U.S. patent application number 15/953108 was filed with the patent office on 2018-08-16 for cereblon ligands and bifunctional compounds comprising the same.
The applicant listed for this patent is Arvinas, Inc.. Invention is credited to Michael Berlin, Andrew P. Crew, Craig M. Crews, Hanqing Dong, Keith R. Hornberger, Yimin Qian, Lawrence B. Snyder, Jing Wang, Kurt Zimmermann.
Application Number | 20180228907 15/953108 |
Document ID | / |
Family ID | 63106267 |
Filed Date | 2018-08-16 |
United States Patent
Application |
20180228907 |
Kind Code |
A1 |
Crew; Andrew P. ; et
al. |
August 16, 2018 |
CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS COMPRISING THE SAME
Abstract
The description relates to cereblon E3 ligase binding compounds,
including bifunctional compounds comprising the same, which find
utility as modulators of targeted ubiquitination, especially
inhibitors of a variety of polypeptides and other proteins which
are degraded and/or otherwise inhibited by bifunctional compounds
according to the present disclosure. In particular, the description
provides compounds, which contain on one end a ligand which binds
to the cereblon E3 ubiquitin ligase and on the other end a moiety
which binds a target protein such that the target protein is placed
in proximity to the ubiquitin ligase to effect degradation (and
inhibition) of that protein. Compounds can be synthesized that
exhibit a broad range of pharmacological activities consistent with
the degradation/inhibition of targeted polypeptides of nearly any
type.
Inventors: |
Crew; Andrew P.; (Guilford,
CT) ; Crews; Craig M.; (New Haven, CT) ; Dong;
Hanqing; (Madison, CT) ; Hornberger; Keith R.;
(Southbury, CT) ; Wang; Jing; (Milford, CT)
; Qian; Yimin; (Plainsboro, NJ) ; Zimmermann;
Kurt; (Durham, CT) ; Berlin; Michael;
(Flemington, NJ) ; Snyder; Lawrence B.;
(Killingworth, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arvinas, Inc. |
New Haven |
CT |
US |
|
|
Family ID: |
63106267 |
Appl. No.: |
15/953108 |
Filed: |
April 13, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14792414 |
Jul 6, 2015 |
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15953108 |
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14686640 |
Apr 14, 2015 |
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14792414 |
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62171090 |
Jun 4, 2015 |
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61979351 |
Apr 14, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/506 20130101;
A61P 35/00 20180101; A61K 31/501 20130101; A61K 45/06 20130101;
A61K 31/496 20130101; C07D 401/04 20130101; A61K 47/545 20170801;
A61K 31/551 20130101; C07D 401/14 20130101; A61K 31/437 20130101;
A61K 31/497 20130101; C07D 471/04 20130101; A61K 47/55
20170801 |
International
Class: |
A61K 47/55 20060101
A61K047/55; C07D 401/04 20060101 C07D401/04; C07D 401/14 20060101
C07D401/14; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61K 31/496 20060101 A61K031/496; A61K 31/551 20060101
A61K031/551; A61K 45/06 20060101 A61K045/06; A61K 31/501 20060101
A61K031/501; A61K 31/506 20060101 A61K031/506; A61K 31/497 20060101
A61K031/497 |
Claims
1. A cereblon E3 ubiquitin ligase binding compound having a
chemical structure selected from: ##STR00598## ##STR00599##
wherein: W is selected from the group consisting of CH.sub.2, CHR,
C.dbd.O, SO.sub.2, NH, N, optionally substituted cyclopropyl group,
optionally substituted cyclobutyl group, and N-alkyl; W.sub.3 is
selected from C or N; each X is independently selected from the
group consisting of O, S, and H.sub.2, Y is selected from the group
consisting of CH.sub.2, --C.dbd.CR', NH, N-alkyl, N-aryl,
N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is selected
from the group consisting of O, S, and H.sub.2; G and G' are
independently selected from the group consisting of H, alkyl
(linear, branched, optionally substituted), OH, R'OCOOR,
R'OCONRR'', CH.sub.2-heterocyclyl optionally substituted with R',
and benzyl optionally substituted with R'; Q.sub.1, Q.sub.2,
Q.sub.3, and Q.sub.4 represent a carbon C substituted with a group
independently selected from R', N or N-oxide; A is independently
selected from the group H, alkyl (linear, branched, optionally
substituted), cycloalkyl, Cl and F; R comprises --CONR'R'', --OR',
--NR'R'', --SR', --SO.sub.2R', --SO.sub.2NR'R'', --CR'R''--,
--CR'NR'R''--, (--CR'O).sub.n'R'', -aryl, -hetaryl, -alkyl (linear,
branched, optionally substituted), -cycloalkyl, -heterocyclyl,
--P(O)(OR')R'', --P(O)R'R'', --OP(O)(OR')R'', --OP(O)R'R'', --Cl,
--F, --Br, --I, --CF.sub.3, --CN, --NR'SO.sub.2NR'R'',
--NR'CONR'R'', --CONR'COR'', --NR'C(.dbd.N--CN)NR'R'',
--C(.dbd.N--CN)NR'R'', --NR'C(.dbd.N--CN)R'',
--NR'C(.dbd.C--NO.sub.2)NR'R'', --SO.sub.2NR'COR'', --NO.sub.2,
--CO.sub.2R', --C(C.dbd.N--OR')R'', --CR'.dbd.CR'R'', --CCR',
--S(C.dbd.O)(C.dbd.N--R')R'', --SF.sub.5 and --OCF.sub.3; R' and
R'' are independently selected from the group consisting of a bond,
H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, --C(.dbd.O)R,
heterocyclyl, each of which is optionally substituted; n' integer
from 1-10; represents a single bond or a double bond; represents a
bond that may be stereospecific ((R) or (S)) or non-stereospecific;
and Rn comprises 1-4 independent functional groups, optionally
substituted linear or branched alkyl (e.g., a C1-C6 linear or
branched alkyl optionally substituted with one or more halogen,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted aryl (e.g., an optionally substituted C5-C7
aryl), optionally substituted alkyl-aryl (e.g., an alkyl-aryl
comprising at least one of an optionally substituted C1-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof),
optionally substituted alkoxyl group (e.g., a methoxy, ethoxy,
butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl may be
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted ##STR00600## (e.g., optionally substituted
with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted ##STR00601## (e.g., optionally substituted with one or
more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a
C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and each
of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6, n is an
integer from 1-10 (e.g., 1-4).
2. A bifunctional compound having the chemical structure:
CLM-L-PTM, or a pharmaceutically acceptable salt, enantiomer,
stereoisomer, solvate, polymorph or prodrug thereof, wherein: the
PTM is a small molecule comprising a protein targeting moiety; the
L is a bond or a chemical linking moiety covalently coupling the
CLM and the PTM; and the CLM is a small molecule cereblon E3
ubiquitin ligase binding moiety of claim 1, wherein when n is 2, 3,
or 4, then at least one of R.sub.n or W is modified to be
covalently joined to the linker group (L) or a PTM.
3. The bifunctional compound according to claim 2, wherein the CLM
is linked to the PTM, the chemical linker group (L), or a
combination thereof via W, X, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R', Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5.
4. The bifunctional compound according to claim 2 or 3, wherein the
PTM is a moiety that binds BRD4, BRaf, Estrogen Receptor (ER), or
Androgen Receptor (AR).
5. The bifunctional compound according to any of claims 2-4,
wherein the compound further comprises a second E3 ubiquitin ligase
binding moiety coupled through a linker group.
6. The bifunctional compound according to claim 5, wherein the
second E3 ubiquitin ligase binding moiety binds or targets an E3
ubiquitin ligase selected from the group consisting of Von
Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog 2
(MLM), and inhibitors of apoptosis proteins (ILM).
7. The bifunctional compound according to any of claims 2-6,
wherein the CLM is represented by a chemical structure selected
from the group consisting of: ##STR00602## ##STR00603##
##STR00604##
8. The bifunctional compound according to any of claims 2-7,
wherein the linker (L) comprises a chemical structural unit
represented by the formula: -(A.sup.L)q- wherein: (A.sup.L).sub.q
is a group which is connected to at least one of the CLM, the PTM,
or a combination thereof; q is an integer greater than or equal to
1; each A.sup.L is independently selected from the group consisting
of, a bond, CR.sup.L1R.sup.L2, O, S, SO, SO.sub.2, NR.sup.L3,
SO.sub.2NR.sup.L3, SONR.sup.L3, CONR.sup.L3, NR.sup.L3CONR.sup.L4,
NR.sup.L3SO.sub.2NR.sup.L4, CO, CR.sup.L1.dbd.CR.sup.L2, C.ident.C,
SiR.sup.L1R.sup.L2, P(O)R.sup.L1, P(O)OR.sup.L1,
NR.sup.L3C(.dbd.NCN)NR.sup.L4, NR.sup.L3C(.dbd.NCN),
NR.sup.L3C(.dbd.CNO.sub.2)NR.sup.L4, C.sub.3-11cycloalkyl
optionally substituted with 0-6 R.sup.L1 and/or R.sup.L2 groups,
C.sub.3-11heteocyclyl optionally substituted with 0-6 R.sup.L1
and/or R.sup.L2 groups, aryl optionally substituted with 0-6
R.sup.L1 and/or R.sup.L2 groups, heteroaryl optionally substituted
with 0-6 R.sup.L1 and/or R.sup.L2 groups, where R.sup.L1 or
R.sup.L2, each independently are optionally linked to other groups
to form cycloalkyl and/or heterocyclyl moiety, optionally
substituted with 0-4 R.sup.L5 groups; and R.sup.L1, R.sup.L2,
R.sup.L3, R.sup.L4 and R.sup.L5 are, each independently, H, halo,
C.sub.1-8alkyl, OC.sub.1-8alkyl, SC.sub.1-8alkyl, NHC.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, C.sub.3-11cycloalkyl, aryl, heteroaryl,
C.sub.3-11heterocyclyl, OC.sub.1-8cycloalkyl, SC.sub.1-8cycloalkyl,
NHC.sub.1-8cycloalkyl, N(C.sub.1-8cycloalkyl).sub.2,
N(C.sub.1-8cycloalkyl)(C.sub.1-8alkyl), OH, NH.sub.2, SH,
SO.sub.2C.sub.1-8alkyl, P(O)(OC.sub.1-8alkyl)(C.sub.1-8alkyl),
P(O)(OC.sub.1-8alkyl).sub.2, CC--C.sub.1-8alkyl, CCH,
CH.dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.C(C.sub.1-8alkyl).sub.2, Si(OH).sub.3,
Si(C.sub.1-8alkyl).sub.3, Si(OH)(C.sub.1-8alkyl).sub.2,
COC.sub.1-8alkyl, CO.sub.2H, halogen, CN, CF.sub.3, CHF.sub.2,
CH.sub.2F, NO.sub.2, SF.sub.5, SO.sub.2NHC.sub.1-8alkyl,
SO.sub.2N(C.sub.1-8alkyl).sub.2, SONHC.sub.1-8alkyl,
SON(C.sub.1-8alkyl).sub.2, CONHC.sub.1-8alkyl,
CON(C.sub.1-8alkyl).sub.2, N(C.sub.1-8alkyl)CONH(C.sub.1-8alkyl),
N(C.sub.1-8alkyl)CON(C.sub.1-8alkyl).sub.2, NHCONH(C.sub.1-8alkyl),
NHCON(C.sub.1-8alkyl).sub.2, NHCONH.sub.2,
N(C.sub.1-8alkyl)SO.sub.2NH(C.sub.1-8alkyl), N(C.sub.1-8alkyl)
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH(C.sub.1-8alkyl), NH
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH.sub.2.
9. The bifunctional compound according to any of claims 2-8,
wherein A.sup.L is selected from the group consisting of:
--N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O-
(CH2).sub.r-OCH2-,
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH-
2).sub.r-OCH2-,
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH-
2).sub.r-O--;
--N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O-
(CH2).sub.r-O--;
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH2).-
sub.r-O--;
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub-
.q-O(CH2).sub.r-OCH2-; ##STR00605## ##STR00606## ##STR00607##
wherein m, n, o, p, q, and r of the linker are independently 0, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;
when the number is zero, there is no N--O or O--O bond R of the
linker is H, methyl and ethyl; X of the linker is H and F
##STR00608## where m of the linker can be 2, 3, 4, 5; ##STR00609##
##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614##
##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619##
##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624##
##STR00625## where each n and m of the linker can independently be
0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20.
10. The bifunctional compound according to any of claims 2-8,
wherein A.sup.L is selected from the group consisting of:
##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630##
##STR00631## ##STR00632## ##STR00633## ##STR00634## wherein each m
and n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
11. The bifunctional compound of any of claims 2-8, wherein A.sup.L
is selected from the group consisting of: ##STR00635## ##STR00636##
##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641##
##STR00642## ##STR00643## ##STR00644## ##STR00645## ##STR00646##
##STR00647## ##STR00648## ##STR00649## ##STR00650## ##STR00651##
##STR00652## ##STR00653## ##STR00654## ##STR00655## ##STR00656##
##STR00657## ##STR00658## ##STR00659## ##STR00660## ##STR00661##
##STR00662## ##STR00663## ##STR00664## ##STR00665## ##STR00666##
##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671##
##STR00672## ##STR00673## ##STR00674## ##STR00675## wherein each m,
n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
12. The bifunctional compound according to any of claims 2-8,
wherein A.sup.L is selected from the group consisting of:
##STR00676## ##STR00677## ##STR00678## ##STR00679## ##STR00680##
##STR00681## ##STR00682## ##STR00683## ##STR00684## ##STR00685##
##STR00686## ##STR00687## ##STR00688## ##STR00689##
##STR00690##
13. The bifunctional compound according to any of claims 2-8,
wherein A.sup.L is selected from: ##STR00691## ##STR00692##
##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697##
##STR00698## ##STR00699## wherein: `X" in above structures can be
linear chain with atoms ranging from 2 to 14, and the mentioned
chain can contain heteroatoms such as oxygen; and "Y" in above
structures can be O, N, S(O).sub.n (n=0, 1, 2).
14. The bifunctional compound according to any of claims 2-7,
wherein the linker (L) comprises a structure selected from:
##STR00700## wherein: W.sup.L1 and W.sup.L2 are each independently
absent, a 4-8 membered ring with 0-4 heteroatoms, optionally
substituted with R.sup.Q, each R.sup.Q is independently a H, halo,
OH, CN, CF.sub.3, C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted), C.sub.1-C.sub.6 alkoxy (linear, branched,
optionally substituted), or 2 R.sup.Q groups taken together with
the atom they are attached to, form a 4-8 membered ring system
containing 0-4 heteroatoms; Y.sup.L1 is each independently a bond,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted)
and optionally one or more C atoms are replaced with O; or
C.sub.1-C.sub.6 alkoxy (linear, branched, optionally substituted);
n is 0-10; and a dashed line indicates the attachment point to the
PTM or CLM moieties.
15. The bifunctional compound according to any of claims 2-7,
wherein the linker comprises a structure selected from:
##STR00701## wherein: W.sup.L1 and W.sup.L2 are each independently
absent, aryl, heteroaryl, cyclic, heterocyclic, C.sub.1-6 alkyl and
optionally one or more C atoms are replaced with O, C.sub.1-6
alkene and optionally one or more C atoms are replaced with O,
C.sub.1-6 alkyne and optionally one or more C atoms are replaced
with O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each
optionally substituted with R.sup.Q, each R.sup.Q is independently
a H, halo, OH, CN, CF.sub.3, hydroxyl, nitro, C.ident.CH, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkyl (linear,
branched, optionally substituted), C.sub.1-C.sub.6 alkoxy (linear,
branched, optionally substituted), OC.sub.1-3alkyl (optionally
substituted by 1 or more --F), OH, NH.sub.2, NR.sup.Y1R.sup.Y2, CN,
or 2 R.sup.Q groups taken together with the atom they are attached
to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y.sup.L1 is each independently a bond, NR.sup.YL1, O, S,
NR.sup.YL2, CR.sup.YL1R.sup.YL2, C.dbd.O, C.dbd.S, SO, SO.sub.2,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted)
and optionally one or more C atoms are replaced with O;
C.sub.1-C.sub.6 alkoxy (linear, branched, optionally substituted);
Q.sup.L is a 3-6 membered alicyclic or aromatic ring with 0-4
heteroatoms, optionally bridged, optionally substituted with 0-6
R.sup.Q, each R.sup.Q is independently H, C.sub.1-6 alkyl (linear,
branched, optionally substituted by 1 or more halo, C.sub.1-6
alkoxyl), or 2 R.sup.Q groups taken together with the atom they are
attached to, form a 3-8 membered ring system containing 0-2
heteroatoms); R.sup.YL1, R.sup.YL2 are each independently H, OH,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C.sub.1-6 alkoxyl), or R.sup.1, R.sup.2 together with
the atom they are attached to, form a 3-8 membered ring system
containing 0-2 heteroatoms); n is 0-10; and a dashed line indicates
the attachment point to the PTM or CLM moieties.
16. The bifunctional compound according to any of claims 2-8,
wherein the linker (L) is a polyethylenoxy group optionally
substituted with aryl or phenyl comprising from 1 to 10 ethylene
glycol units.
17. The bifunctional compound according to any of claims 2-16,
wherein the PTM is an estrogen receptor (ER) binding moiety
represented by the chemical structure: ##STR00702## wherein:
X.sub.PTM is O or C.dbd.O; each of X.sub.PTM1 and X.sub.PTM2 is
independently selected from N or CH; R.sub.PTM1 is independently
selected from OH, O(CO)R.sub.P, O-lower alkyl, wherein R.sub.PTM is
an alkyl or aryl group in the ester; R.sub.PTM2 and R.sub.PTM4 are
independently selected from H, OH, halogen, CN, CF.sub.3,
SO.sub.2-alkyl, O-lower alkyl; R.sub.PTM3 and R.sub.PTM5 are
independently selected from H, halogen; PTM-I has at least one
R.sub.PTM2 and at least one R.sub.PTM3 on each respective rings;
and the indicates the site of attachment of at least one of the
linker, the CLM, a CLM', or a combination thereof.
18. The bifunctional compound according to any of claims 2-16,
wherein the PTM is an estrogen receptor (ER) binding moiety
represented by the chemical structure: ##STR00703## wherein: each
X.sub.PTM is independently CH, N; indicates the site of attachment
of at least one of the linker (L), the CLM, a CLM', ULM, an ILM, a
VLM, MLM, a ULM', a ILM', a VLM', a MLM', or a combination thereof;
each R.sub.PTM1 is independently OH, halogen, alkoxy, methoxy,
ethoxy, O(CO)R.sub.PTM, wherein the substitution can be a mono-,
di- or tri-substitution and the R.sub.PTM is alkyl or cycloalkyl
group with 1 to 6 carbons or aryl groups; each R.sub.PTM2 is
independently H, halogen, CN, CF.sub.3, liner or branched alkyl,
alkoxy, methoxy, ethoxy, wherein the substitution can be mono- or
di-substitution; each R.sub.PTM3 is independently H, halogen,
wherein the substitution can be mono- or di-substitution; and
R.sub.PTM4 is a H, alkyl, methyl, ethyl.
19. The bifunctional compound according to any of claims 2-16,
wherein the PTM is an androgen receptor (AR) binding moiety (ABM)
represented by a structure selected from the group consisting of:
##STR00704## wherein: W.sup.1 is aryl, heteroaryl, bicyclic, or
biheterocyclic, each independently substituted by 1 or more H,
halo, hydroxyl, nitro, CN, C.ident.CH, C.sub.1-6 alkyl (linear,
branched, optionally substituted; for example, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), C.sub.1-6
alkoxyl (linear, branched, optionally substituted; for example,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; Y.sup.1, Y.sup.2 are each
independently NR.sup.Y1, O, S, SO2, heteroaryl, or aryl; Y.sup.3,
Y.sup.4, Y.sup.5 are each independently a bond, O, NR.sup.Y2,
CR.sup.Y1R.sup.Y2, C.dbd.O, C.dbd.S, SO, SO.sub.2, heteroaryl, or
aryl; Q is a 3-6 membered ring with 0-4 heteroatoms, optionally
substituted with 0-6 R.sup.Q, each R.sup.Q, is independently H,
C.sub.1-6 alkyl (linear, branched, optionally substituted, for
example, optionally substituted by 1 or more halo, C.sub.1-6
alkoxyl), halogen, C.sub.1-6alkoxy, or 2 R.sup.Q groups taken
together with the atom they are attached to, form a 3-8 membered
ring system containing 0-2 heteroatoms); R.sup.1, R.sup.2, R.sup.a,
R.sup.b, R.sup.Y1, R.sup.Y2 are each independently H, C.sub.1-6
alkyl (linear, branched, optionally substituted; for example,
optionally substituted by 1 or more halo, C.sub.1-6 alkoxyl),
halogen, C.sub.1-6alkoxy, cyclic, heterocyclic or R.sup.1, R.sup.2
together with the atom they are attached to, form a 3-8 membered
ring system containing 0-2 heteroatoms); W.sup.2 is a bond,
C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, O, aryl, heteroaryl,
alicyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl,
each optionally substituted by 1-10 R.sup.W2; each R.sup.W2 is
independently H, halo, C.sub.1-6 alkyl (linear or branched
optionally substituted; for example, optionally substituted by 1 or
more F), --OR.sup.W2A, C.sub.3-6 cycloalkyl, C.sub.4-6
cycloheteroalkyl, C.sub.1-6 alkyl (optionally substituted),
heterocyclic (optionally substituted), aryl (optionally
substituted), or heteroaryl (optionally substituted), bicyclic
hereoaryl or aryl, OC.sub.1-3alkyl (optionally substituted; for
example, optionally substituted by 1 or more --F), OH, NH.sub.2,
NR.sup.Y1R.sup.Y2, CN; R.sup.W2A is H, C.sub.1-6 alkyl (linear,
branched), or C.sub.1-6heteroalkyl (linear, branched), each
optionally substituted by a cycloalkyl, cycloheteroalkyl, aryl,
heterocyclic, heteroaryl, halo, or OC.sub.1-3alkyl; and the dashed
line indicates the site of attachment of at least one of the
linker, the CLM, a CLM', or a combination thereof.
20. The bifunctional compound according to any of claims 2-16,
wherein the PTM is a BET/BRD4 targeting moiety comprising a group
according to the chemical structure PTM-a: ##STR00705## wherein:
Y.sub.1, Y.sub.2 and Y.sub.3 are independently selected from the
group of carbon, nitrogen or oxygen and together with the atoms to
form an aromatic fused ring. A and B are independently selected
from the group of a 5-membered aromatic ring, a 6-membered aromatic
ring, a heteroaromatic ring, a carbocyclic, a thiophene a pyrrole
ring, a pyridine, a pyrimidine, a pyrazine, a pyrazole ring each
optionally substituted with alkyl, alkoxy, halogen, an aromatic and
a heteroaromatic ring; wherein ring A is fused to the central
azepine (Y1=C) or diazepine (Y1=N) moiety; and Z1 is selected from
the group of methyl or analkyl group, and wherein the dashed line
indicates the site of attachment of at least one of the linker, the
CLM, a CLM', or a combination thereof.
21. The bifunctional compound according to any of claims 2-16,
wherein the PTM is a BRaf targeting moiety that is represented by
at least one of chemical structures PTM-Ia, PTM-Ib, PTM-IIa,
PTM-IIb, PTM-IIIa, PTM-IIIb, PTM-IVa, PTM-IVb: ##STR00706##
wherein: double dotted bonds are aromaric bonds; V.sub.PTM,
W.sub.PTM, X.sub.PTM, Y.sub.PTM, Z.sub.PTM is one of the following
combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S,
C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH,
C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH,
C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C;
R.sub.PTM1 is covalently joined to a ULM, a chemical linker group
(L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM', a VLM', a
MLM', or combination thereof; R.sub.PTM2 is hydrogen, halogen,
aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R.sub.PTM3
is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic
alkyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein
M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl,
aryl or heterocycle; R.sub.PTM4 is hydrogen, halogen, aryl, methyl,
ethyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein
M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl,
aryl or heterocycle; each of R.sub.PTM5 and R.sub.PTM22 is
independently selected from the group consisting of ##STR00707##
X.sub.PTM1, X.sub.PTM2, X.sub.PTM3, X.sub.PTM4, X.sub.PTM5,
X.sub.PTM6, X.sub.PTM7, X.sub.PTM8, X.sub.PTM9, X.sub.PTM10,
X.sub.PTM11, X.sub.PTM12, X.sub.PTM13, X.sub.PTM14, X.sub.PTM15,
X.sub.PTM16, X.sub.PTM17, X.sub.PTM18, X.sub.PTM19, X.sub.PTM20,
X.sub.PTM21, X.sub.PTM22, X.sub.PTM23, X.sub.PTM24, X.sub.PTM25,
X.sub.PTM26, X.sub.PTM27, X.sub.PTM28, X.sub.PTM29, X.sub.PTM30,
X.sub.PTM31, X.sub.PTM32, X.sub.PTM33, X.sub.PTM34, X.sub.PTM35,
X.sub.PTM36, X.sub.PTM37, X.sub.PTM38 are independently selected
from CH or N; R.sub.PTM5a is selected from the group consisting of:
H, optionally substituted amide (e.g., optionally substituted with
an alkyl, methyl, ethyl, propyl, or butyl group), optionally
substituted amine, ##STR00708## --NHC(O)R.sub.PTM5; R.sub.PTM6a and
R.sub.PTM6b are each independently selected from hydrogen, halogen,
or C.sub.1-C.sub.6 alkyl (linear, branched, optionally
substituted); R.sub.PTM6 is either of the following groups: absent,
hydrogen, halogen, aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle. R.sub.PTM7
is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH.sub.3,
NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O
and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle. R.sub.PTM8, R.sub.PTM9 or R.sub.PTM10 are
independently selected from the group consisting of absent,
hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl,
heterocycle, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R.sub.PTM11
is absent, hydrogen, halogen, methyl, ethyl, OCH.sub.3, NHCH.sub.3
or M1-CH.sub.2--CH.sub.2-M2 in which Ml, wherein CH.sub.2, O and
NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R.sub.PTM12, R.sub.PTM13, R.sub.PTM14, R.sub.PTM15, R.sub.PTM16,
R.sub.PTM17, R.sub.PTM18, R.sub.PTM19 are independently Selected
from the group consisting of absent, hydrogen, halogen, aryl,
heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl,
OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is
CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or heterocycle; R.sub.PTM20 is a small group containing less than
four non-hydrogen atoms; R.sub.PTM21 is selected from the group
consisting of trifluoromethyl, chloro, bromo, fluoro, methyl,
ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH.sub.3,
NHCH.sub.3, dimethylamino or M1-CH.sub.2--CH.sub.2-M2, wherein M1
is CH.sub.2, O or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or heterocycle; R.sub.PTM25a and R.sub.PTM25b are each
independently selected from hydrogen, halogen, or C.sub.1-C.sub.6
alkyl (linear, branched, optionally substituted); R.sub.PTM23,
R.sub.PTM24, R.sub.PTM28, R.sub.PTM29, R.sub.PTM30, R.sub.PTM31,
R.sub.PTM32 are independently selected from the group consisting of
absent, bond, hydrogen, halogen, aryl (optionally substituted),
heteroaryl (optionally substituted), cycloalkyl (optionally
substituted), heterocycle (optionally substituted), methyl, ethyl
(optionally substituted), other alkyl (linear, branched, optionally
substituted), OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl
(linear, branched, optionally substituted), cyclic alkyl
(optionally substituted), aryl (optionally substituted) or
heterocycle (optionally substituted); R.sub.PTM25 is selected from
absent, hydrogen, halogen, C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted), OCH.sub.3, NHCH.sub.3 or SCH.sub.3;
R.sub.PTM26 is selected from absent, hydrogen, halogen,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted),
OCH3, NHCH.sub.3 or SCH.sub.3; R.sub.PTM27 is selected from the
group consisting of absent, hydrogen, halogen, C.sub.1-C.sub.6
alkyl (linear, branched, optionally substituted), OCH.sub.3,
NHCH.sub.3 or SCH.sub.3; and at least one of R.sub.PTM8, R.sub.PTM9
or R.sub.PTM10, R.sub.PTM12, R.sub.PTM13, R.sub.PTM16, R.sub.PTM24,
R.sub.PTM29, and R.sub.PTM32 is modified to be covalently joined to
a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM, a
ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof.
22. The bifunctional compound according to claim 21, wherein: when
R.sub.PTM9 is the covalently joined position, R.sub.PTM7 and
R.sub.PTM8 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM7 and
R.sub.PTM8 are attached; or when R.sub.PTM8 is the covalently
joined position, R.sub.PTM9 and R.sub.PTM10 are connected together
via a covalent bond in a way to form a bicyclic group with the ring
to which R.sub.PTM9 and R.sub.PTM10 are attached; or when RPTM10 is
the covalently joined position, RPTM8 and RPTM9 are connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which RPTM8 and RPTM9 are attached; or when R.sub.PTM12
is the covalently joined position, R.sub.PTM13 and R.sub.PTM14 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM13 and R.sub.PTM14 are
attached, and/or R.sub.PTM15 and R.sub.PTM16 are connected together
via a covalent bond in a way to form a bicyclic group with the ring
to which R.sub.PTM15 and R.sub.PTM16 are attached; or when
R.sub.PTM13 is the covalently joined position, R.sub.PTM12 and
R.sub.PTM16 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM12 and
R.sub.PTM16 are attached, and/or R.sub.PTM15 and R.sub.PTM16 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM15 and R.sub.PTM16 are
attached; or when R.sub.PTM16 is the covalently joined position,
R.sub.PTM12 and R.sub.PTM13 are connected together via a covalent
bond in a way to form a bicyclic group with the ring to which
R.sub.PTM12 and R.sub.PTM13 are attached, and/or R.sub.PTM13 and
R.sub.PTM14 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM13 and
R.sub.PTM14 are attached; or when R.sub.PTM24 is the covalently
joined position, R.sub.PTM31 and R.sub.PTM32 are connected together
via a covalent bond in a way to form a bicyclic group with the ring
to which R.sub.PTM31 and R.sub.PTM32 are attached, or R.sub.PTM29
and R.sub.PTM30 are connected together via a covalent bond in a way
to form a bicyclic group with the ring to which R.sub.PTM29 and
R.sub.PTM30 are attached; or when R.sub.PTM29 is the covalently
joined position, R.sub.PTM24 and R.sub.PTM32 are connected together
via a covalent bond in a way to form a bicyclic group with the ring
to which R.sub.PTM24 and R.sub.PTM32 are attached, and/or
R.sub.PTM31 and R.sub.PTM32 are connected together via a covalent
bond in a way to form a bicyclic group with the ring to which
R.sub.PTM31 and R.sub.PTM32 are attached; or when R.sub.PTM32 is
the covalently joined position, R.sub.PTM24 and R.sub.PTM29 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM24 and R.sub.PTM29 are
attached, and/or R.sub.PTM29 and R.sub.PTM30 are connected together
via a covalent bond in a way to form a bicyclic group with the ring
to which R.sub.PTM29 and R.sub.PTM30 are attached.
