupled to form a bis-acetylene
linkage. In other embodiments, three monomers of formula (17) may
be reacted to give a trimer of formula (11), where p is 3.
[0592] In another embodiment, three monomers of formula (18) may be
reacted to give a trimer of formula (12). In a further embodiment,
two monomers of formula (19) may be reacted to give a dimer of
formula (13) or (14). In some such embodiments, each U represents
--NH.sub.2 or --NH(Me).
[0593] As a further example, a monomer of formula (17) or (18) may
be reacted with a monomer of formula (6) to provide an
unsymmetrical dimer of formula (7) or (8), respectively. For
example, an alkyne containing monomer of formula (17) or (18) may
be reacted with an azido containing monomer of formula (6) to
provide a dimer of formula (7) or (8), wherein L comprises a
triazole ring.
[0594] In a further example, two monomers of formula (19A) may be
reacted to provide a compound of formulae (13B)-(13D).
[0595] The compounds of the invention typically contain one or more
chiral centers. The invention expressly includes each diastereomer,
as well as each enantiomer of each diastereomer of the compounds
described and mixtures thereof, particularly racemic mixtures of
single diastereomers such as the ones described, and highly
enriched enantiomers having an enantiomeric excess (e.e.) of
greater than 90% or greater than about 95%. Substituent groups may
also include one or more chiral centers, and each enantiomer and
diastereomer of these substituents as well as mixtures thereof are
all included within the scope of the invention. Similarly, where
double bonds are present, the compounds can exist in some cases as
either cis or trans isomers; the invention includes each isomer
individually as well as mixtures of isomers.
[0596] Merely as examples of selected compounds of the invention,
Table 3 and Table 4 illustrate a number of compounds of formulae
(I) and (IA). These compounds represent selected preferred species,
and other species that include combinations of the features in the
compounds specifically depicted are also preferred.
[0597] The compounds of the invention may be isolated as salts
where an ionizable group such as a basic amine or a carboxylic acid
is present. The invention includes the salts of these compounds
that have pharmaceutically acceptable counterions. Such salts are
well known in the art, and include, for example, salts of acidic
groups formed by reaction with organic or inorganic bases, and
salts of basic groups formed by reaction with organic or inorganic
acids, as long as the counterions introduced by the reaction are
acceptable for pharmaceutical uses. Examples of inorganic bases
with alkali metal hydroxides (e.g., sodium hydroxide, potassium
hydroxide, etc.), alkaline earth metal hydroxides (e.g., of
calcium, magnesium, etc.), and hydroxides of aluminum, ammonium,
etc.
[0598] Examples of organic bases that could be used include
trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, etc. Examples of inorganic acids that
could be used include hydrochloric acid, hydrobromic acid, nitric
acid, sulfuric acid, phosphoric acid, etc. Examples of organic
acids include formic acid, oxalic acid, acetic acid, tartaric acid,
methanesulfonic acid, benzenesulfonic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
etc. Also included are salts with basic amino acids such as
arginine, lysine, ornithine, etc., and salts with acidic amino
acids such as aspartic acid, glutamic acid, etc.
[0599] The compounds of the invention can be used to prepare
pharmaceutical compositions containing at least one compound of any
of formulae (I), (IA), (1A), (3A), (1)-(5), (7)-(16), and
(13A)-(13D). Such compositions can be optimized for various
conditions and routes of administration using guidance that is
widely relied on for such purposes including Remington's
Pharmaceutical Sciences, latest edition, Mack Publishing Co.,
Easton, Pa., which is incorporated herein by reference. The
compositions comprise a compound of the invention admixed with at
least one pharmaceutically acceptable excipient, and preferably
with at least one such excipient other than water or a solvent such
as DMSO.
[0600] The compounds of the invention are suitable to treat a wide
variety of cancers. In particular, they are suitable to treat
neuroblastoma, glioblastoma, breast carcinoma, melanoma, prostate
carcinoma, pancreatic carcinoma, hepatocellular carcinoma, colon
carcinoma, and small-cell and non-small cell lung carcinoma.
[0601] The compounds of the invention are also suitable to treat
various autoimmune disorders, particularly rheumatoid arthritis,
lupus, vasculitis, glomerulonephritis, type-I diabetes, pernicious
anemia, myasthenia gravis, Guillain-Barre syndrome, and infections
with autoimmune effects such as AIDS, malaria, Chagas disease, and
Lyme disease.
[0602] The compounds of the invention are not on their own very
cytotoxic: they depend for their activity on potentiation of the
effects of other effectors, which may be natural, endogenous
substances, or they may be additional therapeutic substances. For
example, Smac mimics have been shown to strongly potentiate the
activity of TRAIL or etoposide when co-administered. Accordingly,
the compounds of the invention may be used in conjunction with or
in combination with an additional therapeutic having anticancer
effects. Such additional therapeutic can be a drug, or it can be a
radiation treatment. Where an additional drug is administered, it
is typically one known to have cytostatic, cytotoxic or
antineoplastic activity. These agents include, for example,
antimetabolites such as cytarabine, fludaragine,
5-fluoro-2'-deoxyuridine, gemcitabine, hydroxyurea, methotrexate;
DNA active agents such as bleomycin, chlorambucil, cisplatin,
cyclophosphamide, intercalating agents such as adriamycin and
mitoxantrone; protein synthesis inhibitors such as L-asparaginase,
cycloheximide, puromycin; topoisomerase I inhibitors such as
camptothecin or topotecan; topoisomerase II inhibitors such as
etoposide and teniposide; microtubule inhibitors such as colcemid,
colchicines, paclitaxel, vinblastine and vincristine; and kinase
inhibitors such as flavopiridol, staurosporin, and
hydroxystaurosporine. Preferred additional drugs for
co-administration with the compounds of the invention include those
that affect Hsp90 (heat-shock protein 90). Suitable Hsp90
inhibitors include ansamycin derivatives such as geldanomycin and
geldanomycin derivatives including
17-(allylamino)-17-desmethoxygeldanamycin (17-AAG), its dihydro
derivative, 17-AAGH.sub.2, and 17-amino derivatives of geldanamycin
such as 17-dimethylaminoethylamino-17-demethoxy-geldanamycin
(17-DMAG), 11-oxogeldanamycin, and 5,6-dihydrogeldanamycin, which
are disclosed in U.S. Pat. Nos. 4,261,989; 5,387,584; and
5,932,566, each of which is incorporated herein by reference. Other
suitable Hsp90 inhibitors include radicicol and oximes and other
analogs thereof, disclosed in Soga, et al., Curr. Cancer Drug
Targets (2003) 3:359-369, and in Yamamoto, et al., Angew. Chem.
(2003) 42:1280-1284; and in Moulin, et al., J. Amer. Chem. Soc.
(2005) 127:6999-7004; purine derivatives such as PU3, PU24FCI and
PUH64 (see Chiosis et al., ACS Chem. Biol. (2006) 1(5):279-284 and
those disclosed in PCT Application No. WO 2002/0236075; related
heterocyclic derivatives disclosed in PCT Application No. WO
2005/028434; and 3,4-diarylpyrazole compounds disclosed in Cheung,
et al., Bioorg. Med. Chem. Lett. (2005) 15:3338-3343. Antibodies or
antibody fragments that selectively bind to Hsp90 may also be
administered as drugs to cause inhibition of Hsp90, and can be used
in combination with the compounds of the invention.
[0603] Natural effectors such as TRAIL, a TRAIL receptor antibody,
and TNF-.alpha. and TNF-.beta. can also be administered as drugs
for this purpose, and are also preferred, as are active fragments
of these peptides.
[0604] Where a compound of the invention is utilized to potentiate
the effects of another therapeutic, the two agents may be
co-administered, or they may be administered separately where their
administration is timed so the two agents act concurrently or
sequentially. Accordingly, the compositions of the invention
include at least one compound of formulae (I), (IA), (1A), (3A),
(1)-(5), (7)-(16), and (13A)-(13D) and can optionally include one
or more additional cytotoxic or cytostatic therapeutic such as, but
not limited to, those disclosed above. Similarly, the methods of
the invention include methods wherein a subject diagnosed as in
need of treatment for inflammation and/or cancer is treated with at
least one compound of the invention, and is simultaneously or
concurrently treated with one or more of the additional therapeutic
agents described above.
[0605] Formulations of the compounds and compositions of the
invention may be prepared in a manner suitable for systemic
administration or topical or local administration. Systemic
formulations include those designed for injection (e.g.,
intramuscular, intravenous or subcutaneous injection) and those
prepared for transdermal, transmucosal, or oral administration. The
formulation will generally include a diluent as well as, in some
cases, adjuvants, buffers, preservatives and the like. The
compounds can be administered also in liposomal compositions or as
microemulsions.
[0606] Injection methods are sometimes appropriate routes for
administration of the compounds for systemic treatments and
sometimes also for localized treatments. These include methods for
intravenous, intramuscular, subcutaneous, and other methods for
internal delivery that bypass the mucosal and dermal barriers to
deliver the composition directly into the subject's living
tissues.
[0607] For injection, formulations can be prepared in conventional
forms as liquid solutions or suspensions or as solid forms suitable
for solution or suspension in liquid prior to injection or as
emulsions. Suitable excipients include, for example, water, saline,
dextrose, glycerol and the like. Such compositions may also contain
amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, pH buffering agents and the like, such as, for
example, sodium acetate, sorbitan monolaurate, and so forth.
[0608] Various sustained release systems for drugs have also been
devised and can be utilized with the compounds of the invention.
See, for example, U.S. Pat. No. 5,624,677. The present compositions
can be utilized in such controlled-release delivery systems where
appropriate.
[0609] Systemic administration may also include relatively
noninvasive methods such as the use of suppositories, transdermal
patches, transmucosal delivery and intranasal administration. Oral
administration is also suitable for compounds of the invention,
which are more robust than the Smac peptide itself and are thus
advantageously more orally bioavailable. Suitable forms include
syrups, capsules, tablets, and the like as in understood in the
art.
[0610] Selection of a particular route of administration for a
given subject and indication is well within the ordinary level of
skill in the art. For example, rectal delivery as a suppository is
often appropriate where the subject experiences nausea and vomiting
that precludes effective oral delivery. Transdermal patches are
commonly capable of delivering a controlled-release dosage over
several days or to a specific locus, and are thus suitable for
subjects where these effects are desired.
[0611] Transmucosal delivery is also appropriate for some of the
compositions and methods of the invention. Thus the compositions of
the invention may be administered transmucosally using technology
and formulation methods that are known in the art.
[0612] For administration to animal or human subjects, the dosage
of a compound of the invention is typically 10-2400 mg per
administration. However, dosage levels are highly dependent on the
nature of the condition, the condition of the patient, the judgment
of the practitioner, and the frequency and mode of administration.
Selection of a dosage of such compounds is within the skill of an
ordinary artisan, and may be accomplished by starting at a
relatively low dosage and increasing the dosage until an acceptable
effect is achieved.
[0613] Frequency of administration of the compounds of the
invention can also be readily determined by one skilled in the art
using well known techniques. For example, the patient may be
administered a low dosage of a compound or composition of the
invention at a low frequency such as once per day or less often;
and the dosage and/or frequency of administration may be
systematically increased until a desired effect is achieved in the
patient.
[0614] Many suitable monomers are readily prepared by known
methods, including the extensive body of literature describing
synthesis of peptides and peptide mimetics. Examples of the
synthesis of certain monomers are included herein. Representative
monomers are shown in Table 5.
[0615] The invention includes monomers of formula (6) and methods
of using such monomers to make compounds of formulas (1)-(5) and
(7)-(9). Certain amine and azide containing monomers can be
prepared as shown in Schemes 1, 6 and 7. It will be understood that
similar monomers possessing different absolute or relative
stereochemistry could be made by varying the chirality of the
starting materials utilized, or through standard functional group
manipulations which are known to those of skill in the art. For
example, double-inversion of the 4-hydroxyl substituent on compound
I in Scheme 1, e.g., by tosylation, treatment with iodide, followed
by displacement with azide anion, would provide an isomer of
compound II where the 2- and 4-substituents have the relative trans
stereochemistry. Many other suitable monomers can be prepared by
methods that are known in the art. A preferred method for making
the compounds of formula (1) involves reaction of two monomers of
formula (6) with a third molecule containing at least two reactive
centers.
[0616] For example, compounds of formula (1) where L comprises a
bis-amide linker can be prepared by acylation of two amine
containing monomers of formula (6) with a diacid, which may be
optionally activated as a diacyl halide, mixed anhydride, activated
ester, bis-sulfonyl halide, or the like. Such compounds may be
symmetrical or unsymmetrical. This reaction is illustrated in
Schemes 4 and 6. For compounds of formula (2), three amine
containing monomers of formula (6) may be reacted with a triacid
derivative, as shown in Scheme 5.
[0617] Compounds of formula (1) having a diacetylenic in the linker
L can be made, as described by Harran, et al., US 2005/0197403, by
dimerizing two acetylenic monomers in the presence of a copper
salt.