23. The bifunctional compound according to any of claims 2-23,
wherein the PTM has a structure selected from the group consisting
of: ##STR00709## ##STR00710## ##STR00711## ##STR00712##
##STR00713## ##STR00714## ##STR00715## ##STR00716## wherein: R is
H, a lower alkyl, a bond, or a chemical moiety coupling the CLM to
the PTM; and Linker is a bond or a chemical linker moiety coupling
the CLM to the PTM, including pharmaceutically acceptable salt
forms thereof.
24. The bifunctional compound according to claim 2, wherein the
compound is selected from the group consisting of compounds
1-52.
25. A composition comprising an effective amount of a bifunctional
compound of any of claims 2-24, and a pharmaceutically acceptable
carrier.
26. The composition of claim 25, wherein the composition further
comprises at least one of additional bioactive agent or another
bifunctional compound of any of claims 2-24.
27. The composition of claim 26, wherein the additional bioactive
agent is anti-cancer agent, an anti-neurodegenerative agent, an
antimicrobial agent, an antiviral agent, an anti-HIV agent, or an
antifungal agent.
28. A composition comprising an effective amount of at least one
compound of any of claims 2-24 and a pharmaceutically acceptable
carrier, additive, and/or excipient for treating a disease or
disorder in a subject, the method comprising administering the
composition to a subject in need thereof, wherein the compound is
effective in treating or ameliorating at least one symptom of the
disease or disorder.
29. The composition of claim 28, wherein the disease or disorder is
associated with the accumulation and/or aggregation of the target
protein.
30. The composition of claim 28 or 29, wherein the disease or
disorder is selected from the group consisting of asthma,
autoimmune diseases such as multiple sclerosis, various cancers,
ciliopathies, cleft palate, diabetes, heart disease, hypertension,
inflammatory bowel disease, mental retardation, mood disorder,
obesity, refractive error, infertility, Angelman syndrome, Canavan
disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic
fibrosis, Duchenne muscular dystrophy, Haemochromatosis,
Haemophilia, Klinefelter's syndrome, Neurofibromatosis,
Phenylketonuria, Polycystic kidney disease, (PKD1) or 4 (PKD2)
Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease,
Turner syndrome.
31. The composition of claim 28 or 29, wherein the disease or
disorder is selected from the group consisting of Alzheimer's
disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease),
Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention
deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic
fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's
disease, Coronary heart disease, Dementia, Depression, Diabetes
mellitus type 1, Diabetes mellitus type 2, Epilepsy,
Guillain-Barresyndrome, Irritable bowel syndrome, Lupus, Metabolic
syndrome, Multiple sclerosis, Myocardial infarction, Obesity,
Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,
Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia,
Stroke, Thromboangiitis obliterans, Tourette syndrome,
Vasculitis.
32. The composition of claim 28 or 29, wherein the disease or
disorder is selected from the group consisting of
aceruloplasminemia, Achondrogenesis type II, achondroplasia,
Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,
Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase
deficiency, adenylosuccinate lyase deficiency, Adrenogenital
syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase
deficiency, Alkaptonuria, Alexander disease, Alkaptonuric
ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase
inhibitor, emphysema, amyotrophic lateral sclerosis Alstrom
syndrome, Alexander disease, Amelogenesis imperfecta, ALA
dehydratase deficiency, Anderson-Fabry disease, androgen
insensitivity syndrome, Anemia Angiokeratoma Corporis Diffusum,
Angiomatosis retinae (von Hippel-Lindau disease) Apert syndrome,
Arachnodactyly (Marfan syndrome), Stickler syndrome, Arthrochalasis
multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type)
ataxia telangiectasia, Rett syndrome, primary pulmonary
hypertension, Sandhoff disease, neurofibromatosis type II,
Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,
familial, Benjamin syndrome, beta-thalassemia, Bilateral Acoustic
Neurofibromatosis (neurofibromatosis type II), factor V Leiden
thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti),
Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich
syndrome (Turner syndrome), Bourneville disease (tuberous
sclerosis), prion disease, Birt-Hogg-Dube syndrome, Brittle bone
disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome
(Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis
(hemochromatosis), Bulbospinal muscular atrophy (Kennedy's
disease), Burger-Grutz syndrome (lipoprotein lipase deficiency),
CGD Chronic granulomatous disorder, Campomelic dysplasia,
biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du
chat, CAVD (congenital absence of the vas deferens), Caylor
cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic
porphyria), cystic fibrosis, congenital hypothyroidism,
Chondrodystrophy syndrome (achondroplasia),
otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome,
galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia,
Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous
polyposis), Congenital erythropoietic porphyria, Congenital heart
disease, Methemoglobinemia/Congenital methaemoglobinaemia,
achondroplasia, X-linked sideroblastic anemia, Connective tissue
disease, Conotruncal anomaly face syndrome, Cooley's Anemia
(beta-thalassemia), Copper storage disease (Wilson's disease),
Copper transport disease (Menkes disease), hereditary
coproporphyria, Cowden syndrome, Craniofacial dysarthrosis (Crouzon
syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne
syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome
(myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome,
primary hyperoxaluria, spondyloepimetaphyseal dysplasia (Strudwick
type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher
syndrome, Degenerative nerve diseases including de Grouchy syndrome
and Dejerine-Sottas syndrome, developmental disabilities, distal
spinal muscular atrophy, type V, androgen insensitivity syndrome,
Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's
syndrome, Dihydrotestosterone receptor deficiency, androgen
insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic
protoporphyria Erythroid 5-aminolevulinate synthetase deficiency,
Erythropoietic porphyria, erythropoietic protoporphyria,
erythropoietic uroporphyria, Friedreich's ataxia, familial
paroxysmal polyserositis, porphyria cutanea tarda, familial
pressure sensitive neuropathy, primary pulmonary hypertension
(PPH), Fibrocystic disease of the pancreas, fragile X syndrome,
galactosemia, genetic brain disorders, Giant cell hepatitis
(Neonatal hemochromatosis), Gronblad-Strandberg syndrome
(pseudoxanthoma elasticum), Gunther disease (congenital
erythropoietic porphyria), haemochromatosis, Hallgren syndrome,
sickle cell anemia, hemophilia, hepatoerythropoietic porphyria
(HEP), Hippel-Lindau disease (von Hippel-Lindau disease),
Huntington's disease, Hutchinson-Gilford progeria syndrome
(progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic
anemia, Immune system disorders, including X-linked severe combined
immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome,
Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome,
Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,
Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,
Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch
syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease,
Metabolic disorders, including Kniest dysplasia, Marfan syndrome,
Movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke
syndrome, Multiple neurofibromatosis, Nance-Insley syndrome,
Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack
syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease,
Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic
fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers
syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary
hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary
hypertension, primary senile degenerative dementia, prion disease,
progeria (Hutchinson Gilford Progeria Syndrome), progressive
chorea, chronic hereditary (Huntington) (Huntington's disease),
progressive muscular atrophy, spinal muscular atrophy, propionic
acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary
arterial hypertension, PXE (pseudoxanthoma elasticum), Rb
(retinoblastoma), Recklinghausen disease (neurofibromatosis type
I), Recurrent polyserositis, Retinal disorders, Retinoblastoma,
Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome,
Roussy-Levy syndrome, severe achondroplasia with developmental
delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome,
sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome,
sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital
(spondyloepiphyseal dysplasia congenita), SED Strudwick
(spondyloepimetaphyseal dysplasia, Strudwick type), SEDc
(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type
(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen
syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome,
South-African genetic porphyria (variegate porphyria),
infantile-onset ascending hereditary spastic paralysis, Speech and
communication disorders, sphingolipidosis, Tay-Sachs disease,
spinocerebellar ataxia, Stickler syndrome, stroke, androgen
insensitivity syndrome, tetrahydrobiopterin deficiency,
beta-thalassemia, Thyroid disease, Tomaculous neuropathy
(hereditary neuropathy with liability to pressure palsies),
Treacher Collins syndrome, Triplo X syndrome (triple X syndrome),
Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von
Hippel-Lindau disease), Vision impairment and blindness (Alstrom
syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo
Fledelius Syndrome, Weissenbacher-Zweymuller syndrome,
Wolf-Hirschhorn syndrome, Wolff Periodic disease,
Weissenbacher-Zweymuller syndrome and Xeroderma pigmentosum.
33. The composition of any of claims 28-32, further comprising an
additional bioactive agent.
34. The composition of claim 33, wherein the additional bioactive
agent is at least one of an anti-cancer agent, an
anti-neurodegenerative agent, an antimicrobial agent, an antiviral
agent, an anti-HIV agent, an antifungal agent, or a combination
thereof.
35. The composition of claim 34, wherein said anticancer agent is
selected from the group consisting of everolimus, trabectedin,
abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744,
ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364,
AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,
PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor,
an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1
modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor,
a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK
inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT
inhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a
checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a
Map kinase kinase (mek) inhibitor, a VEGF trap antibody,
pemetrexed, erlotinib, dasatanib, nilotinib, decatanib,
panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171,
batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine,
rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab,
gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,
cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR.sub.1
KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx
102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380,
sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,
doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine,
vincristine, temozolomide, ZK-304709, seliciclib; PD0325901,
AZD-6244, capecitabine, L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane,
letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated
estrogen, bevacizumab, IMC-1C11, CHIR-258);
3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone,
vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t)
6,Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu
t)-Leu-Arg-Pro-Azgly-NH.sub.2 acetate
[C.sub.59H.sub.84N.sub.18Oi.sub.4-(C.sub.2H.sub.4O.sub.2).sub.x
where x=1 to 2.4], goserelin acetate, leuprolide acetate,
triptorelin pamoate, medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;
TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF
antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib,
BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide
hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,
sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide,
L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine,
chlorambucil, cisplatin, cladribine, clodronate, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin, fludarabine, fludrocortisone,
fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,
methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin,
porfimer, procarbazine, raltitrexed, rituximab, streptozocin,
teniposide, testosterone, thalidomide, thioguanine, thiotepa,
tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard,
uracil mustard, estramustine, altretamine, floxuridine,
5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine,
vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat,
BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, droloxifene,
idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,
denileukin diftitox, gefitinib, bortezimib, paclitaxel,
cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550,
BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,
ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene,
idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK
222584, VX-745, PD 184352, rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,
wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,
erythropoietin, granulocyte colony-stimulating factor,
zolendronate, prednisone, cetuximab, granulocyte macrophage
colony-stimulating factor, histrelin, pegylated interferon alfa-2a,
interferon alfa-2a, pegylated interferon alfa-2b, interferon
alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,
all-transretinoic acid, ketoconazole, interleukin-2, megestrol,
immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab
tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab, arsenic trioxide, cortisone, editronate, mitotane,
cyclosporine, liposomal daunorubicin, Edwina-asparaginase,
strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,
palonosetron, aprepitant, diphenhydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol,
dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim,
erythropoietin, epoetin alfa, darbepoetin alfa and mixtures
thereof.
36. A method for inducing degradation of a target protein in a cell
comprising administering an effective amount of a compound of any
of claims 1-24 to the cell, wherein the compound effectuates
degradation of the target protein.
37. A composition comprising an effective amount of a compound of
any of claims 2-24 for use in a method for treating cancer, said
method comprising administering the composition to a patient in
need thereof, wherein the composition is effectuates for the
treatment or alleviation of at least one symptom of cancer in the
patient.
38. The composition of claim 37, wherein the cancer is
squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,
hepatocellular carcinomas, and renal cell carcinomas, cancer of the
bladder, bowel, breast, cervix, colon, esophagus, head, kidney,
liver, lung, neck, ovary, pancreas, prostate, and stomach;
leukemias; benign and malignant lymphomas, particularly Burkitt's
lymphoma and Non-Hodgkin's lymphoma; benign and malignant
melanomas; myeloproliferative diseases; multiple myeloma, sarcomas,
including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma,
liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial
sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas,
gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,
medulloblastomas, pineal cell tumors, meningiomas, meningeal
sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast
cancer, prostate cancer, cervical cancer, uterine cancer, lung
cancer, ovarian cancer, testicular cancer, thyroid cancer,
astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer,
liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's
disease, Wilms' tumor or teratocarcinomas, T-lineage Acute
lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma
(T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B
ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma,
B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia
chromosome positive CML.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present disclosure is a Continuation-in-Part of U.S.
Non-Provisional application Ser. No. 14/686,640, filed 14 Apr.
2015, which claim priority to U.S. Provisional Application No.
61/979,351, filed 14 Apr. 2014, and a Continuation-in-Part of U.S.
Non-Provisional application Ser. No. 14/792,414, filed 6 Jul. 2015,
which claims priority to U.S. Provisional Application No.
61/979,351, filed 14 Apr. 2014, and U.S. Provisional Application
No. 62/171,090, filed 4 Jun. 2015, all of which are incorporated
herein by reference in their entirety.
INCORPORATION BY REFERENCE
[0002] U.S. patent application Ser. No. 15/230,354, filed on Aug.
5, 2016, published as U.S. Patent Application Publication No.
2017/0065719; and U.S. patent application Ser. No. 15/801,243,
filed on 1 Nov. 2017; and U.S. patent application Ser. No.
15/206,497 filed 11 Jul. 2016; and U.S. patent application Ser. No.
15/209,648 filed 13 Jul. 2016; and U.S. patent application Ser. No.
15/730,728, filed on Oct. 11, 2017; U.S. patent application Ser.
No. 15/829,541, filed on Dec. 1, 2017; U.S. patent application Ser.
No. 15/881,318, filed on Jan. 26, 2018; and U.S. patent application
Ser. No. 14/686,640, filed on Apr. 14, 2015, published as U.S.
Patent Application Publication No. 2015/0291562; and U.S. patent
application Ser. No. 14/792,414, filed on Jul. 6, 2015, published
as U.S. Patent Application Publication No. 2016/0058872; and U.S.
patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,
published as U.S. Patent Application Publication No. 2014/0356322;
and U.S. patent application Ser. No. 15/074,820, filed on Mar. 18,
2016, published as U.S. Patent Application Publication No.
2016/0272639; and U.S. patent application Ser. No. 15/885,671,
filed on 31 Jan. 2018, are incorporated herein by reference in
their entirety. Furthermore, all references cited herein are
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0003] The description provides imide-based compounds, including
bifunctional compounds comprising the same, and associated methods
of use. The bifunctional compounds are useful as modulators of
targeted ubiquitination, especially with respect to a variety of
polypeptides and other proteins, which are degraded and/or
otherwise inhibited by bifunctional compounds according to the
present disclosure.
BACKGROUND
[0004] Most small molecule drugs bind enzymes or receptors in tight
and well-defined pockets. On the other hand, protein-protein
interactions are notoriously difficult to target using small
molecules due to their large contact surfaces and the shallow
grooves or flat interfaces involved. E3 ubiquitin ligases (of which
hundreds are known in humans) confer substrate specificity for
ubiquitination, and therefore, are more attractive therapeutic
targets than general proteasome inhibitors due to their specificity
for certain protein substrates. The development of ligands of E3
ligases has proven challenging, in part due to the fact that they
must disrupt protein-protein interactions. However, recent
developments have provided specific ligands which bind to these
ligases. For example, since the discovery of nutlins, the first
small molecule E3 ligase inhibitors, additional compounds have been
reported that target E3 ligases but the field remains
underdeveloped.
[0005] One E3 ligase with therapeutic potential is the von
Hippel-Lindau (VHL) tumor suppressor. VHL comprises the substrate
recognition subunit/E3 ligase complex VCB, which includes elongins
B and C, and a complex including Cullin-2 and Rbx1. The primary
substrate of VHL is Hypoxia Inducible Factor 1.alpha.
(HIF-1.alpha.), a transcription factor that upregulates genes such
as the pro-angiogenic growth factor VEGF and the red blood cell
inducing cytokine erythropoietin in response to low oxygen levels.
We generated the first small molecule ligands of Von Hippel Lindau
(VHL) to the substrate recognition subunit of the E3 ligase, VCB,
an important target in cancer, chronic anemia and ischemia, and
obtained crystal structures confirming that the compound mimics the
binding mode of the transcription factor HIF-1.alpha., the major
substrate of VHL.
[0006] Cereblon is a protein that in humans is encoded by the CRBN
gene. CRBN orthologs are highly conserved from plants to humans,
which underscores its physiological importance. Cereblon forms an
E3 ubiquitin ligase complex with damaged DNA binding protein 1
(DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This
complex ubiquitinates a number of other proteins. Through a
mechanism which has not been completely elucidated, cereblon
ubquitination of target proteins results in increased levels of
fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10
(FGF10). FGF8 in turn regulates a number of developmental
processes, such as limb and auditory vesicle formation. The net
result is that this ubiquitin ligase complex is important for limb
outgrowth in embryos. In the absence of cereblon, DDB1 forms a
complex with DDB2 that functions as a DNA damage-binding
protein.
[0007] Thalidomide, which has been approved for the treatment of a
number of immunological indications, has also been approved for the
treatment of certain neoplastic diseases, including multiple
myeloma. In addition to multiple myeloma, thalidomide and several
of its analogs are also currently under investigation for use in
treating a variety of other types of cancer. While the precise
mechanism of thalidomide's anti-tumor activity is still emerging,
it is known to inhibit angiogenesis. Recent literature discussing
the biology of the imides includes Lu et al Science 343, 305 (2014)
and Kronke et al Science 343, 301 (2014).
[0008] Significantly, thalidomide and its analogs e.g.
pomolinamiode and lenalinomide, are known to bind cereblon. These
agents bind to cereblon, altering the specificity of the complex to
induce the ubiquitination and degradation of Ikaros (IKZF1) and
Aiolos (IKZF3), transcription factors essential for multiple
myeloma growth. Indeed, higher expression of cereblon has been
linked to an increase in efficacy of imide drugs in the treatment
of multiple myeloma.
[0009] An ongoing need exists in the art for effective treatments
for disease, especially hyperplasias and cancers, such as multiple
myeloma. However, non-specific effects, and the inability to target
and modulate certain classes of proteins altogether, such as
transcription factors, remain as obstacles to the development of
effective anti-cancer agents. As such, small molecule therapeutic
agents that leverage or potentiate cereblon's substrate specificity
and, at the same time, are "tunable" such that a wide range of
protein classes can be targetted and modulated with specificity
would be very useful as a therapeutic.
BRIEF SUMMARY OF THE INVENTION
[0010] The present disclosure describes bifunctional compounds
which function to recruit endogenous proteins to an E3 Ubiquitin
Ligase for degradation, and methods of using the same. In
particular, the present disclosure provides bifunctional or
proteolysis targeting chimeric (PROTAC) compounds, which find
utility as modulators of targeted ubiquitination of a variety of
polypeptides and other proteins, which are then degraded and/or
otherwise inhibited by the bifunctional compounds as described
herein. An advantage of the compounds provided herein is that a
broad range of pharmacological activities is possible, consistent
with the degradation/inhibition of targeted polypeptides from
virtually any protein class or family. In addition, the description
provides methods of using an effective amount of the compounds as
described herein for the treatment or amelioration of a disease
condition, such as cancer, e.g., multiple myeloma.
[0011] As such, in one aspect the disclosure provides novel
imide-based compounds as described herein.
[0012] In an additional aspect, the disclosure provides
bifunctional or PROTAC compounds, which comprise an E3 Ubiquitin
Ligase binding moiety (i.e., a ligand for an E3 Ubiquitin Ligase or
"ULM" group), and a moiety that binds a target protein (i.e., a
protein/polypeptide targeting ligand or "PTM" group) such that the
target protein/polypeptide is placed in proximity to the ubiquitin
ligase to effect degradation (and inhibition) of that protein. In a
preferred embodiment, the ULM is a cereblon E3 Ubiquitin Ligase
binding moiety (i.e., a "CLM"). For example, the structure of the
bifunctional compound can be depicted as:
[0013] The respective positions of the PTM and CLM moieties as well
as their number as illustrated herein is provided by way of example
only and is not intended to limit the compounds in any way. As
would be understood by the skilled artisan, the bifunctional
compounds as described herein can be synthesized such that the
number and position of the respective functional moieties can be
varied as desired.
[0014] In certain embodiments, the bifunctional compound further
comprises a chemical linker ("L"). In this example, the structure
of the bifunctional compound can be depicted as:
where PTM is a protein/polypeptide targeting moiety, L is a linker,
and CLM is a cereblon E3 ubiquitin ligase binding moiety.
[0015] In certain preferred embodiments, the E3 Ubiquitin Ligase is
cereblon. As such, in certain additional embodiments, the CLM of
the bifunctional compound comprises chemistries such as imide,
amide, thioamide, thioimide derived moieties. In additional
embodiments, the CLM comprises a phthalimido group or an analog or
derivative thereof. In still additional embodiments, the CLM
comprises a phthalimido-glutarimide group or an analog or
derivative thereof. In still other embodiments, the CLM comprises a
member of the group consisting of thalidomide, lenalidomide,
pomalidomide, and analogs or derivatives thereof.
[0016] In certain embodiments, the compounds as described herein
comprise multiple CLMs, multiple PTMs, multiple chemical linkers or
a combination thereof.
[0017] In any aspect or embodiment described herein, the ULM
(ubiquitination ligase modulator) can be Von Hippel-Lindau E3
ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3
ubiquitin ligase binding moiety (CLM), or a mouse double minute 2
homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP
E3 ubiquitin ligase binding moiety (i.e., a "ILM"). In any aspect
or embodiments described herein, the bifunctional compound includes
at least one additional E3 ligase binding moiety selected from the
group consisting of VLM, VLM', CLM, CLM', MLM, MLM', ILM, ILM', or
a combination thereof. For example, there can be at least 1, 2, 3,
4, or 5 additional E3 ligase binding moieties.
[0018] In an additional aspect, the description provides
therapeutic compositions comprising an effective amount of a
compound as described herein or salt form thereof, and a
pharmaceutically acceptable carrier. The therapeutic compositions
modulate protein degradation in a patient or subject, for example,
an animal such as a human, and can be used for treating or
ameliorating disease states or conditions which are modulated
through the degraded protein. In certain embodiments, the
therapeutic compositions as described herein may be used to
effectuate the degradation of proteins of interest for the
treatment or amelioration of a disease, e.g., cancer. In yet
another aspect, the present disclosure provides a method of
ubiquitinating/degrading a target protein in a cell. In certain
embodiments, the method comprises administering a bifunctional
compound as described herein comprising an CLM and a PTM,
preferably linked through a linker moiety, as otherwise described
herein, wherein the CLM is coupled to the PTM and wherein the CLM
recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase,
preferably an E3 ubiquitin ligase such as, e.g., cereblon) and the
PTM recognizes the target protein such that degradation of the
target protein will occur when the target protein is placed in
proximity to the ubiquitin ligase, thus resulting in
degradation/inhibition of the effects of the target protein and the
control of protein levels. The control of protein levels afforded
by the present disclosure provides treatment of a disease state or
condition, which is modulated through the target protein by
lowering the level of that protein in the cells of a patient.
[0019] In an additional aspect, the description provides a method
for assessing (i.e., determining and/or measuring) a CLM's binding
affinity. In certain embodiments, the method comprises providing a
test agent or compound of interest, for example, an agent or
compound having an imide moiety, e.g., a phthalimido group,
phthalimido-glutarimide group, derivatized thalidomide, derivatized
lenalidomide or derivatized pomalidomide, and comparing the
cereblon binding affinity and/or inhibitory activity of the test
agent or compound as compared to an agent or compound known to bind
and/or inhibit the activity of cereblon.
[0020] In still another aspect, the description provides methods
for treating or emeliorating a disease, disorder or symptom thereof
in a subject or a patient, e.g., an animal such as a human,
comprising administering to a subject in need thereof a composition
comprising an effective amount, e.g., a therapeutically effective
amount, of a compound as described herein or salt form thereof, and
a pharmaceutically acceptable carrier, wherein the composition is
effective for treating or ameliorating the disease or disorder or
symptom thereof in the subject.
[0021] In another aspect, the description provides methods for
identifying the effects of the degradation of proteins of interest
in a biological system using compounds according to the present
disclosure.
[0022] The preceding general areas of utility are given by way of
example only and are not intended to be limiting on the scope of
the present disclosure and appended claims. Additional objects and
advantages associated with the compositions, methods, and processes
of the present disclosure will be appreciated by one of ordinary
skill in the art in light of the instant claims, description, and
examples. For example, the various aspects and embodiments of the
invention may be utilized in numerous combinations, all of which
are expressly contemplated by the present description. These
additional advantages objects and embodiments are expressly
included within the scope of the present disclosure. The
publications and other materials used herein to illuminate the
background of the invention, and in particular cases, to provide
additional details respecting the practice, are incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The accompanying drawings, which are incorporated into and
form a part of the specification, illustrate several embodiments of
the present disclosure and, together with the description, serve to
explain the principles of the invention. The drawings are only for
the purpose of illustrating an embodiment of the invention and are
not to be construed as limiting the invention. Further objects,
features and advantages of the invention will become apparent from
the following detailed description taken in conjunction with the
accompanying figures showing illustrative embodiments of the
invention, in which:
[0024] FIGS. 1A and 1B. Illustration of general principle for
PROTAC function. (A) Exemplary PROTACs comprise a protein targeting
moiety (PTM; darkly shaded rectangle), a ubiquitin ligase binding
moiety (ULM; lightly shaded triangle), and optionally a linker
moiety (L; black line) coupling or tethering the PTM to the ULM.
(B) Illustrates the functional use of the PROTACs as described
herein. Briefly, the ULM recognizes and binds to a specific E3
Ubiquitin Ligase, and the PTM binds and recruits a target protein
bringing it into close proximity to the E3 Ubiquitin Ligase.
Typically, the E3 Ubiquitin Ligase is complexed with an E2
ubiquitin-conjugating protein, and either alone or via the E2
protein catalyzes attachment of ubiquitin (dark circles) to a
lysine on the target protein via an isopeptide bond. The
poly-ubiquitinated protein (far right) is then targeted for
degration by the proteosomal machinery of the cell.
DETAILED DESCRIPTION
[0025] The following is a detailed description provided to aid
those skilled in the art in practicing the present disclosure.
Those of ordinary skill in the art may make modifications and
variations in the embodiments described herein without departing
from the spirit or scope of the present disclosure. All
publications, patent applications, patents, figures and other
references mentioned herein are expressly incorporated by reference
in their entirety.
[0026] Presently described are compositions and methods that relate
to the surprising and unexpected discovery that an E3 Ubiquitin
Ligase protein, e.g., cereblon, ubiquitinates a target protein once
it and the target protein are placed in proximity by a bifunctional
or chimeric construct that binds the E3 Ubiquitin Ligase protein
and the target protein. Accordingly the present disclosure provides
such compounds and compositions comprising an E3 Ubiquintin Ligase
binding moiety ("ULM") coupled to a protein target binding moiety
("PTM"), which result in the ubiquitination of a chosen target
protein, which leads to degradation of the target protein by the
proteasome (see FIGS. 1A and 1B). The present disclosure also
provides a library of compositions and the use thereof.
[0027] In certain aspects, the present disclosure provides
compounds which comprise a ligand, e.g., a small molecule ligand
(i.e., having a molecular weight of below 2,000, 1,000, 500, or 200
Daltons), which is capable of binding to a ubiquitin ligase, such
as IAP, VHL, MDM2, or cereblon. The compounds also comprise a
moiety that is capable of binding to target protein, in such a way
that the target protein is placed in proximity to the ubiquitin
ligase to effect degradation (and/or inhibition) of that protein.
Small molecule can mean, in addition to the above, that the
molecule is non-peptidyl, that is, it is not generally considered a
peptide, e.g., comprises fewer than 4, 3, or 2 amino acids. In
accordance with the present description, the PTM, ULM or PROTAC
molecule can be a small molecule.
[0028] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. The
terminology used in the description is for describing particular
embodiments only and is not intended to be limiting of the
invention.
[0029] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise (such as in the case
of a group containing a number of carbon atoms in which case each
carbon atom number falling within the range is provided), between
the upper and lower limit of that range and any other stated or
intervening value in that stated range is encompassed within the
invention. The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either both of those included limits
are also included in the invention.
[0030] The following terms are used to describe the present
invention. In instances where a term is not specifically defined
herein, that term is given an art-recognized meaning by those of
ordinary skill applying that term in context to its use in
describing the present invention.
[0031] The articles "a" and "an" as used herein and in the appended
claims are used herein to refer to one or to more than one (i.e.,
to at least one) of the grammatical object of the article unless
the context clearly indicates otherwise. By way of example, "an
element" means one element or more than one element.
[0032] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0033] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of."
[0034] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
[0035] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from anyone or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
nonlimiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0036] It should also be understood that, in certain methods
described herein that include more than one step or act, the order
of the steps or acts of the method is not necessarily limited to
the order in which the steps or acts of the method are recited
unless the context indicates otherwise.
[0037] The terms "co-administration" and "co-administering" or
"combination therapy" refer to both concurrent administration
(administration of two or more therapeutic agents at the same time)
and time varied administration (administration of one or more
therapeutic agents at a time different from that of the
administration of an additional therapeutic agent or agents), as
long as the therapeutic agents are present in the patient to some
extent, preferably at effective amounts, at the same time. In
certain preferred aspects, one or more of the present compounds
described herein, are coadministered in combination with at least
one additional bioactive agent, especially including an anticancer
agent. In particularly preferred aspects, the co-administration of
compounds results in synergistic activity and/or therapy, including
anticancer activity.
[0038] The term "compound", as used herein, unless otherwise
indicated, refers to any specific chemical compound disclosed
herein and includes tautomers, regioisomers, geometric isomers, and
where applicable, stereoisomers, including optical isomers
(enantiomers) and other stereoisomers (diastereomers) thereof, as
well as pharmaceutically acceptable salts and derivatives,
including prodrug and/or deuterated forms thereof where applicable,
in context. Deuterated small molecules contemplated are those in
which one or more of the hydrogen atoms contained in the drug
molecule have been replaced by deuterium.
[0039] Within its use in context, the term compound generally
refers to a single compound, but also may include other compounds
such as stereoisomers, regioisomers and/or optical isomers
(including racemic mixtures) as well as specific enantiomers or
enantiomerically enriched mixtures of disclosed compounds. The term
also refers, in context to prodrug forms of compounds which have
been modified to facilitate the administration and delivery of
compounds to a site of activity. It is noted that in describing the
present compounds, numerous substituents and variables associated
with same, among others, are described. It is understood by those
of ordinary skill that molecules which are described herein are
stable compounds as generally described hereunder. When the bond is
shown, both a double bond and single bond are represented or
understood within the context of the compound shown and well-known
rules for valence interactions.