[0618] The acetylenic linking groups can be readily modified to
produce other linkers; for example, catalytic hydrogenation of such
bis-acetylenic compounds would provide the partially or fully
saturated-linker compounds.
[0619] The acetylenic linking groups may also undergo cycloaddition
reactions. For example, cycloaddition reactions of a bis-acetylenic
dimer of formula (1) with an alkyl bis-azide provides fused
triazoles.
[0620] In addition, two azido monomers of formula (6) may undergo
dimerization concomitantly with cycloaddition with a bis-acetylene
containing molecule, to form a dimer wherein the linker comprises
two triazole rings. Alternatively, an azide containing monomer of
formula (6), may undergo cycloaddition with an acetylene containing
monomer to form a dimer containing a triazole ring as part of the
linker.
[0621] A wide variety of methods for forming such dimeric compounds
are known in the art, and may be employed with suitably
functionalized monomers. For example, hydroxyl substituted aryl or
arylalkyl groups may be modified to form aryl triflates or other
suitable functional groups, which may undergo cross-coupling
reactions, for example with alkynes, to form dimeric structures.
One of skill in the art would recognize that such compounds may
undergo further chemical transformations, for example, partial or
complete hydrogenation to form alkenyl or saturated linkers.
[0622] Additionally, hydroxyl or amino substituted monomers may be
alkylated, for example with allylic or propargylic halides, to form
other linkers or other functionalized monomers. Such monomers can
undergo dimerization or trimerization reactions, and may be further
modified after dimerization or trimerization
[0623] Alkylamine containing monomers may undergo dimerization by
further reaction at the amine center, for example by N-alkylation,
acylation, sulfonylation, or carbamoylation, to produce dimers
wherein the linkage represents as Q-L-Q' comprises a substituted
amine, or an amide, sulfonamide or urea. In addition, alkylamine
monomers may undergo reaction to provide additional monomers
containing functional groups suitable for dimerization, for
example, by alkylation with propargyl halides to provide acetylene
containing monomers.
[0624] The invention includes monomers of formula (19A), and
methods of using such monomers to make compounds of formulas (13B)
to (13D). Certain alcohol and alkynyl containing monomers can be
prepared as shown in Scheme 9. Certain amine and azide containing
monomers can be prepared as shown in Scheme 10.
[0625] Many other suitable monomers can be prepared by methods that
are known in the art. One preferred method for making the compounds
of formula (13B) involves reaction of two monomers of formula (19A)
with a third molecule containing at least two reactive centers.
[0626] For example, compounds of formula (13B) where J-K-J'
comprises a bis-amide linker can be prepared by acylation of two
amine-containing monomers of formula (19A) with a diacid, which may
be optionally activated as a diacyl halide, mixed anhydride,
activated ester, bis-sulfonyl halide, or the like. Such compounds
may be symmetrical or unsymmetrical. This reaction is illustrated
in Scheme 10.
[0627] Compounds of formula (13B) having a linker K comprising a
diacetylenic moiety can be made, as described by Harran, et al., US
2005/0197403, by dimerizing two acetylenic monomers of formula
(19A) in the presence of a copper salt, as shown in Scheme 9. The
acetylenic linking groups can be readily modified to produce other
linkers; for example, catalytic hydrogenation of such
bis-acetylenic compounds provides the partially or fully
saturated-linker compounds.
[0628] The acetylenic linking groups may also undergo cycloaddition
reactions. For example, cycloaddition reactions of a bis-acetylenic
dimer of formula (13A) with an alkyl bis-azide will provide a
linker containing two triazole rings.
[0629] In addition, two azido monomers of formula (19A) may undergo
dimerization concomitantly with cycloaddition with a bis-acetylene
containing molecule, to form a dimer wherein the linker comprises
two triazole rings. Alternatively, an azide containing monomer of
formula (19A), may undergo cycloaddition with an acetylene
containing monomer to form a dimer containing a triazole ring as
part of the linker.
[0630] Alkylamine containing monomers may undergo dimerization by
further reaction at the amine center, for example by N-alkylation,
acylation, sulfonylation, or carbamoylation, to produce dimers
wherein the linkage represented as J-K-J' comprises a substituted
amine, or an amide, sulfonamide or urea.
[0631] Preparation of the compounds of the invention from such
precursors can be achieved using methods known in the art.
Accordingly, synthesis of these compounds is within the ordinary
skill in the art. Synthetic methods for making selected compounds
of the invention are also provided herein.
Synthetic Scheme 1:
[0632] Compound II was prepared according to H. Marusawa et al.,
Bioorg. Med. Chem. (2002) 1399-1415. II was treated with acid to
deprotect the Boc group and coupled to Boc-Tle-OH to make III. By
repeating the similar Boc deprotection and coupling steps, Compound
IV was synthesized. Hydrolysis of the methyl ester and amide
formation gave the corresponding peptide V. The azide group on the
4 position of the proline was reduced to free amine to give
compound VI
##STR00050##
Synthetic Schemes 2-5:
[0633] By taking advantage of the copper(I) catalyzed azide-alkyne
[3+2] cycloaddition, the compound V was able to be used to
synthesize a series of dimerized compounds VII or VIII. On the
other hand, compound VI can be coupled with di-acid or its
derivatives by the amide formation reaction to make a number of
dimerized compounds IX or trimerized compounds X.
##STR00051##
##STR00052##
##STR00053##
##STR00054##
##STR00055##
##STR00056## ##STR00057##
Synthetic Schemes 8-9:
[0634] Compounds of formulae (13 and 13A-D) were prepared according
to Schemes 8-10. A protected monomer of formula (19) was prepared
as shown in Scheme 8. Amide coupling of the free carboxylic acid
from Scheme 8 with an amino alkyne derivative provided a monomer of
formula (19A). Cross-coupling of two terminal alkyne monomers
provided a diynyl linked dimer of formula (13A), which was
hydrogenated to give a dimer with a saturate alkylene linker.
##STR00058##
##STR00059## ##STR00060##
Synthetic Scheme 10:
[0635] Scheme 10 describes the preparation of azido-containing
monomer of formula (19A), which was reduced to the corresponding
amino-containing monomer and dimerized by formation of amide bonds
between two monomers units and a benzene dicarboxylic acid, to
provide a dimer of formula (13A).
##STR00061## ##STR00062##
[0636] Scheme 11 describes the preparation of the compound 104,
described in Examples 43-49.
##STR00063##
##STR00064##
[0637] Scheme 12 describes the synthesis of compound 51, described
in Examples 50-56.
##STR00065##
[0638] Scheme 13 describes the synthesis of compound 57, described
in Examples 57-63.
##STR00066##
[0639] Scheme 14 describes the synthesis of compound 32, described
in Examples 64-70.
General Methods:
[0640] NMR spectra were acquired at a proton frequency 400 MHz.
.sup.1H chemical shifts are reported with Me.sub.4Si (0.00 ppm),
CHCl.sub.3 (7.24 ppm) or CD.sub.2HOD (3.3 ppm) as internal
standards. .sup.13C chemical shifts are reported with CDCl.sub.3
(77.23 ppm) or CD.sub.3OD (49.00 ppm) as internal standards.
[0641] HPLC analysis used an AGILENT.RTM. LC/MS instrument (1100
series) with an AGILENT.RTM. ECLIPSE.TM. XBD-C18 column
(4.6.times.150 mm, 5 micron packing) operating at a flow rate of
1.00 mL/min. A linear acetonitrile/water gradient was used, with
0.05% TFA in each solvent. Initial solvent composition was 20%
acetonitrile, increasing to 100% acetonitrile over 10 min. After
holding at 100% acetonitrile for 5 min., the composition was
returned to 20% acetonitrile over 2 min. and held at that
composition for 3 min. to complete the cycle. Eluent was monitored
by MS, along with UV at 220 and 254 nm
[0642] Standard abbreviations are used throughout the experimental
sections and will be understood by one of skill in the art. For
example, hydrochloric acid (HCl); lithium hydroxide (LiOH);
methanol (MeOH); water (H.sub.2O); ethyl acetate (EtOAc); sodium
sulfate (Na.sub.2SO.sub.4); dimethylformamide (DMF);
N-Hydroxybenzotriazole (HOBT); diisopropylethylamine (DIPEA);
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC);
sodium bicarbonate (NaHCO.sub.3); tert-butoxycarbonyl (Boc);
triphenyl phosphine (PPh.sub.3); methyl t-butyl ether (MeOtBu);
N-methyl morpholine (NMM); copper (I) iodide (CuI); triethylamine
(TEA); dichloromethane (DCM); sodium azide (NaN.sub.3);
trifluoroacetic acid (TFA); palladium on charcoal (Pd/C); lithium
borohydride (LiBH.sub.4); potassium carbonate (K.sub.2CO.sub.3);
benzenethiol (PhSH); sodium hydride (NaH); copper (II) acetate
(Cu(OAc).sub.2); dimethylsulfoxide (DMSO). Amino acids are referred
to herein using the standard 3-letter code; e.g., alanine is
sometimes referred to herein as Ala, and tert-leucine may be
referred to as Tle.
General Procedure A (for Deprotection of Boc):
[0643] To a solution of the substrate in methylene chloride was
added trifluoroacetic acid (5 eq) at room temperature. The solution
was stirred at room temperature for 2-3 hrs and monitored by thin
layer chromatography (TLC). After all the starting material has
been consumed, the solvents and trifluoroacetic acid were removed
under reduced pressure to give the desired product.
General Procedure B (for Deprotection of Boc):
[0644] To a solution of the substrate in methylene chloride was
added HCl in dioxane (4N, 4 eq) at room temperature. The solution
was stirred at room temperature for 1-2 hr and monitored by TLC.
After all the starting material has been consumed, the solvents and
HCl were removed under reduced pressure. The residue was
lyophilized to give the desired product.
General Procedure C (for Hydrolysis of the Methyl Esters):
[0645] To a well-stirred solution of the substrate in a mixture of
5:1 MeOH/H.sub.2O was added LiOH at 0.degree. C. After stirring for
18 hours, 1N HCl was added until the pH=4. EtOAc was used to
extract the product and the combined organic layers were washed
with brine and dried over Na.sub.2SO.sub.4. The solution was
concentrated under reduced pressure to give the desired
product.
General Procedure D (for Preparation of Amides):
[0646] To a well-stirred mixture of the acid (1 eq.) and amine salt
(1.1 eq) in DMF at 0.degree. C., were added HOBT (1.1 eq.) and
DIPEA (2.25 eq.) in this order. After 5-10 min, EDC (1.1 eq.) was
added. The mixture was stirred for 1 hour at 0.degree. C., then
slowly warmed up to room temperature and stirred for 18 hours at
room temperature. The reaction mixture was concentrated under
vacuum. The residue was diluted with EtOAc and washed by HCl
solution (1 N), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give the desired product.
General Procedure E (for Preparation of Amides):
[0647] To a well-stirred mixture of the acid substrate in DMF at
0.degree. C., was added HOBT (1.1 eq), DIPEA (1.5 eq) and EDC (1.1
eq) in this order. After 10 minutes, the free amine substrate (1.1
eq) was added. The mixture was stirred for 1 hour at 0.degree. C.,
then slowly warmed up to room temperature and stirred for 18 hours
at room temperature. The reaction mixture was concentrated under
vacuum. The residue was diluted with EtOAc and washed by HCl
solution (1 N), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give the desired product.
General Description of In Vitro and In Vivo Assays
[0648] The in vitro and in vivo activities of the compounds of the
invention may be determined using techniques that are known in the
art. For example, Bockbrader, et al., Oncogene (2005) 24:7381-7388
discloses assays for determination of the effect of Smac mimics
using cell culture assays and in vitro assays for caspase
activation. Accordingly, in addition to guidance from symptomology,
treatment with the compounds, compositions and methods of the
invention can be monitored by methods known in the art for
determining the effects of Smac mimetic compounds.
[0649] The following examples are included for illustrative
purposes only and are not intended to represent or limit the scope
of the subject matter claimed herein.