[0040] The term "Ubiquitin Ligase" refers to a family of proteins
that facilitate the transfer of ubiquitin to a specific substrate
protein, targeting the substrate protein for degradation. For
example, cereblon is an E3 Ubiquitin Ligase protein that alone or
in combination with an E2 ubiquitin-conjugating enzyme causes the
attachment of ubiquitin to a lysine on a target protein, and
subsequently targets the specific protein substrates for
degradation by the proteasome. Thus, E3 ubiquitin ligase alone or
in complex with an E2 ubiquitin conjugating enzyme is responsible
for the transfer of ubiquitin to targeted proteins. In general, the
ubiquitin ligase is involved in polyubiquitination such that a
second ubiquitin is attached to the first; a third is attached to
the second, and so forth. Polyubiquitination marks proteins for
degradation by the proteasome. However, there are some
ubiquitination events that are limited to mono-ubiquitination, in
which only a single ubiquitin is added by the ubiquitin ligase to a
substrate molecule. Mono-ubiquitinated proteins are not targeted to
the proteasome for degradation, but may instead be altered in their
cellular location or function, for example, via binding other
proteins that have domains capable of binding ubiquitin. Further
complicating matters, different lysines on ubiquitin can be
targeted by an E3 to make chains. The most common lysine is Lys48
on the ubiquitin chain. This is the lysine used to make
polyubiquitin, which is recognized by the proteasome.
[0041] The term "patient" or "subject" is used throughout the
specification to describe an animal, preferably a human or a
domesticated animal, to whom treatment, including prophylactic
treatment, with the compositions according to the present
disclosure is provided. For treatment of those infections,
conditions or disease states which are specific for a specific
animal such as a human patient, the term patient refers to that
specific animal, including a domesticated animal such as a dog or
cat or a farm animal such as a horse, cow, sheep, etc. In general,
in the present disclosure, the term patient refers to a human
patient unless otherwise stated or implied from the context of the
use of the term.
[0042] The term "effective" is used to describe an amount of a
compound, composition or component which, when used within the
context of its intended use, effects an intended result. The term
effective subsumes all other effective amount or effective
concentration terms, which are otherwise described or used in the
present application.
Compounds and Compositions
[0043] In one aspect, the description provides compounds comprising
an E3 Ubiquitin Ligase binding moiety ("ULM") that is a cereblon E3
Ubiquitin Ligase binding moiety ("CLM"). In one embodiment, the CLM
is coupled to a chemical linker (L) according to the structure:
L-CLM (I)
wherein L is a chemical linker group and CLM is a cereblon E3
Ubiquitin Ligase binding moiety. The number and/or relative
positions of the moieties in the compounds illustrated herein is
provided by way of example only. As would be understood by the
skilled artisan, compounds as described herein can be synthesized
with any desired number and/or relative position of the respective
functional moieties.
[0044] The terms ULM and CLM are used in their inclusive sense
unless the context indicates otherwise. For example, the term ULM
is inclusive of all ULMs, including those that bind cereblon (i.e.,
CLMs). Further, the term CLM is inclusive of all possible cereblon
E3 Ubiquitin Ligase binding moieties.
[0045] In another aspect, the present disclosure provides
bifunctional or multifunctional PROTAC compounds useful for
regulating protein activity by inducing the degradation of a target
protein. In certain embodiments, the compound comprises a CLM
coupled, e.g., linked covalently, directly or indirectly, to a
moiety that binds a target protein (i.e., protein targeting moiety
or "PTM"). In certain embodiments, the CLM and PTM are joined or
coupled via a chemical linker (L). The CLM recognizes the cereblon
E3 ubiquitin ligase and the PTM recognizes a target protein and the
interaction of the respective moieties with their targets
facilitates the degradation of the target protein by placing the
target protein in proximity to the ubiquitin ligase protein. An
exemplary bifunctional compound can be depicted as:
PTM-CLM (II)
[0046] In certain embodiments, the bifunctional compound further
comprises a chemical linker ("L"). For example, the bifunctional
compound can be depicted as:
PTM-L-CLM (III)
wherein PTM is a protein/polypeptide targeting moiety, L is a
linker, and CLM is a cereblon E3 ligase binding moiety.
[0047] In certain embodiments, the compounds as described herein
comprise multiple PTMs (targeting the same or different protein
targets), multiple CLMs, one or more ULMs (i.e., moieties that bind
specifically to another E3 Ubiquitin Ligase, e.g., VHL) or a
combination thereof. In any of the aspects of embodiments described
herein, the PTMs, CLMs, and ULMs can be coupled directly or via one
or more chemical linkers or a combination thereof. In additional
embodiments, where a compound has multiple ULMs, the ULMs can be
for the same E3 Ubiquintin Ligase or each respective ULM can bind
specifically to a different E3 Ubiquitin Ligase. In still further
embodiments, where a compound has multiple PTMs, the PTMs can bind
the same target protein or each respective PTM can bind
specifically to a different target protein.
[0048] In another embodiment, the description provides a compound
which comprises a plurality of CLMs coupled directly or via a
chemical linker moiety (L). For example, a compound having two CLMs
can be depicted as:
CLM-CLM or (IV)
CLM-L-CLM (V)
[0049] In certain embodiments, where the compound comprises
multiple CLMs, the CLMs are identical. In additional embodiments,
the compound comprising a plurality of CLMs further comprises at
least one PTM coupled to a CLM directly or via a chemical linker
(L) or both. In certain additional embodiments, the compound
comprising a plurality of CLMs further comprises multiple PTMs. In
still additional embodiments, the PTMs are the same or, optionally,
different. In still further embodiments, wherein the PTMs are
different the respective PTMs may bind the same protein target or
bind specifically to a different protein target.
[0050] In additional embodiments, the description provides a
compound comprising at least two different CLMs coupled directly or
via a chemical linker (L) or both. For example, such a compound
having two different CLMs can be depicted as:
CLM-CLM' or (VI)
CLM-L-CLM' (VII)
wherein CLM' indicates a cereblon E3 Ubiquitin Ligase binding
moiety that is structurally different from CLM. In certain
embodiments, the compound may comprise a plurality of CLMs and/or a
plurality of CLM's. In further embodiments, the compound comprising
at least two different CLMs, a plurality of CLMs, and/or a
plurality of CLM's further comprises at least one PTM coupled to a
CLM or a CLM' directly or via a chemical linker or both. In any of
the embodiments described herein, a compound comprising at least
two different CLMs can further comprise multiple PTMs. In still
additional embodiments, the PTMs are the same or, optionally,
different. In still further embodiments, wherein the PTMs are
different the respective PTMs may bind the same protein target or
bind specifically to a different protein target. In still further
embodiments, the PTM itself is a ULM or CLM (or ULM' or CLM').
[0051] In a preferred embodiment, the CLM comprises a moiety that
is a ligand of the cereblon E3 Ubiquitin Ligase (CRBN). In certain
embodiments, the CLM comprises a chemotype from the "imide" class
of of molecules. In certain additional embodiments, the CLM
comprises a phthalimido group or an analog or derivative thereof.
In still additional embodiments, the CLM comprises a
phthalimido-glutarimide group or an analog or derivative thereof.
In still other embodiments, the CLM comprises a member of the group
consisting of thalidomide, lenalidomide, pomalidomide, and analogs
or derivatives thereof.
[0052] In additional embodiments, the description provides the
compounds as described herein including their enantiomers,
diastereomers, solvates and polymorphs, including pharmaceutically
acceptable salt forms thereof, e.g., acid and base salt forms.
[0053] Exemplary Cereblon Binding and/or Inhibiting Compounds
[0054] In one aspect the description provides compounds useful for
binding and/or inhibiting cereblon E3 Ubiquitin Ligase binding
moiety. In certain embodiments, the compound has a chemical
structure that includes at least one of (e.g., the compound has a
chemical structure selected from the group consisting of):
[0055] Neo-Imide Compounds
[0056] In one aspect the description provides compounds useful for
binding and/or inhibiting cereblon. In certain embodiments, the
compound is selected from the group consisting of chemical
structures:
##STR00001##
wherein: [0057] W of Formulas (a) through (e) is independently
selected from the group CH.sub.2, CHR, C.dbd.O, SO.sub.2, NH,
cyclopropyl group, cyclobutyl group, and N-alkyl; [0058] W.sub.3 is
selected from C or N; [0059] X of Formulas (a) through (e) is
independently selected from the group O, S and H.sub.2, [0060] Y of
Formulas (a) through (e) is independently selected from the group
CH.sub.2, --C.dbd.CR', NH, N-alkyl, N-aryl, N-hetaryl,
N-cycloalkyl, N-heterocyclyl, O, and S; [0061] Z of Formulas (a)
through (e) is independently selected from the group O, and S or
H.sub.2 except that both X and Z cannot be H.sub.2, [0062] G and G'
of Formulas (a) through (e) are independently selected from the
group H, alkyl (linear, branched, optionally substituted), OH,
R'OCOOR, R'OCONRR'', CH.sub.2-heterocyclyl optionally substituted
with R', and benzyl optionally substituted with R'; [0063] Q1-Q4 of
Formulas (a) through (e) represent a carbon C substituted with a
group independently selected from R', N or N-oxide; [0064] A of
Formulas (a) through (e) is independently selected from the group
H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl
and F; [0065] R of Formulas (a) through (e) comprises, but is not
limited to: --CONR'R'', --OR', --NR'R'', --SR', --SO.sub.2R',
--SO.sub.2NR'R'', --CR'R''--, --CR'NR'R''--, (--CR'O).sub.n'R'',
-aryl, -hetaryl, -alkyl (linear, branched, optionally substituted),
-cycloalkyl, -heterocyclyl, --P(O)(OR')R'', --P(O)R'R'',
--OP(O)(OR')R'', --OP(O)R'R'', --Cl, --F, --Br, --I, --CF.sub.3,
--CN, --NR'SO.sub.2NR'R'', --NR'CONR'R'', --CONR'COR'',
--NR'C(.dbd.N--CN)NR'R'', --C(.dbd.N--CN)NR'R'',
--NR'C(.dbd.N--CN)R'', --NR'C(.dbd.C--NO.sub.2)NR'R'',
--SO.sub.2NR'COR'', --NO.sub.2, --CO.sub.2R', --C(C.dbd.N--OR')R'',
--CR'.dbd.CR'R'', --CCR', --S(C.dbd.O)(C.dbd.N--R')R'', --SF.sub.5
and --OCF.sub.3 [0066] R' and R'' of Formulas (a) through (e) are
independently selected from a bond, H, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclic, --C(.dbd.O)R, heterocyclyl, each of which
is optionally substituted; [0067] n' of Formulas (a) through (e) is
an integer from 1-10 (e.g., 1-4); [0068] of Formulas (a) through
(e) represents a bond that may be stereospecific ((R) or (S)) or
non-stereospecific; [0069] represents a single bond or a double
bond; [0070] represents a bond that may be stereospecific ((R) or
(S)) or non-stereospecific; and [0071] Rn comprises 1-4 independent
functional groups, optionally substituted linear or branched alkyl
(e.g., a C1-C6 linear or branched alkyl optionally substituted with
one or more halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl
(e.g., C5-C7 aryl)), optionally substituted aryl (e.g., an
optionally substituted C5-C7 aryl), optionally substituted
alkyl-aryl (e.g., an alkyl-aryl comprising at least one of an
optionally substituted C1-C6 alkyl, an optionally substituted C5-C7
aryl, or combinations thereof), optionally substituted alkoxyl
group (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or
hexoxy; wherein the alkoxyl may be substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
##STR00002##
[0071] (e.g., optionally substituted with one or more halogen,
alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
##STR00003##
(e.g., optionally substituted with one or more halogen, alkyl,
haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or
aryl (e.g., C5-C7 aryl)), or atoms; and each of x, y, and z are
independently 0, 1, 2, 3, 4, 5, or 6,
[0072] Exemplary CLMs
[0073] In any of the compounds described herein, the CLM comprises
a chemical structure selected from the group:
##STR00004##
wherein: [0074] W of Formulas (a) through (e) is independently
selected from the group CH.sub.2, CHR, C.dbd.O, SO.sub.2, NH, N,
optionally substituted cyclopropyl group, optionally substituted
cyclobutyl group, and N-alkyl; [0075] W.sub.3 is selected from C or
N; [0076] X of Formulas (a) through (e) is independently selected
from the group O, S and H.sub.2; [0077] Y of Formulas (a) through
(e) is independently selected from the group CH2, --C.dbd.CR', NH,
N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
[0078] Z of Formulas (a) through (e) is independently selected from
the group O, and S or H2 except that both X and Z cannot be H2;
[0079] G and G' of Formulas (a) through (e) are independently
selected from the group H, alkyl (linear, branched), OH, R'OCOOR,
R'OCONRR'', CH.sub.2-heterocyclyl optionally substituted with R',
and benzyl optionally substituted with R'; [0080] Q1-Q4 of Formulas
(a) through (e) represent a carbon C substituted with a group
independently selected from R', N or N-oxide; [0081] A of Formulas
(a) through (e) is independently selected from the group H, alkyl
(linear, branched, optionally substituted), cycloalkyl, Cl and F;
[0082] R of Formulas (a) through (e) comprises, but is not limited
to: --CONR'R'', --OR', --NR'R'', --SR', --SO2R', --SO2NR'R'',
--CR'R''--, --CR'NR'R''--, (--CR'O).sub.n'R'', -aryl, -hetaryl,
-alkyl (linear, branched, optionally substituted), -cycloalkyl,
-heterocyclyl, --P(O)(OR')R'', --P(O)R'R'', --OP(O)(OR')R'',
--OP(O)R'R'', --Cl, --F, --Br, --I, --CF3, --CN, --NR'SO2NR'R'',
--NR'CONR'R'', --CONR'COR'', --NR'C(.dbd.N--CN)NR'R'',
--C(.dbd.N--CN)NR'R'', --NR'C(.dbd.N--CN)R'',
--NR'C(.dbd.C--NO2)NR'R'', --SO2NR'COR'', --NO2, --CO2R',
--C(C.dbd.N--OR')R'', --CR'.dbd.CR'R'', --CCR',
--S(C.dbd.O)(C.dbd.N--R')R'', --SF5 and --OCF3 [0083] R' and R'' of
Formulas (a) through (e) are independently selected from a bond, H,
alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, --C(.dbd.O)R,
heterocyclyl, each of which is optionally substituted; [0084] n' of
Formulas (a) through (e) is an integer from 1-10 (e.g., 1-4);
[0085] represents a single bond or a double bond; [0086] of
Formulas (a) through (e) represents a bond that may be
stereospecific ((R) or (S)) or non-stereospecific; [0087] Rn
comprises 1-4 independent functional groups, optionally substituted
linear or branched alkyl (e.g., a C1-C6 linear or branched alkyl
optionally substituted with one or more halogen, cycloalkyl (e.g.,
a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted aryl (e.g., an optionally substituted C5-C7 aryl),
optionally substituted alkyl-aryl (e.g., an alkyl-aryl comprising
at least one of an optionally substituted C1-C6 alkyl, an
optionally substituted C5-C7 aryl, or combinations thereof),
optionally substituted alkoxyl group (e.g., a methoxy, ethoxy,
butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl may be
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
##STR00005##
[0087] (e.g., optionally substituted with one or more halogen,
alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
##STR00006##
(e.g., optionally substituted with one or more halogen, alkyl,
haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or
aryl (e.g., C5-C7 aryl)), or atoms; and
[0088] each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or
6.
[0089] In certain embodiments described herein, the CLM or ULM
comprises a chemical structure selected from the group:
##STR00007##
[0090] wherein: [0091] W of Formula (g) is independently selected
from the group CH.sub.2, C.dbd.O, NH, and N-alkyl; [0092] R of
Formula (g) is independently selected from a H, methyl, alkyl
(e.g., a or C1-C6 alkyl (linear, branched, optionally
substituted)); [0093] of Formula (g) represents a bond that may be
stereospecific ((R) or (S)) or non-stereospecific; and [0094] Rn
comprises 1-4 independent functional groups, optionally substituted
linear or branched alkyl (e.g., a C1-C6 linear or branched alkyl
optionally substituted with one or more halogen, cycloalkyl (e.g.,
a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted aryl (e.g., an optionally substituted C5-C7 aryl),
optionally substituted alkyl-aryl (e.g., an alkyl-aryl comprising
at least one of an optionally substituted C1-C6 alkyl, an
optionally substituted C5-C7 aryl, or combinations thereof),
optionally substituted alkoxyl group (e.g., a methoxy, ethoxy,
butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl may be
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
##STR00008##
[0094] (e.g., optionally substituted with one or more halogen,
alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
##STR00009##
(e.g., optionally substituted with one or more halogen, alkyl,
haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or
aryl (e.g., C5-C7 aryl)), or atoms.
[0095] In any of the embodiments described herein, the W, X, Y, Z,
G, G', R, R', R'', Q1-Q4, A, and Rn of Formulas (a) through (g) can
independently be covalently coupled to a linker and/or a linker to
which is attached one or more PTM, ULM, CLM or CLM' groups.
[0096] More specifically, non-limiting examples of CLMs include
those shown below as well as those "hybrid" molecules that arise
from the combination of 1 or more of the different features shown
in the molecules below.
##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## ##STR00027## ##STR00028##
[0097] The term "independently" is used herein to indicate that the
variable, which is independently applied, varies independently from
application to application.
[0098] The term "alkyl" shall mean within its context a linear,
branch-chained or cyclic fully saturated hydrocarbon radical or
alkyl group, preferably a C.sub.1-C.sub.10, more preferably a
C.sub.1-C.sub.6, alternatively a C.sub.1-C.sub.3 alkyl group, which
may be optionally substituted. Examples of alkyl groups are methyl,
ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,
n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,
cyclobutyl, cyclopentyl, cyclopen-tylethyl, cyclohexylethyl and
cyclohexyl, among others. In certain embodiments, the alkyl group
is end-capped with a halogen group (At, Br, Cl, F, or I). In
certain preferred embodiments, compounds according to the present
disclosure which may be used to covalently bind to dehalogenase
enzymes. These compounds generally contain a side chain (often
linked through a polyethylene glycol group) which terminates in an
alkyl group which has a halogen substituent (often chlorine or
bromine) on its distal end which results in covalent binding of the
compound containing such a moiety to the protein.
[0099] The term "Alkoxy" refers to an alkyl group singularly bonded
to oxygen.
[0100] The term "Alkenyl" refers to linear, branch-chained or
cyclic C.sub.2-C.sub.10 (preferably C.sub.2-C.sub.6) hydrocarbon
radicals containing at least one C.dbd.C bond.
[0101] The term "Alkynyl" refers to linear, branch-chained or
cyclic C.sub.2-C.sub.10 (preferably C.sub.2-C.sub.6) hydrocarbon
radicals containing at least one C.ident.C bond.
[0102] The term "alkylene" when used, refers to a
--(CH.sub.2).sub.n-- group (n is an integer generally from 0-6),
which may be optionally substituted. When substituted, the alkylene
group preferably is substituted on one or more of the methylene
groups with a C.sub.1-C.sub.6 alkyl group (including a cyclopropyl
group or a t-butyl group), but may also be substituted with one or
more halo groups, preferably from 1 to 3 halo groups or one or two
hydroxyl groups, O--(C.sub.1-C.sub.6 alkyl) groups or amino acid
sidechains as otherwise disclosed herein. In certain embodiments,
an alkylene group may be substituted with a urethane or alkoxy
group (or other group) which is further substituted with a
polyethylene glycol chain (of from 1 to 10, preferably 1 to 6,
often 1 to 4 ethylene glycol units) to which is substituted
(preferably, but not exclusively on the distal end of the
polyethylene glycol chain) an alkyl chain substituted with a single
halogen group, preferably a chlorine group. In still other
embodiments, the alkylene (often, a methylene) group, may be
substituted with an amino acid sidechain group such as a sidechain
group of a natural or unnatural amino acid, for example, alanine,
.beta.-alanine, arginine, asparagine, aspartic acid, cysteine,
cystine, glutamic acid, glutamine, glycine, phenylalanine,
histidine, isoleucine, lysine, leucine, methionine, proline,
serine, threonine, valine, tryptophan or tyrosine.
[0103] The term "unsubstituted" shall mean substituted only with
hydrogen atoms. A range of carbon atoms which includes C.sub.0
means that carbon is absent and is replaced with H. Thus, a range
of carbon atoms which is C.sub.0-C.sub.6 includes carbons atoms of
1, 2, 3, 4, 5 and 6 and for C.sub.0, H stands in place of
carbon.
[0104] The term "substituted" or "optionally substituted" shall
mean independently (i.e., where more than substituent occurs, each
substituent is independent of another substituent) one or more
substituents (independently up to five substitutents, preferably up
to three substituents, often 1 or 2 substituents on a moiety in a
compound according to the present disclosure and may include
substituents which themselves may be further substituted) at a
carbon (or nitrogen) position anywhere on a molecule within
context, and includes as substituents hydroxyl, thiol, carboxyl,
cyano (C.ident.N), nitro (NO.sub.2), halogen (preferably, 1, 2 or 3
halogens, especially on an alkyl, especially a methyl group such as
a trifluoromethyl), an alkyl group (preferably, C.sub.1-C.sub.10,
more preferably, C.sub.1-C.sub.6), aryl (especially phenyl and
substituted phenyl for example benzyl or benzoyl), alkoxy group
(preferably, C.sub.1-C.sub.6 alkyl or aryl, including phenyl and
substituted phenyl), thioether (C.sub.1-C.sub.6 alkyl or aryl),
acyl (preferably, C.sub.1-C.sub.6 acyl), ester or thioester
(preferably, C.sub.1-C.sub.6 alkyl or aryl) including alkylene
ester (such that attachment is on the alkylene group, rather than
at the ester function which is preferably substituted with a
C.sub.1-C.sub.6 alkyl or aryl group), preferably, C.sub.1-C.sub.6
alkyl or aryl, halogen (preferably, F or Cl), amine (including a
five- or six-membered cyclic alkylene amine, further including a
C.sub.1-C.sub.6 alkyl amine or a C.sub.1-C.sub.6 dialkyl amine
which alkyl groups may be substituted with one or two hydroxyl
groups) or an optionally substituted --N(C.sub.0-C.sub.6
alkyl)C(O)(O--C.sub.1-C.sub.6 alkyl) group (which may be optionally
substituted with a polyethylene glycol chain to which is further
bound an alkyl group containing a single halogen, preferably
chlorine substituent), hydrazine, amido, which is preferably
substituted with one or two C.sub.1-C.sub.6 alkyl groups (including
a carboxamide which is optionally substituted with one or two
C.sub.1-C.sub.6 alkyl groups), alkanol (preferably, C.sub.1-C.sub.6
alkyl or aryl), or alkanoic acid (preferably, C.sub.1-C.sub.6 alkyl
or aryl). Substituents according to the present disclosure may
include, for example--SiR.sub.1subR.sub.2subR.sub.3sub groups where
each of R.sub.1sub and R.sub.2sub is as otherwise described herein
and R.sub.3sub is H or a C.sub.1-C.sub.6 alkyl group, preferably
R.sub.1sub, R.sub.2sub, R.sub.3sub in this context is a
C.sub.1-C.sub.3 alkyl group (including an isopropyl or t-butyl
group). Each of the above-described groups may be linked directly
to the substituted moiety or alternatively, the substituent may be
linked to the substituted moiety (preferably in the case of an aryl
or heteraryl moiety) through an optionally substituted
--(CH.sub.2).sub.m-- or alternatively an optionally substituted
--(OCH.sub.2).sub.m--, --(OCH.sub.2CH.sub.2).sub.m-- or
--(CH.sub.2CH.sub.2O).sub.m-- group, which may be substituted with
any one or more of the above-described substituents. Alkylene
groups --(CH.sub.2).sub.m-- or --(CH.sub.2).sub.n-- groups or other
chains such as ethylene glycol chains, as identified above, may be
substituted anywhere on the chain. Preferred substitutents on
alkylene groups include halogen or C.sub.1-C.sub.6 (preferably
C.sub.1-C.sub.3) alkyl groups, which may be optionally substituted
with one or two hydroxyl groups, one or two ether groups
(O--C.sub.1-C.sub.6 groups), up to three halo groups (preferably
F), or a sidechain of an amino acid as otherwise described herein
and optionally substituted amide (preferably carboxamide
substituted as described above) or urethane groups (often with one
or two C.sub.0-C.sub.6 alkyl substitutents, which group(s) may be
further substituted). In certain embodiments, the alkylene group
(often a single methylene group) is substituted with one or two
optionally substituted C.sub.1-C.sub.6 alkyl groups, preferably
C.sub.1-C.sub.4 alkyl group, most often methyl or O-methyl groups
or a sidechain of an amino acid as otherwise described herein. In
the present disclosure, a moiety in a molecule may be optionally
substituted with up to five substituents, preferably up to three
substituents. Most often, in the present disclosure, moieties which
are substituted are substituted with one or two substituents.
[0105] The term "substituted" (each substituent being independent
of any other substituent) shall also mean within its context of use
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, amido,
carboxamido, sulfone, including sulfonamide, keto, carboxy,
C.sub.1-C.sub.6 ester (oxyester or carbonylester), C.sub.1-C.sub.6
keto, urethane --O--C(O)--NR.sub.1subR.sub.2sub or
--N(R.sub.1sub)--C(O)--R.sub.1sub, nitro, cyano and amine
(especially including a C.sub.1-C.sub.6
alkylene-NR.sub.1subR.sub.2sub, a mono- or di-C.sub.1-C.sub.6 alkyl
substituted amines which may be optionally substituted with one or
two hydroxyl groups). Each of these groups contain unless otherwise
indicated, within context, between 1 and 6 carbon atoms. In certain
embodiments, preferred substituents will include for example,
--NH--, --NHC(O)--, --O--, .dbd.O, --(CH.sub.2).sub.m-- (here, m
and n are in context, 1, 2, 3, 4, 5 or 6), --S--, --S(O)--,
SO.sub.2-- or --NH--C(O)--NH--, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.nSH, --(CH.sub.2).sub.nCOOH, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.n--C(O)--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.nOC(O)--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.nC(O)O--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.nNHC(O)--R.sub.1sub,
--(CH.sub.2).sub.nC(O)--NR.sub.1subR.sub.2sub,
--(OCH.sub.2).sub.nOH, --(CH.sub.2O).sub.nCOOH, C.sub.1-C.sub.6
alkyl, --(OCH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl),
--(OCH.sub.2).sub.nNHC(O)--R.sub.1sub,
--(CH.sub.2O).sub.nC(O)--NR.sub.1subR.sub.2sub,
--S(O).sub.2.sup.-R.sub.S, --S(O)--R.sub.S (R.sub.S is
C.sub.1-C.sub.6 alkyl or a
--(CH.sub.2).sub.m--NR.sub.1subR.sub.2sub group), NO.sub.2, CN or
halogen (F, Cl, Br, I, preferably F or Cl), depending on the
context of the use of the substituent. R.sub.1sub and R.sub.2sub
are each, within context, H or a C.sub.1-C.sub.6 alkyl group (which
may be optionally substituted with one or two hydroxyl groups or up
to three halogen groups, preferably fluorine). The term
"substituted" shall also mean, within the chemical context of the
compound defined and substituent used, an optionally substituted
aryl or heteroaryl group or an optionally substituted heterocyclic
group as otherwise described herein. Alkylene groups may also be
substituted as otherwise disclosed herein, preferably with
optionally substituted C.sub.1-C.sub.6 alkyl groups (methyl, ethyl
or hydroxymethyl or hydroxyethyl is preferred, thus providing a
chiral center), a sidechain of an amino acid group as otherwise
described herein, an amido group as described hereinabove, or a
urethane group O--C(O)--NR.sub.1subR.sub.2sub group where
R.sub.1sub and R.sub.2sub are as otherwise described herein,
although numerous other groups may also be used as substituents.
Various optionally substituted moieties may be substituted with 3
or more substituents, preferably no more than 3 substituents and
preferably with 1 or 2 substituents. It is noted that in instances
where, in a compound at a particular position of the molecule
substitution is required (principally, because of valency), but no
substitution is indicated, then that substituent is construed or
understood to be H, unless the context of the substitution suggests
otherwise.
[0106] The term "aryl" or "aromatic", in context, refers to a
substituted (as otherwise described herein) or unsubstituted
monovalent aromatic radical having a single ring (e.g., benzene,
phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl,
phenanthrenyl, etc.) and can be bound to the compound according to
the present disclosure at any available stable position on the
ring(s) or as otherwise indicated in the chemical structure
presented. Other examples of aryl groups, in context, may include
heterocyclic aromatic ring systems, "heteroaryl" groups having one
or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)
such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole,
pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring
systems such as indole, quinoline, indolizine, azaindolizine,
benzofurazan, etc., among others, which may be optionally
substituted as described above. Among the heteroaryl groups which
may be mentioned include nitrogen-containing heteroaryl groups such
as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine,
pyrazole, imidazole, triazole, triazine, tetrazole, indole,
isoindole, indolizine, azaindolizine, purine, indazole, quinoline,
dihydroquinoline, tetrahydroquinoline, isoquinoline,
dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,
phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,
acridine, phenanthridine, carbazole, carbazoline, pyrimidine,
phenanthroline, phenacene, oxadiazole, benzimidazole,
pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine;
sulfur-containing aromatic heterocycles such as thiophene and
benzothiophene; oxygen-containing aromatic heterocycles such as
furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and
aromatic heterocycles comprising 2 or more hetero atoms selected
from among nitrogen, sulfur and oxygen, such as thiazole,
thiadizole, isothiazole, benzoxazole, benzothiazole,
benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine,
pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole,
pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and
oxazole, among others, all of which may be optionally
substituted.
[0107] The term "substituted aryl" refers to an aromatic
carbocyclic group comprised of at least one aromatic ring or of
multiple condensed rings at least one of which being aromatic,
wherein the ring(s) are substituted with one or more substituents.