Example 1
(2S,4S)-methyl
4-azido-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolid-
ine-2-carboxylate
##STR00067##
[0651] Compound II was treated with trifluoroacetic acid using the
general procedure A to deprotect the BOC group. The resulting
trifluoroacetic acid salt was coupled to Boc-Tle-OH using the
general procedure D to prepare the title compound of Example 1.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 2
(2S,4S)-methyl
4-azido-1-((S)-2-(S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3,3-
-dimethylbutanoyl)pyrrolidine-2-carboxylate
##STR00068##
[0653] The title compound of Example 1 was treated with
trifluoroacetic acid using the general procedure A to deprotect the
BOC group. The resulting trifluoroacetic acid salt was coupled to
Boc-N-Me-Ala-OH using the general procedure D to prepare the title
compound of Example 2. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 3
tert-butyl
(S)-1-((S)-1-((2S,4S)-4-azido-2-((R)-1,2,3,4-tetrahydronaphthal-
en-1-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxo-
propan-2-yl(methyl)carbamate
##STR00069##
[0655] The title compound of Example 2 was treated with LiOH using
the general procedure C to hydrolyze the methyl ester. The
resulting acid was coupled to (R)-tetrahydro-1-naphthylamine using
the general procedure D to prepare the title compound of Example 3.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 4
tert-butyl
(S)-1-((S)-1-((2S,4S)-4-amino-2-((R)-1,2,3,4-tetrahydronaphthal-
en-1-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxo-
propan-2-yl(methyl)carbamate
##STR00070##
[0657] To a solution of the title compound of Example 3 (1.7 g, 2.9
mmol) in 10.6 mL dry THF was added Ph.sub.3P (765 mg, 2.9 mmol) at
room temperature. Water (78.3 .mu.L, 4.35 mmol) was added drop wise
and the reaction mixture was allowed to stir for 16 hours at room
temperature. A 1:1 mixture of water/MeOtBu was added to quench the
reaction. The two phases were separated. The aqueous phase was
extracted by EtOAc twice, and then the combined organic phase was
washed by brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was chromatographed on silica gel,
eluting with EtOAc, the 5% to 15% MeOH/methylene chloride to give
the title compound as a white foam-like solid. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 5
##STR00071##
[0659] The title compound of Example 3 (500 mg, 0.86 mmol) was
dissolved in a 1:1 mixture of t-butanol and water (30 mL) at room
temperature. NMM (118 .mu.L, 1.08 mmol), CuI (82 mg, 0.43 mmol) and
1,6-heptadiyne (49 .mu.L, 0.43 mmol) were added in this order. The
suspension was vigorously stirred at room temperature for 24 hours.
The reaction mixture was diluted with MeOH and filtered through a
CELITE.RTM. pad and rinsed with MeOH. The combined filtrate was
concentrated under vacuum. The remaining aqueous solution was
extracted by EtOAc three times. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The residue
was chromatographed on silica gel, eluting with EtOAc, then 5% to
10% MeOH/methylene chloride to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 6
##STR00072##
[0661] The title compound of Example 5 (410 mg, 0.33 mmol) in 1 mL
methylene chloride was treated with HCl/dioxane (4M, 1.2 mL) using
the general procedure B to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 7
##STR00073##
[0663] The title compound of Example 3 (500 mg, 0.86 mmol) was
dissolved in a 1:1 mixture of t-butanol and water (20 mL) at room
temperature. NMM (118 .mu.L, 1.08 mmol), CuI (82 mg, 0.43 mmol) and
1,3-diethynylbenzene (57 .mu.L, 0.43 mmol) were added in this
order. The suspension was vigorously stirred at 60.degree. C. for
24 hours. The reaction mixture was diluted with MeOH and filtered
through a CELITE.RTM. pad and rinsed by MeOH. The combined filtrate
was concentrated under vacuum. The remaining aqueous solution was
extracted by EtOAc three times. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The residue
was chromatographed on silica gel, eluting with EtOAc, 5%
MeOH/EtOAc and then 8% MeOH/methylene chloride to give the title
compound as a white solid. .sup.1H NMR (CDCl.sub.3): consistent
with proposed structure.
Example 8
##STR00074##
[0665] The title compound of Example 5 (468 mg, 0.36 mmol) in 1 mL
methylene chloride was treated with HCl/dioxane (4M, 1.2 mL) using
the general procedure B to give the title compound as a pale yellow
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 9
##STR00075##
[0667] The title compound of Example 4 (600 mg, 1.08 mmol) was
dissolved in methylene chloride (25 mL) at 0.degree. C. TEA (226
.mu.L, 1.62 mmol) was added and the mixture was stirred for 10 min,
to which isophthaloyl dichloride (109 mg, 0.54 mmol) was added. The
reaction mixture was kept stirring for 1 hour at 0.degree. C., and
then slowly warmed up to room temperature and stirred overnight.
Water was added to quench the reaction. The two phases were
separated and the aqueous phase extracted by methylene chloride
twice. The combined organic phase was washed by HCl solution (1M),
saturated NaHCO.sub.3 solution and brine. The organic phase was
dried over sodium sulfate and concentrated under reduced pressure.
The residue was chromatographed on silica gel, eluting with EtOAc,
the 3% to 10% MeOH/methylene chloride to give the title compound as
a white solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 10
##STR00076##
[0669] The title compound of Example 9 (632 mg, 0.51 mmol) in 1.5
mL methylene chloride was treated with HCl/dioxane (4M, 2 mL) using
the general procedure B to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 11
##STR00077##
[0671] The title compound of Example 4 (400 mg, 0.72 mmol) was
dissolved in methylene chloride (15 mL) at 0.degree. C. TEA (125
.mu.L, 0.9 mmol) was added and the mixture was stirred for 10 min,
to which 1,3,5-Benzenetricarbonyl trichloride (63 mg, 0.24 mmol)
was added. The reaction mixture was kept stiffing for 1 hour at
0.degree. C., and then slowly warmed up to room temperature and
stirred overnight. The reaction mixture was diluted with 50 mL
methylene chloride and then washed by HCl solution (1M), saturated
NaHCO.sub.3 solution and brine. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The residue
was chromatographed on silica gel, eluting with 2% to 10%
MeOH/methylene chloride to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 12
##STR00078##
[0673] The title compound of Example 11 (410 mg, 0.22 mmol) in 0.5
mL methylene chloride was treated with HCl/dioxane (4M, 0.5 mL)
using the general procedure B to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 13
##STR00079##
[0675] The title compound of Example 4 (80 mg, 0.14 mmol) was
dissolved in methylene chloride (4 mL) at 0.degree. C. HOBT (20 mg,
0.15 mmol) and TEA (47 .mu.L, 0.34 mmol) were added, followed by
the addition of glutaric acid (8.8 mg, 0.67 mmol). The mixture was
stirred for 10 min, to which EDC (28.5 mg, 0.15 mmol) was added.
The reaction mixture was kept stirring for 1 hour at 0.degree. C.,
and then slowly warmed up to room temperature and stirred
overnight. The reaction mixture was diluted with 50 mL methylene
chloride and then washed by HCl solution (1M), saturated
NaHCO.sub.3 solution and brine. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The residue
was chromatographed on silica gel, eluting with EtOAc and then 2%
to 8% MeOH/methylene chloride to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 14
##STR00080##
[0677] The title compound of Example 13 (45 mg, 0.037 mmol) in 0.2
mL methylene chloride was treated with HCl/dioxane (4M, 0.2 mL)
using the general procedure B to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 15
##STR00081##
[0679] Compound 4-trans-hydroxy-(L)-N-Boc-Proline was coupled to
(R)-tetrahydro-1-naphthylamine using the general procedure E to
prepare the title compound. .sup.1H NMR (CDCl.sub.3): consistent
with proposed structure.
Example 16
##STR00082##
[0681] To a solution of the title compound of Example 15 (15.2 g,
42 mmol) in DCM (120 mL) at 0.degree. C., was added TEA (7.7 mL, 55
mmol). MsCl (3.92 mL. 50.6 mmol) was added slowly and the resulting
solution was stirred at 0.degree. C. for 5 hours. 50 mL DCM was
added. The mixture was washed by HCl solution (1 N), saturated
NaHCO.sub.3 solution and brine. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the crude mesylate as an oil, which was used immediately without
further purification. The oil was dissolved in DMSO (180 mL) and
NaN.sub.3 (5.5 g, 84 mmol) was added. After heating at 90.degree.
C. for 8 hours, the solution was cooled to room temperature. Water
(100 mL) was added and the mixture was extracted with EtOAc twice.
The combined organic phase was washed by brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the title compound as a white solid. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 17
##STR00083##
[0683] The title compound of Example 16 was treated with TFA using
the general procedure A to deprotect the BOC group. The resulting
TFA salt was coupled to Boc-Tle-OH using the general procedure D to
prepare the title compound. .sup.1H NMR (CDCl.sub.3): consistent
with proposed structure.
Example 18
##STR00084##
[0685] The title compound of Example 17 was treated with HCl using
the general procedure B to deprotect the BOC group. The resulting
HCl salt was coupled to Boc-NMe-Ala-OH using the general procedure
D to prepare the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 19
##STR00085##
[0687] To a solution of the title compound of Example 18 (2.62 g,
4.5 mmol) in 100 mL MeOH, was added 10% Pd/C (262 mg, 10% w/w) at
room temperature under N.sub.2 atmosphere. The mixture was then
charged with a hydrogen balloon and stirred for 8 hours at room
temperature. After all the starting material has been consumed, the
mixture was filtered through a CELITE.RTM. pad and concentrated
under reduced pressure to give a white solid as the title compound.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 20
##STR00086##
[0689] The title compound of Example 19 (600 mg, 1.08 mmol) was
dissolved in DCM (25 mL) at 0.degree. C. TEA (226 .mu.L, 1.62 mmol)
was added and the mixture was stirred for 10 min, to which
isophthaloyl dichloride (109 mg, 0.54 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred overnight. Water was added to
quench the reaction. The two phases were separated and the aqueous
phase was extracted by DCM twice. The combined organic phase was
washed by HCl solution (1M), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over sodium sulfate and
concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with EtOAc, the 3% to 10%
MeOH/DCM to give the title compound as a white solid. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 21
##STR00087##
[0691] The title compound of example 22 is commercially available.
(It could also be prepared from 4-trans-hydroxy-(L)-N-Boc-Proline:
H. Marusawa et al., Bioorg. Med. Chem. 1399-1415, 2002).
Example 22
##STR00088##
[0693] The title compound of Example 21 (2.5 g, 10.2 mmol) was
dissolved in DCM (100 mL) at 0.degree. C. TEA (2.13 mL, 15.3 mmol)
was added and the mixture was stirred for 10 min, to which
isophthaloyl dichloride (1.02 g, 5 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred overnight. Water was added to
quench the reaction. The two phases were separated and the aqueous
phase extracted by DCM twice. The combined organic phase was washed
by HCl solution (1M), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over sodium sulfate and concentrated under
reduced pressure to give the title compound as a white solid.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 23
##STR00089##
[0695] To a solution of the title compound of Example 22 (3.1 g, 5
mmol) in THF (100 mL) was added LiBH.sub.4 (540 mg, 25 mmol) in two
batches at 0.degree. C. After the reaction mixture was stirred at
0.degree. C. for 12 hours, 50 mL 1N HCl solution was slowly added
to quench the reaction. The mixture was then extracted by EtOAc
three times. The combined organic phase was washed by saturated
NaHCO.sub.3 solution and brine, dried over sodium sulfate and
concentrated under reduced pressure to give the title compound as a
white solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 24
##STR00090##
[0697] To a solution of the title compound of Example 23 (2.81 g, 5
mmol) in DCM (35 mL), was added TEA (1.84 mL, 13.2 mmol) at
0.degree. C. MsCl (0.93 mL, 12 mmol) was slowly added and the
resulting solution was stirred at 0.degree. C. for 1 hours. 20 mL
DCM was added. The mixture was washed by HCl solution (1 N),
saturated NaHCO.sub.3 solution and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the crude mesylate as an oil, which was used immediately
without further purification. The oil was dissolved in DMSO (45
mL). NaN.sub.3 (1.3 g, 20 mmol) was added. After heating at
90.degree. C. for 4 hours, the solution was cooled to room
temperature. Water (40 mL) was added and the mixture was extracted
with EtOAc twice. The combined organic phase was washed by brine,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was chromatographed on silica gel, eluting
with 30% to 90% EtOAc/Hexane to give the title compound as a pale
yellow solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 25
##STR00091##
[0699] The title compound of Example 24 (1.5 g, 2.4 mmol) and
toluene sulfonyl cyanide (888 mg, 4.9 mmol) were mixed in a sealed
tube. The solids were then heated to 90.degree. C. and melt to a
dark brown color liquid. After stiffing for 24 hours at 90.degree.
C., the mixture was cooled to room temperature. Add 3 mL DCM to
dissolve the solids. The residue was chromatographed on silica gel,
eluting with 30% to 95% EtOAc/Hexane to give the title compound.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 26
##STR00092##
[0701] To a solution of the title compound of Example 25 (940 mg,
0.96 mmol) in CH.sub.3CN (30 mL) was added K.sub.2CO.sub.3 (800 mg,
5.8 mmol) at room temperature. While stirring, the white suspension
was added by PhSH (0.79 mL, 7.7 mmol). After stirring for 12 hours
at room temperature, the reaction mixture was quenched by
NaHCO.sub.3 saturated solution. The two phases were separated and
the aqueous phase was extracted by EtOAc twice. The combined
organic phase was washed by brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 30% to 95% EtOAc/Hexane
to give the title compound as a white solid. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 27
##STR00093##
[0703] The title compound of Example 26 (165 mg, 0.19 mmol) in 0.2
mL DCM was treated with HCl/Dioxane (4M, 0.4 mL) using the general
procedure B to deprotect the Boc group. The resulting amine salt
and Boc-Tle-OH (86 mg, 0.37 mmol) was dissolved in DMF (4 mL) at
0.degree. C. To the above solution was added HOBT (50 mg, 0.37
mmol) and DIPEA (147 .mu.L, 0.84 mmol) in this order. After 5
minutes, EDC (72 mg, 0.37 mmol) was added. The reaction mixture was
stirred for 1 hour at 0.degree. C., then slowly warmed up to room
temperature and stirred for 18 hours at room temperature. The
reaction mixture was concentrated under vacuum. The residue was
diluted with EtOAc and washed by HCl solution (1 N), saturated
NaHCO.sub.3 solution and brine. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the desired product. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 28
##STR00094##
[0705] The title compound of Example 27 was treated with HCl and
then coupled to Boc-NMe-Ala-OH using a similar procedure as was
used to prepare the title compound 14 to prepare the title compound
15. The crude product was chromatographed on silica gel, eluting
with 30% to 95% EtOAc/Hexane to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 29
##STR00095##
[0707] The title compound of Example 28 was treated with HCl using
the general procedure B to give the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
[0708] The following examples are included for illustrative
purposes only and are not intended to represent or limit the scope
of the subject matter claimed herein.