For example, an aryl group can comprise a substituent(s) selected
from: --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--C(O)(C.sub.0-C.sub.6) alkyl,
--(CH.sub.2).sub.n--C(O)O(C.sub.0-C.sub.6)alkyl,
--(CH.sub.2).sub.n--OC(O)(C.sub.0-C.sub.6)alkyl, amine, mono- or
di-(C.sub.1-C.sub.6 alkyl) amine wherein the alkyl group on the
amine is optionally substituted with 1 or 2 hydroxyl groups or up
to three halo (preferably F, Cl) groups, OH, COOH, C.sub.1-C.sub.6
alkyl, preferably CH.sub.3, CF.sub.3, OMe, OCF.sub.3, NO.sub.2, or
CN group (each of which may be substituted in ortho-, meta- and/or
para-positions of the phenyl ring, preferably para-), an optionally
substituted phenyl group (the phenyl group itself is preferably
substituted with a linker group attached to a PTM group, including
a ULM group), and/or at least one of F, Cl, OH, COOH, CH.sub.3,
CF.sub.3, OMe, OCF.sub.3, NO.sub.2, or CN group (in ortho-, meta-
and/or para-positions of the phenyl ring, preferably para-), a
naphthyl group, which may be optionally substituted, an optionally
substituted heteroaryl, preferably an optionally substituted
isoxazole including a methylsubstituted isoxazole, an optionally
substituted oxazole including a methylsubstituted oxazole, an
optionally substituted thiazole including a methyl substituted
thiazole, an optionally substituted isothiazole including a methyl
substituted isothiazole, an optionally substituted pyrrole
including a methylsubstituted pyrrole, an optionally substituted
imidazole including a methylimidazole, an optionally substituted
benzimidazole or methoxybenzylimidazole, an optionally substituted
oximidazole or methyloximidazole, an optionally substituted diazole
group, including a methyldiazole group, an optionally substituted
triazole group, including a methylsubstituted triazole group, an
optionally substituted pyridine group, including a
halo-(preferably, F) or methylsubstitutedpyridine group or an
oxapyridine group (where the pyridine group is linked to the phenyl
group by an oxygen), an optionally substituted furan, an optionally
substituted benzofuran, an optionally substituted
dihydrobenzofuran, an optionally substituted indole, indolizine or
azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted
quinoline, and combinations thereof.
[0108] "Carboxyl" denotes the group --C(O)OR, where R is hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or
substituted heteroaryl, whereas these generic substituents have
meanings which are identical with definitions of the corresponding
groups defined herein.
[0109] The term "heteroaryl" or "hetaryl" can mean but is in no way
limited to an optionally substituted quinoline (which may be
attached to the pharmacophore or substituted on any carbon atom
within the quinoline ring), an optionally substituted indole
(including dihydroindole), an optionally substituted indolizine, an
optionally substituted azaindolizine (2, 3 or 4-azaindolizine) an
optionally substituted benzimidazole, benzodiazole, benzoxofuran,
an optionally substituted imidazole, an optionally substituted
isoxazole, an optionally substituted oxazole (preferably methyl
substituted), an optionally substituted diazole, an optionally
substituted triazole, a tetrazole, an optionally substituted
benzofuran, an optionally substituted thiophene, an optionally
substituted thiazole (preferably methyl and/or thiol substituted),
an optionally substituted isothiazole, an optionally substituted
triazole (preferably a 1,2,3-triazole substituted with a methyl
group, a triisopropylsilyl group, an optionally substituted
--(CH.sub.2).sub.m--O--C.sub.1-C.sub.6 alkyl group or an optionally
substituted --(CH.sub.2).sub.m--C(O)--O--C.sub.1-C.sub.6 alkyl
group), an optionally substituted pyridine (2-, 3, or 4-pyridine)
or a group according to the chemical structure:
##STR00029##
[0110] wherein [0111] S.sup.c is CHR.sup.SS, NR.sup.URE, or O;
[0112] R.sup.HET is H, CN, NO.sub.2, halo (preferably Cl or F),
optionally substituted C.sub.1-C.sub.6 alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo
groups (e.g. CF.sub.3), optionally substituted O(C.sub.1-C.sub.6
alkyl) (preferably substituted with one or two hydroxyl groups or
up to three halo groups) or an optionally substituted acetylenic
group --C.ident.C--R.sub.a where R.sub.a is H or a C.sub.1-C.sub.6
alkyl group (preferably C.sub.1-C.sub.3 alkyl); [0113] R.sup.SS is
H, CN, NO.sub.2, halo (preferably F or Cl), optionally substituted
C.sub.1-C.sub.6 alkyl (preferably substituted with one or two
hydroxyl groups or up to three halo groups), optionally substituted
O--(C.sub.1-C.sub.6 alkyl) (preferably substituted with one or two
hydroxyl groups or up to three halo groups) or an optionally
substituted --C(O)(C.sub.1-C.sub.6 alkyl) (preferably substituted
with one or two hydroxyl groups or up to three halo groups); [0114]
R.sup.URE is H, a C.sub.1-C.sub.6 alkyl (preferably H or
C.sub.1-C.sub.3 alkyl) or a --C(O)(C.sub.1-C.sub.6 alkyl), each of
which groups is optionally substituted with one or two hydroxyl
groups or up to three halogen, preferably fluorine groups, or an
optionally substituted heterocycle, for example piperidine,
morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
piperidine, piperazine, each of which is optionally substituted,
and [0115] Y.sup.C is N or C--R.sup.YC, where R.sup.YC is H, OH,
CN, NO.sub.2, halo (preferably Cl or F), optionally substituted
C.sub.1-C.sub.6 alkyl (preferably substituted with one or two
hydroxyl groups or up to three halo groups (e.g. CF.sub.3),
optionally substituted O(C.sub.1-C.sub.6 alkyl) (preferably
substituted with one or two hydroxyl groups or up to three halo
groups) or an optionally substituted acetylenic group
--C.ident.C--R.sub.a where R.sub.a is H or a C.sub.1-C.sub.6 alkyl
group (preferably C.sub.1-C.sub.3 alkyl).
[0116] The term "Heterocycle" refers to a cyclic group which
contains at least one heteroatom, e.g., N, O or S, and may be
aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl
moieties are subsumed under the definition of heterocycle,
depending on the context of its use. Exemplary heteroaryl groups
are described hereinabove.
[0117] Exemplary heterocyclics include: azetidinyl, benzimidazolyl,
1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,
benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,
dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,
1,4-dioxane, fury, homopiperidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, indolinyl, indolyl, isoquinolinyl,
isothiazolidinyl, isothiazoyl, isoxazolidinyl, isoxazolyl,
morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone,
2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl,
piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
quinolinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl,
tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiane among
others.
[0118] Heterocyclic groups can be optionally substituted with a
member selected from the group consisting of alkoxy, substituted
alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,
substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido,
cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SOaryl,
--SO-heteroaryl, --SO2-alkyl, --SO2-substituted alkyl, --SO2-aryl,
oxo (.dbd.O), and --SO2-heteroaryl. Such heterocyclic groups can
have a single ring or multiple condensed rings. Examples of
nitrogen heterocycles and heteroaryls include, but are not limited
to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,
pyridazine, indolizine, isoindole, indole, indazole, purine,
quinolizine, isoquinoline, quinoline, phthalazine,
naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,
carbazole, carboline, phenanthridine, acridine, phenanthroline,
isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,
imidazolidine, imidazoline, piperidine, piperazine, indoline,
morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as
N-alkoxy-nitrogen containing heterocycles. The term "heterocyclic"
also includes bicyclic groups in which any of the heterocyclic
rings is fused to a benzene ring or a cyclohexane ring or another
heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,
tetrahydroquinolyl, and the like).
[0119] The term "cycloalkyl" can mean but is in no way limited to
univalent groups derived from monocyclic or polycyclic alkyl groups
or cycloalkanes, as defined herein, e.g., saturated monocyclic
hydrocarbon groups having from three to twenty carbon atoms in the
ring, including, but not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and the like. The term
"substituted cycloalkyl" can mean but is in no way limited to a
monocyclic or polycyclic alkyl group and being substituted by one
or more substituents, for example, amino, halogen, alkyl,
substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto
or sulfo, whereas these generic substituent groups have meanings
which are identical with definitions of the corresponding groups as
defined in this legend.
[0120] The term "hydrocarbyl" shall mean a compound which contains
carbon and hydrogen and which may be fully saturated, partially
unsaturated or aromatic and includes aryl groups, alkyl groups,
alkenyl groups and alkynyl groups.
[0121] The term "lower alkyl" refers to methyl, ethyl or propyl
[0122] The term "lower alkoxy" refers to methoxy, ethoxy or
propoxy.
[0123] More specifically, non-limiting examples of CLMs include
those shown below as well as "hybrid" molecules or compounds that
arise from combining 1 or more featrues of the following
compounds:
##STR00030## ##STR00031##
[0124] wherein: [0125] W is independently selected from the group
CH.sub.2, CHR, C.dbd.O, SO.sub.2, NH, and N-alkyl; [0126] R.sup.1
is selected from the group absent, H, CH, CN, C1-C3 alkyl; [0127]
R.sup.2 is H or a C1-C3 alkyl; [0128] R.sup.3 is selected from H,
alkyl, substituted alkyl, alkoxy, substituted alkoxy; [0129]
R.sup.4 is methyl or ethyl; [0130] R.sup.5 is H or halo; [0131]
R.sup.6 is H or halo; [0132] R of the CLM is H; [0133] R' is H or
an attachment point for a PTM, a PTM', a chemical linker group (L),
a ULM, a CLM, a CLM', [0134] Q1 and Q2 are each independently C or
N substituted with a group independently selected from H or C1-C3
alkyl; [0135] is a single or double bond; and [0136] Rn comprises a
functional group or an atom.
[0137] In any of the embodiments described herein, the W, R.sup.1,
R.sup.2, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Rn can
independently be covalently coupled to a linker and/or a linker to
which is attached one or more PTM, ULM, ULM', CLM or CLM'
groups.
[0138] In any of the embodiments described herein, the R.sup.1,
R.sup.2, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Rn can
independently be covalently coupled to a linker and/or a linker to
which is attached one or more PTM, ULM, ULM', CLM or CLM'
groups.
[0139] In any of the embodiments described herein, the Q.sub.1,
Q.sub.2, Q.sub.3, Q.sub.4, and Rn can independently be covalently
coupled to a linker and/or a linker to which is attached one or
more PTM, ULM, ULM', CLM or CLM' groups.
[0140] In any aspect or embodiment described herein, R.sub.n is
modified to be covalently joined to the linker group (L), a PTM, a
ULM, a second CLM having the same chemical structure as the CLM, a
CLM', a second linker, or any multiple or combination thereof.
[0141] Exemplary Linkers
[0142] In certain embodiments, the compounds as described herein
include one or more CLMs chemically linked or coupled to one or
more PTMs (e.g., PTM and/or PTM'), ULMs (e.g., ULM, ULM', and/or
CLM') via a chemical linker (L). In certain embodiments, the linker
group L is a group comprising one or more covalently connected
structural units (e.g., -A.sup.L.sub.1 . . . (A.sup.L).sub.q- or
-(A.sup.L).sub.q-), wherein A.sub.1 is a group coupled to PTM, and
Aq is a group coupled to at least one of a ULM, a ULM', a CLM, a
CLM', or a combination thereof. In certain embodiments,
A.sup.L.sub.1 links a CLM or CLM' directly to another ULM, PTM, or
combination thereof. In other embodiments, A.sup.L.sub.1 links a
CLM or CLM' indirectly to another ULM, PTM, or combination thereof
through A.sub.q.
[0143] In any aspect or embodiment described herein, the linker
group L is a bond or a chemical linker group represented by the
formula -(A.sup.L).sub.q-, wherein A is a chemical moiety and q is
an integer from 1-100, and wherein L is covalently bound to the PTM
and the ULM, and provides for sufficient binding of the PTM to the
protein target and the ULM to an E3 ubiquitin ligase to result in
target protein ubiquitination.
[0144] In certain embodiments, the linker group is
-(A.sup.L).sub.q-, wherein [0145] (A.sup.L).sub.q-is a group which
is connected to at least one of a ULM moiety, a PTM moiety, or a
combination thereof; [0146] q of the linker is an integer greater
than or equal to 1; [0147] each A.sup.L is independently selected
from the group consisting of a bond, CR.sup.L1R.sup.L2, O, S, SO,
SO.sub.2, NR.sup.L3, SO.sub.2NR.sup.L3, SONR.sup.L3, CONR.sup.L3,
NR.sup.L3CONR.sup.L4, NR.sup.L3SO.sub.2NR.sup.L4, CO,
CR.sup.L1.dbd.CR.sup.L2, C.ident.C, SiR.sup.L1R.sup.L2,
P(O)R.sup.L1, P(O)OR.sup.L1, NR.sup.L3C(.dbd.NCN)NR.sup.L4,
NR.sup.L3C(.dbd.NCN), NR.sup.L3C(.dbd.CNO.sub.2)NR.sup.L4,
C.sub.3-11 cycloalkyl optionally substituted with 0-6 R.sup.L1
and/or R.sup.L2 groups, C.sub.5-13 spirocycloalkyl optionally
substituted with 0-9 R.sup.L1 and/or R.sup.L2 groups,
C.sub.3-11heterocyclyl optionally substituted with 0-6 R.sup.L1
and/or R.sup.L2 groups, C.sub.5-13 spiroheterocycloalkyl optionally
substituted with 0-8 R.sup.L1 and/or R.sup.L2 groups, aryl
optionally substituted with 0-6 R.sup.L1 and/or R.sup.L2 groups,
heteroaryl optionally substituted with 0-6 R.sup.L1 and/or R.sup.L2
groups, where R.sup.L1 or R.sup.L2, each independently are
optionally linked to other groups to form cycloalkyl and/or
heterocyclyl moiety, optionally substituted with 0-4 R.sup.L5
groups; and [0148] R.sup.L1, R.sup.L2, R.sup.L3, R.sup.L4 and
R.sup.L5 are, each independently, H, halo, C.sub.1-8alkyl,
OC.sub.1-8alkyl, SC.sub.1-8alkyl, NHC.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, C.sub.3-11cycloalkyl, aryl, heteroaryl,
C.sub.3-11heterocyclyl, OC.sub.1-8cycloalkyl, SC.sub.1-8cycloalkyl,
NHC.sub.1-8cycloalkyl, N(C.sub.1-8cycloalkyl).sub.2,
N(C.sub.1-8cycloalkyl)(C.sub.1-8alkyl), OH, NH.sub.2, SH,
SO.sub.2C.sub.1-8alkyl, P(O)(OC.sub.1-8alkyl)(C.sub.1-8alkyl),
P(O)(OC.sub.1-8alkyl).sub.2, CC--C.sub.1-8alkyl, CCH,
CH.dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.C(C.sub.1-8alkyl).sub.2, Si(OH).sub.3,
Si(C.sub.1-8alkyl).sub.3, Si(OH)(C.sub.1-8alkyl).sub.2,
COC.sub.1-8alkyl, CO.sub.2H, halogen, CN, CF.sub.3, CHF.sub.2,
CH.sub.2F, NO.sub.2, SF.sub.5, SO.sub.2NHC.sub.1-8alkyl,
SO.sub.2N(C.sub.1-8alkyl).sub.2, SONHC.sub.1-8alkyl,
SON(C.sub.1-8alkyl).sub.2, CONHC.sub.1-8alkyl,
CON(C.sub.1-8alkyl).sub.2, N(C.sub.1-8alkyl)CONH(C.sub.1-8alkyl),
N(C.sub.1-8alkyl)CON(C.sub.1-8alkyl).sub.2, NHCONH(C.sub.1-8alkyl),
NHCON(C.sub.1-8alkyl).sub.2, NHCONH.sub.2,
N(C.sub.1-8alkyl)SO.sub.2NH(C.sub.1-8alkyl), N(C.sub.1-8alkyl)
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH(C.sub.1-8alkyl), NH
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH.sub.2.
[0149] In certain embodiments, q of the linker is an integer
greater than or equal to 0. In certain embodiments, q is an integer
greater than or equal to 1.
[0150] In certain embodiments, e.g., where q is greater than 2,
A.sup.L.sub.q is a group which is connected to a ULM or ULM' moiety
(such as CLM or CLM'), and A.sup.L.sub.1 and A.sup.L.sub.q are
connected via structural units of the linker (L).
[0151] In certain embodiments, e.g., where q of the linker is 2,
A.sup.L.sub.q is a group which is connected to A.sup.L.sub.1 and to
a ULM or a ULM' moiety (such as CLM or CLM').
[0152] In certain embodiments, e.g., where q of the linker is 1,
the structure of the linker group L is -A.sup.L.sub.1-, and
A.sup.L.sub.1 is a group which is connected to a ULM or ULM' moiety
(such as CLM or CLM') and a PTM moiety.
[0153] In certain embodiments, the linker (L) comprises a group
represented by a general structure selected from the group
consisting of: [0154] NR(CH.sub.2).sub.n-(lower alkyl)-,
--NR(CH.sub.2).sub.n-(lower alkoxyl)-, --NR(CH.sub.2).sub.n-(lower
alkoxyl)-OCH.sub.2--, --NR(CH.sub.2).sub.n-(lower alkoxyl)-(lower
alkyl)-OCH.sub.2--, --NR(CH.sub.2).sub.n-(cycloalkyl)-(lower
alkyl)-OCH.sub.2--, --NR(CH.sub.2).sub.n-(hetero cycloalkyl)-,
--NR(CH.sub.2CH.sub.2O).sub.n-(lower alkyl)-O--CH.sub.2--,
--NR(CH.sub.2CH.sub.2O).sub.n-(hetero cycloalkyl)-O--CH.sub.2--,
--NR(CH.sub.2CH.sub.2O).sub.n-Aryl-O--CH.sub.2--,
--NR(CH.sub.2CH.sub.2O).sub.n-(hetero aryl)-O--CH.sub.2--,
--NR(CH.sub.2CH.sub.2O).sub.n-(cyclo alkyl)-O-(hetero
aryl)-O--CH.sub.2--, --NR(CH.sub.2CH.sub.2O).sub.n-(cyclo
alkyl)-O-Aryl-O--CH.sub.2--, --NR(CH.sub.2CH.sub.2O).sub.n-(lower
alkyl)-NH-Aryl-O--CH.sub.2--, --NR(CH.sub.2CH.sub.2O).sub.n-(lower
alkyl)-O-Aryl-CH.sub.2,
--NR(CH.sub.2CH.sub.2O).sub.n-cycloalkyl-O-Aryl-,
--NR(CH.sub.2CH.sub.2O).sub.n-cycloalkyl-O-(heteroaryl)l-,
--NR(CH.sub.2CH.sub.2).sub.n-(cycloalkyl)-O-(heterocycle)-CH.sub.2,
--NR(CH.sub.2CH.sub.2).sub.n-(heterocycle)-(heterocycle)-CH.sub.2,
--N(R1R2)-(heterocycle)-CH.sub.2; where
[0155] n of the linker can be 0 to 10;
[0156] R of the linker can be H, lower alkyl;
[0157] R1 and R2 of the linker can form a ring with the connecting
N.
[0158] In certain embodiments, the A.sup.L group is represented by
a general structure selected from the group consisting of: [0159]
N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(C-
H2).sub.r-OCH2-,
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.oO(CH2).sub.p-O(CH2).sub.q-O(CH2-
).sub.r-OCH2-,
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.oO(CH2).sub.p-O(CH2).sub.q-O(CH2-
).sub.r-O--;
--N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O-
(CH2).sub.r-O--;
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH2).-
sub.r-O--;
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub-
.q-O(CH2).sub.r-OCH2-;
##STR00032## ##STR00033##
[0159] wherein [0160] m, n, o, p, q, and r of the linker are
independently 0, 1, 2, 3, 4, 5, 6; 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, or 20; [0161] when the number is zero, there is no
N--O or O--O bond [0162] R of the linker is H, methyl and ethyl;
[0163] X of the linker is H and F
[0163] ##STR00034## [0164] where m of the linker can be 2, 3, 4,
5;
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042##
[0165] where each n and m of the linker can independently be 0, 1,
2, 3, 4, 5, 6.
[0166] In any aspect or embodiment described herein, the A.sup.L
group is selected from the group consisting of:
##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047##
[0167] wherein each m and n is independently selected from 0, 1, 2,
3, 4, 5, or 6.
[0168] In any aspect or embodiment described herein, A.sup.L group
is selected from the group consisting of:
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068##
wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0169] In any aspect or embodiment described herein, the A.sup.L
group is selected from the group consisting of:
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081##
[0170] In additional embodiments, the linker (L) comprises a
structure selected from, but not limited to the structure shown
below, where a dashed line indicates the attachment point to the
PTM or ULM moieties:
##STR00082##
wherein: [0171] W.sup.L1 and W.sup.L2 are each independently
absent, a 4-8 membered ring with 0-4 heteroatoms, optionally
substituted with R.sup.Q, each R.sup.Q is independently a H, halo,
OH, CN, CF.sub.3, C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted), C.sub.1-C.sub.6 alkoxy (linear, branched,
optionally substituted), or 2 R.sup.Q groups taken together with
the atom they are attached to, form a 4-8 membered ring system
containing 0-4 heteroatoms; [0172] Y.sup.L1 is each independently a
bond, C.sub.1-C.sub.6 alkyl (linear, branched, optionally
substituted) and optionally one or more C atoms are replaced with
O; or C.sub.1-C.sub.6 alkoxy (linear, branched, optionally
substituted); [0173] n is 0-10; and [0174] a dashed line indicates
the attachment point to the PTM or ULM moieties.
[0175] In additional embodiments, the linker (L) comprises a
structure selected from, but not limited to the structure shown
below, where a dashed line indicates the attachment point to the
PTM or ULM moieties:
##STR00083##
wherein: [0176] W.sup.L1 and W.sup.L2 are each independently
absent, aryl, heteroaryl, cyclic, heterocyclic, C.sub.1-6 alkyl and
optionally one or more C atoms are replaced with O, C.sub.1-6
alkene and optionally one or more C atoms are replaced with O,
C.sub.1-6 alkyne and optionally one or more C atoms are replaced
with O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each
optionally substituted with R.sup.Q, each R.sup.Q is independently
a H, halo, OH, CN, CF.sub.3, hydroxyl, nitro, C.ident.CH, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkyl (linear,
branched, optionally substituted), C.sub.1-C.sub.6 alkoxy (linear,
branched, optionally substituted), OC.sub.1-3alkyl (optionally
substituted by 1 or more --F), OH, NH.sub.2, NR.sup.Y1R.sup.Y2, CN,
or 2 R.sup.Q groups taken together with the atom they are attached
to, form a 4-8 membered ring system containing 0-4 heteroatoms;
[0177] Y.sup.L1 is each independently a bond, NR.sup.YL1, O, S,
NR.sup.YL2, CR.sup.YL1R.sup.YL2, C.dbd.O, C.dbd.S, SO, SO.sub.2,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted)
and optionally one or more C atoms are replaced with O;
C.sub.1-C.sub.6 alkoxy (linear, branched, optionally substituted);
[0178] Q.sup.L is a 3-6 membered alicyclic or aromatic ring with
0-4 heteroatoms, optionally bridged, optionally substituted with
0-6 R.sup.Q, each R.sup.Q is independently H, C.sub.1-6 alkyl
(linear, branched, optionally substituted by 1 or more halo,
C.sub.1-6 alkoxyl), or 2 R.sup.Q groups taken together with the
atom they are attached to, form a 3-8 membered ring system
containing 0-2 heteroatoms); [0179] R.sup.YL1, R.sup.YL2 are each
independently H, OH, C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), or R.sup.1,
R.sup.2 together with the atom they are attached to, form a 3-8
membered ring system containing 0-2 heteroatoms); [0180] n is 0-10;
and [0181] a dashed line indicates the attachment point to the PTM
or ULM moieties.
[0182] In additional embodiments, the linker group is optionally
substituted (poly)ethyleneglycol having between 1 and about 100
ethylene glycol units, between about 1 and about 50 ethylene glycol
units, between 1 and about 25 ethylene glycol units, between about
1 and 10 ethylene glycol units, between 1 and about 8 ethylene
glycol units and 1 and 6 ethylene glycol units, between 2 and 4
ethylene glycol units, or optionally substituted alkyl groups
interdispersed with optionally substituted, O, N, S, P or Si atoms.
In certain embodiments, the linker is substituted with an aryl,
phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain
embodiments, the linker may be asymmetric or symmetrical.
[0183] In any of the embodiments of the compounds described herein,
the linker group may be any suitable moiety as described herein. In
one embodiment, the linker is a substituted or unsubstituted
polyethylene glycol group ranging in size from about 1 to about 12
ethylene glycol units, between 1 and about 10 ethylene glycol
units, about 2 about 6 ethylene glycol units, between about 2 and 5
ethylene glycol units, between about 2 and 4 ethylene glycol
units.
[0184] In another embodiment, the present disclosure is directed to
a compound which comprises a PTM group, which binds to a target
protein or polypeptide, which is ubiquitinated by an ubiquitin
ligase and is chemically linked directly to the ULM group (such as
CLM) or through a linker moiety L, or PTM is alternatively a ULM'
group (such as CLM') which is also a ubiquitin ligase binding
moiety, which may be the same or different than the ULM group as
described above and is linked directly to the ULM group directly or
through the linker moiety; and L is a linker moiety as described
above which may be present or absent and which chemically
(covalently) links ULM to PTM, or a pharmaceutically acceptable
salt, enantiomer, stereoisomer, solvate or polymorph thereof.
[0185] In certain embodiments, the linker group L is a group
comprising one or more covalently connected structural units
independently selected from the group consisting of:
##STR00084##
The X is selected from the group consisting of O, N, S, S(O) and
SO.sub.2; n is integer from 1 to 5; R.sup.L1 is hydrogen or
alkyl,
##STR00085##
is a mono- or bicyclic aryl or heteroaryl optionally substituted
with 1-3 substituents selected from alkyl, halogen, haloalkyl,
hydroxy, alkoxy or cyano;
##STR00086##
is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionally
substituted with 1-3 substituents selected from alkyl, halogen,
haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment
can be optionally substituted with 1, 2 or 3 substituents selected
from the group consisting of alkyl, halogen, haloalkyl, hydroxy,
alkoxy and cyano. In an embodiment, the linker group L comprises up
to 10 covalently connected structural units, as described
above.
[0186] Although the ULM group and PTM group may be covalently
linked to the linker group through any group which is appropriate
and stable to the chemistry of the linker, in preferred aspects of
the present disclosure, the linker is independently covalently
bonded to the ULM group and the PTM group preferably through an
amide, ester, thioester, keto group, carbamate (urethane), carbon
or ether, each of which groups may be inserted anywhere on the ULM
group and PTM group to provide maximum binding of the ULM group on
the ubiquitin ligase and the PTM group on the target protein to be
degraded. (It is noted that in certain aspects where the PTM group
is a ULM group, the target protein for degradation may be the
ubiquitin ligase itself). In certain preferred aspects, the linker
may be linked to an optionally substituted alkyl, alkylene, alkene
or alkyne group, an aryl group or a heterocyclic group on the ULM
and/or PTM groups.
[0187] In additional embodiments, q is an integer from 1 to 100, 1
to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to
20, or 1 to 10.
[0188] In certain embodiments, the linker (L) is selected from the
group consisting of:
##STR00087## ##STR00088## ##STR00089## ##STR00090##
[0189] In additional embodiments, the linker group is optionally
substituted (poly)ethyleneglycol having between 1 and about 100
ethylene glycol units, between about 1 and about 50 ethylene glycol
units, between 1 and about 25 ethylene glycol units, between about
1 and 10 ethylene glycol units, between 1 and about 8 ethylene
glycol units and 1 and 6 ethylene glycol units, between 2 and 4
ethylene glycol units, or optionally substituted alkyl groups
interdispersed with optionally substituted, O, N, S, P or Si atoms.
In certain embodiments, the linker is substituted with an aryl,
phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain
embodiments, the linker may be asymmetric or symmetrical.
[0190] In any of the embodiments of the compounds described herein,
the linker group may be any suitable moiety as described herein. In
one embodiment, the linker is a substituted or unsubstituted
polyethylene glycol group ranging in size from about 1 to about 12
ethylene glycol units, between 1 and about 10 ethylene glycol
units, about 2 about 6 ethylene glycol units, between about 2 and 5
ethylene glycol units, between about 2 and 4 ethylene glycol
units.
[0191] Although the CLM (or ULM) group and PTM group may be
covalently linked to the linker group through any group which is
appropriate and stable to the chemistry of the linker, in preferred
aspects of the present disclosure, the linker is independently
covalently bonded to the CLM group and the PTM group preferably
through an amide, ester, thioester, keto group, carbamate
(urethane), carbon or ether, each of which groups may be inserted
anywhere on the CLM group and PTM group to provide maximum binding
of the CLM group on the ubiquitin ligase and the PTM group on the
target protein to be degraded. (It is noted that in certain aspects
where the PTM group is a ULM group, the target protein for
degradation may be the ubiquitin ligase itself). In certain
preferred aspects, the linker may be linked to an optionally
substituted alkyl, alkylene, alkene or alkyne group, an aryl group
or a heterocyclic group on the CLM and/or PTM groups.
[0192] In certain embodiments, "L" can be linear chains with linear
atoms from 4 to 24, the carbon atom in the linear chain can be
substituted with oxygen, nitrogen, amide, fluorinated carbon, etc.,
such as the following:
##STR00091## ##STR00092##
[0193] In certain embodiments, "L" can be nonlinear chains, and can
be aliphatic or aromatic or heteroaromatic cyclic moieties, some
examples of "L" include but not be limited to the following:
##STR00093## ##STR00094##
wherein: [0194] `X" in above structures can be linear chain with
atoms ranging from 2 to 14, and the mentioned chain can contain
heteroatoms such as oxygen; and [0195] "Y" in above structures can
be O, N, S(O)-- (n=0, 1, 2).
[0196] Exemplary PTMs
[0197] In preferred aspects of the present disclosure, the PTM
group is a group, which binds to target proteins. Targets of the
PTM group are numerous in kind and are selected from proteins that
are expressed in a cell such that at least a portion of the
sequences is found in the cell and may bind to a PTM group. The
term "protein" includes oligopeptides and polypeptide sequences of
sufficient length that they can bind to a PTM group according to
the present disclosure. Any protein in a eukaryotic system or a
microbial system, including a virus, bacteria or fungus, as
otherwise described herein, are targets for ubiquitination mediated
by the compounds according to the present disclosure. Preferably,
the target protein is a eukaryotic protein. In certain aspects, the
protein binding moiety is a haloalkane (preferably a
C.sub.1-C.sub.10 alkyl group which is substituted with at least one
halo group, preferably a halo group at the distal end of the alkyl
group, i.e., away from the linker or CLM group), which may
covalently bind to a dehalogenase enzyme in a patient or subject or
in a diagnostic assay.
[0198] PTM groups according to the present disclosure include, for
example, include any moiety which binds to a protein specifically
(binds to a target protein) and includes the following non-limiting
examples of small molecule target protein moieties: Hsp90
inhibitors, kinase inhibitors, androgen receptor inhibitors, HDM2
& MDM2 inhibitors, compounds targeting Human BET
Bromodomain-containing proteins, HDAC inhibitors, human lysine
methyltransferase inhibitors, angiogenesis inhibitors, nuclear
hormone receptor compounds, immunosuppressive compounds, and
compounds targeting the aryl hydrocarbon receptor (AHR), among
numerous others. The compositions described below exemplify some of
the members of these nine types of small molecule target protein
binding moieties. Such small molecule target protein binding
moieties also include pharmaceutically acceptable salts,
enantiomers, solvates and polymorphs of these compositions, as well
as other small molecules that may target a protein of interest.
These binding moieties are linked to the ubiquitin ligase binding
moiety preferably through a linker in order to present a target
protein (to which the protein target moiety is bound) in proximity
to the ubiquitin ligase for ubiquitination and degradation.
[0199] Any protein, which can bind to a protein target moiety or
PTM group and acted on or degraded by a ubiquitin ligase is a
target protein according to the present disclosure. In general,
target proteins may include, for example, structural proteins,
receptors, enzymes, cell surface proteins, proteins pertinent to
the integrated function of a cell, including proteins involved in
catalytic activity, aromatase activity, motor activity, helicase
activity, metabolic processes (anabolism and catabolism),
antioxidant activity, proteolysis, biosynthesis, proteins with
kinase activity, oxidoreductase activity, transferase activity,
hydrolase activity, lyase activity, isomerase activity, ligase
activity, enzyme regulator activity, signal transducer activity,
structural molecule activity, binding activity (protein, lipid
carbohydrate), receptor activity, cell motility, membrane fusion,
cell communication, regulation of biological processes,
development, cell differentiation, response to stimulus, behavioral
proteins, cell adhesion proteins, proteins involved in cell death,
proteins involved in transport (including protein transporter
activity, nuclear transport, ion transporter activity, channel
transporter activity, carrier activity, permease activity,
secretion activity, electron transporter activity, pathogenesis,
chaperone regulator activity, nucleic acid binding activity,
transcription regulator activity, extracellular organization and
biogenesis activity, translation regulator activity. Proteins of
interest can include proteins from eurkaryotes and prokaryotes
including humans as targets for drug therapy, other animals,
including domesticated animals, microbials for the determination of
targets for antibiotics and other antimicrobials and plants, and
even viruses, among numerous others.
[0200] In still other embodiments, the PTM group is a haloalkyl
group, wherein said alkyl group generally ranges in size from about
1 or 2 carbons to about 12 carbons in length, often about 2 to 10
carbons in length, often about 3 carbons to about 8 carbons in
length, more often about 4 carbons to about 6 carbons in length.
The haloalkyl groups are generally linear alkyl groups (although
branched-chain alkyl groups may also be used) and are end-capped
with at least one halogen group, preferably a single halogen group,
often a single chloride group. Haloalkyl PT, groups for use in the
present disclosure are preferably represented by the chemical
structure --(CH.sub.2).sub.v--Halo where v is any integer from 2 to
about 12, often about 3 to about 8, more often about 4 to about 6.
Halo may be any halogen, but is preferably Cl or Br, more often
Cl.
[0201] In another embodiment, the present disclosure provides a
library of compounds. The library comprises more than one compound
wherein each composition has a formula of A-B, wherein A is a
ubiquitin pathway protein binding moiety (preferably, an E3
ubiquitin ligase moiety as otherwise disclosed herein) and B is a
protein binding member of a molecular library, wherein A is coupled
(preferably, through a linker moiety) to B, and wherein the
ubiquitin pathway protein binding moiety recognizes an ubiquitin
pathway protein, in particular, an E3 ubiquitin ligase, such as
cereblon. In a particular embodiment, the library contains a
specific cereblon E3 ubiquitin ligase binding moiety bound to
random target protein binding elements (e.g., a chemical compound
library). As such, the target protein is not determined in advance
and the method can be used to determine the activity of a putative
protein binding element and its pharmacological value as a target
upon degradation by ubiquitin ligase.
[0202] The present disclosure may be used to treat a number of
disease states and/or conditions, including any disease state
and/or condition in which proteins are dysregulated and where a
patient would benefit from the degradation of proteins.
[0203] In an additional aspect, the description provides
therapeutic compositions comprising an effective amount of a
compound as described herein or salt form thereof, and a
pharmaceutically acceptable carrier, additive or excipient, and
optionally an additional bioactive agent. The therapeutic
compositions modulate protein degradation in a patient or subject,
for example, an animal such as a human, and can be used for
treating or ameliorating disease states or conditions which are
modulated through the degraded protein. In certain embodiments, the
therapeutic compositions as described herein may be used to
effectuate the degradation of proteins of interest for the
treatment or amelioration of a disease, e.g., cancer (such as
prostate cancer) and Kennedy's Disease. In certain additional
embodiments, the disease is prostate cancer.
[0204] In alternative aspects, the present disclosure relates to a
method for treating a disease state or ameliorating the symptoms of
a disease or condition in a subject in need thereof by degrading a
protein or polypeptide through which a disease state or condition
is modulated comprising administering to said patient or subject an
effective amount, e.g., a therapeutically effective amount, of at
least one compound as described hereinabove, optionally in
combination with a pharmaceutically acceptable carrier, additive or
excipient, and optionally an additional bioactive agent, wherein
the composition is effective for treating or ameliorating the
disease or disorder or symptom thereof in the subject. The method
according to the present disclosure may be used to treat a large
number of disease states or conditions including cancer, by virtue
of the administration of effective amounts of at least one compound
described herein. The disease state or condition may be a disease
caused by a microbial agent or other exogenous agent such as a
virus, bacteria, fungus, protozoa or other microbe or may be a
disease state, which is caused by overexpression of a protein,
which leads to a disease state and/or condition.
[0205] In another aspect, the description provides methods for
identifying the effects of the degradation of proteins of interest
in a biological system using compounds according to the present
disclosure.
[0206] The term "target protein" is used to describe a protein or
polypeptide, which is a target for binding to a compound according
to the present disclosure and degradation by ubiquitin ligase
hereunder. Such small molecule target protein binding moieties also
include pharmaceutically acceptable salts, enantiomers, solvates
and polymorphs of these compositions, as well as other small
molecules that may target a protein of interest. These binding
moieties are linked to CLM or ULM groups through linker groups
L.
[0207] Target proteins which may be bound to the protein target
moiety and degraded by the ligase to which the ubiquitin ligase
binding moiety is bound include any protein or peptide, including
fragments thereof, analogues thereof, and/or homologues thereof.
Target proteins include proteins and peptides having any biological
function or activity including structural, regulatory, hormonal,
enzymatic, genetic, immunological, contractile, storage,
transportation, and signal transduction. In certain embodiments,
the target proteins include structural proteins, receptors,
enzymes, cell surface proteins, proteins pertinent to the
integrated function of a cell, including proteins involved in
catalytic activity, aromatase activity, motor activity, helicase
activity, metabolic processes (anabolism and catabolism),
antioxidant activity, proteolysis, biosynthesis, proteins with
kinase activity, oxidoreductase activity, transferase activity,
hydrolase activity, lyase activity, isomerase activity, ligase
activity, enzyme regulator activity, signal transducer activity,
structural molecule activity, binding activity (protein, lipid
carbohydrate), receptor activity, cell motility, membrane fusion,
cell communication, regulation of biological processes,
development, cell differentiation, response to stimulus, behavioral
proteins, cell adhesion proteins, proteins involved in cell death,
proteins involved in transport (including protein transporter
activity, nuclear transport, ion transporter activity, channel
transporter activity, carrier activity, permease activity,
secretion activity, electron transporter activity, pathogenesis,
chaperone regulator activity, nucleic acid binding activity,
transcription regulator activity, extracellular organization and
biogenesis activity, translation regulator activity. Proteins of
interest can include proteins from eukaryotes and prokaryotes,
including microbes, viruses, fungi and parasites, including humans,
microbes, viruses, fungi and parasites, among numerous others, as
targets for drug therapy, other animals, including domesticated
animals, microbials for the determination of targets for
antibiotics and other antimicrobials and plants, and even viruses,
among numerous others.
[0208] More specifically, a number of drug targets for human
therapeutics represent protein targets to which protein target
moiety may be bound and incorporated into compounds according to
the present disclosure. These include proteins which may be used to
restore function in numerous polygenic diseases, including for
example B7.1 and B7, TINFR1 m, TNFR2, NADPH oxidase, Bcl IBax and
other partners in the apotosis pathway, C5a receptor, HMG-CoA
reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase
type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1,
CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,
cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins,
i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine
protease, thymidylate synthase, purine nucleoside phosphorylase,
GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase,
chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV
1 integrase, influenza, neuramimidase, hepatitis B reverse
transcriptase, sodium channel, multi drug resistance (MDR), protein
P-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine
kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR,
ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L,
newokinins and receptors, inosine monophosphate dehydrogenase, p38
MAP Kinase, RaslRaflMEWERK pathway, interleukin-1 converting
enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase,
glycinamide ribonucleotide formyl transferase, rhinovirus 3C
protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus
(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent
kinases, vascular endothelial growth factor, oxytocin receptor,
microsomal transfer protein inhibitor, bile acid transport
inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine
receptor, noradrenaline reuptake receptor, endothelin receptors,
neuropeptide Y and receptor, estrogen receptors, androgen receptors
(AR), adenosine receptors, adenosine kinase and AMP deaminase,
purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7),
farnesyltransferases, geranylgeranyl transferase, TrkA a receptor
for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin
receptor, integrin receptor, Her-21 neu, telomerase inhibition,
cytosolic phospholipaseA2 and EGF receptor tyrosine kinase.
Additional protein targets include, for example, ecdysone
20-monooxygenase, ion channel of the GABA gated chloride channel,
acetylcholinesterase, voltage-sensitive sodium channel protein,
calcium release channel, and chloride channels. Still further
target proteins include Acetyl-CoA carboxylase, adenylosuccinate
synthetase, protoporphyrinogen oxidase, and
enolpyruvylshikimate-phosphate synthase.
[0209] Haloalkane dehalogenase enzymes are another target of
specific compounds according to the present disclosure. Compounds
according to the present disclosure which contain chloroalkane
peptide binding moieties (C.sub.1-C.sub.12 often about
C.sub.2-C.sub.10 alkyl halo groups) may be used to inhibit and/or
degrade haloalkane dehalogenase enzymes which are used in fusion
proteins or related dioagnostic proteins as described in
PCT/US2012/063401 filed Dec. 6, 2011 and published as WO
2012/078559 on Jun. 14, 2012, the contents of which is incorporated
by reference herein.
[0210] These various protein targets may be used in screens that
identify compound moieties which bind to the protein and by
incorporation of the moiety into compounds according to the present
disclosure, the level of activity of the protein may be altered for
therapeutic end result.
[0211] The term "protein target moiety" or PTM is used to describe
a small molecule which binds to a target protein or other protein
or polypeptide of interest and places/presents that protein or
polypeptide in proximity to an ubiquitin ligase such that
degradation of the protein or polypeptide by ubiquitin ligase may
occur. Non-limiting examples of small molecule target protein
binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2
inhibitors, compounds targeting Human BET Bromodomain-containing
proteins, HDAC inhibitors, human lysine methyltransferase
inhibitors, angiogenesis inhibitors, immunosuppressive compounds,
and compounds targeting the aryl hydrocarbon receptor (AHR), among
numerous others. The compositions described below exemplify some of
the members of these nine types of small molecule target
protein.
[0212] Exemplary protein target moieties according to the present
disclosure include, haloalkane halogenase inhibitors, Hsp90
inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting
Human BET Bromodomain-containing proteins, HDAC inhibitors, human
lysine methyltransferase inhibitors, angiogenesis inhibitors,
immunosuppressive compounds, and compounds targeting the aryl
hydrocarbon receptor (AHR).
[0213] The compositions described below exemplify some of the
members of these types of small molecule target protein binding
moieties. Such small molecule target protein binding moieties also
include pharmaceutically acceptable salts, enantiomers, solvates
and polymorphs of these compositions, as well as other small
molecules that may target a protein of interest. References which
are cited hereinbelow are incorporated by reference herein in their
entirety.
[0214] I. Heat Shock Protein 90 (HSP90) Inhibitors:
[0215] HSP90 inhibitors as used herein include, but are not limited
to:
[0216] 1. The HSP90 inhibitors identified in Vallee, et al.,
"Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part
I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent
Inhibitors of the HSP90 Molecular Chaperone (2011) J. Med. Chem.
54: 7206, including YKB
(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide):
##STR00095##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via the terminal amide group;
[0217] 2. The HSP90 inhibitor p54 (modified)
(8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):
##STR00096##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via the terminal acetylene group;
[0218] 3. The HSP90 inhibitors (modified) identified in Brough, et
al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential
Therapeutic Agents for the Treatment of Cancer", J. MED. CHEM. vol:
51, pag:196 (2008), including the compound 2GJ
(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylme-
thyl)phenyl]isoxazole-3-carboxamide) having the structure:
##STR00097##
derivatized, where a linker group L or a -(L-CLM) group is
attached, for example, via the amide group (at the amine or at the
alkyl group on the amine);
[0219] 4. The HSP90 inhibitors (modified) identified in Wright, et
al., Structure-Activity Relationships in Purine-Based Inhibitor
Binding to HSP90 Isoforms, Chem Biol. 2004 June; 11(6):775-85,
including the HSP90 inhibitor PU3 having the structure:
##STR00098##
derivatized where a linker group L or -(L-CLM) is attached, for
example, via the butyl group; and
[0220] 5. The HSP90 inhibitor geldanamycin
((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,-
16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] (derivatized) or
any of its derivatives (e.g.
17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or
17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin
("17-DMAG")) (derivatized, where a linker group L or a -(L-CLM)
group is attached, for example, via the amide group).
[0221] II. Kinase and Phosphatase Inhibitors:
[0222] Kinase inhibitors as used herein include, but are not
limited to:
[0223] 1. Erlotinib Derivative Tyrosine Kinase Inhibitor:
##STR00099##
where R is a linker group L or a -(L-CLM) group attached, for
example, via the ether group;
[0224] 2. The kinase inhibitor sunitinib (derivatized):
##STR00100##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the pyrrole moiety;
[0225] 3. Kinase Inhibitor sorafenib (derivatized):
##STR00101##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the amide moiety;
[0226] 4. The kinase inhibitor desatinib (derivatized):
##STR00102##
derivatized where R is a linker group L or a -(L-CLM) attached, for
example, to the pyrimidine;
[0227] 5. The kinase inhibitor lapatinib (derivatized):
##STR00103##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via the terminal methyl of the sulfonyl methyl
group;
[0228] 6. The kinase inhibitor U09-CX-5279 (derivatized):
##STR00104##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via the amine (aniline), carboxylic acid or amine
alpha to cyclopropyl group, or cyclopropyl group;
[0229] 7. The kinase inhibitors identified in Millan, et al.,
Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of
Chronic Obstructive Pulmonary Disease, J. MED. CHEM. vol:54,
pag:7797 (2011), including the kinase inhibitors Y1W and Y1X
(Derivatized) having the structures:
##STR00105##
[0230]
YIX(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine--
6-yl]sulfanyl}benzyl)urea, derivatized where a linker group L or a
-(L-CLM) group is attached, for example, via the .sup.ipropyl
group;
##STR00106##
[0231] YIW
[0232]
1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[-
1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea derivatized
where a linker group L or a -(L-CLM) group is attached, for
example, preferably via either the i-propyl group or the t-butyl
group;
[0233] 8. The kinase inhibitors identified in Schenkel, et al.,
Discovery of Potent and Highly Selective Thienopyridine Janus
Kinase 2 Inhibitors J. Med. Chem., 2011, 54 (24), pp 8440-8450,
including the compounds 6TP and 0TP (Derivatized) having the
structures:
##STR00107##
[0234] 6TP
[0235]
4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyri-
dine-7-carboxamide Thienopyridine 19 derivatized where a linker
group L or a -(L-CLM) group is attached, for example, via the
terminal methyl group bound to amide moiety;
##STR00108##
[0236] 0TP
[0237]
4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine--
7-carboxamide Thienopyridine 8 derivatized where a linker group L
or a -(L-CLM)group is attached, for example, via the terminal
methyl group bound to the amide moiety;
[0238] 9. The kinase inhibitors identified in Van Eis, et al.,
"2,6-Naphthyridines as potent and selective inhibitors of the novel
protein kinase C isozymes", Biorg. Med. Chem. Lett. 2011 Dec. 15;
21(24):7367-72, including the kinase inhibitor 07U having the
structure:
##STR00109##
[0239] 07U
[0240]
2-methyl-N.about.1.about.-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]p-
ropane-1,2-diamine derivatized where a linker group L or a
-(L-CLM)group is attached, for example, via the secondary amine or
terminal amino group;
[0241] 10. The kinase inhibitors identified in Lountos, et al.,
"Structural Characterization of Inhibitor Complexes with Checkpoint
Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J. STRUCT.
BIOL. vol:176, pag:292 (2011), including the kinase inhibitor YCF
having the structure:
##STR00110##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via either of the terminal hydroxyl groups;
[0242] 11. The kinase inhibitors identified in Lountos, et al.,
"Structural Characterization of Inhibitor Complexes with Checkpoint
Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J. STRUCT.
BIOL. vol:176, pag:292 (2011), including the kinase inhibitors XK9
and NXP (derivatized) having the structures:
##STR00111##
[0243] XK9
[0244]
N-{4-[(1E)-N--(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-n-
itro-1H-indole-2-carboxamide;
##STR00112##
[0245] NXP
[0246]
N-{4-[(1E)-N-CARBAMIMIDOYLETHANEHYDRAZONOYL]PHENYL}-1H-INDOLE-3-CAR-
BOXAMIDE derivatized where a linker group L or a -(L-CLM) group is
attached, for example, via the terminal hydroxyl group (XK9) or the
hydrazone group (NXP);
[0247] 12. The kinase inhibitor afatinib (derivatized)
(N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-
-6-quinazolinyl]-4(dimethylamino)-2-butenamide) (Derivatized where
a linker group L or a -(L-CLM) group is attached, for example, via
the aliphatic amine group);
[0248] 13. The kinase inhibitor fostamatinib (derivatized)
([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-
-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl
disodium phosphate hexahydrate) (Derivatized where a linker group L
or a -(L-CLM) group is attached, for example, via a methoxy
group);
[0249] 14. The kinase inhibitor gefitinib (derivatized)
(N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinaz-
olin-4-amine):
##STR00113##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, via a methoxy or ether group;
[0250] 15. The kinase inhibitor lenvatinib (derivatized)
(4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6--
carboxamide) (derivatized where a linker group L or a -(L-CLM)
group is attached, for example, via the cyclopropyl group);
[0251] 16. The kinase inhibitor vandetanib (derivatized)
(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-
quinazolin-4-amine) (derivatized where a linker group L or a
-(L-CLM) group is attached, for example, via the methoxy or
hydroxyl group);
[0252] 17. The kinase inhibitor vemurafenib (derivatized)
(propane-1-sulfonic acid
{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-
-phenyl}-amide), derivatized where a linker group L or a -(L-CLM)
group is attached, for example, via the sulfonyl propyl group;
[0253] 18. The kinase inhibitor Gleevec (derivatized):
##STR00114##
derivatized where R as a linker group L or a -(L-CLM) group is
attached, for example, via the amide group or via the aniline amine
group;
[0254] 19. The kinase inhibitor pazopanib (derivatized) (VEGFR3
inhibitor):
##STR00115##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety or via the aniline
amine group;
[0255] 20. The kinase inhibitor AT-9283 (Derivatized) Aurora Kinase
Inhibitor
##STR00116##
where R is a linker group L or a -(L-CLM) group attached, for
example, to the phenyl moiety);
[0256] 21. The kinase inhibitor TAE684 (derivatized) ALK
inhibitor
##STR00117##
where R is a linker group L or a -(L-CLM) group attached, for
example, to the phenyl moiety);
[0257] 22. The kinase inhibitor nilotanib (derivatized) Abl
inhibitor:
##STR00118##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety or the aniline amine
group;
[0258] 23. Kinase Inhibitor NVP-BSK805 (derivatized) JAK2
Inhibitor
##STR00119##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety or the diazole
group;
[0259] 24. Kinase Inhibitor crizotinib Derivatized Alk
Inhibitor
##STR00120##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety or the diazole
group;
[0260] 25. Kinase Inhibitor JNJ FMS (derivatized) Inhibitor
##STR00121##
derivatized where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety;
[0261] 26. The kinase inhibitor foretinib (derivatized) Met
Inhibitor
##STR00122##
derivatized where R is a linker group L or a -(L-CLM)group
attached, for example, to the phenyl moiety or a hydroxyl or ether
group on the quinoline moiety;
[0262] 27. The allosteric Protein Tyrosine Phosphatase Inhibitor
PTP1B (derivatized):
##STR00123##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R, as indicated;
[0263] 28. The inhibitor of SHP-2 Domain of Tyrosine Phosphatase
(derivatized):
##STR00124##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R;
[0264] 29. The inhibitor (derivatized) of BRaf
(BRaf.sup.V600E)/MEK:
##STR00125##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R;
[0265] 30. Inhibitor (derivatized) of Tyrosine Kinase ABL
##STR00126##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R;
[0266] 31. The kinase inhibitor OSI-027 (derivatized) mTORC1/2
inhibitor
##STR00127##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R;
[0267] 32. The kinase inhibitor OSI-930 (derivatized) c-Kit/KDR
inhibitor
##STR00128##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R; and
[0268] 33. The kinase inhibitor OSI-906 (derivatized) IGF1R/IR
inhibitor
##STR00129##
derivatized where a linker group L or a -(L-CLM) group is attached,
for example, at R.
[0269] Wherein, in any of the embodiments described in sections
I-XVII, "R" designates a site for attachment of a linker group L or
a -(L-CLM)group on the piperazine moiety.
[0270] III. HDM2/MDM2 Inhibitors:
[0271] HDM2/MDM2 inhibitors as used herein include, but are not
limited to:
[0272] 1. The HDM2/MDM2 inhibitors identified in Vassilev, et al.,
In vivo activation of the p53 pathway by small-molecule antagonists
of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et
al., Targeted intracellular protein degradation induced by a small
molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett.
18 (2008) 5904-5908, including (or additionally) the compounds
nutlin-3, nutlin-2, and nutlin-1 (derivatized) as described below,
as well as all derivatives and analogs thereof:
##STR00130##
(derivatized where a linker group L or a -(L-CLM)group is attached,
for example, at the methoxy group or as a hydroxyl group);
##STR00131##
(derivatized where a linker group L or a -(L-CLM) group is
attached, for example, at the methoxy group or hydroxyl group);
##STR00132##
(derivatized where a linker group L or a -(L-CLM) group is
attached, for example, via the methoxy group or as a hydroxyl
group); and
[0273] 2. Trans-4-Iodo-4'-Boranyl-Chalcone
##STR00133##
[0274] (derivatized where a linker group L or a a linker group L or
a -(L-CLM) group is attached, for example, via a hydroxy
group).
[0275] IV. Compounds Targeting Human BET Bromodomain-Containing
Proteins:
[0276] In certain embodiments, "PTM" can be ligands binding to
Bromo- and Extra-terminal (BET) proteins BRD2, BRD3 and BRD4.
Compounds targeting Human BET Bromodomain-containing proteins
include, but are not limited to the compounds associated with the
targets as described below, where "R" or "linker" designates a site
for linker group L or a -(L-CLM) group attachment, for example:
[0277] 1. JQ1, Filippakopoulos et al. Selective inhibition of BET
bromodomains. Nature (2010):
##STR00134## ##STR00135##
[0278] 2. I-BET, Nicodeme et al. Supression of Inflammation by a
Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and
Characterization of Small Molecule Inhibitors of the BET Family
Bromodomains. J. Med Chem. (2011):
##STR00136##
[0279] 3. Compounds described in Hewings et al.
3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J.
Med. Chem. (2011) 54 6761-6770.
##STR00137##
[0280] 4. I-BET151, Dawson et al. Inhibition of BET Recruitment to
Chromatin as an Effective Treatment for MLL-fusion Leukemia. Nature
(2011):
##STR00138##
[0281] 5. Carbazole type (US 2015/0256700)
##STR00139##
[0282] 6. Pyrrolopyridone type (US 2015/0148342)
##STR00140##
[0283] 7. Tetrahydroquinoline type (WO 2015/074064)
##STR00141##
[0284] 8. Triazolopyrazine type (WO 2015/067770)
##STR00142##
[0285] 9. Pyridone type (WO 2015/022332)
##STR00143##
[0286] 10. Quinazolinone type (WO 2015/015318)
##STR00144##
[0287] 11. Dihydropyridopyrazinone type (WO 2015/011084)
##STR00145##
[0288] (Where R or L or linker, in each instance, designates a site
for attachment, for example, of a linker group L or a -(L-CLM)
group).
[0289] In any aspect or embodiment described herein, the claimed
structure the PTM may be composed of tricyclic diazepine or
tricyclic azepine as a BET/BRD4 targeting moiety (PTM-a), where the
dashed lines indicate the linker connection trajectory and three
sites are defined to which linkers may be attached:
##STR00146##
wherein: [0290] A and B are independently an aromatic ring, a
heteroaromatic ring, a 5-membered carbocyclic, a 6-membered
carbocyclic, a 5-membered heterocyclic, a 6-membered heterocyclic,
a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a
pyrazine, optionally substituted by alkyl, aloxy, halogen, nitrile
or another aromatic or heteroaromatic ring, where A is fused to the
central azepine (Y1=C) or diazepine (Y1=N) moiety; [0291] Y1, Y2,
and Y3 and Y4 can be carbon, nitrogen or oxygen for to form a fused
5-membered aromatic ring as triazole or isoxazole; and [0292] Z1 is
methyl, or lower alkyl group.
[0293] The fragment of PTM-a as BET/BRD4 targeting moiety is
described in the literature (WO 2016/069578; WO2014/001356;
WO2016/050821; WO 2015/195863; WO 2014/128111).
[0294] In any aspect or embodiment described herein comprising the
structure CLM-L-PTM-a, PTM-a can be represented by the following
general structures, where dashed line indicates a possible linker
connection point. In structure PTM-aa through PTM-ai, the
substitution pattern of X and Y can be mono- or
bis-substitution.
##STR00147## ##STR00148## ##STR00149##
[0295] In any aspect or embodiment described herein, the structures
of PTM-a as the BET/BRD4 targeting moiety includes, wherein the
dashed line indicates the connection point between the BET/BRD4
targeting moiety and the linkers:
##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154##
##STR00155## ##STR00156## ##STR00157##
[0296] V. HDAC Inhibitors:
[0297] HDAC Inhibitors (derivatized) include, but are not limited
to:
[0298] 1. Finnin, M. S. et al. Structures of Histone Deacetylase
Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193
(1999).
##STR00158##
(Derivatized where "R" designates a site for attachment, for
example, of a linker group L or a -(L-CLM) group); and
[0299] 2. Compounds as defined by formula (I) of PCT WO0222577
("DEACETYLASE INHIBITORS") (Derivatized where a linker group L or a
-(L-CLM) group is attached, for example, via the hydroxyl
group);
[0300] VI. Human Lysine Methyltransferase Inhibitors:
[0301] Human Lysine Methyltransferase inhibitors include, but are
not limited to:
[0302] 1. Chang et al. Structural Basis for G9a-Like protein Lysine
Methyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009)
16(3) 312.
##STR00159##
[0303] (Derivatized where "R" designates a site for attachment, for
example, of a linker group L or a -(L-CLM) group);
[0304] 2. Liu, F. et al Discovery of a
2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective
Inhibitor of Histone Methyltransferase G9a. J. Med. Chem. (2009)
52(24) 7950.
##STR00160##
[0305] (Derivatized where "R" designates a potential site for
attachment, for example, of a linker group L or a -(L-CLM)
group);
[0306] 3. Azacitidine (derivatized)
(4-amino-1-.beta.-D-ribofuranosyl-1,3,5-triazin-2(1H)-one)
(Derivatized where a linker group L or a -(L-CLM) group is
attached, for example, via the hydroxy or amino groups); and
[0307] 4. Decitabine (derivatized)
(4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1, 3,
5-triazin-2(1H)-one) (Derivatized where a linker group L or a
-(L-CLM) group is attached, for example, via either of the hydroxy
groups or at the amino group).
[0308] VII. Angiogenesis Inhibitors:
[0309] Angiogenesis inhibitors include, but are not limited to:
[0310] 1. GA-1 (derivatized) and derivatives and analogs thereof,
having the structure(s) and binding to linkers as described in
Sakamoto, et al., Development of Protacs to target cancer-promoting
proteins for ubiquitination and degradation, Mol Cell Proteomics
2003 December; 2(12):1350-8;
[0311] 2. Estradiol (derivatized), which may be bound to a linker
group L or a -(L-CLM) group as is generally described in
Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for
ubiquitination and degradation in breast and prostate cancer,
Oncogene (2008) 27, 7201-7211;
[0312] 3. Estradiol, testosterone (derivatized) and related
derivatives, including but not limited to DHT and derivatives and
analogs thereof, having the structure(s) and binding to a linker
group L or a -(L-CLM) group as generally described in Sakamoto, et
al., Development of Protacs to target cancer-promoting proteins for
ubiquitination and degradation, Mol Cell Proteomics 2003 December;
2(12):1350-8; and
[0313] 4. Ovalicin, fumagillin (derivatized), and derivatives and
analogs thereof, having the structure(s) and binding to a linker
group L or a -(L-CLM) group as is generally described in Sakamoto,
et al., Protacs: chimeric molecules that target proteins to the
Skp1-Cullin-F box complex for ubiquitination and degradation Proc
Natl Acad Sci USA. 2001 Jul. 17; 98(15):8554-9 and U.S. Pat. No.
7,208,157.
[0314] VIII. Immunosuppressive Compounds:
[0315] Immunosuppressive compounds include, but are not limited
to:
[0316] 1. AP21998 (derivatized), having the structure(s) and
binding to a linker group L or a -(L-CLM) group as is generally
described in Schneekloth, et al., Chemical Genetic Control of
Protein Levels: Selective in Vivo Targeted Degradation, J. AM.
CHEM. SOC. 2004, 126, 3748-3754;
[0317] 2. Glucocorticoids (e.g., hydrocortisone, prednisone,
prednisolone, and methylprednisolone) (Derivatized where a linker
group L or a -(L-CLM) group is to bound, e.g. to any of the
hydroxyls) and beclometasone dipropionate (Derivatized where a
linker group or a -(L-CLM) is bound, e.g. to a proprionate);
[0318] 3. Methotrexate (Derivatized where a linker group or a
-(L-CLM) group can be bound, e.g. to either of the terminal
hydroxyls);
[0319] 4. Ciclosporin (Derivatized where a linker group or a
-(L-CLM) group can be bound, e.g. at any of the butyl groups);
[0320] 5. Tacrolimus (FK-506) and rapamycin (Derivatized where a
linker group L or a -(L-CLM) group can be bound, e.g. at one of the
methoxy groups); and
[0321] 6. Actinomycins (Derivatized where a linker group L or a
-(L-CLM) group can be bound, e.g. at one of the isopropyl
groups).