Example 30
##STR00096##
[0710] (L)-Proline methyl ester was coupled to
N-Boc-.alpha.-tert-butyl-glycine using the general procedure D to
prepare the title compound. .sup.1H NMR (CDCl.sub.3): consistent
with proposed structure.
Example 31
##STR00097##
[0712] The title compound of Example 30 was treated with
HCl/Dioxane using the general procedure B to remove the BOC group.
The resulting HCl salt was coupled to Boc-NMe-Ala-OH using the
general procedure D to prepare the title compound. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 32
##STR00098##
[0714] The title compound of Example 31 was treated with LiOH using
the general procedure C to hydrolyze the methyl ester and give the
title compound. .sup.1H NMR (CDCl.sub.3): consistent with proposed
structure.
Example 33
##STR00099##
[0716] At 0.degree. C., to a solution of Boc-L-cyclohexylglycinol
(250 mg, 1.03 mmol) in 3 mL THF was added NaH (41 mg, 1.03 mmol).
The suspension was stirred for 5 minutes and was added by the
propargyl bromide solution (80% w % in toluene, 153 .mu.L, 1.03
mmol). The reaction mixture was stirred for 1 hour at 0.degree. C.,
then slowly warmed up to room temperature and stirred for 4 hours
at room temperature. The reaction was quenched by HCl solution (0.5
N, 2 mL). The mixture was extracted by EtOAc twice. The combined
organic phase was washed by saturated NaHCO.sub.3 solution and
brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 34
##STR00100##
[0718] The title compound of Example 33 (287 mg, 1.03 mmol) in 1 mL
DCM was treated with HCl/Dioxane (4M, 2 mL) using the general
procedure B to remove the Boc group. The resulting HCl salt and the
title compound 28 (387 mg, 0.94 mmol) was dissolved in DMF (10 mL)
at 0.degree. C. To the above solution were added HOBT (139 mg, 1.03
mmol) and DIPEA (404 .mu.L, 2.32 mmol). After 5 minutes, EDC (197
mg, 1.03 mmol) was added. The reaction mixture was stirred for 1
hour at 0.degree. C., then slowly warmed up to room temperature and
stirred for 12 hours at room temperature. The reaction mixture was
concentrated under vacuum. The residue was diluted with EtOAc and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give the title compound.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 35
##STR00101##
[0720] The title compound of example 34 (290 mg, 0.5 mmol) was
dissolved in 16 mL CH.sub.3CN, to which Cu(OAc).sub.2 (91 mg, 0.5
mmol) was added. The suspension was heated to 90.degree. C. and
gently refluxed for 30 minutes. When all the starting material was
consumed, the reaction mixture was cooled to room temperature,
quenched by 2% NH.sub.3.H.sub.2O solution and extracted by EtOAc
three times. The combined organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
product was chromatographed on silica gel, eluting with 50%
EtOAc/Hexane and then pure EtOAc to give the title compound.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 36
##STR00102##
[0722] The title compound of Example 35 (216 mg, 0.19 mmol) in 0.4
mL DCM was treated with HCl/Dioxane (4M, 0.8 mL) using the general
procedure B to give the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 37
##STR00103##
[0724] To a solution of the title compound of Example 36 (20 mg,
0.02 mmol) in 2 mL MeOH was added Pd/C (2 mg, 10% w/w) at room
temperature under N.sub.2 atmosphere. The mixture was charged with
a hydrogen balloon and stirred for 12 hours at room temperature.
After all the starting material had been consumed, the mixture was
filtered through a Celite.RTM. pad and concentrated under reduced
pressure to give the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 38
##STR00104##
[0726] To a solution of the Boc-L-cyclohexylglycinol (1 g, 4.1
mmol) in DCM (15 mL) was added TEA (0.71 mL, 5.1 mmol) at 0.degree.
C. Methyl sulfonyl chloride (0.37 mL 5.1 mmol) was added slowly and
the solution was stirred at 0.degree. C. for 3 hours. The reaction
mixture was diluted with 15 mL DCM. The mixture was washed by HCl
solution (1 N), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give the crude mesylate as an oil, which
was used immediately without further purification. The oil was
dissolved in DMSO (20 mL), to which NaN.sub.3 (540 mg, 8.2 mmol)
was added. After heating at 70.degree. C. for 6 hours, the solution
was cooled to room temperature. Water (20 mL) was added and the
mixture was extracted with EtOAc twice. The combined organic phase
was washed by brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give the title compound. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 39
##STR00105##
[0728] The title compound of Example 38 (654 mg, 2.44 mmol) in 2.5
mL DCM was treated with HCl/Dioxane (4M, 5 mL) using the general
procedure B to remove the Boc group. The resulting HCl salt and the
title compound of Example 3 (919 mg, 2.22 mmol) was dissolved in
DMF (40 mL) at 0.degree. C. To the above solution were added HOBT
(330 mg, 2.44 mmol) and DIPEA (956 .mu.L, 5.49 mmol). After 5
minutes, EDC (468 mg, 2.44 mmol) was added. The reaction mixture
was stirred for 1 hour at 0.degree. C., then slowly warmed up to
room temperature and stirred for 12 hours at room temperature. The
reaction mixture was concentrated under vacuum. The residue was
diluted with EtOAc and washed by HCl solution (1 N), saturated
NaHCO.sub.3 solution and brine. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the title compound. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 40
##STR00106##
[0730] To a solution of the title compound of Example 39 (1.03 g,
1.83 mmol) in 18 mL MeOH was added Pd/C (103 mg, 10% w/w) at room
temperature under N.sub.2 atmosphere. The mixture was charged with
a hydrogen balloon and stirred for 8 hours at room temperature.
After all the starting material had been consumed, the mixture was
filtered through a Celite.RTM. pad and concentrated under reduced
pressure to give the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 41
##STR00107##
[0732] The title compound of Example 40 (250 mg, 0.44 mmol) was
dissolved in DCM (8 mL) at 0.degree. C. TEA (93 .mu.L, 0.66 mmol)
was added. The solution was stirred for 10 min, to which
isophthaloyl dichloride (45 mg, 0.22 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., slowly warmed up to
RT and stirred overnight. Water was added to quench the reaction.
The two phases were separated and the aqueous phase was extracted
by DCM twice. The combined organic phase was washed by HCl solution
(1M), Saturated NaHCO.sub.3 solution and brine. The organic phase
was dried over sodium sulfate and concentrated under reduced
pressure. The residue was chromatographed on silica gel, eluting
with 50% Hexane/EtOAc, then pure EtOAc to give the title compound.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 42
##STR00108##
[0734] The title compound of Example 41 (69 mg, 0.057 mmol) in 0.1
mL DCM was treated with HCl/Dioxane (4M, 0.25 mL) using the general
procedure B to give the title compound. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 43
##STR00109##
[0736] At 0.degree. C., to a well-stirred mixture of
4-trans-hydroxy-(L)-N-Boc-Proline (10 g, 43.2 mmol) in 200 mL DMF
was added HOBT (6.13 g, 45.4 mmol), DIPEA (11.9 mL, 68.1 mmol) and
EDC (8.7 g, 45.4 mmol) in this order. After 10 minutes,
(R)-tetrahydro-1-naphthylamine (6.5 mL, 45.4 mmol) was added. The
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (150 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give the title compound
(crude yield 15.2 g). The crude was used directly in next step
without purification. The product and relative purity was confirmed
by LC-MS.
Example 44
##STR00110##
[0738] To a solution of the title compound of Example 43 (15.2 g,
42 mmol) in DCM (120 mL) was added TEA (7.7 mL, 55 mmol) at
0.degree. C. Methyl sulfonyl chloride (3.92 mL. 50.6 mmol) was
added slowly and the solution was stirred at 0.degree. C. for 5
hours. 50 mL DCM was added. The mixture was washed by HCl solution
(1 N), saturated NaHCO.sub.3 solution and brine. The organic phase
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give the crude mesylate as an oil, which was used
immediately without further purification. The oil was dissolved in
DMSO (180 mL), to which NaN.sub.3 (5.5 g, 84 mmol) was added. After
heating at 90.degree. C. for 8 hours, the solution was cooled to
room temperature. Water (100 mL) was added and the mixture was
extracted with EtOAc twice. The combined organic phase was washed
by brine, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to give the title compound (crude yield 15.2 g).
The crude was used directly in next step without purification. The
product and relative purity was confirmed by LC-MS.
Example 45
##STR00111##
[0740] To a solution of the title compound of Example 44 (11.4 g,
29.5 mmol) in 30 mL DCM was added HCl/Dioxane (4N, 29.5 mL, 118
mmol) at room temperature. The solution was stirred at room
temperature for 3 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt (9.48
g).
[0741] The resulting amine salt (9.48 g) and
N-Boc-.alpha.-tert-butyl-glycine (6.5 g, 28.1 mmol) was dissolved
in 250 mL DMF at 0.degree. C., to which HOBT (3.99 g, 29.5 mmol)
and DIPEA (11.6 mL, 66.4 mmol) were added. After 5 minutes, EDC
(5.66 g, 29.5 mmol) was added. The reaction mixture was stirred for
1 hour at 0.degree. C., then slowly warmed up to room temperature
and stirred for 12 hours at room temperature. The reaction mixture
was concentrated under vacuum to remove the DMF. The residue was
diluted with EtOAc (200 mL) and washed by HCl solution (1 N),
saturated NaHCO.sub.3 solution and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the title compound (crude yield 14.8 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 46
##STR00112##
[0743] To a solution of the title compound of Example 45 (14.8 g)
in 30 mL DCM was added HCl/Dioxane (4N, 28.1 mL, 112 mmol) at room
temperature. The solution was stirred at room temperature for 3
hours and monitored by LC-MS. After all the starting material had
been consumed, the solvents and HCl were removed under reduced
pressure to give the free amine salt.
[0744] The resulting amine salt and N-Boc-N-methyl-alanine (5.4 g,
26.8 mmol) was dissolved in 225 mL DMF at 0.degree. C., to which
HOBT (3.8 g, 28.1 mmol) and DIPEA (11 mL, 63.2 mmol) were added.
After 5 minutes, EDC (5.4 g, 28.1 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (180 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 30% to 95% EtOAc/Hexane
gradually to give the title compound (14.9 g, 77.6% for 7 steps
based on the beginning starting material
4-trans-hydroxy-(L)-N-Boc-Proline). The product and relative purity
was confined by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 47
##STR00113##
[0746] To a solution of the title compound of Example 46 (14.9 g,
25.6 mmol) in 100 mL MeOH, was added 10% Pd/C (1.49 g, 10% w/w) at
room temperature under N.sub.2 atmosphere. The reaction mixture was
then vacuumed, charged with a hydrogen balloon and stirred for 8
hours at room temperature. After all the starting material has been
consumed, the mixture was filtered through a CELITE.RTM. pad and
concentrated under reduced pressure to give a white solid as the
title compound (crude yield 14.0 g, 98%). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 48
##STR00114##
[0748] The title compound of Example 47 (2.0 g, 3.6 mmol) was
dissolved in DMF (36 mL) at 0.degree. C. HOBT (551 mg, 3.6 mmol)
and 5-amino-isophthalic acid (352 mg, 1.8 mmol) were added,
followed by the addition of DIPEA (0.94 mL, 5.4 mmol) and EDC (609
mg, 3.6 mmol). The reaction mixture was stirred for 1 hour at
0.degree. C., and then slowly warmed up to room temperature and
stirred overnight. DMF was removed under vacuum and the residue was
diluted with 40 mL EtOAc. The resulting solution was washed by HCl
solution (1M), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over sodium sulfate and concentrated under
reduced pressure. The residue was chromatographed on silica gel,
eluting with 50% to 95% EtOAc/Hexane, then 2% to 15% MeOH/DCM
gradually to give the title compound (1.38 g with 95% purity and
364 mg with 90% purity, 71.8%). The product and relative purity was
confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 49
##STR00115##
[0750] To a solution of the title compound of Example 48 (1.38 g,
1.08 mmol) in 10 mL DCM was added HCl/Dioxane (4N, 4.2 mL, 16.8
mmol) at room temperature. The solution was stirred at room
temperature for 3 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt as an
pale yellow color solid, which was dissolved in 18 mL water. The
above solution was filtered through a 0.45 .mu.m syringe filter and
lyophilized to give the title compound as an off white foam-like
solid (1.24 g, 70.3% for 3 steps from title compound of Example 4).
The product and relative purity was confirmed by LC-MS. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 50
##STR00116##
[0752] At 0.degree. C., to a well-stirred mixture of
4-trans-hydroxy-(L)-N-Boc-Proline (11.56 g, 50 mmol) in 250 mL DMF
was added HOBT (6.76 g, 50 mmol), DIPEA (13.1 mL, 75 mmol) and EDC
(9.58 g, 50 mmol) in this order. After 10 minutes,
D-.alpha.-methylbenzyl amine (6.36 mL, 50 mmol) was added. The
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (150 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give the title compound
(crude yield 15.95 g). The crude was used directly in next step
without purification. The product and relative purity was confirmed
by LC-MS.
Example 51
##STR00117##
[0754] To a solution of the title compound of Example 50 (15.95 g,
.about.47.7 mmol) in DCM (150 mL) was added TEA (8.32 mL, 59.7
mmol) at 0.degree. C. Methyl sulfonyl chloride (4.44 mL. 57.3 mmol)
was added slowly and the solution was stirred at 0.degree. C. for 5
hours. 50 mL DCM was added. The mixture was washed by HCl solution
(1 N), saturated NaHCO.sub.3 solution and brine. The organic phase
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give the crude mesylate as a white foam-like solid,
which was used immediately without further purification. The solid
was dissolved in DMSO (200 mL), to which NaN.sub.3 (6.20 g, 95.4
mmol) was added. After heating at 90.degree. C. for 8 hours, the
solution was cooled to room temperature. Water (100 mL) was added
and the mixture was extracted with EtOAc twice. The combined
organic phase was washed by brine twice, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the title compound (crude yield 17.54 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 52
##STR00118##
[0756] To a solution of the title compound of Example 5117.54 g,
.about.47.7 mmol) in 30 mL DCM was added HCl/Dioxane (4N, 35.8 mL,
140.3 mmol) at room temperature. The solution was stirred at room
temperature for 4 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt (15.89
g).
[0757] The resulting amine salt (2.48 g, .about.7.44 mmol) and
N-Boc-.alpha.-tert-butyl-glycine (1.94 g, 8.4 mmol) was dissolved
in 75 mL DMF at 0.degree. C., to which HOBT (1.14 g, 8.4 mmol) and
DIPEA (3.3 mL, 18.9 mmol) were added. After 5 minutes, EDC (1.61 g,
8.4 mmol) was added. The reaction mixture was stirred for 1 hour at
0.degree. C., then slowly warmed up to room temperature and stirred
for 12 hours at room temperature. The reaction mixture was
concentrated under vacuum to remove the DMF. The residue was
diluted with EtOAc (50 mL) and washed by HCl solution (1 N),
saturated NaHCO.sub.3 solution and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the title compound (crude yield 4.0 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 53
##STR00119##
[0759] To a solution of the title compound of Example 52 (4.0 g,
.about.7.44 mmol) in 30 mL DCM was added HCl/Dioxane (4N, 5.6 mL,
22.4 mmol) at room temperature. The solution was stirred at room
temperature for 3 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt.
[0760] The resulting amine salt and N-Boc-N-methyl-alanine (1.67 g,
8.2 mmol) was dissolved in 74 mL DMF at 0.degree. C., to which HOBT
(1.11 g, 8.2 mmol) and DIPEA (3.2 mL, 18.4 mmol) were added. After
5 minutes, EDC (1.57 g, 8.2 mmol) was added. The reaction mixture
was stirred for 1 hour at 0.degree. C., then slowly warmed up to
room temperature and stirred for 12 hours at room temperature. The
reaction mixture was concentrated under vacuum to remove the DMF.
The residue was diluted with EtOAc (50 mL) and washed by HCl
solution (1 N), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The residue was chromatographed on silica
gel, eluting with 30% to 95% EtOAc/Hexane gradually to give the
title compound (3.8 g, 87.4% for 7 steps based on the beginning
starting material 4-trans-hydroxy-(L)-N-Boc-Proline). The product
and relative purity was confirmed by LC-MS.
Example 54
##STR00120##
[0762] To a solution of the title compound of Example 53 (3.48 g,
6.2 mmol) in 100 mL MeOH, was added 10% Pd/C (348 mg, 10% w/w) at
room temperature under N.sub.2 atmosphere. The reaction mixture was
then vacuumed, charged with a hydrogen balloon and stirred for 8
hours at room temperature. After all the starting material has been
consumed, the mixture was filtered through a CELITE.RTM. pad and
concentrated under reduced pressure to give a white solid as the
title compound (crude yield 3.3 g, .about.100%). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 55
##STR00121##
[0764] The title compound of Example 54 (2.445 g, 4.61 mmol) was
dissolved in DMF (46 mL) at 0.degree. C. HOBT (623 mg, 4.61 mmol)
and 3,5-pyrazole dicarboxylic acid monohydrate (402 mg, 2.31 mmol)
were added, followed by the addition of DIPEA (1.00 mL, 5.76 mmol)
and EDC (884 mg, 4.61 mmol). The reaction mixture was stirred for 1
hour at 0.degree. C., and then slowly warmed up to room temperature
and stirred for 12 hours at room temperature. DMF was removed under
vacuum and the residue was diluted with 30 mL EtOAc. The resulting
solution was washed by HCl solution (1M), saturated NaHCO.sub.3
solution and brine. The organic phase was dried over sodium sulfate
and concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 50% to 90%
EtOAc/Hexane, then 2% to 10% MeOH/DCM gradually to give the title
compound (1.756 g with 96% purity and 788 mg with 90% purity,
87.5%). The product and relative purity was confirmed by LCMS.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 56
##STR00122##
[0766] To a solution of the title compound of Example 55 (1.756 g,
1.48 mmol) in 5.9 mL DCM was added HCl/Dioxane (4N, 2.96 mL, 11.8
mmol) at room temperature. The solution was stirred at room
temperature for 4 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt as an
white color solid, which was dissolved in 10 mL water. The above
solution was filtered through a 0.45 .mu.m syringe filter, rinsed
with water twice and lyophilized to give the title compound as a
white foam-like solid (1.51 g, 84.5% for 3 steps from title
compound of Example 4). The product and relative purity was
confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 57
##STR00123##
[0768] At 0.degree. C., to a well-stirred mixture of
4-trans-hydroxy-(L)-N-Boc-Proline (11.56 g, 50 mmol) in 250 mL DMF
was added HOBT (6.76 g, 50 mmol), DIPEA (13.1 mL, 75 mmol) and EDC
(9.58 g, 50 mmol) in this order. After 10 minutes,
D-.alpha.-methylbenzyl amine (6.36 mL, 50 mmol) was added. The
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (150 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give the title compound
(crude yield 15.95 g). The crude was used directly in next step
without purification. The product and relative purity was confirmed
by LC-MS.
Example 58
##STR00124##
[0770] To a solution of the title compound of Example 57 (15.95 g,
.about.47.7 mmol) in DCM (150 mL) was added TEA (8.32 mL, 59.7
mmol) at 0.degree. C. Methyl sulfonyl chloride (4.44 mL. 57.3 mmol)
was added slowly and the solution was stirred at 0.degree. C. for 5
hours. 50 mL DCM was added. The mixture was washed by HCl solution
(1 N), saturated NaHCO.sub.3 solution and brine. The organic phase
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give the crude mesylate as a white foam-like solid,
which was used immediately without further purification. The solid
was dissolved in DMSO (200 mL), to which NaN.sub.3 (6.20 g, 95.4
mmol) was added. After heating at 90.degree. C. for 8 hours, the
solution was cooled to room temperature. Water (100 mL) was added
and the mixture was extracted with EtOAc twice. The combined
organic phase was washed by brine twice, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the title compound (crude yield 17.54 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 59
##STR00125##
[0772] To a solution of the title compound of Example 58 (17.54 g,
.about.47.7 mmol) in 35 mL DCM was added HCl/Dioxane (4N, 35.8 mL,
140.3 mmol) at room temperature. The solution was stirred at room
temperature for 4 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt (15.89
g).
[0773] The resulting amine salt (1.605 g, .about.4.82 mmol) and
N-Boc-Isoleucine (1.26 g, 5.43 mmol) was dissolved in 54 mL DMF at
0.degree. C., to which HOBT (831 mg, 5.43 mmol) and DIPEA (2.13 mL,
12.2 mmol) were added. After 5 minutes, EDC (1.04 g, 5.43 mmol) was
added. The reaction mixture was stirred for 1 hour at 0.degree. C.,
then slowly warmed up to room temperature and stirred for 12 hours
at room temperature. The reaction mixture was concentrated under
vacuum to remove the DMF. The residue was diluted with EtOAc (30
mL) and washed by HCl solution (1 N), saturated NaHCO.sub.3
solution and brine. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the title compound (crude yield 2.505 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 60
##STR00126##
[0775] To a solution of the title compound of Example 59 (2.505 g,
.about.4.82 mmol) in 8 mL DCM was added HCl/Dioxane (4N, 4 mL, 16
mmol) at room temperature. The solution was stirred at room
temperature for 3 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt.
[0776] The resulting amine salt and N-Boc-N-methyl-alanine (1.08 g,
5.31 mmol) was dissolved in 53 mL DMF at 0.degree. C., to which
HOBT (813 mg, 5.31 mmol) and DIPEA (2.08 mL, 11.9 mmol) were added.
After 5 minutes, EDC (1.02 g, 5.31 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (30 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 30% to 95% EtOAc/Hexane
gradually to give the title compound (2.23 g with 96% purity and
0.28 g with 87% purity, 84.8% for 7 steps based on the beginning
starting material 4-trans-hydroxy-(L)-N-Boc-Proline). The product
and relative purity was confirmed by LC-MS.
Example 61
##STR00127##
[0778] To a solution of the title compound of Example 60 (2.23 g,
4.0 mmol) in 80 mL MeOH, was added 10% Pd/C (223 mg, 10% w/w) at
room temperature under N.sub.2 atmosphere. The reaction mixture was
then vacuumed, charged with a hydrogen balloon and stirred for 8
hours at room temperature. After all the starting material has been
consumed, the mixture was filtered through a CELITE.RTM. pad and
concentrated under reduced pressure to give a white solid as the
title compound (crude yield 1.98 g). The crude was used directly in
next step without purification. The product and relative purity was
confined by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 62
##STR00128##
[0780] The title compound of Example 61 (1.98 g, 3.73 mmol) was
dissolved in DMF (37 mL) at 0.degree. C. HOBT (566 mg, 3.73 mmol)
and 5-amino-isophthalic acid (338 mg, 1.86 mmol) were added,
followed by the addition of DIPEA (0.966 mL, 5.5 mmol) and EDC (709
mg, 3.73 mmol). The reaction mixture was stirred for 1 hour at
0.degree. C., and then slowly warmed up to room temperature and
stirred for 12 hours at room temperature. DMF was removed under
vacuum and the residue was diluted with 30 mL EtOAc. The resulting
solution was washed by HCl solution (1M), saturated NaHCO.sub.3
solution and brine. The organic phase was dried over sodium sulfate
and concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 50% to 90%
EtOAc/Hexane, then 2% to 15% MeOH/DCM gradually to give the title
compound (1.17 g with 97% purity and 764 mg with 90% purity,
81.2%). The product and relative purity was confirmed by LC-MS.
.sup.1H NMR (CDCl.sub.3): consistent with proposed structure.
Example 63
##STR00129##
[0782] To a solution of the title compound of Example 62 (1.17 g,
0.97 mmol) in 8 mL DCM was added HCl/Dioxane (4N, 3.9 mL, 15.6
mmol) at room temperature. The solution was stirred at room
temperature for 4 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt as an
white color solid, which was dissolved in 8 mL water. The above
solution was filtered through a 0.45 .mu.m syringe filter, rinsed
with water twice and lyophilized to give the title compound as a
white foam-like solid (1.03 g, 70.9% for 3 steps from title
compound of Example 4). The product and relative purity was
confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 64
##STR00130##
[0784] At 0.degree. C., to a well-stirred mixture of
4-trans-hydroxy-(L)-N-Boc-Proline (10 g, 43.2 mmol) in 200 mL DMF
was added HOBT (6.13 g, 45.4 mmol), DIPEA (11.9 mL, 68.1 mmol) and
EDC (8.7 g, 45.4 mmol) in this order. After 10 minutes,
(R)-tetrahydro-1-naphthylamine (6.5 mL, 45.4 mmol) was added. The
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (150 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give the title compound
(crude yield 15.2 g). The crude was used directly in next step
without purification. The product and relative purity was confirmed
by LC-MS.