[0322] IX. Compounds Targeting the Aryl Hydrocarbon Receptor
(AHR):
[0323] Compounds targeting the aryl hydrocarbon receptor (AHR)
include, but are not limited to:
[0324] 1. Apigenin (Derivatized in a way which binds to a linker
group L or a -(L-CLM) group as is generally illustrated in Lee, et
al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the
PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume
8, Issue 17, pages 2058-2062, Nov. 23, 2007); and
[0325] 2. SR1 and LGC006 (derivatized such that a linker group L or
a -(L-CLM) is bound), as described in Boitano, et al., Aryl
Hydrocarbon Receptor Antagonists Promote the Expansion of Human
Hematopoietic Stem Cells, Science 10 Sep. 2010: Vol. 329 no. 5997
pp. 1345-1348.
[0326] X. Compounds targeting RAF Receptor (Kinase):
##STR00161##
[0327] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment, for example).
[0328] Any protein, which can bind to a protein target moiety or
PTM group and acted on or degraded by an ubiquitin ligase (e.g.,
RAF) is a target protein according to the present disclosure.
[0329] In any aspect or embodiment described herein, the PTM
targets and/or binds RAF (i.e., a Raf or BRaf targeting moiety).
For example, in any aspect or embodiment described herein, the PTM
may comprise a chemical group selected from the group of chemical
structures consisting of PTM-Ia or PTM-Ib:
##STR00162##
wherein: [0330] double dotted bonds are aromaric bonds; [0331]
V.sub.PTM, W.sub.PTM, X.sub.PTM, Y.sub.PTM, Z.sub.PTM is one of the
following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C,
CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N,
CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C,
N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N,
N, C; [0332] X.sub.PTM35, X.sub.PTM36, X.sub.PTM37, and X.sub.PTM38
are independently selected from CH and N; [0333] R.sub.PTM1 is
covalently joined to a ULM, a chemical linker group (L), a CLM, an
ILM, a VLM, MLM, a ULM', a CLM', a ILM', a VLM', a MLM', or
combination thereof; [0334] R.sub.PTM2 is hydrogen, halogen, aryl,
methyl, ethyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle; [0335] R.sub.PTM3 is absent, hydrogen,
aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH.sub.3,
NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O
and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle; [0336] R.sub.PTM4 is hydrogen, halogen, aryl, methyl,
ethyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein
M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl,
aryl or heterocycle; and [0337] R.sub.PTM5 is selected from the
group consisting of
##STR00163##
[0338] In any aspect or embodiment described herein, the PTM may
comprise a chemical group selected from the group of chemical
structures consisting of PTM-IIa or PTM-IIb:
##STR00164##
wherein: [0339] X.sub.PTM1, X.sub.PTM2, X.sub.PTM3, X.sub.PTM4,
X.sub.PTM5, and X.sub.PTM6 are independently selected from CH or N;
[0340] R.sub.PTM5a is selected from the group consisting of: bond,
optionally substituted amine, optionally substituted amide (e.g.,
optionally substituted with an alkyl, methyl, ethyl, propyl, or
butyl group), H,
[0340] ##STR00165## --NHC(O)R.sub.PTM5; [0341] R.sub.PTM5 is
selected from the group consisting of
[0341] ##STR00166## [0342] R.sub.PTM6a and R.sub.PTM6b are each
independently selected from hydrogen, halogen, or optionally
substituted C.sub.1-C.sub.6 alkyl (linear, branched, optionally
substituted); [0343] R.sub.PTM6 is absent, hydrogen, halogen, aryl,
methyl, ethyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle; [0344] R.sub.PTM7 is absent, hydrogen,
halogen, aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O or NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [0345]
R.sub.PTM8, R.sub.PTM9 or R.sub.PTM10 are independently selected
from the group consisting of absent, hydrogen, halogen, aryl,
heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl,
OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is
CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or heterocycle; [0346] R.sub.PTM11 is absent, hydrogen, halogen,
methyl, ethyl, OCH.sub.3, NH CH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O or NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle; and [0347] at least one of R.sub.PTM8,
R.sub.PTM9 or R.sub.PTM10 is modified to be covalently joined to a
ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM, a
ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof.
[0348] In certain embodiments, the PTM may comprise a chemical
group selected from the group of chemical structures consisting
of:
##STR00167##
wherein R.sub.PTM5, R.sub.PTM6a, R.sub.PTM6b, R.sub.PTM6,
R.sub.PTM7, R.sub.PTM8, R.sub.PTM9, R.sub.PTM10, R.sub.PTM11 are as
described herein.
[0349] In some embodiments, when R.sub.PTM9 is the covalently
joined position, R.sub.PTM7 and R.sub.PTM8 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM7 and R.sub.PTM8 are attached.
[0350] In other embodiments, when R.sub.PTM8 is the covalently
joined position, R.sub.PTM9 and R.sub.PTM10 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM9 and R.sub.PTM10 are attached.
[0351] In further embodiments, when R.sub.PTM10 is the covalently
joined position, Rp.sub.PTM8 and R.sub.PTM9 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM8 and R.sub.PTM9 are attached.
[0352] In any aspect or embodiment described herein, the PTM may
comprise a chemical group selected from the group of chemical
structures consisting of PTM-III:
##STR00168##
wherein:
[0353] X.sub.PTM7, X.sub.PTM8, X.sub.PTM9, X.sub.PTM10,
X.sub.PTM11, X.sub.PTM12, X.sub.PTM13, X.sub.PTM14, X.sub.PTM15,
X.sub.PTM16, X.sub.PTM17, X.sub.PTM18, X.sub.PTM19, X.sub.PTM20 are
independently CH or N; [0354] R.sub.PTM12, R.sub.PTM13,
R.sub.PTM14, R.sub.PTM15, R.sub.PTM16, R.sub.PTM17, R.sub.PTM18,
R.sub.PTM19 are independently selected from the group consisting of
absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl,
heterocycle, methyl, ethyl, other alkyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [0355]
R.sub.PTM20 is a small group containing less than four non-hydrogen
atoms; [0356] R.sub.PTM21 is selected from the group consisting of
trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl,
isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, OCH.sub.3, NHCH.sub.3, dimethylamino or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O or NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and [0357]
at least one of R.sub.PTM12, R.sub.PTM13 and R.sub.PTM16 is
modified to be covalently joined to a ULM, a chemical linker group
(L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM', a VLM', a
MLM', or combination thereof.
[0358] In some embodiments, when R.sub.PTM12 is the covalently
joined position, R.sub.PTM13 and R.sub.PTM14 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM13 and R.sub.PTM14 are attached; and/or
R.sub.PTM15 and R.sub.PTM16 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM15 and R.sub.PTM16 are attached.
[0359] In other embodiments, when R.sub.PTM13 is the covalently
joined position, R.sub.PTM12 and R.sub.PTM16 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM12 and R.sub.PTM16 are attached; and/or
R.sub.PTM15 and R.sub.PTM16 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM15 and R.sub.PTM16 are attached.
[0360] In further embodiments, when R.sub.PTM16 is the covalently
joined position, R.sub.PTM12 and R.sub.PTM13 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM12 and R.sub.PTM13 are attached; and/or
R.sub.PTM13 and R.sub.PTM14 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM13 and R.sub.PTM14 are attached.
[0361] In any aspect or embodiment described herein, the PTM may
comprise a chemical group selected from the group of chemical
structures consisting of PTM-IVa or PTM-IVb:
##STR00169##
wherein: [0362] X.sub.PTM21, X.sub.PTM22, X.sub.PTM23, X.sub.PTM24,
X.sub.PTM25, X.sub.PTM26, X.sub.PTM27, X.sub.PTM28, X.sub.PTM29,
X.sub.PTM30, X.sub.PTM31, X.sub.PTM32, X.sub.PTM33, X.sub.PTM34 are
independently CH or N; [0363] R.sub.PTM22 is selected from the
group consisting of
[0363] ##STR00170## [0364] R.sub.PTM25a and R.sub.PTM25b are each
independently selected from hydrogen, halogen, or C.sub.1-C.sub.6
alkyl (linear, branched, optionally substituted); [0365]
R.sub.PTM23, R.sub.PTM24, R.sub.PTM28, R.sub.PTM29, R.sub.PTM30,
R.sub.PTM31, R.sub.PTM32 are independently selected from the group
consisting of absent, bond, hydrogen, halogen, aryl (optionally
substituted), heteroaryl (optionally substituted), cycloalkyl
(optionally substituted), heterocycle (optionally substituted),
methyl, ethyl (optionally substituted), other alkyl (linear,
branched, optionally substituted), OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl (linear, branched, optionally substituted),
cyclic alkyl (optionally substituted), aryl (optionally
substituted) or heterocycle (optionally substituted); and [0366]
R.sub.PTM25 is absent, hydrogen, halogen, C.sub.1-C.sub.6 alkyl
(linear, branched, optionally substituted), OCH3, NHCH.sub.3 or
SCH.sub.3; [0367] R.sub.PTM26 is absent, hydrogen, halogen,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted),
OCH3, NHCH.sub.3 or SCH.sub.3; [0368] R.sub.PTM27 is selected from
the group consisting of absent, hydrogen, halogen, C.sub.1-C.sub.6
alkyl (linear, branched, optionally substituted), OCH.sub.3,
NHCH.sub.3 or SCH.sub.3; and [0369] at least one of R.sub.PTM24,
R.sub.PTM29, R.sub.PTM32 is modified to be covalently joined to a
ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM, a
ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof.
[0370] In some embodiments, when R.sub.PTM24 is the covalently
joined position, R.sub.PTM31 and R.sub.PTM32 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM31 and R.sub.PTM32 are attached; or
R.sub.PTM29 and R.sub.PTM30 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM29 and R.sub.PTM30 are attached.
[0371] In other embodiments, when R.sub.PTM29 is the covalently
joined position, R.sub.PTM24 and R.sub.PTM32 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM24 and R.sub.PTM32 are attached; and/or
R.sub.PTM31 and R.sub.PTM32 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM31 and R.sub.PTM32 are attached.
[0372] In further embodiments, when R.sub.PTM32 is the covalently
joined position, R.sub.PTM24 and R.sub.PTM29 can be connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which R.sub.PTM24 and R.sub.PTM29 are attached; and/or
R.sub.PTM29 and R.sub.PTM30 can be connected together via a
covalent bond in a way to form a bicyclic group with the ring to
which R.sub.PTM29 and R.sub.PTM30 are attached.
[0373] In any aspect or embodiments described herein, the PTM is
selected from the group consisting of chemical structures PTM-1,
PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8:
##STR00171## ##STR00172## ##STR00173##
[0374] XI. Compounds Targeting FKBP:
##STR00174##
[0375] (Derivatized where "R" designates a site for a linker group
L or a -(L-CLM) group attachment, for example).
[0376] XII. Compounds Targeting Androgen Receptor (AR)
[0377] 1. RU59063 Ligand (Derivatized) of Androgen Rceptor
##STR00175##
[0378] (Derivatized where "R" designates a site for a linker group
L or a -(L-CLM) group attachment, for example).
[0379] 2. SARM Ligand (derivatized) of Androgen Receptor
##STR00176##
[0380] (Derivatized where "R" designates a site for a linker group
L or a -(L-CLM) group attachment, for example).
[0381] 3. Androgen Receptor Ligand DHT (derivatized)
##STR00177##
[0382] (Derivatized where "R" designates a site for a linker group
L or -(L-CLM) group attachment, for example).
[0383] 4. MDV3100 Ligand (derivatized)
##STR00178##
[0384] 5. ARN-509 Ligand (derivatized)
##STR00179##
[0385] 6. Hexahydrobenzisoxazoles
##STR00180##
[0386] 7. Tetramethylcyclobutanes
##STR00181##
[0387] 8. In any aspect or embodiment described herein, the PTM is
a chemical moiety that binds to the androgen receptor (AR). Various
androgen receptor binding compounds have been described in
literature, including various androgen derivatives such as
testosterone, dihydrotestosterone, and metribolone (also known as
methyltrienolone or R1881), and non-steroidal compounds such as
bicalutamide, enzalutamide, some of which are described above.
Those of ordinary skill in the art would appreciate that these
androgen receptor binding compounds could be potentially used as an
androgen binding moiety (ABM) in a PROTAC compound. Such literature
includes, but not limited to, G. F. Allan et. al, Nuclear Receptor
Signaling, 2003, 1, e009; R. H. Bradbury et. al, Bioorganic &
Medicinal Chemistry Letters, 2011 5442-5445; C. Guo et. al,
Bioorganic & Medicinal Chemistry Letters, 2012 2572-2578; P. K.
Poutiainen et. al, J. Med. Chem. 2012, 55, 6316-6327 A. Pepe et.
al, J. Med. Chem. 2013, 56, 8280-8297; M. E. Jung et al, J. Med.
Chem. 2010, 53, 2779-2796, which are incorporated by reference
herein
[0388] In any aspect or embodiment described herein, the ABM
comprises a structure selected from, but not limited to the
structures shown below, wherein a dashed line indicates the
attachment point of a linker moiety or a ULM, such as a CLM:
##STR00182##
wherein: [0389] W.sup.1 is aryl, heteroaryl, bicyclic, or
biheterocyclic, each independently substituted by 1 or more H,
halo, hydroxyl, nitro, CN, C.ident.CH, C.sub.1-6 alkyl (linear,
branched, optionally substituted; for example, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), C.sub.1-6
alkoxyl (linear, branched, optionally substituted; for example,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; [0390] Y.sup.1, Y.sup.2 are each
independently NR.sup.Y1, O, S; [0391] Y.sup.3, Y.sup.4, Y.sup.5 are
each independently a bond, O, NR.sup.Y2, CR.sup.Y1R.sup.Y2,
C.dbd.O, C.dbd.S, SO, SO.sub.2, heteroaryl, or aryl; [0392] Q is a
3-6 membered ring with 0-4 heteroatoms, optionally substituted with
0-6 R.sup.Q, each R.sup.Q, is independently H, C.sub.1-6 alkyl
(linear, branched, optionally substituted; for example, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), halogen,
C.sub.1-6 alkoxy, or 2 R.sup.Q groups taken together with the atom
they are attached to, form a 3-8 membered ring system containing
0-2 heteroatoms); [0393] R.sup.1, R.sup.2, R.sup.a, R.sup.b,
R.sup.Y1, R.sup.Y2 are each independently H, C.sub.1-6 alkyl
(linear, branched, optionally substituted; for example, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), halogen,
C.sub.1-6 alkoxy, cyclic, heterocyclic, or R.sup.1, R.sup.2
together with the atom they are attached to, form a 3-8 membered
ring system containing 0-2 heteroatoms); [0394] W.sup.2 is a bond,
C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, O, aryl, heteroaryl,
alicyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl,
each optionally substituted by 1-10 R.sup.W2; [0395] each R.sup.W2
is independently H, halo, C.sub.1-6 alkyl (linear, branched,
optionally substituted; for example, optionally substituted by 1 or
more F), --OR.sup.W2A, C.sub.3-6 cycloalkyl, C.sub.4-6
cycloheteroalkyl, C.sub.1-6 alicyclic (optionally substituted),
heterocyclic (optionally substituted), aryl (optionally
substituted), or heteroaryl (optionally substituted), bicyclic
hereoaryl or aryl, OC.sub.1-3alkyl (optionally substituted), OH,
NH.sub.2, NR.sup.Y1R.sup.Y2, CN; and [0396] R.sup.W2A is H,
C.sub.1-6 alkyl (linear, branched), or C.sub.1-6heteroalkyl
(linear, branched), each optionally substituted by a cycloalkyl,
cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or
OC.sub.1-3alkyl.
[0397] In any aspect or embodiment described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0398] In any aspect or embodiment described herein, W.sup.1 is
##STR00183##
wherein each R.sub.22 is independently halo, H, optionally
substituted alkyl, haloalkyl, cyano, or nitro; and each R.sub.23 is
independently H, halo, CF.sub.3, optionally substituted alkyl,
alkoxy, haloalkyl, cyano, or nitro.
[0399] In any aspect or embodiment described herein, W.sup.1 is
selected from the group consisting of:
##STR00184##
[0400] In any aspect or embodiment described herein, the ABM
comprises a structure selected from the following structures shown
below, where a indicates tha attachment point of a linker or a
ULM:
##STR00185##
wherein: [0401] R.sup.Q2 is a H, halogen, CH.sub.3 or CF.sub.3;
[0402] R.sup.Q3 is H, halo, hydroxyl, nitro, CN, C.ident.CH,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C.sub.1-6 alkoxyl), C.sub.1-6 alkoxyl (linear, branched,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; [0403] Y.sup.3, Y.sup.4, Y.sup.5
are each independently a bond, O, NR.sup.Y2, CR.sup.Y1R.sup.Y2,
C.dbd.O, heteroaryl, or aryl, [0404] R.sup.Y1, R.sup.Y2 are each
independently H, or C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl, cyclic, or
heterocyclic); and [0405] R.sup.Q each independently is H,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted by
1 or more halo, or C.sub.1-6 alkoxyl), or two R.sup.Q together with
the atom they are attached to, form a 3-8 membered ring system
containing 0-2 heteroatoms.
[0406] In any aspect or embodiment described herein, each R.sup.Q
is independently H or CH.sub.3. In another embodiment R.sup.Q3 is
CN.
[0407] In any aspect or embodiment described herein, the ABM
comprises a structure selected from the following structures shown
below, where a indicates the attachment point of a linker or a
ULM:
##STR00186##
wherein: [0408] R.sup.2 is a H, halogen, CN, CH.sub.3 or CF.sub.3;
and [0409] R.sup.Q3 is H, halo, hydroxyl, nitro, CN, C.ident.CH,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C.sub.1-6 alkoxyl), C.sub.1-6 alkoxyl (linear, branched,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; [0410] Y.sup.3, Y.sup.4, Y.sup.5
are each independently a bond, O, NR.sup.Y2, CR.sup.Y1R.sup.Y2,
C.dbd.O, heteroaryl, or aryl; and [0411] R.sup.Y1, R.sup.Y2 are
each independently H or C.sub.1-6 alkyl (linear, branched,
optionally substituted by 1 or more halo, C.sub.1-6 alkoxyl,
cyclic, or heterocyclic); and [0412] X is N or C.
[0413] In any aspect or embodiment described herein, R.sup.Q3 is a
CN.
[0414] In any aspect or embodiment described herein, the ABM
comprises a structure shown below, where a dashed line indicates
the attachment point of a linker moiety or a ULM or a CLM:
##STR00187##
wherein: [0415] W.sup.1 is
[0415] ##STR00188## [0416] each R.sub.22 is independently H or
--CN; [0417] each R.sub.23 is independently H, halo,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted),
C.sub.1-C.sub.6 alkoxy, or --CF.sub.3; [0418] Y.sup.3 is a bond or
O; [0419] Y.sup.4 is a bond or NH; [0420] Y.sup.5 is a bond,
C.dbd.O, C.sub.1-C.sub.6 heteroaryl, or C.sub.1-C.sub.6 aryl;
[0421] R.sup.1, R.sup.2, are each independently H, or
C.sub.1-C.sub.6 alkyl (linear or branched, optionally substituted;
for example, optionally substituted by 1 or more halo, or C.sub.1-6
alkoxyl); [0422] W.sup.2 is a bond, C.sub.1-6 aryl, C.sub.1-6
heteroaryl, C.sub.1-6 alicyclic, or C.sub.1-6 heterocyclic,
biheterocyclic, biaryl, or biheteroaryl, each optionally
substituted by 1-10 R.sup.W2; and [0423] each R.sup.W2 is
independently H, or halo; and [0424] represents a bond that may be
stereospecific ((R) or (S)) or non-stereospecific.
[0425] In any aspect or embodiment described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0426] In any aspect or embodiment described herein, W.sup.1 is
selected from the group consisting of:
##STR00189##
[0427] In any aspect or embodiment described herein, W.sup.2 is
selected from the group consisting of:
##STR00190## ##STR00191##
[0428] In any aspect or embodiment described herein, the ABM
comprises a structure selected from, but not limited to the
structures shown below, where a dashed line indicates the
attachment point of a linker moiety or a ULM:
##STR00192##
wherein: [0429] W.sup.1 is
[0429] ##STR00193## [0430] each R.sub.22 is independently H or
--CN; [0431] each R.sub.23 is independently H, halo, or --CF.sub.3;
[0432] Y.sup.1, Y.sup.2 are each independently O or S; [0433]
R.sup.1, R.sup.2, are each independently H or a methyl group;
[0434] W.sup.2 is a bond, C.sub.1-6 aryl, or heteroaryl, each
optionally substituted by 1, 2 or 3 R.sup.W2; and [0435] each
R.sup.W2 is independently H, halo, C.sub.1-6 alkyl (optionally
substituted by 1 or more F), OC.sub.1-3alkyl (optionally
substituted by 1 or more --F).
[0436] In any of the embodiments described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0437] In certain additional embodiments, W.sup.1 is selected from
the group consisting of:
##STR00194##
[0438] In any aspect or embodiment described herein, W2 is selected
from the group consisting of:
##STR00195##
[0439] In any aspect or embodiment described herein, ABM is
selected from the group consisting of:
##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200##
##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205##
##STR00206## ##STR00207## ##STR00208## ##STR00209##
##STR00210##
[0440] In any aspect or embodiment described herein, the ABM
comprises the structure:
##STR00211##
wherein: [0441] W.sup.1 is aryl, or heteroaryl, each independently
substituted by 1 or more H, halo, hydroxyl, nitro, CN, C.ident.CH,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C.sub.1-6 alkoxyl), C.sub.1-6 alkoxyl (linear, branched,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; [0442] Y.sup.3, Y.sup.4, Y.sup.5
are each independently a bond, O, NR.sup.Y2, CR.sup.Y1R.sup.Y2,
C.dbd.O, C.dbd.S, SO, SO.sub.2, heteroaryl, or aryl; [0443] Q is a
4 membered alicyclic ring with 0-2 heteroatoms, optionally
substituted with 0-6 R.sup.Q, each R.sup.Q is independently H,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C.sub.1-6 alkoxyl), or 2 R.sup.Q groups taken together
with the atom they are attached to, form a 3-8 membered ring system
containing 0-2 heteroatoms); [0444] R.sup.Y1, R.sup.Y2 are each
independently H, C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl); [0445] W.sup.2
is a bond, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, O, C.sub.1-6
alicyclic, heterocyclic, aryl, biheterocyclic, biaryl, or
biheteroaryl, or heteroaryl, each optionally substituted by 1, 2 or
3 R.sup.W2; and [0446] each R.sup.W2 is independently H, halo,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more F), C.sub.1-6 heteroalkyl (linear, branched, optionally
substituted), --OR.sup.W2A OC.sub.1-3alkyl (optionally substituted
by 1 or more --F), C.sub.3-6 cycloalkyl, C.sub.4-6 cycloheteroalkyl
(optionally substituted), C.sub.1-6 alkyl (optionally substituted),
C.sub.1-6 alicyclic (optionally substituted), heterocyclic
(optionally substituted), aryl (optionally substituted), heteroaryl
(optionally substituted), bicyclic hereoaryl (optionally
substituted), bicyclic aryl, OH, NH.sub.2, NR.sup.Y1R.sup.Y2, or
CN; and [0447] R.sup.W2A is H, C.sub.1-6 alkyl (linear, branched),
or C.sub.1-6 heteroalkyl (linear, branched), each optionally
substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic,
heteroaryl, halo, or OC.sub.1-3alkyl.
[0448] In any aspect or embodiment described herein, the
description provides an androgen receptor binding compound
comprising a structure of:
##STR00212##
wherein: [0449] W.sup.1 is aryl, heteroaryl, bicyclic, or
biheterocyclic, each independently substituted by 1 or more H,
halo, hydroxyl, nitro, CN, C.ident.CH, C.sub.1-6 alkyl (linear,
branched, optionally substituted by 1 or more halo, C.sub.1-6
alkoxyl), C.sub.1-6 alkoxyl (linear, branched, optionally
substituted by 1 or more halo), C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or CF.sub.3; [0450] Y.sup.1, Y.sup.2 are each
independently NR.sup.Y1, O, or S; [0451] Y.sup.3, Y.sup.4, Y.sup.5
are each independently a bond, O, NR.sup.Y2, CR.sup.Y1R.sup.Y2,
C.dbd.O, C.dbd.S, SO, SO.sub.2, heteroaryl, or aryl; [0452] Q is a
3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
optionally substituted with 0-6 R.sup.Q, each R.sup.Q, is
independently H, C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), or 2 R.sup.Q
groups taken together with the atom they are attached to, form a
3-8 membered ring system containing 0-2 heteroatoms); [0453]
R.sup.1, R.sup.2, R.sup.a, R.sup.b, R.sup.Y1, R.sup.Y2 are each
independently H, C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), or R.sup.1,
R.sup.2 together with the atom they are attached to, form a 3-8
membered ring system containing 0-2 heteroatoms); [0454] W.sup.2 is
a bond, C.sub.1-6 alkyl, C.sub.1-6heteroalkyl, O, C.sub.1-6
alicyclic, heterocyclic, aryl, biheterocyclic, biaryl, or
biheteroaryl, or heteroaryl, each optionally substituted by 1, 2 or
3 R.sup.W2; [0455] each R.sup.W2 is independently H, halo,
C.sub.1-6 alkyl (linear, branched, optionally substituted by 1 or
more F), C.sub.1-6heteroalkyl (linear, branched, optionally
substituted), --OR.sup.W2A, OC.sub.1-3alkyl (optionally substituted
by 1 or more --F), C.sub.3-6 cycloalkyl, C.sub.4-6
cycloheteroalkyl, C.sub.1-6 alkyl (optionally substituted),
C.sub.1-6 alicyclic (optionally substituted), heterocyclic
(optionally substituted), aryl (optionally substituted), or
heteroaryl (optionally substituted), bicyclic hereoaryl or aryl,
OH, NH.sub.2, NR.sup.Y1R.sup.Y2, CN; and [0456] R.sup.W2A is H,
C.sub.1-6 alkyl (linear, branched), or C.sub.1-6heteroalkyl
(linear, branched), each optionally substituted by a cycloalkyl,
cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or
OC.sub.1-3alkyl.
[0457] In any aspect or embodiment described herein, an androgen
receptor binding moiety has a structure of:
##STR00213##
wherein: [0458] W.sup.1 is
[0458] ##STR00214## [0459] each R.sub.22 is independently H or
--CN; [0460] each R.sub.23 is independently H, halo, or --CF.sub.3;
[0461] Y.sup.3 is a bond or O; [0462] Q is a 4 member ring,
optionally substituted with 0-4 R.sup.Q, each R.sup.Q is
independently H or methyl; [0463] Y4 is a bond or NH; [0464] Y5 is
a bond, a C.dbd.O, or a C.dbd.S; and [0465] each W.sup.2 is
independently a bond, C1-6 aryl or heteroaryl, each optionally
substituted by 1, 2 or 3 R.sup.W2, each R.sup.W2 is independently
H, halo, a 6 member alicyclic ring with 1 or 2 heteroatoms or a 5
member aromatic ring with 1 or 2 or 3 heteroatoms.
[0466] In any aspect or embodiment described herein, W.sup.2 is
selected from the group consisting of:
##STR00215##
[0467] In any aspect or embodiment described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0468] In any aspect or embodiment described herein, W.sup.1 is
selected from the group consisting of:
##STR00216##
[0469] In any aspect or embodiment described herein, an androgen
binding moiety has a structure of:
##STR00217##
wherein: [0470] W.sup.1 is aryl, independently substituted by 1 or
more halo, CN; [0471] Y.sup.3 are each independently a bond,
NR.sup.Y2, CR.sup.Y1R.sup.Y2, C.dbd.O; [0472] Q is a 5 membered
aromatic ring with 1 or 2 heteroatoms; [0473] R.sup.Y1, R.sup.Y2
are each independently H, C.sub.1-6 alkyl (linear, branched);
[0474] W.sup.2 is a bond, aryl, or heteroaryl, each optionally
substituted by 1, 2 or 3 R.sup.W2; and each R.sup.W2 is
independently H, halo, C.sub.1-6 alkyl (optionally substituted by 1
or more F), OC.sub.1-3alkyl (optionally substituted by 1 or more
--F).
[0475] In any aspect or embodiment described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0476] In any aspect or embodiment described herein, W.sup.1 is
##STR00218##
wherein each R.sub.22 is independently halo or CN; and each
R.sub.23 is independently H or halo.
[0477] In any aspect or embodiment described herein, W.sup.1 is
selected from the group consisting of:
##STR00219##
[0478] In any aspect or embodiment described herein, Q is
##STR00220##
[0479] In any aspect or embodiment described herein, W.sup.2 is
##STR00221##
[0480] In any aspect or embodiment described herein,
(Y.sup.3).sub.0-5 is
##STR00222##
[0481] In any aspect or embodiment described herein, the ABM
comprises a structure selected from, but not limited to the
structures shown below, where a dashed line indicates the
attachment point of a linker moiety or a ULM, such as a CLM:
##STR00223##
wherein: [0482] W.sup.1 is
[0482] ##STR00224## [0483] each R.sub.22 is independently H or
--CN; [0484] each R.sub.23 is independently H, halo, or --CF.sub.3;
[0485] Y.sup.1, Y.sup.2 are each independently O or S; [0486]
Y.sup.3, Y.sup.4, Y.sup.5 are each independently a bond, O,
NR.sup.Y2, CR.sup.Y1R.sup.Y2, C.dbd.O, C.dbd.S, SO, or SO.sub.2;
[0487] R.sup.1, R.sup.2, are each independently H or a methyl
group; [0488] W.sup.2 is a bond, C.sub.1-6 aryl, or heteroaryl,
each optionally substituted by 1, 2 or 3 R.sup.W2; and [0489] each
R.sup.W2 is independently H, halo, C.sub.1-6 alkyl (optionally
substituted by 1 or more F), C.sub.3-6 cycloalkyl, C.sub.4-6
cycloheteroalkyl, OC.sub.1-3alkyl (optionally substituted by 1 or
more --F).
[0490] In any aspect or embodiment described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0491] In any aspect or embodiment described herein, W.sup.1 is
selected from the group consisting of:
##STR00225##
[0492] In any aspect or embodiment described herein, W2 is selected
from the group consisting of:
##STR00226##
[0493] In any aspect or embodiment described herein, the ABM
comprises a structure shown below, where a dashed line indicates
the attachment point of a linker moiety or a ULM or a CLM:
##STR00227##
wherein: [0494] W.sup.1 is
[0494] ##STR00228## [0495] each R.sub.22 is independently H or
--CN; [0496] each R.sub.23 is independently H, halo, or --CF.sub.3;
[0497] Y.sup.3 is a bond or O; [0498] Y.sup.4 is a bond or NH;
[0499] Y.sup.5 is a bond, C.dbd.O, C.sub.1-C.sub.6 heteroaryl, or
C.sub.1-C.sub.6 aryl; [0500] R.sup.1, R.sup.2, are each
independently H, or C.sub.1-C.sub.6 alkyl (linear or branched,
optionally substituted by 1 or more halo, or C.sub.1-6 alkoxyl);
[0501] W.sup.2 is a bond, C.sub.1-6 aryl, C.sub.1-6 heteroaryl,
C.sub.1-6 alicyclic, or C.sub.1-6 heterocyclic, each optionally
substituted by 1-10 R.sup.W2; and [0502] each R.sup.W2 is
independently H, or halo; and
[0503] represents a bond that may be stereospecific ((R) or (S)) or
non-stereospecific.
[0504] In any of the embodiments described herein, the W.sup.2 is
covalently coupled to one or more ULM or CLM groups, or a linker to
which is attached one or more ULM or CLM groups as described
herein.
[0505] In certain additional embodiments, W.sup.1 is selected from
the group consisting of:
##STR00229##
[0506] In certain additional embodiments, W.sup.2 is selected from
the group consisting of:
##STR00230## ##STR00231##
[0507] In certain embodiments, the androgen receptor binding
compound of ABM is selected from the group consisting of: [0508]
trans-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;
[0509]
cis-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitril-
e; [0510] trans
6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyri-
dazine-3-carboxamide; [0511] trans tert-Butyl
N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate;
[0512] trans
4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benz-
amide; [0513] trans
5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyra-
zine-2-carboxamide; [0514] trans
2-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyri-
midine-5-carboxamide; [0515]
4-Methoxy-N-[(1r,3)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utyl]benzamide; [0516] trans
1-(2-Hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycl-
obutyl]-1H-pyrazole-4-carboxamide; [0517] trans
6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyri-
dine-3-carboxamide; [0518] trans
4-[(5-Hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrame-
thylcyclobutyl]benzamide; and [0519] trans tert-Butyl
2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]car-
bamoyl}phenyl)aminopentyl}oxy)acetate; and [0520]
N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenz-
amide.
[0521] XIII. Compounds Targeting Estrogen Receptor (ER)
ICI-182780
[0522] 1. Estrogen Receptor Ligand
##STR00232##
[0523] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment).
[0524] In any embodiment or aspect described herein, the PTM may be
represented by the Formula PTM-I:
##STR00233##
wherein: [0525] X.sub.PTM is O or C.dbd.O;
[0526] each of X.sub.PTM1 and X.sub.PTM2 is independently selected
from N or CH; [0527] R.sub.PTM1 is independently selected from OH,
O(CO)R.sub.PTM, O-lower alkyl, wherein R.sub.PTM is an alkyl or
aryl group in the ester; [0528] at least one R.sub.PTM2, each
independently selected from H, OH, halogen, CN, CF.sub.3,
SO.sub.2-alkyl, O-lower alkyl; [0529] at least one R.sub.PTM3, each
independently selected from H, halogen; and [0530] the dashed line
indicates the site of attachment of at least one linker, CLM, CLM',
PTM, PTM', or a combination thereof.
[0531] In any embodiment or aspect described herein, the PTM may be
represented by the Formula PTM-I:
##STR00234##
wherein: [0532] X.sub.PTM is O or C.dbd.O;
[0533] each of X.sub.PTM1 and X.sub.PTM2 is independently selected
from N or CH; [0534] R.sub.PTM1 is independently selected from OH,
O(CO)R.sub.P, O-lower alkyl, wherein R.sub.PTM is an alkyl or aryl
group in the ester; [0535] each R.sub.PTM2 is independently
selected from H, OH, halogen, CN, CF.sub.3, SO.sub.2-alkyl, O-lower
alkyl; [0536] each R.sub.PTM3 is independently selected from H,
halogen; [0537] the PTM-I comprises as least one R.sub.PTM2, at
least one R.sub.PTM3, or a combination thereof on the respective
rings; and [0538] the dashed line indicates the site of attachment
of at least one linker, CLM, CLM', PTM, PTM', or a combination
thereof.
[0539] In any embodiment or aspect described herein, PTM-I has at
least one of: two R.sub.PTM2, two R.sub.PTM3, or a combination
thereof.
[0540] In any embodiment or aspect described herein, the PTM may be
represented by the Formula PTM-II:
##STR00235##
wherein: [0541] X.sub.PTM is O or C.dbd.O; [0542] each of
X.sub.PTM1 and X.sub.PTM2 is independently selected from N or CH;
[0543] R.sub.PTM1 is independently selected from OH,
O(CO)R.sub.PTM, O-lower alkyl, wherein R.sub.PTM is an alkyl or
aryl group in the ester; [0544] R.sub.PTM2 and R.sub.PTM4 are
independently selected from H, OH, halogen, CN, CF.sub.3,
SO.sub.2-alkyl, O-lower alkyl; [0545] R.sub.PTM3 and R.sub.PTM5 are
independently selected from H, halogen; and [0546] the dashed line
indicates the site of attachment of at least one linker, CLM, CLM',
PTM, PTM', or a combination thereof.
[0547] In aspect or embodiment described herein, O(CO)R.sub.PTM
functions as a prodrug of the corresponding phenol in Formula PTM-I
or PTM-II.
[0548] In any embodiment or aspect described herein, the O-lower
alkyl of PTM-I or PTM-II an alkyl chain with carbon number 1 to
3.
[0549] In aspect or embodiment described herein, the present
disclosure provides a compound or PTM of Formula (I.sub.PTM):
##STR00236##
wherein: [0550] each X.sub.PTM is independently CH, N; [0551]
indicates the site of attachment of at least one linker, CLM, CLM',
PTM, PTM', or a combination thereof; [0552] each R.sub.PTM1 is
independently OH, halogen, O(CO)R.sub.PTM, where R.sub.PTM is alkyl
or cycloalkyl group with 1 to 6 carbons or aryl groups,
substitution can be mono-, di- or tri-substituted; [0553] each
R.sub.PTM2 is independently H, halogen, CN, CF.sub.3, alkoxy,
substitution can be mono- or di-substitution; and [0554] each
R.sub.PTM3 is independently H, halogen, substitution can be mono-
or di-substitution.
[0555] In any aspect or embodiment described herein, the PTM is
represented by the Formula (II.sub.PTM):
##STR00237##
wherein: [0556] X.sub.PTM is CH, N; [0557] indicates the site of
attachment of at least one linker, CLM, CLM', PTM, PTM', ULM, an
ILM, a VLM, MLM, a ULM', a ILM', a VLM', a MLM', or a combination
thereof; [0558] each R.sub.PTM1 is independently OH, halogen (e.g.,
F); [0559] each R.sub.PTM2 is independently H, halogen (e.g., F),
CF.sub.3, substitution can be mono- or di-substitution; and [0560]
each R.sub.PTM3 is independently halogen (e.g. F), substitution can
be mono- or di-substitution.
[0561] In certain embodiments, at least one of: [0562] X.sub.PTM of
Formula (II.sub.PTM) is CH; [0563] R.sub.PTM1 of Formula
(II.sub.PTM) is OH; [0564] R.sub.PTM2 of Formula (II.sub.PTM) is H;
[0565] each R.sub.PTM3 of Formula (II.sub.PTM) is independently H
or F; or [0566] a combination thereof.
[0567] XIV. Compounds Targeting Thyroid Hormone Receptor (TR)
[0568] 1. Thyroid Hormone Receptor Ligand (derivatized)
##STR00238##
[0569] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment and MOMO indicates a methoxymethoxy
group).
[0570] XV. Compounds Targeting HIV Protease
[0571] 1. Inhibitor of HIV Protease (derivatized)
##STR00239##
[0572] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment). See, J. Med. Chem. 2010, 53,
521-538.
[0573] 2. Inhibitor of HIV Protease
##STR00240##
[0574] (Derivatized where "R" designates a potential site for
linker group L or -(L-CLM) group attachment). See, J. Med. Chem.
2010, 53, 521-538.
[0575] XVI. Compounds Targeting HIV Integrase
[0576] 1. Inhibitor of HIV Integrase (derivatized)
##STR00241##
[0577] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment). See, J. Med. Chem. 2010, 53,
6466.
[0578] 2. Inhibitor of HIV Integrase (derivatized)
##STR00242##
[0579] 3. Inhibitor of HIV integrase Isetntress (derivatized)
##STR00243##
[0580] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment). See, J. Med. Chem. 2010, 53,
6466.
[0581] XVII. Compounds Targeting HCV Protease
[0582] 1. Inhibitors of HCV Protease (derivatized)
##STR00244##
[0583] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment).
[0584] XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and
-2 (APT1 and APT2)
[0585] 1. Inhibitor of APT1 and APT2 (derivatized)
##STR00245##
[0586] (Derivatized where "R" designates a site for linker group L
or -(L-CLM) group attachment). See, Angew. Chem. Int. Ed. 2011, 50,
9838-9842, where L is a linker group as otherwise described herein
and said CLM group is as otherwise described herein such that
-(L-CLM) binds the CLM group to a PTMgroup as otherwise described
herein.
[0587] VIV. Compound Targeting Tau Protein
[0588] In any aspect or embodiment described herein, the PTM may
include a Tau protein binding moieties. For example, the PTM may be
represented by Formula I, Formula II, Formula III, Formula IV,
Formula V, Formula VI, Formula, VII, Formula, VIII, Formula IX,
Formula X, or Formula XI:
##STR00246##
wherein: [0589] A, B, C, D, E, and F are independently selected
from an optionally substituted 5- or 6-membered aryl or heteroaryl
ring, an optionally substituted 4- to 7-membered cycloalkyl or a
heterocycloalkyl, where contact between circles indicates ring
fusion; and [0590] L.sub.PTM is selected from a bond, an alkyl, an
alkenyl or an alkynyl, optionally interrupted by one or more rings
(i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or
more functional groups selected from the groups --O--, --S--,
--NR.sup.1.sub.PTM-- (where R.sup.1.sub.PTM is selected from H or
alkyl), --N.dbd.N--, --S(O)--, --SO.sub.2--, --C(O)--, --NHC(O)--,
--C(O)NH--, --NHSO.sub.2--, --NHC(O)NH--, --NHC(O)O--, or
--OC(O)NH--, wherein the said functional group are optionally
located at either end of the linker.
[0591] In any aspect or embodiment described herein, aryl and
heteroaryl rings of A, B, C, D, E, and F of PTM are optionally
substituted with 1-3 substituents each independently selected from
alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy,
amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and
cyano, wherein the said alkyl and alkenyl groups are further
optionally substituted.
[0592] In any aspect or embodiment described herein, the rings of
at least one of A, B, C, F, or a combination thereof is selected
from optionally substituted 5- or 6-membered aryl or heteroaryl
rings;
[0593] In any aspect or embodiment described herein, the PTM has
the chemical structure of Formula I, wherein: [0594] A, B and C
rings are independently 5- or 6-membered fused aryl or heteroaryl
rings; [0595] L.sub.PTM is selected from a bond or an alkyl, and
[0596] D is selected from a 6-membered aryl, heteroaryl or
heterocycloalkyl, [0597] wherein A, B, C and D are optionally
substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy,
amino, alkylamino, dialkylamino or cyano.
[0598] In any aspect or embodiment described herein, The PTM has
the chemical structure of Formula I, wherein: [0599] A and C are a
phenyl or a 6-membered heteroaryl ring; [0600] B is a 5-membered
heteroaryl ring; [0601] L.sub.PTM is a bond; and [0602] D is a
6-membered heteroaryl or a 6-membered heterocycloalkyl ring; [0603]
wherein each A, B, C and D is optionally independently substituted
with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino,
dialkylamino or cyano, and wherein a nitrogen atom of any of the A,
B, C and D rings is not directly connected to a heteroatom or to a
carbon atom, to which another heteroatom is directly attached.
[0604] In any aspect or embodiment described herein, the PTM has
the chemical structure of Formula III or IV, wherein A, B and C are
5- or 6-membered fused aryl or heteroaryl rings, L.sub.PTM is
selected from a bond or an alkyl, and D and E are 5- or 6-membered
fused aryl or heteroaryl rings, wherein A, B, C, D and E are
optionally substituted with alkyl, haloalkyl, halogen, hydroxyl,
alkoxy, amino, alkylamino, dialkylamino or cyano.
[0605] In any aspect or embodiment described herein, the PTM is
represented by following chemical structure:
##STR00247## ##STR00248## ##STR00249##
wherein: [0606] R.sup.1, R.sup.2 and R.sup.3 are independently
selected from H, methyl, ethyl, 2-fluoroethyl and
2,2,2-trifluoroethyl; [0607] R.sup.4 and R.sup.5 are independently
selected from H, methyl, ethyl and halogen; and [0608] R.sup.6 is 1
to 2 substituents independently selected from H, methyl, ethyl and
halogen, wherein the PTM is coupled to a ULM via L.
[0609] In any of the aspects or embodiments described herein, the
PTM is covalently coupled to one or more ULM (VLM or CLM) groups,
or a linker to which is attached one or more ULM (VLM or CLM)
groups as described herein.
[0610] In any aspect or embodiment described herein, PTM is
represented by chemical structure:
##STR00250## ##STR00251## ##STR00252## ##STR00253##
##STR00254##
wherein: [0611] R.sup.1, R.sup.2 and R.sup.3 are independently
selected from H, optionally substituted alkyl, methyl, ethyl,
2-fluoroethyl and 2,2,2-trifluoroethyl; and [0612] R.sup.7,
R.sup.8, R.sup.9 and R.sup.10 are 1 to 8 substituents independently
selected from H, optionally substituted alkyl, haloalkyl, halogen,
hydroxyl, alkoxy, amino, dialkylamino, aceylamino, trifluoromethyl
or cyano, and wherein the PTM is coupled to a ULM (VLM or CLM) via
L.
[0613] In any aspect or embodiment described herein, PTM is
represented by chemical structure:
##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259##
##STR00260##
[0614] In any aspect or embodiment described herein, the linker
attachment point to PTM is as indicated by the dotted line:
##STR00261##
[0615] Therapeutic Compositions
[0616] Pharmaceutical compositions comprising combinations of an
effective amount of at least one bifunctional compound as described
herein, and one or more of the compounds otherwise described
herein, all in effective amounts, in combination with a
pharmaceutically effective amount of a carrier, additive or
excipient, represents a further aspect of the present
disclosure.
[0617] The present disclosure includes, where applicable, the
compositions comprising the pharmaceutically acceptable salts, in
particular, acid or base addition salts of compounds as described
herein. The acids which are used to prepare the pharmaceutically
acceptable acid addition salts of the aforementioned base compounds
useful according to this aspect are those which form non-toxic acid
addition salts, i.e., salts containing pharmacologically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,
lactate, citrate, acid citrate, tartrate, bitartrate, succinate,
maleate, fumarate, gluconate, saccharate, benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among numerous
others.
[0618] Pharmaceutically acceptable base addition salts may also be
used to produce pharmaceutically acceptable salt forms of the
compounds or derivatives according to the present disclosure. The
chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of the present compounds
that are acidic in nature are those that form non-toxic base salts
with such compounds. Such non-toxic base salts include, but are not
limited to those derived from such pharmacologically acceptable
cations such as alkali metal cations (eg., potassium and sodium)
and alkaline earth metal cations (eg, calcium, zinc and magnesium),
ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines,
among others.
[0619] The compounds as described herein may, in accordance with
the disclosure, be administered in single or divided doses by the
oral, parenteral or topical routes. Administration of the active
compound may range from continuous (intravenous drip) to several
oral administrations per day (for example, Q.I.D.) and may include
oral, topical, parenteral, intramuscular, intravenous,
sub-cutaneous, transdermal (which may include a penetration
enhancement agent), buccal, sublingual and suppository
administration, among other routes of administration. Enteric
coated oral tablets may also be used to enhance bioavailability of
the compounds from an oral route of administration. The most
effective dosage form will depend upon the pharmacokinetics of the
particular agent chosen as well as the severity of disease in the
patient. Administration of compounds according to the present
disclosure as sprays, mists, or aerosols for intra-nasal,
intra-tracheal or pulmonary administration may also be used. The
present disclosure therefore also is directed to pharmaceutical
compositions comprising an effective amount of compound as
described herein, optionally in combination with a pharmaceutically
acceptable carrier, additive or excipient. Compounds according to
the present disclosureion may be administered in immediate release,
intermediate release or sustained or controlled release forms.
Sustained or controlled release forms are preferably administered
orally, but also in suppository and transdermal or other topical
forms. Intramuscular injections in liposomal form may also be used
to control or sustain the release of compound at an injection
site.
[0620] The compositions as described herein may be formulated in a
conventional manner using one or more pharmaceutically acceptable
carriers and may also be administered in controlled-release
formulations. Pharmaceutically acceptable carriers that may be used
in these pharmaceutical compositions include, but are not limited
to, ion exchangers, alumina, aluminum stearate, lecithin, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as prolamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
[0621] The compositions as described herein may be administered
orally, parenterally, by inhalation spray, topically, rectally,
nasally, buccally, vaginally or via an implanted reservoir. The
term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intraperitoneally or
intravenously.
[0622] Sterile injectable forms of the compositions as described
herein may be aqueous or oleaginous suspension. These suspensions
may be formulated according to techniques known in the art using
suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-acceptable
diluent or solvent, for example as a solution in 1, 3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose, any bland fixed oil
may be employed including synthetic mono- or di-glycerides. Fatty
acids, such as oleic acid and its glyceride derivatives are useful
in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as Ph. Helv or similar alcohol.
[0623] The pharmaceutical compositions as described herein may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried corn starch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0624] Alternatively, the pharmaceutical compositions as described
herein may be administered in the form of suppositories for rectal
administration. These can be prepared by mixing the agent with a
suitable non-irritating excipient, which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0625] The pharmaceutical compositions as described herein may also
be administered topically. Suitable topical formulations are
readily prepared for each of these areas or organs. Topical
application for the lower intestinal tract can be effected in a
rectal suppository formulation (see above) or in a suitable enema
formulation. Topically-acceptable transdermal patches may also be
used.
[0626] For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water. In certain
preferred aspects of the invention, the compounds may be coated
onto a stent which is to be surgically implanted into a patient in
order to inhibit or reduce the likelihood of occlusion occurring in
the stent in the patient.
[0627] Alternatively, the pharmaceutical compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0628] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0629] The pharmaceutical compositions as described herein may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0630] The amount of compound in a pharmaceutical composition as
described herein that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host and
disease treated, the particular mode of administration. Preferably,
the compositions should be formulated to contain between about 0.05
milligram to about 750 milligrams or more, more preferably about 1
milligram to about 600 milligrams, and even more preferably about
10 milligrams to about 500 milligrams of active ingredient, alone
or in combination with at least one other compound according to the
present disclosure.
[0631] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease or condition being treated.
[0632] A patient or subject in need of therapy using compounds
according to the methods described herein can be treated by
administering to the patient (subject) an effective amount of the
compound according to the present disclosure including
pharmaceutically acceptable salts, solvates or polymorphs, thereof
optionally in a pharmaceutically acceptable carrier or diluent,
either alone, or in combination with other known erythopoiesis
stimulating agents as otherwise identified herein.
[0633] These compounds can be administered by any appropriate
route, for example, orally, parenterally, intravenously,
intradermally, subcutaneously, or topically, including
transdermally, in liquid, cream, gel, or solid form, or by aerosol
form.
[0634] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutically effective amount for the desired
indication, without causing serious toxic effects in the patient
treated. A preferred dose of the active compound for all of the
herein-mentioned conditions is in the range from about 10 ng/kg to
300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5
to about 25 mg per kilogram body weight of the recipient/patient
per day. A typical topical dosage will range from 0.01-5% wt/wt in
a suitable carrier.
[0635] The compound is conveniently administered in any suitable
unit dosage form, including but not limited to one containing less
than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active
ingredient per unit dosage form. An oral dosage of about 25-250 mg
is often convenient.
[0636] The active ingredient is preferably administered to achieve
peak plasma concentrations of the active compound of about
0.00001-30 mM, preferably about 0.1-30 .mu.M. This may be achieved,
for example, by the intravenous injection of a solution or
formulation of the active ingredient, optionally in saline, or an
aqueous medium or administered as a bolus of the active ingredient.
Oral administration is also appropriate to generate effective
plasma concentrations of active agent.
[0637] The concentration of active compound in the drug composition
will depend on absorption, distribution, inactivation, and
excretion rates of the drug as well as other factors known to those
of skill in the art. It is to be noted that dosage values will also
vary with the severity of the condition to be alleviated. It is to
be further understood that for any particular subject, specific
dosage regimens should be adjusted over time according to the
individual need and the professional judgment of the person
administering or supervising the administration of the
compositions, and that the concentration ranges set forth herein
are exemplary only and are not intended to limit the scope or
practice of the claimed composition. The active ingredient may be
administered at once, or may be divided into a number of smaller
doses to be administered at varying intervals of time.
[0638] Oral compositions will generally include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound or its prodrug derivative can
be incorporated with excipients and used in the form of tablets,
troches, or capsules. Pharmaceutically compatible binding agents,
and/or adjuvant materials can be included as part of the
composition.
[0639] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a dispersing
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring. When the dosage unit form is a capsule, it can
contain, in addition to material of the above type, a liquid
carrier such as a fatty oil. In addition, dosage unit forms can
contain various other materials which modify the physical form of
the dosage unit, for example, coatings of sugar, shellac, or
enteric agents.
[0640] The active compound or pharmaceutically acceptable salt
thereof can be administered as a component of an elixir,
suspension, syrup, wafer, chewing gum or the like. A syrup may
contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
[0641] The active compound or pharmaceutically acceptable salts
thereof can also be mixed with other active materials that do not
impair the desired action, or with materials that supplement the
desired action, such as erythropoietin stimulating agents,
including EPO and darbapoietin alfa, among others. In certain
preferred aspects of the invention, one or more compounds according
to the present disclosure are coadministered with another bioactive
agent, such as an erythropoietin stimulating agent or a would
healing agent, including an antibiotic, as otherwise described
herein.
[0642] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parental preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic.
[0643] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0644] In one embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art.
[0645] Liposomal suspensions may also be pharmaceutically
acceptable carriers. These may be prepared according to methods
known to those skilled in the art, for example, as described in
U.S. Pat. No. 4,522,811 (which is incorporated herein by reference
in its entirety). For example, liposome formulations may be
prepared by dissolving appropriate lipid(s) (such as stearoyl
phosphatidyl ethanolamine, stearoyl phosphatidyl choline,
arachadoyl phosphatidyl choline, and cholesterol) in an inorganic
solvent that is then evaporated, leaving behind a thin film of
dried lipid on the surface of the container. An aqueous solution of
the active compound are then introduced into the container. The
container is then swirled by hand to free lipid material from the
sides of the container and to disperse lipid aggregates, thereby
forming the liposomal suspension.
[0646] Therapeutic Methods
[0647] In an additional aspect, the description provides
therapeutic compositions comprising an effective amount of a
compound as described herein or salt form thereof, and a
pharmaceutically acceptable carrier. The therapeutic compositions
modulate protein degradation in a patient or subject, for example,
an animal such as a human, and can be used for treating or
ameliorating disease states or conditions which are modulated
through the degraded protein.
[0648] The terms "treat", "treating", and "treatment", etc., as
used herein, refer to any action providing a benefit to a patient
for which the present compounds may be administered, including the
treatment of any disease state or condition which is modulated
through the protein to which the present compounds bind. Disease
states or conditions, including cancer, which may be treated using
compounds according to the present disclosure are set forth
hereinabove.
[0649] The description provides therapeutic compositions as
described herein for effectuating the degradation of proteins of
interest for the treatment or amelioration of a disease, e.g.,
cancer. In certain additional embodiments, the disease is multiple
myeloma. As such, in another aspect, the description provides a
method of ubiquitinating/degrading a target protein in a cell. In
certain embodiments, the method comprises administering a
bifunctional compound as described herein comprising, e.g., a CLM
and a PTM, preferably linked through a linker moiety, as otherwise
described herein, wherein the CLM is coupled to the PTM and wherein
the CLM recognizes a ubiquitin pathway protein (e.g., an ubiquitin
ligase, preferably an E3 ubiquitin ligase such as, e.g., cereblon)
and the PTM recognizes the target protein such that degradation of
the target protein will occur when the target protein is placed in
proximity to the ubiquitin ligase, thus resulting in
degradation/inhibition of the effects of the target protein and the
control of protein levels. The control of protein levels afforded
by the present disclosure provides treatment of a disease state or
condition, which is modulated through the target protein by
lowering the level of that protein in the cell, e.g., cell of a
patient. In certain embodiments, the method comprises administering
an effective amount of a compound as described herein, optionally
including a pharmaceutically acceptable excipient, carrier,
adjuvant, another bioactive agent or combination thereof.
[0650] In additional embodiments, the description provides methods
for treating or emeliorating a disease, disorder or symptom thereof
in a subject or a patient, e.g., an animal such as a human,
comprising administering to a subject in need thereof a composition
comprising an effective amount, e.g., a therapeutically effective
amount, of a compound as described herein or salt form thereof, and
a pharmaceutically acceptable excipient, carrier, adjuvant, another
bioactive agent or combination thereof, wherein the composition is
effective for treating or ameliorating the disease or disorder or
symptom thereof in the subject.
[0651] In another aspect, the description provides methods for
identifying the effects of the degradation of proteins of interest
in a biological system using compounds according to the present
disclosure.
[0652] In another embodiment, the present disclosure is directed to
a method of treating a human patient in need for a disease state or
condition modulated through a protein where the degradation of that
protein will produce a therapeutic effect in that patient, the
method comprising administering to a patient in need an effective
amount of a compound according to the present disclosure,
optionally in combination with another bioactive agent. The disease
state or condition may be a disease caused by a microbial agent or
other exogenous agent such as a virus, bacteria, fungus, protozoa
or other microbe or may be a disease state, which is caused by
overexpression of a protein, which leads to a disease state and/or
condition
[0653] The term "disease state or condition" is used to describe
any disease state or condition wherein protein dysregulation (i.e.,
the amount of protein expressed in a patient is elevated) occurs
and where degradation of one or more proteins in a patient may
provide beneficial therapy or relief of symptoms to a patient in
need thereof. In certain instances, the disease state or condition
may be cured.
[0654] Disease states of conditions which may be treated using
compounds according to the present disclosure include, for example,
asthma, autoimmune diseases such as multiple sclerosis, various
cancers, ciliopathies, cleft palate, diabetes, heart disease,
hypertension, inflammatory bowel disease, mental retardation, mood
disorder, obesity, refractive error, infertility, Angelman
syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth
disease, Cystic fibrosis, Duchenne muscular dystrophy,
Haemochromatosis, Haemophilia, Klinefelter's syndrome,
Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,
(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease,
Tay-Sachs disease, Turner syndrome.
[0655] Further disease states or conditions which may be treated by
compounds according to the present disclosure include Alzheimer's
disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease),
Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention
deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic
fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's
disease, Coronary heart disease, Dementia, Depression, Diabetes
mellitus type 1, Diabetes mellitus type 2, Epilepsy,
Guillain-Barresyndrome, Irritable bowel syndrome, Lupus, Metabolic
syndrome, Multiple sclerosis, Myocardial infarction, Obesity,
Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,
Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia,
Stroke, Thromboangiitis obliterans, Tourette syndrome,
Vasculitis.
[0656] Still additional disease states or conditions which can be
treated by compounds according to the present disclosure include
aceruloplasminemia, Achondrogenesis type II, achondroplasia,
Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,
Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase
deficiency, adenylosuccinate lyase deficiency, Adrenogenital
syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase
deficiency, Alkaptonuria, Alexander disease, Alkaptonuric
ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase
inhibitor, emphysema, amyotrophic lateral sclerosis Alstrom
syndrome, Alexander disease, Amelogenesis imperfecta, ALA
dehydratase deficiency, Anderson-Fabry disease, androgen
insensitivity syndrome, Anemia Angiokeratoma Corporis Diffusum,
Angiomatosis retinae (von Hippel-Lindau disease) Apert syndrome,
Arachnodactyly (Marfan syndrome), Stickler syndrome, Arthrochalasis
multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type)
ataxia telangiectasia, Rett syndrome, primary pulmonary
hypertension, Sandhoff disease, neurofibromatosis type II,
Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,
familial, Benjamin syndrome, beta-thalassemia, Bilateral Acoustic
Neurofibromatosis (neurofibromatosis type II), factor V Leiden
thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti),
Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich
syndrome (Turner syndrome), Bourneville disease (tuberous
sclerosis), prion disease, Birt-Hogg-Dube syndrome, Brittle bone
disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome
(Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis
(hemochromatosis), Bulbospinal muscular atrophy (Kennedy's
disease), Burger-Grutz syndrome (lipoprotein lipase deficiency),
CGD Chronic granulomatous disorder, Campomelic dysplasia,
biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du
chat, CAVD (congenital absence of the vas deferens), Caylor
cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic
porphyria), cystic fibrosis, congenital hypothyroidism,
Chondrodystrophy syndrome (achondroplasia),
otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome,
galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia,
Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous
polyposis), Congenital erythropoietic porphyria, Congenital heart
disease, Methemoglobinemia/Congenital methaemoglobinaemia,
achondroplasia, X-linked sideroblastic anemia, Connective tissue
disease, Conotruncal anomaly face syndrome, Cooley's Anemia
(beta-thalassemia), Copper storage disease (Wilson's disease),
Copper transport disease (Menkes disease), hereditary
coproporphyria, Cowden syndrome, Craniofacial dysarthrosis (Crouzon
syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne
syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome
(myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome,
primary hyperoxaluria, spondyloepimetaphyseal dysplasia (Strudwick
type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher
syndrome, Degenerative nerve diseases including de Grouchy syndrome
and Dejerine-Sottas syndrome, developmental disabilities, distal
spinal muscular atrophy, type V, androgen insensitivity syndrome,
Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's
syndrome, Dihydrotestosterone receptor deficiency, androgen
insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic
protoporphyria Erythroid 5-aminolevulinate synthetase deficiency,
Erythropoietic porphyria, erythropoietic protoporphyria,
erythropoietic uroporphyria, Friedreich's ataxia, familial
paroxysmal polyserositis, porphyria cutanea tarda, familial
pressure sensitive neuropathy, primary pulmonary hypertension
(PPH), Fibrocystic disease of the pancreas, fragile X syndrome,
galactosemia, genetic brain disorders, Giant cell hepatitis
(Neonatal hemochromatosis), Gronblad-Strandberg syndrome
(pseudoxanthoma elasticum), Gunther disease (congenital
erythropoietic porphyria), haemochromatosis, Hallgren syndrome,
sickle cell anemia, hemophilia, hepatoerythropoietic porphyria
(HEP), Hippel-Lindau disease (von Hippel-Lindau disease),
Huntington's disease, Hutchinson-Gilford progeria syndrome
(progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic
anemia, Immune system disorders, including X-linked severe combined
immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome,
Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome,
Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,
Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,
Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch
syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease,
Metabolic disorders, including Kniest dysplasia, Marfan syndrome,
Movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke
syndrome, Multiple neurofibromatosis, Nance-Insley syndrome,
Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack
syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease,
Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic
fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers
syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary
hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary
hypertension, primary senile degenerative dementia, prion disease,
progeria (Hutchinson Gilford Progeria Syndrome), progressive
chorea, chronic hereditary (Huntington) (Huntington's disease),
progressive muscular atrophy, spinal muscular atrophy, propionic
acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary
arterial hypertension, PXE (pseudoxanthoma elasticum), Rb
(retinoblastoma), Recklinghausen disease (neurofibromatosis type
I), Recurrent polyserositis, Retinal disorders, Retinoblastoma,
Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome,
Roussy-Levy syndrome, severe achondroplasia with developmental
delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome,
sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome,
sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital
(spondyloepiphyseal dysplasia congenita), SED Strudwick
(spondyloepimetaphyseal dysplasia, Strudwick type), SEDc
(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type
(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen
syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome,
South-African genetic porphyria (variegate porphyria),
infantile-onset ascending hereditary spastic paralysis, Speech and
communication disorders, sphingolipidosis, Tay-Sachs disease,
spinocerebellar ataxia, Stickler syndrome, stroke, androgen
insensitivity syndrome, tetrahydrobiopterin deficiency,
beta-thalassemia, Thyroid disease, Tomaculous neuropathy
(hereditary neuropathy with liability to pressure palsies),
Treacher Collins syndrome, Triplo X syndrome (triple X syndrome),
Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von
Hippel-Lindau disease), Vision impairment and blindness (Alstrom
syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo
Fledelius Syndrome, Weissenbacher-Zweymuller syndrome,
Wolf-Hirschhorn syndrome, Wolff Periodic disease,
Weissenbacher-Zweymuller syndrome and Xeroderma pigmentosum, among
others.