Example 65
##STR00131##
[0786] To a solution of the title compound of Example 64 (15.2 g,
42 mmol) in DCM (120 mL) was added TEA (7.7 mL, 55 mmol) at
0.degree. C. Methyl sulfonyl chloride (3.92 mL. 50.6 mmol) was
added slowly and the solution was stirred at 0.degree. C. for 5
hours. 50 mL DCM was added. The mixture was washed by HCl solution
(1 N), saturated NaHCO3 solution and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the crude mesylate as an oil, which was used immediately
without further purification. The oil was dissolved in DMSO (180
mL), to which NaN.sub.3 (5.5 g, 84 mmol) was added. After heating
at 90.degree. C. for 8 hours, the solution was cooled to room
temperature. Water (100 mL) was added and the mixture was extracted
with EtOAc twice. The combined organic phase was washed by brine,
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the title compound (crude yield 15.2 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 66
##STR00132##
[0788] To a solution of the title compound of Example 65 (11.4 g,
29.5 mmol) in 30 mL DCM was added HCl/Dioxane (4N, 29.5 mL, 118
mmol) at room temperature. The solution was stirred at room
temperature for 3 hours and monitored by LC-MS. After all the
starting material had been consumed, the solvents and HCl were
removed under reduced pressure to give the free amine salt (9.48
g).
[0789] The resulting amine salt (9.48 g) and
N-Boc-.alpha.-tert-butyl-glycine (6.5 g, 28.1 mmol) was dissolved
in 250 mL DMF at 0.degree. C., to which HOBT (3.99 g, 29.5 mmol)
and DIPEA (11.6 mL, 66.4 mmol) were added. After 5 minutes, EDC
(5.66 g, 29.5 mmol) was added. The reaction mixture was stirred for
1 hour at 0.degree. C., then slowly warmed up to room temperature
and stirred for 12 hours at room temperature. The reaction mixture
was concentrated under vacuum to remove the DMF. The residue was
diluted with EtOAc (200 mL) and washed by HCl solution (1 N),
saturated NaHCO.sub.3 solution and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the title compound (crude yield 14.8 g). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS.
Example 67
##STR00133##
[0791] To a solution of the title compound of Example 66 (14.8 g)
in 30 mL DCM was added HCl/Dioxane (4N, 28.1 mL, 112 mmol) at room
temperature. The solution was stirred at room temperature for 3
hours and monitored by LC-MS. After all the starting material had
been consumed, the solvents and HCl were removed under reduced
pressure to give the free amine salt.
[0792] The resulting amine salt and N-Boc-N-methyl-alanine (5.4 g,
26.8 mmol) was dissolved in 225 mL DMF at 0.degree. C., to which
HOBT (3.8 g, 28.1 mmol) and DIPEA (11 mL, 63.2 mmol) were added.
After 5 minutes, EDC (5.4 g, 28.1 mmol) was added. The reaction
mixture was stirred for 1 hour at 0.degree. C., then slowly warmed
up to room temperature and stirred for 12 hours at room
temperature. The reaction mixture was concentrated under vacuum to
remove the DMF. The residue was diluted with EtOAc (180 mL) and
washed by HCl solution (1 N), saturated NaHCO.sub.3 solution and
brine. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was
chromatographed on silica gel, eluting with 30% to 95% EtOAc/Hexane
gradually to give the title compound (14.9 g, 77.6% for 7 steps
based on the beginning starting material
4-trans-hydroxy-(L)-N-Boc-Proline). The product and relative purity
was confined by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent with
proposed structure.
Example 68
##STR00134##
[0794] To a solution of the title compound of Example 67 (14.9 g,
25.6 mmol) in 100 mL MeOH, was added 10% Pd/C (1.49 g, 10% w/w) at
room temperature under N.sub.2 atmosphere. The reaction mixture was
then vacuumed, charged with a hydrogen balloon and stirred for 8
hours at room temperature. After all the starting material has been
consumed, the mixture was filtered through a CELITE.RTM. pad and
concentrated under reduced pressure to give a white solid as the
title compound (crude yield 14.0 g, 98%). The crude was used
directly in next step without purification. The product and
relative purity was confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3):
consistent with proposed structure.
Example 69
##STR00135##
[0796] The title compound of Example 68 (3.29 g, 5.91 mmol) was
dissolved in DMF (60 mL) at 0.degree. C. HOBT (799 mg, 5.91 mmol)
and 5-amino-isophthalic acid (535 mg, 2.95 mmol) were added,
followed by the addition of DIPEA (2.3 mL, 13.3 mmol) and EDC (1.13
g, 5.91 mmol). The reaction mixture was stirred for 1 hour at
0.degree. C., and then slowly warmed up to room temperature and
stirred overnight. DMF was removed under vacuum and the residue was
diluted with 100 mL EtOAc. The resulting solution was washed by HCl
solution (1M), saturated NaHCO.sub.3 solution and brine. The
organic phase was dried over sodium sulfate and concentrated under
reduced pressure. The residue was chromatographed on silica gel,
eluting with 50% to 90% EtOAc/Hexane, then 2% to 10% MeOH/DCM
gradually to give the title compound (3.17 g, 85.4%). The product
and relative purity was confirmed by LC-MS. .sup.1H NMR
(CDCl.sub.3): consistent with proposed structure.
Example 70
##STR00136##
[0798] To a solution of the title compound of Example 69 (3.17 g,
2.52 mmol) in 10 mL DCM was added HCl/Dioxane (4N, 5 mL, 20 mmol)
at room temperature. The solution was stirred at room temperature
for 3 hours and monitored by LC-MS. After all the starting material
had been consumed, the solvents and HCl were removed under reduced
pressure to give the free amine salt as an pale yellow color solid,
which was dissolved in 18 mL water. The above solution was filtered
through a 0.45 .mu.m syringe filter and lyophilized to give the
title compound as an off white foam-like solid (2.81 g, 80.0% for 3
steps from title compound of Example 4). The product and relative
purity was confirmed by LC-MS. .sup.1H NMR (CDCl.sub.3): consistent
with proposed structure.
Example 71
In Vitro IAP (BIR) Binding/Interaction Assay
[0799] Interaction between mimetics and IAPs was examined by
GST-mediated pull-down assays. Approximately 0.4 mg of a
recombinant IAP fragment (second and third BIR motifs of XIAP) is
bound to 200 ml of glutathione resin as a GST-fusion protein and
incubated with 0.5 mg of radiolabeled mimetics at room temperature.
After extensive washing with an assay buffer containing 25 mM Tris,
pH 8.0, 150 mM NaCl, and 2 mM dithiothreitol (DTT), the complex is
eluted with 5 mM reduced glutathione and visualized by SDS-PAGE
with Coomassie staining.
[0800] This assay demonstrates that the tested mimetics
specifically bind IAP. Each assay includes as an internal reference
the compound of formula:
##STR00137##
Example 72
Fluorescent Polarization Assay
[0801] Increasing concentrations of Smac compounds are incubated
with 2 nM of labeled peptide (fluorescein labeled 10mer peptide
with AVPI 4 amino acids at its N terminus-Alexa Fluor 488) and
truncated XIAP containing only BIR1, BIR2, and BIR3 domains at room
temperature for 1 hour. Fluorescence reading, indicative of the
bound portion of the labeled peptide, is measured in
milipolarization units (mP). The more compound added, less
fluorescein labeled peptide bind to the protein due to the
competitive binding and less fluorescence signal is released.
[0802] Based on this principle, we obtain the K.sub.i value that
evaluates compound's binding affinity.
Example 73
In Vitro Caspase-3 Activation Assay
[0803] Caspase3 in most cell extracts can be activated by the
addition of 1 mM dATP through the mitochondria caspase pathway.
Hela S3 cells we use to make cell extract express higher XIAP,
hence after addition of dATP in Hela S100, the induced caspase3 is
blocked by IAPs. Taking advantage of this feature, we use 100 nM of
synthetic Smac mimetic compound to test its ability to eliminate
IAPs in the Hela S100 and fully induce Caspase3 activity. The In
Vitro Caspase3 assay is carried out at 30.degree. C., incubating
100 nM compounds with 30 ug of Hela S100, 1 mM dATP, 10 uM Caspase3
fluorogenic substrate (Caspase3 Substrate II, Fluorogenic, #235425
from Calbiochem). The readout is caspase-3 activity represented by
relative fluorogenic unit, which is recorded kinetically. The slope
in linear region of the curve for each compound is calculated.
[0804] Percent activity data is presented by comparing activity of
the test compound with activity of the reference compound in
Caspase-3 activation assay in vitro. The ratio of each synthetic
compound's slope versus the slope of control reflects in vitro
caspase-3 activation ability of compounds.
Example 74
Cell Viability Assay in HCC461 Cells
[0805] HCC461 cells plated in 96 well plates at 5.times.10.sup.4/ml
cell density are treated with 50.times. synthetic Smac mimetic
compounds (final concentration range between 30 uM and 0.001 uM).
After 48 hrs incubation at 37.degree. C. and 5% CO.sub.2, viability
of the cells are measured using Cell Proliferation Reagent WST-1
assay kit (Roche Cat #11 644 807 001).
[0806] WST-1 Assay Principle:
[0807] The tetrazolium salts are cleaved to formazan by cellular
enzymes. An expansion in the number of viable cells results in an
increase in the overall activity of mitochondrial dehydrogenases in
the samples. This augmentation in the enzyme activity leads to an
increase in the amount of formazan dye formed, which directly
correlates to the number of metabolically active cells in the
culture. Quantification of the formazan dye produced by
metabolically active cells by using a microplate (ELISA) reader at
420-480 nm.
Example 75
Synergism of TRAIL and Smac Mimetic Compounds in PANC-1 Cells
[0808] PANC-1 cells plated in 96 well plates at 5.times.10.sup.4/ml
cell density are pre-treated with 100 nm compounds for 4 hrs at
37.degree. C. and 5% CO.sub.2. The cells are then treated with
50.times.TRAIL (final concentration range between 2400 ng/ml and
0.08 ng/ml). After 48 hrs incubation at 37.degree. C. and 5%
CO.sub.2, viability of the cells are measured using Cell
Proliferation Reagent WST-1 assay kit (Roche Cat #11 644 807 001).
Comparison between viability of cells when treated with TRAIL alone
versus when treated with TRAIL+100 nm Smac mimetic compound gives
us synergism picture.
[0809] WST-1 Assay Principle:
[0810] The tetrazolium salts are cleaved to formazan by cellular
enzymes. An expansion in the number of viable cells results in an
increase in the overall activity of mitochondrial dehydrogenases in
the samples. This augmentation in the enzyme activity leads to an
increase in the amount of formazan dye formed, which directly
correlates to the number of metabolically active cells in the
culture. Quantification of the formazan dye produced by
metabolically active cells by using a microplate (ELISA) reader at
420-480 nm.
Example 76
Representative Biodata
[0811] Representative bioassay data using assays described in
Examples 71 and 73-75 are provided in Tables 1 and 2. Each table
represents the data from a different experiment, using the
reference compound described in Example 71 as an internal
reference.
TABLE-US-00001 TABLE 1 Representative Biodata Synergy with TRAIL in
PANC-1 ng/ml IC.sub.50 (uM) in IC.sub.50 for % cell viability TRAIL
+ Compound Ki (uM) in Activity at assay in IC.sub.50 for 100 nm No.
FP assay 100 nM HCC461 TRAIL compound Ref cpd 0.35 100 0.082
>2400 36.71 12 0.40 104 0.002 >2400 24.14 13 0.30 108 0.026
>2400 36.66 14 0.44 86 0.026 >2400 26.55 15 0.45 116 0.009
>2400 16.82 16 0.40 115 0.074 >2400 26.57 17 0.50 92 0.019
>2400 25.40 18 0.35 107 0.033 >2400 13.75 19 0.45 120 0.007
>2400 26.95 20 0.222 >2400 1388.10 21 0.101 >2400 36.12 22
0.263 >2400 >2400
TABLE-US-00002 TABLE 2 Representative Biodata Synergy with TRAIL in
PANC-1 ng/ml IC.sub.50 (uM) in IC.sub.50 for % cell viability TRAIL
+ Compound Ki (uM) in Activity at assay in IC.sub.50 for 100 nm No.
FP assay 100 nM HCC461 TRAIL compound Ref cpd 0.15 0.063 >2400
26.03 23 0.05 0.002 >2400 6.05 24 0.35 0.021 >2400 7.86 25
0.25 0.024 >2400 5.71 26 0.32 0.023 >2400 14.78 27 0.25 0.082
>2400 60.94 28 0.23 0.002 >2400 6.66 29 0.24 0.005 >2400
5.00 30 0.29 0.008 >2400 5.60 31 0.34 0.003 >2400 5.98 32
0.23 0.015 >2400 6.09
[0812] The compounds of Examples 6, 8, 10, 12, 14, 29, 36, 37, 42,
49, 56, 63, and 70 will mimic the activity of Smac, and are thus
useful in the treatment of disorders that can be treated with Smac
or a Smac mimetic, such as those disorders discussed herein.
[0813] Using methods similar to those described in the Examples,
the compounds of Table 3 and Table 4 can readily be prepared and
shown to be Smac mimetics.
TABLE-US-00003 TABLE 3 Dimeric Structures RECORD NUMBER STRUCTURE 1
##STR00138## 2 ##STR00139## 3 ##STR00140## 4 (Example 10)
##STR00141## 5 ##STR00142## 6 ##STR00143## 7 ##STR00144## 8
##STR00145## 9 ##STR00146## 10 ##STR00147## 11 (Example 29)
##STR00148## 12 ##STR00149## 13 ##STR00150## 14 ##STR00151## 15
##STR00152## 16 ##STR00153## 17 ##STR00154## 18 ##STR00155## 19
##STR00156## 20 ##STR00157## 21 ##STR00158## 22 ##STR00159## 23
##STR00160## 24 ##STR00161## 25 ##STR00162## 26 ##STR00163## 27
##STR00164## 28 ##STR00165## 29 ##STR00166## 30 ##STR00167## 31
##STR00168## 32 ##STR00169## 33 ##STR00170## 34 (Example 6)
##STR00171## 35 ##STR00172## 36 ##STR00173## 37 ##STR00174## 38
(Example 8) ##STR00175## 39 ##STR00176## 40 ##STR00177## 41
##STR00178## 42 ##STR00179## 43 ##STR00180## 44 ##STR00181## 45
##STR00182## 46 ##STR00183## 47 ##STR00184## 48 ##STR00185## 49
##STR00186## 50 ##STR00187## 51 ##STR00188## 52 ##STR00189## 53
##STR00190## 54 ##STR00191## 55 ##STR00192## 56 ##STR00193## 57
##STR00194## 58 ##STR00195## 59 ##STR00196## 60 ##STR00197## 61
##STR00198## 62 ##STR00199## 63 ##STR00200## 64 ##STR00201## 65
##STR00202## 66 ##STR00203## 67 ##STR00204## 68 ##STR00205## 69
##STR00206## 70 ##STR00207## 71 ##STR00208## 72 ##STR00209## 73
##STR00210## 74 ##STR00211## 75 ##STR00212## 76 ##STR00213## 77
##STR00214## 78 ##STR00215## 79 ##STR00216## 80 ##STR00217## 81
##STR00218## 82 ##STR00219## 83 ##STR00220## 84 ##STR00221## 85
##STR00222## 86 ##STR00223## 87 ##STR00224## 88 ##STR00225## 89
##STR00226## 90 ##STR00227## 91 ##STR00228## 92 ##STR00229## 93
##STR00230## 94 ##STR00231## 95 ##STR00232## 96 ##STR00233## 97
##STR00234## 98 ##STR00235## 99 ##STR00236## 100 ##STR00237## 101
(Example 36) ##STR00238## 102 (Example 37) ##STR00239## 103
(example 42) ##STR00240## 104 (example 49) ##STR00241##
TABLE-US-00004 TABLE 4 Trimeric Structures RECORD NUMBER STRUCTURE
105 (Example 12) ##STR00242## 106 ##STR00243## 107 ##STR00244##
TABLE-US-00005 TABLE 5 Monomers RECORD NUMBER STRUCTURE M-1
(Example 1) ##STR00245## M-2 (Example 2) ##STR00246## M-3 (Example
3) ##STR00247## M-4 (Example 4) ##STR00248## M-5 (Example 15)
##STR00249## M-6 (Example 16) ##STR00250## M-7 (Example 17)
##STR00251## M-8 (Example 18) ##STR00252## M-9 (Example 19)
##STR00253## M-10 (Example 21) ##STR00254## M-11 ##STR00255## M-12
##STR00256## M-13 ##STR00257## M-14 ##STR00258## M-15 ##STR00259##
M-16 ##STR00260## M-17 (Example 33) ##STR00261## M-18 (Example 34)
##STR00262## M-19 ##STR00263## M-20 ##STR00264## M-21 (Example 38)
##STR00265## M-22 (Example 39) ##STR00266## M-23 (Example 40)
##STR00267## M-24 ##STR00268## M-25 ##STR00269## M-26 ##STR00270##
M-27 ##STR00271## M-28 ##STR00272##
[0814] The following embodiments are provided as non-limiting
examples only. The foregoing examples are provided only to
illustrate the invention, which further includes those combinations
and modifications that are apparent to one of ordinary skill from
the present disclosures.
Representative Embodiments
[0815] A1. A compound of formula (1):
##STR00273##
[0816] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0817] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0818] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y or Y' groups can cyclize to form a 3-6 membered ring that can
be saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0819] each W and W' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0820] each X and X' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W or W', provided that each X and X'
comprises at least one aryl or heteroaryl ring;
[0821] each Q and Q' independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, or optionally
substituted C1-C8 alkyl, or optionally substituted C1-C8
heteroalkyl; or one or both of Q and Q' may be a bond when L
comprises a ring;
[0822] each n and n' is independently 0-3;
[0823] each m and m' is independently 0-4;
[0824] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0825] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0826] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q'.
[0827] A2. The compound of embodiment A1, wherein L comprises a
C1-C14 alkylene, C1-C14 heteroalkylene, C2-C14 alkenylene, C2-C14
heteroalkenylene, C2-C14 alkynylene, or a C2-C14 heteroalkynylene
group, each of which may be optionally substituted.
[0828] A3. The compound of embodiment A2, wherein L is a C2-C14
alkynylene or a C2-C14 heteroalkynylene group.
[0829] A4. The compound of embodiment A1, wherein L comprises at
least one optionally substituted carbocyclic, heterocyclic,
aromatic or heteroaromatic ring that is part of or is fused to the
linker which forms the shortest path between Q and Q'.
[0830] A5. The compound of embodiment A4, wherein said aromatic or
heteroaromatic ring is an optionally substituted 5- or 6-membered
aromatic or heteroaromatic ring.
[0831] A6. The compound of embodiment A5, wherein said optionally
substituted 5- or 6-membered aromatic or heteroaromatic ring is
selected from the group consisting of phenyl, pyridyl, pyrazinyl,
triazinyl, pyrazolyl, and thiophenyl, each of which may be
optionally substituted.
[0832] A7. The compound of embodiment A4, wherein L comprises at
least one triazole ring.
[0833] A8. The compound of any one of embodiments A1 to A7, wherein
each n and n' is 1, and each of m and m' is 0 or 1, and wherein Y
and Y', if present, are the same.
[0834] A9. The compound of any one of embodiments A1 to A8, wherein
each R.sup.1 and R.sup.1' is H or methyl.
[0835] A10. The compound of any one of embodiments A1 to A9,
wherein each Z and Z' is a 1-aminoalkyl group represented by the
formula --CH(R.sup.3)NR.sup.4.sub.2, where R.sup.3 and each R.sup.4
is independently H or C1-C4 alkyl.
[0836] A11. The compound of any one of embodiments A1 to A10,
wherein each X and X' independently comprises an optionally
substituted phenyl ring; or two phenyl rings, each of which may be
optionally substituted; or a tetrahydronaphthyl, indanyl or
fluorenyl ring system.
[0837] A12. The compound of any one of embodiments A1 to A11,
wherein each W and W' represents --C(O)NR(CHR).sub.p--, where p is
0-2, and each R independently represents H, C1-C4 alkyl or C1-C4
heteroalkyl.
[0838] A13. The compound of any one of embodiments A1 to A12,
wherein each Q and Q' is --NR.sup.2--, where each R.sup.2 is
independently H or C1-C4 alkyl.
[0839] A14. The compound of any one of embodiments A1 to A12,
wherein at least one of Q and Q' is a bond.
[0840] A15. The compound of embodiment A1, having the formula
(3A):
##STR00274##
[0841] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0842] wherein Ra is H and Rb is R.sup.5;
[0843] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0844] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0845] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0846] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0847] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, or optionally substituted C1-C8 alkyl, or
optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L
comprises a ring;
[0848] m is 0-4;
[0849] p is 2-3;
[0850] Z represents an optionally substituted C1-C6 aminoalkyl
group of the formula --CH(R.sup.3)NR.sup.4.sub.2;
[0851] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0852] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and
[0853] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0854] A16. The compound of embodiment A15, having the formula
(4):
##STR00275##
[0855] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0856] wherein R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8
alkynyl, or phenyl, each of which may be optionally
substituted;
[0857] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0858] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0859] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0860] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0861] m is 0-4;
[0862] p is 2 or 3;
[0863] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0864] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and
[0865] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0866] A17. The compound of embodiment A15, having the formula
(5):
##STR00276##
[0867] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0868] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0869] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0870] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene; X represents an optionally substituted
C.sub.5-C.sub.20 ring system comprising at least one aromatic ring
and up to four heteroatoms selected from N, O and S as a ring
member, and can represent either a single 5-15 membered cyclic
group or two 5-10 membered cyclic groups that are both attached to
the same atom of W, provided that each X comprises at least one
aryl or heteroaryl ring;
[0871] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0872] m is 0-4;
[0873] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0874] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and the two
R.sup.4 groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0875] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0876] A18. The compound of embodiment A15, A16 or A17, wherein
R.sup.3 is selected from methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
[0877] A19. The compound of any one of embodiments A15 to A18,
wherein each R.sup.4 is independently H or methyl.
[0878] A20. A compound selected from the group consisting of the
compounds in Tables 3 and 4, or a pharmaceutically acceptable salt
thereof.
[0879] A21. A compound of formula (6):
##STR00277##
[0880] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0881] wherein R.sub.a and R.sub.b are independently H, or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted;
[0882] each Y independently represents C1-C8 alkyl, .dbd.O, OR,
NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two
Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0883] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0884] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0885] n is 0-3;
[0886] m is 0-4;
[0887] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[0888] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted; and
[0889] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[0890] A22. A method of making a compound of formula (1) as in
embodiment A1, comprising reacting a first monomer of formula (6)
with a second monomer of formula (6),
[0891] wherein for each of said first monomer and said second
monomer, U comprises at least one functional group that can be used
to connect said first monomer and said second monomer, either
directly or indirectly, to provide a compound of formula (1).
[0892] A23. A pharmaceutical composition comprising a compound of
formula (1) as in embodiment A1, and at least one pharmaceutically
acceptable excipient.
[0893] A24. The pharmaceutical composition of embodiment A23,
further comprising at least one additional therapeutic agent.
[0894] A25. The pharmaceutical composition of embodiment A24,
wherein the additional therapeutic agent is selected from the group
consisting of TRAIL, etoposide, a TRAIL receptor antibody, an Hsp90
inhibitor, TNF-.alpha., and TNF-.beta..
[0895] A26. A method to treat cancer, inflammation, or an
autoimmune disorder, comprising administering to a subject in need
of such treatment an effective amount of a compound of any one of
embodiments A1 to A20.
[0896] A27. The method of embodiment A26, wherein the subject is
treated with an additional therapeutic agent selected from the
group consisting of TRAIL, etoposide, a TRAIL receptor antibody, an
Hsp90 inhibitor, TNF-.alpha., and TNF-.beta..
[0897] A28. A compound of formula (I):
##STR00278##
[0898] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0899] wherein b is 0 or 1;
[0900] each Q, Q' and Q'', if present, independently represents
--O-- or --NR.sup.2--, where each R.sup.2 is independently H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl
or C1-C4 heteroalkyl; or one or more of Q, Q' and Q'' may be a bond
when L comprises a ring;
[0901] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q', or Q and Q'', or Q' and Q'';
and
[0902] each D, D' and D'', if present, is independently selected
from the group consisting of
##STR00279##
[0903] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0904] each R.sup.1 is independently H or optionally substituted
C1-C8 alkyl;
[0905] each Z independently represents an optionally substituted
C1-C6 aminoalkyl group;
[0906] each Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0907] each W, where present, independently represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0908] each X, where present, independently represents an
optionally substituted C.sub.5-C.sub.20 ring system comprising at
least one aromatic ring and up to four heteroatoms selected from N,
O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring;
[0909] each n, where present, is independently 0-3;
[0910] each m, where present, is independently 0-4; and
[0911] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0912] with the proviso that, when b is 0, D and D' are not the
same and both of the formula
##STR00280##
[0913] B1. A compound of formula (I):
##STR00281##
[0914] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0915] wherein b is 0 or 1;
[0916] each Q, Q' and Q'', if present, independently represents
--O-- or --NR.sup.2--, where each R.sup.2 is independently H,
optionally substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl; or --CH.sub.2--, --CH(OR)--, --CH(R)--, --CH.sub.2O--,
--CH(R)O-- or --(CH.sub.2).sub.4NH--, wherein R is H, C1-C4 alkyl
or C1-C4 heteroalkyl; or one or more of Q, Q' and Q'' may be a bond
when L comprises a ring;
[0917] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q', or Q and Q'', or Q' and Q'';
and
[0918] each D, D' and D'', if present, is independently selected
from the group consisting of
##STR00282##
[0919] wherein each R.sub.a and R.sub.b is independently H, or
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one
of these, each of which may be optionally substituted; or is
optionally substituted phenyl;
[0920] each R.sup.1 is independently H or optionally substituted
C1-C8 alkyl;
[0921] each Z independently represents an optionally substituted
C1-C6 aminoalkyl group;
[0922] each Y, where present, independently represents C1-C8 alkyl,
.dbd.O, OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein
each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and
wherein two Y groups can cyclize to form a 3-6 membered ring that
can be saturated, unsaturated or aromatic, and which ring may
include a heteroatom selected from O, S and N as a ring member and
may be optionally substituted;
[0923] each W, where present, independently represents an
optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0924] each X, where present, independently represents an
optionally substituted C.sub.5-C.sub.20 ring system comprising at
least one aromatic ring and up to four heteroatoms selected from N,
O and S as a ring member, and can represent either a single 5-15
membered cyclic group or two 5-10 membered cyclic groups that are
both attached to the same atom of W, provided that each X comprises
at least one aryl or heteroaryl ring;
[0925] each n, where present, is independently 0-3;
[0926] each m, where present, is independently 0-4; and
[0927] each R.sup.6, where present, is independently H, C1-C8
alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of
these, each of which may be optionally substituted; or is a C8-C14
bicyclic or tricyclic ring system comprising a 5- or 6-membered
saturated or partially unsaturated ring fused to a C5-C6 aryl or
C5-C6 heteroaryl ring, which ring system may be attached to
nitrogen through any available position on the saturated or
aromatic ring;
[0928] with the proviso that, when b is 0, D and D' are not the
same and both of the formula
##STR00283##
[0929] B2. The compound of embodiment B 1, having the formula
(1):
##STR00284##
[0930] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0931] wherein each R.sub.a, R.sub.a', R.sub.b and R.sub.b' is
independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or
a heteroform of one of these, each of which may be optionally
substituted; or is optionally substituted phenyl;
[0932] each Y and Y' independently represents C1-C8 alkyl, .dbd.O,
OR, NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R
is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein
two Y or Y' groups can cyclize to form a 3-6 membered ring that can
be saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[0933] each W and W' independently represents an optionally
substituted C1-C6 alkylene or C1-C6 heteroalkylene;
[0934] each X and X' independently represents an optionally
substituted C.sub.5-C.sub.20 ring system comprising at least one
aromatic ring and up to four heteroatoms selected from N, O and S
as a ring member, and can represent either a single 5-15 membered
cyclic group or two 5-10 membered cyclic groups that are both
attached to the same atom of W or W', provided that each X and X'
comprises at least one aryl or heteroaryl ring;
[0935] each Q and Q' independently represents --O-- or
--NR.sup.2--, where each R.sup.2 is independently H, or optionally
substituted C1-C8 alkyl, or optionally substituted C1-C8
heteroalkyl; or one or both of Q and Q' may be a bond when L
comprises a ring;
[0936] each n and n' is independently 0-3;
[0937] each m and m' is independently 0-4;
[0938] each R.sup.1 and R.sup.1' is independently H or optionally
substituted C1-C8 alkyl;
[0939] each Z and Z' independently represents an optionally
substituted C1-C6 aminoalkyl group; and
[0940] L represents an optionally substituted C1-C24 hydrocarbyl
linker, optionally containing from 1-8 heteroatoms selected from N,
O and S, which linker is 1-18 atoms in length when counted along
the shortest path between Q and Q'.
[0941] B3. The compound of embodiment B1 or B2, wherein each n and
n' is 1, and each of m and m' is 0 or 1, and wherein Y and Y', if
present, are the same.
[0942] B4. The compound of embodiment B 1, B2 or B3, wherein each
R.sup.1 and R.sup.1' is H or methyl.
[0943] B5. The compound of any one of embodiments B1 to B4, wherein
each Z and Z' is a 1-aminoalkyl group represented by the formula
--CH(R.sup.3)NR.sup.4.sub.2, where R.sup.3 and each R.sup.4 is
independently H or C1-C4 alkyl.
[0944] B6. The compound of embodiment B2, having the formula
(3A):
##STR00285##
[0945] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0946] wherein Ra is H and Rb is R.sup.5;
[0947] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0948] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0949] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0950] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0951] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, or optionally substituted C1-C8 alkyl, or
optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L
comprises a ring;
[0952] m is 0-4;
[0953] p is 2-3;
[0954] Z represents an optionally substituted C1-C6 aminoalkyl
group of the formula --CH(R.sup.3)NR.sup.4.sub.2;
[0955] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0956] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and
[0957] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0958] B7. The compound of embodiment B6, having the formula
(4):
##STR00286##
[0959] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0960] wherein R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8
alkynyl, or phenyl, each of which may be optionally
substituted;
[0961] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0962] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[0963] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[0964] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0965] m is 0-4;
[0966] p is 2 or 3;
[0967] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0968] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or optionally substituted C1-C8
heteroalkyl, and the two R.sup.4 groups on one nitrogen can cyclize
to form an optionally substituted azacyclic group having 5-10 ring
members, which azacyclic group may be saturated, unsaturated or
aromatic, and may contain 1-2 additional heteroatoms selected from
N, O and S as a ring member; and
[0969] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0970] B8. The compound of embodiment B6, having the formula
(5):
##STR00287##
[0971] or a pharmaceutically acceptable salt or hydrate form
thereof,
[0972] R.sup.5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
or phenyl, each of which may be optionally substituted;
[0973] each Y represents C1-C8 alkyl, .dbd.O, OR, NR.sub.2, OC(O)R,
NRC(O)R, NRSO.sub.2R or COOR, wherein each R is independently H,
C1-C8 alkyl or C1-C8 heteroalkyl;
[0974] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene; X represents an optionally substituted
C.sub.5-C.sub.20 ring system comprising at least one aromatic ring
and up to four heteroatoms selected from N, O and S as a ring
member, and can represent either a single 5-15 membered cyclic
group or two 5-10 membered cyclic groups that are both attached to
the same atom of W, provided that each X comprises at least one
aryl or heteroaryl ring;
[0975] Q represents --O-- or --NR.sup.2--, where each R.sup.2 is
independently H, optionally substituted C1-C8 alkyl or optionally
substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises
a ring;
[0976] m is 0-4;
[0977] R.sup.3 is H, or an optionally substituted C1-C8 alkyl or
optionally substituted C1-C8 heteroalkyl, and R.sup.3 can cyclize
with R.sup.4 on an adjacent nitrogen atom to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0978] each R.sup.4 is independently H, or an optionally
substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and the two
R.sup.4 groups on one nitrogen can cyclize to form an optionally
substituted azacyclic group having 5-10 ring members, which
azacyclic group may be saturated, unsaturated or aromatic, and may
contain 1-2 additional heteroatoms selected from N, O and S as a
ring member;
[0979] L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14
alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21
arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of
one of these, each of which may be optionally substituted.
[0980] B9. The compound of any one of embodiments B1 to B5, wherein
each X and X' independently comprises an optionally substituted
phenyl ring; or two phenyl rings, each of which may be optionally
substituted; or a tetrahydronaphthyl, indanyl or fluorenyl ring
system.
[0981] B10. The compound of any one of embodiments B1 to B5,
wherein each W and W' represents --C(O)NR(CHR).sub.p--, where p is
0-2, and each R independently represents H, C1-C4 alkyl or C1-C4
heteroalkyl.
[0982] B11. The compound of any one of embodiments B1 to B5,
wherein each Q and Q' is --NR.sup.2--, where each R.sup.2 is
independently H or C1-C4 alkyl.
[0983] B12. The compound of any one of embodiments B1 to B5,
wherein at least one of Q and Q' is a bond.
[0984] B13. The compound of any one of embodiments B1 to B12,
wherein L comprises at least one optionally substituted
carbocyclic, heterocyclic, aromatic or heteroaromatic ring that is
part of or is fused to the linker which forms the shortest path
between Q and Q'.
[0985] B14. The compound of embodiment B13, wherein said aromatic
or heteroaromatic ring is an optionally substituted 5- or
6-membered aromatic or heteroaromatic ring.
[0986] B15. The compound of embodiment B14, wherein said optionally
substituted 5- or 6-membered aromatic or heteroaromatic ring is
selected from the group consisting of phenyl, pyridyl, pyrazinyl,
triazinyl, pyrazolyl, and thiophenyl, each of which may be
optionally substituted.
[0987] B16. The compound of any one of embodiments B1 to B14,
wherein L comprises at least one triazole ring.
[0988] B17. The compound of any one of embodiments B1 to B12,
wherein L comprises a C1-C14 alkylene, C1-C14 heteroalkylene,
C2-C14 alkenylene, C2-C14 heteroalkenylene, C2-C14 alkynylene, or a
C2-C14 heteroalkynylene group, each of which may be optionally
substituted.
[0989] B18. The compound of embodiment B17, wherein L is a C2-C14
alkynylene or a C2-C14 heteroalkynylene group.
[0990] B19. The compound of embodiment B7 or B8, wherein R.sup.3 is
selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
n-butyl, isobutyl, sec-butyl, and tert-butyl.
[0991] B20. The compound of embodiment B7, B8, or B19, wherein each
R.sup.4 is independently H or methyl.
[0992] B21. A compound selected from the group consisting of the
compounds in Tables 3 and 4, or a pharmaceutically acceptable salt
thereof.
[0993] B22. A pharmaceutical composition comprising a compound of
any of the preceding embodiments, and at least one pharmaceutically
acceptable excipient.
[0994] B23. The pharmaceutical composition of embodiment B22,
further comprising at least one additional therapeutic agent.
[0995] B24. The pharmaceutical composition of embodiment B23,
wherein the additional therapeutic agent is selected from the group
consisting of TRAIL, etoposide, a TRAIL receptor antibody, an Hsp90
inhibitor, TNF-.alpha., and TNF-.beta..
[0996] B25. A method to treat cancer, inflammation, or an
autoimmune disorder, comprising administering to a subject in need
of such treatment an effective amount of a compound as defined in
any one of embodiments B1 to B21.
[0997] B26. The method of embodiment B25, wherein the subject is
treated with an additional therapeutic agent selected from the
group consisting of TRAIL, etoposide, a TRAIL receptor antibody, an
Hsp90 inhibitor, TNF-.alpha., and TNF-.beta..
[0998] B27. A compound of formula (6):
##STR00288##
[0999] or a pharmaceutically acceptable salt or hydrate form
thereof,
[1000] wherein R.sub.a and R.sub.b are independently H, or C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of
these, each of which may be optionally substituted;
[1001] each Y independently represents C1-C8 alkyl, .dbd.O, OR,
NR.sub.2, OC(O)R, NRC(O)R, NRSO.sub.2R or COOR, wherein each R is
independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two
Y groups can cyclize to form a 3-6 membered ring that can be
saturated, unsaturated or aromatic, and which ring may include a
heteroatom selected from O, S and N as a ring member and may be
optionally substituted;
[1002] W represents an optionally substituted C1-C6 alkylene or
C1-C6 heteroalkylene;
[1003] X represents an optionally substituted C.sub.5-C.sub.20 ring
system comprising at least one aromatic ring and up to four
heteroatoms selected from N, O and S as a ring member, and can
represent either a single 5-15 membered cyclic group or two 5-10
membered cyclic groups that are both attached to the same atom of
W, provided that each X comprises at least one aryl or heteroaryl
ring;
[1004] n is 0-3;
[1005] m is 0-4;
[1006] R.sup.1 is H or optionally substituted C1-C8 alkyl;
[1007] U represents --OR.sup.8, --OC(O)R.sup.8, --OSO.sub.2R.sup.8,
C.dbd.O, --OC(O)OR.sup.8, --COOR.sup.8, --NR.sup.8.sub.2, azido or
halo, where each R.sup.8 is independently H, or C1-C8 alkyl, C1-C8
alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a
heteroform of one of these, each of which may be optionally
substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12
aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of
which may be optionally substituted; and
[1008] Z is an optionally substituted C1-C6 aminoalkyl group
wherein the amine may be in a protected or unprotected form.
[1009] B28. A method of making a compound of formula (1) as in
embodiment B2, comprising reacting a first monomer of formula (6)
with a second monomer of formula (6),
[1010] wherein for each of said first monomer and said second
monomer, U comprises at least one functional group that can be used
to connect said first monomer and said second monomer, either
directly or indirectly, to provide a compound of formula (1).
[1011] B29. A dimeric or trimeric SMAC mimetic compound for use in
the treatment or amelioration of cancer, inflammation, or an
autoimmune disorder,
[1012] wherein the dimeric or trimeric SMAC mimetic compound is a
compound as defined in any one of embodiments B1 to B21.
[1013] B30. A pharmaceutical composition comprising a dimeric or
trimeric SMAC mimetic compound, useful for the treatment or
amelioration of cancer, inflammation, or an autoimmune disorder,
and at least one pharmaceutically acceptable excipient,
[1014] wherein the dimeric or trimeric SMAC mimetic compound is a
compound as defined in any one of embodiments B1 to B21.
[1015] B30-1. The pharmaceutical composition of embodiment B30,
wherein the dimeric or trimeric SMAC mimetic compound is a compound
as defined in any one of embodiments B2 to B21.
[1016] B31. The pharmaceutical composition of embodiment B30,
further comprising at least one additional therapeutic agent.
[1017] B32. The pharmaceutical composition of embodiment B31,
wherein the additional therapeutic agent is selected from the group
consisting of TRAIL, etoposide, a TRAIL receptor antibody, an Hsp90
inhibitor, TNF-.alpha., and TNF-.beta..
* * * * *