[0657] The term "neoplasia" or "cancer" is used throughout the
specification to refer to the pathological process that results in
the formation and growth of a cancerous or malignant neoplasm,
i.e., abnormal tissue that grows by cellular proliferation, often
more rapidly than normal and continues to grow after the stimuli
that initiated the new growth cease. Malignant neoplasms show
partial or complete lack of structural organization and functional
coordination with the normal tissue and most invade surrounding
tissues, metastasize to several sites, and are likely to recur
after attempted removal and to cause the death of the patient
unless adequately treated. As used herein, the term neoplasia is
used to describe all cancerous disease states and embraces or
encompasses the pathological process associated with malignant
hematogenous, ascitic and solid tumors. Exemplary cancers which may
be treated by the present compounds either alone or in combination
with at least one additional anti-cancer agent include
squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,
hepatocellular carcinomas, and renal cell carcinomas, cancer of the
bladder, bowel, breast, cervix, colon, esophagus, head, kidney,
liver, lung, neck, ovary, pancreas, prostate, and stomach;
leukemias; benign and malignant lymphomas, particularly Burkitt's
lymphoma and Non-Hodgkin's lymphoma; benign and malignant
melanomas; myeloproliferative diseases; sarcomas, including Ewing's
sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma,
myosarcomas, peripheral neuroepithelioma, synovial sarcoma,
gliomas, astrocytomas, oligodendrogliomas, ependymomas,
gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,
medulloblastomas, pineal cell tumors, meningiomas, meningeal
sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast
cancer, prostate cancer, cervical cancer, uterine cancer, lung
cancer, ovarian cancer, testicular cancer, thyroid cancer,
astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer,
liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's
disease, Wilms' tumor and teratocarcinomas. Additional cancers
which may be treated using compounds according to the present
disclosure include, for example, T-lineage Acute lymphoblastic
Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL),
Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B
Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL,
Philadelphia chromosome positive ALL and Philadelphia chromosome
positive CML.
[0658] The term "bioactive agent" is used to describe an agent,
other than a compound according to the present disclosure, which is
used in combination with the present compounds as an agent with
biological activity to assist in effecting an intended therapy,
inhibition and/or prevention/prophylaxis for which the present
compounds are used. Preferred bioactive agents for use herein
include those agents which have pharmacological activity similar to
that for which the present compounds are used or administered and
include for example, anti-cancer agents, antiviral agents,
especially including anti-HIV agents and anti-HCV agents,
antimicrobial agents, antifungal agents, etc.
[0659] The term "additional anti-cancer agent" is used to describe
an anti-cancer agent, which may be combined with compounds
according to the present disclosure to treat cancer. These agents
include, for example, everolimus, trabectedin, abraxane, TLK 286,
AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244
(ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin,
vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263,
a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an
aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an
HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk
inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF
antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1/2
inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a
focal adhesion kinase inhibitor, a Map kinase kinase (mek)
inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,
nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,
nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab,
edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen,
ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110,
BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001,
IPdR.sub.1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta
744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,
ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,
gemcitabine, doxorubicin, liposomal doxorubicin,
5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,
seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane,
letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated
estrogen, bevacizumab, IMC-1C11, CHIR-258);
3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,
AG-013736, AVE-0005, goserelin acetate, leuprolide acetate,
triptorelin pamoate, medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;
TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF
antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib,
BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide
hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,
sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,
L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine,
chlorambucil, cisplatin, cladribine, clodronate, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin, fludarabine, fludrocortisone,
fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,
methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin,
porfimer, procarbazine, raltitrexed, rituximab, streptozocin,
teniposide, testosterone, thalidomide, thioguanine, thiotepa,
tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard,
uracil mustard, estramustine, altretamine, floxuridine,
5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine,
vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat,
BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, droloxifene,
idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,
denileukin diftitox, gefitinib, bortezimib, paclitaxel,
cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550,
BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,
ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene,
idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK
222584, VX-745, PD 184352, rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,
wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,
erythropoietin, granulocyte colony-stimulating factor,
zolendronate, prednisone, cetuximab, granulocyte macrophage
colony-stimulating factor, histrelin, pegylated interferon alfa-2a,
interferon alfa-2a, pegylated interferon alfa-2b, interferon
alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,
all-transretinoic acid, ketoconazole, interleukin-2, megestrol,
immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab
tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab, arsenic trioxide, cortisone, editronate, mitotane,
cyclosporine, liposomal daunorubicin, Edwina-asparaginase,
strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,
palonosetron, aprepitant, diphenhydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol,
dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim,
erythropoietin, epoetin alfa, darbepoetin alfa and mixtures
thereof.
[0660] The term "anti-HIV agent" or "additional anti-HIV agent"
includes, for example, nucleoside reverse transcriptase inhibitors
(NRTI), other non-nucloeoside reverse transcriptase inhibitors
(i.e., those which are not representative of the present
disclosure), protease inhibitors, fusion inhibitors, among others,
exemplary compounds of which may include, for example, 3TC
(Lamivudine), AZT (Zidovudine), (-)-FTC, ddl (Didanosine), ddC
(zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset),
D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV
(Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV
(Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir),
APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20,
among others, fuseon and mixtures thereof, including anti-HIV
compounds presently in clinical trials or in development.
[0661] Other anti-HIV agents which may be used in coadministration
with compounds according to the present disclosure include, for
example, other NNRTI's (i.e., other than the NNRTI's according to
the present disclosure) may be selected from the group consisting
of nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz
(DMP-266), UC-781
(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide-
), etravirine (TMC 125), Trovirdine (Ly300046.HCl), MKC-442
(emivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine
(TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II
(Methyl
3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-diphenylh-
exenoate), Methyl
3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-m-
ethoxybenzoate (Alkenyldiarylmethane analog, Adam analog),
(5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP
(U-104489 or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine
(U-87201E), aurin tricarboxylic acid (SD-095345),
1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperaz-
ine,
1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isoprop-
ylamino)-2-pyridinyl]piperazine,
1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazi-
ne,
1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]pip-
erazine,
1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamin-
o)-2-pyridinyl]piperazine, U88204E, Bis(2-nitrophenyl)sulfone (NSC
633001), Calanolide A (NSC675451), Calanolide B,
6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC
961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT
(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M
(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine),
HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine),
Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B
(NSC649324), Michellamine F,
6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,
6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS,
E-BPTU (NSC 648400), Oltipraz
(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),
N-{2-(2-Chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT
Cl, F derivative),
N-{2-(2,6-Difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT
derivative),
N-{2-(2,6-Difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT
Pyridyl derivative),
N-[2-(3-Fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea,
N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea,
N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639,
L-697,593, L-697,661,
3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)--
thione (2-Pyridinone Derivative),
3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypr-
idin-2(1H)-thione, R82150, R82913, R87232, R88703, R89439
(Loviride), R90385, S-2720, Suramin Sodium, TBZ
(Thiazolobenzimidazole, NSC 625487), Thiazoloisoindol-5-one,
(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-o-
ne, Tivirapine (R86183), UC-38 and UC-84, among others.
[0662] The term "pharmaceutically acceptable salt" is used
throughout the specification to describe, where applicable, a salt
form of one or more of the compounds described herein which are
presented to increase the solubility of the compound in the gastic
juices of the patient's gastrointestinal tract in order to promote
dissolution and the bioavailability of the compounds.
Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic or organic bases and acids,
where applicable. Suitable salts include those derived from alkali
metals such as potassium and sodium, alkaline earth metals such as
calcium, magnesium and ammonium salts, among numerous other acids
and bases well known in the pharmaceutical art. Sodium and
potassium salts are particularly preferred as neutralization salts
of the phosphates according to the present disclosure.
[0663] The term "pharmaceutically acceptable derivative" is used
throughout the specification to describe any pharmaceutically
acceptable prodrug form (such as an ester, amide other prodrug
group), which, upon administration to a patient, provides directly
or indirectly the present compound or an active metabolite of the
present compound.
[0664] General Synthetic Approach
[0665] The synthetic realization and optimization of the
bifunctional molecules as described herein may be approached in a
step-wise or modular fashion. For example, identification of
compounds that bind to the target molecules can involve high or
medium throughput screening campaigns if no suitable ligands are
immediately available. It is not unusual for initial ligands to
require iterative design and optimization cycles to improve
suboptimal aspects as identified by data from suitable in vitro and
pharmacological and/or ADMET assays. Part of the optimization/SAR
campaign would be to probe positions of the ligand that are
tolerant of substitution and that might be suitable places on which
to attach the linker chemistry previously referred to herein. Where
crystallographic or NMR structural data are available, these can be
used to focus such a synthetic effort.
[0666] In a very analogous way one can identify and optimize
ligands for an E3 Ligase, i.e. ULMs/CLMs.
[0667] With PTMs and ULMs (e.g. CLMs) in hand one skilled in the
art can use known synthetic methods for their combination with or
without a linker moiety. Linker moieties can be synthesized with a
range of compositions, lengths and flexibility and functionalized
such that the PTM and ULM groups can be attached sequentially to
distal ends of the linker. Thus a library of bifunctional molecules
can be realized and profiled in in vitro and in vivo
pharmacological and ADMET/PK studies. As with the PTM and ULM
groups, the final bifunctional molecules can be subject to
iterative design and optimization cycles in order to identify
molecules with desirable properties.
Abbreviations
[0668] ACN: acetonitrile [0669] AcOH, acetic acid [0670] ADDP:
1,1'-(azodicarbonyl)dipiperidine [0671] aq., aqueous [0672] BAST:
N,N-bis(2-methoxyethyl)aminosulfur trifluoride [0673] BINAP,
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [0674] Boc,
tert-butoxycarbonyl [0675] Boc.sub.2O, di-tert-butyl decarbonate
[0676] BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate [0677] BPO: benzoyl peroxide [0678] Cbz:
Carbonylbezyloxy [0679] CDCl.sub.3, deuteriochloroform [0680]
CD.sub.3OD, deuteriomethanol [0681] CH.sub.3CN, acetonitrile [0682]
CH.sub.3OH, methanol [0683] CsF, cesium fluoride [0684]
Cs.sub.2CO.sub.3, cesium carbonate [0685] Cu(OAc).sub.2, copper
(II) acetate [0686] Cy.sub.2NMe, dicyclohexylmethylamine [0687]
DAST: diethylaminosulfur trifluoride [0688] DBE: 1,2-dibromoethane
[0689] DCM: dichloromethane [0690] DEAD: diethyl azodicarboxylate
[0691] DIAD: diisopropyl azodicarboxylate [0692] DIBAL:
disiobutylaluminium hydride [0693] DIEA or DIPEA:
diisopropylethylamine [0694] DMA: N,N-dimethylacetamide [0695]
DMAP, N,N-dimethylaminopyridine [0696] DMF: N,N-dimethylformamide
[0697] DMP: Dess-Martin periodinane [0698] DMSO, dimethylsulfoxide
[0699] DMSO-d.sub.6, hexadeuterodimethyl sulfoxide [0700] EA: ethyl
acetate [0701] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
[0702] Et.sub.2NH, diethylamine [0703] EtOAc or EA, ethyl acetate
[0704] HCl, hydrochloric acid [0705] H.sub.2O, water [0706] HBTU:
N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate [0707] HMDS: bis9trimethylsilyl)amine [0708]
HMPA: hexamethylphosphoramide [0709] HPLC, high performance liquid
chromatography [0710] IBX, 2-iodoxybenzoic acid [0711] KOAc,
potassium acetate [0712] LCMS, liquid chromatography/mass
spectrometry [0713] LDA: lithium diisopropylamide [0714] LiOH,
lithium hydroxide [0715] MCPBA: meta-chloroperoxybenzoic acid
[0716] MeOH, methanol [0717] MsCl: methanesulfonyl chloride [0718]
M.W: microwave [0719] N.sub.2, nitrogen [0720] NaH, sodium hydride
[0721] NaBH.sub.3CN, sodium cyanoborohydride [0722]
NaBH(OAc).sub.3, sodium triacetoxyborohydride [0723] NaCl, sodium
chloride [0724] NaHCO.sub.3, sodium bicarbonate [0725] NaI, sodium
iodide [0726] Na.sub.2SO.sub.4, sodium sulfate [0727] NBS:
N-bromosuccinimide [0728] n-BuLi, n-butyllithium [0729] NH.sub.3,
ammonia [0730] NH.sub.4Cl, ammonium chloride [0731] NH.sub.2OH HCl,
hydroxylamine hydrochloride [0732] NMP, N-methylpyrrolidone [0733]
NMR, nuclear magnetic resonance [0734] O.sub.2, oxygen [0735] PCC:
pyridinium chlorochromate [0736] Pd-118 or Pd(dtpf)Cl.sub.2:
1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium [0737]
Pd(aMPhos)Cl.sub.2,
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
[0738] Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium
[0739] Pd(dppf)Cl.sub.2: 1,1'-bis(diphenylphosphino)ferrocene
dichloropalladium [0740] Pd(dba).sub.2:
bis(dibenzylideneacetone)palladium [0741] Pd(OH).sub.2, palladium
hydroxide [0742] Pd(PPh.sub.3).sub.4,
tetrakis(triphenylphosphine)palladium(O) [0743] PE, petroleum ether
[0744] Ph.sub.3P, triphenylphosphine [0745] PPTS: pyridium
p-tolunesulfonate [0746] PTSA: p-toluenesulfonic acid [0747] Py,
pyridine [0748] PyB OP,
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
[0749] rt, room temperature [0750] RuPhos-Pd-G3: XPhos-Pd-G3:
[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1-
,1'-biphenyl)] palladium(II) methanesulfonate [0751] RuPhos-Pd-G2:
Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-a-
mino-1,1'-biphenyl)] palladium(II) [0752] SFC: supercritical fluid
chromatography [0753] TBAF, tetra-n-butylammonium fluoride [0754]
TBDPSCl, tert-butyldiphenylsilyl chloride [0755] TBS,
tert-butyldimethylsilyl [0756] tBuOK, potassium tert-butoxide
[0757] [tBu.sub.3PH]BF.sub.4, tri-tert-butyl phosphonium
tetrafluoroborate [0758] t-BuXPhos-Pd-G3:
[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-ami-
no-1,1'-biphenyl)] palladium(II) methanesulfonate [0759] TEA:
trimethylamine [0760] TFA: trifluoroacetic acid [0761] TLC: thin
layer chromatography [0762] TMP: 2,2,6,6-tetramethylpiperidine
[0763] TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide [0764] TMS OTf,
trimethylsilyl trifluoromethanesulfonate [0765] TosCl or TsCl:
p-toluenesulfonyl chloride [0766] TsCl, p-toluenesufonyl chloride
[0767] TsOH: p-toluenesulfonic acid [0768] XantPhos:
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0769] XPhos:
2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl [0770]
XPhos-Pd-G3:
[(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amin-
o-1,1'-biphenyl)] palladium(II) methanesulfonate [0771] 12354-85-7:
bis(pentamethylcyclopentadienylrhodium dichloride)
A. Exemplary Synthetic Schemes for Exemplary Estrogen Receptor
Binding Moiety Based Compounds
[0772] Synthetic scheme A-1, A-2 through A-5, A-6, and A-7
described the routes used in the preparation of CRBN ligands, as
well as CRBN ligands with partial linker moieties connected.
[0773] General Synthetic Scheme A-1 to Prepare Intermediate.
##STR00262## ##STR00263## ##STR00264##
[0774] General Synthetic Scheme A-2 to Prepare Intermediate.
##STR00265## ##STR00266##
[0775] General Synthetic Scheme A-3 to Prepare Intermediate.
##STR00267## ##STR00268##
[0776] General Synthetic Scheme A-4 to Prepare Intermediate.
##STR00269## ##STR00270## ##STR00271## ##STR00272##
[0777] General Synthetic Scheme A-5 to Prepare Intermediate.
##STR00273## ##STR00274##
[0778] General Synthetic Scheme A-6 to Prepare Intermediate.
##STR00275##
[0779] General Synthetic Scheme A-7 to Prepare Intermediate.
##STR00276##
[0780] Synthetic schemes A-8, A-9, A-10, A-11, A-12, A-13, A-14,
A-15, A-16, and A-17, described the routes used in the preparation
of representative chimeric compounds claimed in this
application.
[0781] General Synthetic Scheme A-8 to Prepare Claimed
Compounds.
##STR00277## ##STR00278##
[0782] General Synthetic Scheme A-9 to Prepare Claimed
Compounds.
##STR00279##
[0783] General Synthetic Scheme A-10 to Prepare Claimed
Compounds.
##STR00280##
[0784] General Synthetic Scheme A-11 to Prepare Claimed
Compounds.
##STR00281## ##STR00282##
[0785] General Synthetic Scheme A-12 to Prepare Claimed
Compounds.
##STR00283##
[0786] General Synthetic Scheme A-13 to Prepare Claimed
Compounds.
##STR00284## ##STR00285## ##STR00286##
[0787] General Synthetic Scheme A-14 to Prepare Claimed
Compounds.
##STR00287## ##STR00288##
[0788] General Synthetic Scheme A-15 to Prepare Claimed
Compounds.
##STR00289## ##STR00290##
[0789] General Synthetic Scheme A-16 to Prepare Claimed
Compounds.
##STR00291##
[0790] General Synthetic Scheme A-17 to Prepare Claimed
Compounds.
##STR00292## ##STR00293##
Exemplary Synthesis of Exemplary Compound 2:
3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1--
yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol--
2-yl}piperidine-2,6-dione
Step 1: Preparation of 5-bromopentanal
##STR00294##
[0792] To a solution of oxalyl dichloride (9.12 g, 72 mmol, 6 mL,
4.00 eq) in dichloromethane (50 mL) was added a solution of
dimethylsulfoxide (5.61 g, 72 mmol, 4.00 eq) in dichloromethane (10
mL) at -70.degree. C. over 30 min, and then 5-bromopentan-1-ol
(3.00 g, 18 mmol, 1.00 eq) was added at below -60.degree. C. The
resulting mixture was stirred at -70.degree. C. for 1 hr.
Thin-layer chromatography (petroleum ether:ethyl acetate=10:1)
showed the reaction was complete. Triethylamine (14.54 g, 144 mmol,
20 mL, 8.00 eq) was added into the mixture and the reaction was
stirred at -60.degree. C. for 30 min. The mixture was poured into
water (20 mL) and stirred for 1 min. The aqueous phase was
extracted with dichloromethane (20 mL.times.3). The combined
organic phase was washed with brine (20 mL.times.2), dried with
anhydrous sodium sulfate, filtered and concentrated in vacuum. The
residue was directly used for the next step without further
purification. 5-bromopentanal (2.80 g, 17 mmol, 94% yield) was
obtained as a colorless oil.
Step 2: Preparation of 5-bromo-1,1-dimethoxypentane
##STR00295##
[0794] To a solution of 5-bromopentanal (2.80 g, 16.97 mmol, 1.00
eq) in methanol (50 mL) was added trimethoxymethane (9.00 g, 85
mmol, 9 mL, 5.00 eq) and 4-methylbenzenesulfonic acid hydrate (161
mg, 0.85 mmol, 0.05 eq) at 25.degree. C. The resulting mixture was
stirred at 25.degree. C. for 16 hr. Thin-layer chromatography
(petroleum ether:ethyl acetate=10:1) showed a major new spot. The
mixture was poured into water (40 mL) and stirred for 1 min. The
aqueous phase was extracted with ethyl acetate (30 mL.times.3). The
combined organic phase was washed with brine (20 mL.times.2), dried
with anhydrous sodium sulfate, filtered and concentrated in vacuum.
The residue was purified by silica gel column chromatography
(petroleum ether:ethyl acetate=15:1). 5-Bromo-1,1-dimethoxy-pentane
(3.50 g, 16.58 mmol, 97% yield) was obtain as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.37 (t, J=5.6 Hz, 1H),
3.41 (s, 2H), 3.33 (s, 6H), 1.95-1.84 (m, 2H), 1.67-1.59 (m, 2H),
1.54-1.45 (m, 2H).
Step 3: Preparation of
(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin
##STR00296##
[0796] To a solution of
4-[(1R,2S)-6-benzyloxy-2-phenyl-tetralin-1-yl]phenol (500 mg, 1.23
mmol, 1.00 eq) in dimethylformamide (5 mL) was added cesium
carbonate (1.2 g, 3.69 mmol, 3.00 eq) and
5-bromo-1,1-dimethoxy-pentane (390 mg, 1.84 mmol, 1.50 eq). The
mixture was stirred at 100.degree. C. for 1 hour. The reaction
mixture was diluted with water (30 mL) and extracted with ethyl
acetate (15 mL.times.2). The combined organic phase was washed with
saturated brine (15 mL.times.2), dried with anhydrous sodium
sulfate, filtered and concentrated in vacuum. The residue was
purified by silica gel column chromatography (petroleum ether:ethyl
acetate=50:1 to 10:1) to give
(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetr-
alin (500 mg, 0.93 mmol, 76% yield) as a white solid. LC/MS (ESI)
m/z: 559.2 [M+23].sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.49-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.37-7.31 (m, 1H), 7.21-7.13
(m, 3H), 6.90-6.85 (m, 2H), 6.82 (dd, J=2.0, 7.2 Hz, 2H), 6.76 (dd,
J=2.4, 8.4 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 6.32 (d, J=8.8 Hz, 2H),
5.07 (s, 2H), 4.38 (t, J=5.6 Hz, 1H), 4.25 (d, J=4.8 Hz, 1H), 3.84
(t, J=6.4 Hz, 2H), 3.41-3.28 (m, 7H), 3.17-2.99 (m, 2H), 2.28-2.13
(m, 1H), 1.87-1.71 (m, 3H), 1.69-1.60 (m, 2H), 1.54-1.42 (m,
2H).
Step 4: Preparation of
(1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol
##STR00297##
[0798] To a solution of
(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin
(500 mg, 0.93 mmol, 1.00 eq) in methanol (20 mL) and
tetrahydrofuran (20 mL) was added palladium on carbon (200 mg, 10%
purity) under nitrogen atmosphere. The suspension was degassed and
purged with hydrogen 3 times. The mixture was stirred under
hydrogen (15 psi) at 25.degree. C. for 12 h. The reaction mixture
was filtered and the filter was concentrated to give
(1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol
(420 mg, crude) as a white solid. LC/MS (ESI) m/z: 469.1
[M+23].sup.+.
Step 5: Preparation of
5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal
##STR00298##
[0800] To a solution of
(1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol
(420 mg, 0.94 mmol, 1.00 eq) in tetrahydrofuran (75 mL) was added
sulfuric acid (2 M in water, 18 mL, 40.00 eq). The mixture was
stirred at 70.degree. C. for 0.5 h. Thin layer chromatography
(petroleum ether:ethyl acetate=3:1) showed the reaction was
completed and a new spot formed. The reaction mixture was diluted
with water (40 mL) and extracted with ethyl acetate (20
mL.times.2). The combined organic phase was washed with saturated
sodium bicarbonate (15 mL) and saturated brine (20 mL.times.2),
dried with anhydrous sodium sulfate, filtered and concentrated in
vacuum to give
5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy] pentanal
(370 mg, 0.92 mmol, 98% yield) as a white solid.
Step 6: Preparation of tert-butyl
4-(7-methoxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate
##STR00299##
[0802] To a mixture of 5-fluoro-7-methoxy-3H-isobenzofuran-1-one (1
g, 5.49 mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (2.05
g, 10.98 mmol, 2 eq) in 1-methylpyrrolidin-2-one (6 mL) was added
N-ethyl-N-isopropylpropan-2-amine (2.84 g, 21.96 mmol, 3.83 mL, 4
eq) in one portion. The mixture was stirred at 100.degree. C. for
12 hours. TLC (ethyl acetate/petroleum ether=1/1, R.sub.f=0.1)
indicated a new spot formed. The reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (40 mL.times.2). The
combined organic layers were washed with water (15 mL), dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate=10/1 to 1:1). Tert-butyl
4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate
(1 g, 2.87 mmol, 52% yield) was obtained as a yellow solid. LC/MS
(ESI) m/z: 349.3 [M+1].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.38 (s, 1H), 6.30 (s, 1H), 5.13 (s, 2H), 3.99 (s, 3H),
3.62-3.59 (m, 4H), 3.42-3.35 (m, 4H), 1.48 (s, 9H).
Step 7: Preparation of
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)-6-methoxybenz-
oic acid
##STR00300##
[0804] To a mixture of tert-butyl
4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate
(1 g, 2.87 mmol, 1 eq) in methyl alcohol (10 mL) and
tetrahydrofuran (10 mL) was added the solution of sodium hydroxide
(459 mg, 11.48 mmol, 4 eq) in water (2 mL). The mixture was stirred
at 20.degree. C. for 1 h. TLC (ethyl acetate/petroleum ether=1/1,
R.sub.f=0) indicated a new spot formed. The reaction mixture was
concentrated under reduced pressure to remove solvent. The residue
was diluted with water (20 mL) and extracted with ethyl acetate (30
mL.times.2). The aqueous phase was adjusted to pH value to
4.about.5 with hydrochloric acid (1.5 N), then filtered and the
solid was collected. The solid was used for the next step without
further purification.
4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzo-
ic acid (700 mg, 1.68 mmol, 58% yield, 88% purity) was obtained as
a white solid. LC/MS (ESI) m/z: 367.3 [M+1].sup.+.
Step 8: Preparation of
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-6-methoxybenzoic
acid
##STR00301##
[0806] To a mixture of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzo-
ic acid (650 mg, 1.77 mmol, 1 eq) and in methyl alcohol (20 mL) was
added manganese dioxide (1.54 g, 17.74 mmol, 10 eq) in one portion
at 20.degree. C. under nitrogen. The mixture was stirred at
50.degree. C. for 12 hours. LC/MS showed the reaction was completed
and desired product was formed. The reaction mixture was filtered
and the solution was concentrated under vacuum. The reaction was
used for the next step without further purification.
4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic
acid (600 mg, 1.65 mmol, 92% yield) was obtained as a yellow solid.
LC/MS (ESI) m/z: 365.3 [M+1].sup.+.
Step 9: Preparation of
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)am-
ino)methyl)-6-methoxybenzoic acid
##STR00302##
[0808] To a mixture of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic
acid (600 mg, 1.65 mmol, 1 eq) and 3-aminopiperidine-2,6-dione (407
mg, 2.47 mmol, 1.5 eq, HCl) in methyl alcohol (10 mL) was added
sodium acetate (203 mg, 2.47 mmol, 1.5 eq) and sodium
cyanoborohydride (310 mg, 4.94 mmol, 3 eq) in one portion at
20.degree. C. The mixture was stirred at 20.degree. C. for 2 h.
LC/MS showed the reaction was completed and desired product was
formed. The reaction mixture was concentrated under vacuum. The
residue was purified by reverse phase flash silica gel
chromatography (120 g SepaFlash silica gel column, eluent of
0.about.60% acetonitrile in water with a flow rate of 30 mL/min).
4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]-
methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 38% yield) was
obtained as a white solid. LC/MS (ESI) m/z: 477.4 [M+1].sup.+.
Step 10: Preparation of tert-butyl
4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazine--
1-carboxylate
##STR00303##
[0810] To a mixture of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]-
methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 1 eq) in
dichloromethane (10 mL) was added
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (181
mg, 0.94 mmol, 1.5 eq), N-hydroxybenzotrizole (128 mg, 0.94 mmol,
1.5 eq), and triethylamine (191 mg, 1.89 mmol, 3 eq). The mixture
was stirred at 20.degree. C. for 1 h. LC/MS showed the reaction was
completed and desired product was formed. The reaction mixture was
quenched by addition of water (15 mL), and then extracted with
dichloromethane (40 mL.times.2). The combined organic layers were
washed with brine (10 mL), dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
preparative TLC (dichloromethane: methyl alcohol=10:1,
R.sub.f=0.60). Tert-butyl
4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-
-carboxylate (260 mg, 0.57 mmol, 90% yield) was obtained as a white
solid. LC/MS (ESI) m/z: 459.4 [M+1].sup.+.
Step 11: Preparation of
3-(7-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)
piperidine-2,6-dione
##STR00304##
[0812] To a mixture of tert-butyl
4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-
-carboxylate (300 mg, 0.65 mmol, 1 eq) in dioxane (10 mL) was added
hydrogen chloride/dioxane (4 M, 17 mL, 105.81 eq) in one portion.
The mixture was stirred at 20.degree. C. for 2 h. The reaction
mixture was concentrated under reduced pressure to remove solvent.
The residue was used for the next step without further
purification.
3-(7-Methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione
(216 mg, 0.55 mmol, 83% yield, HCl salt) was obtained as a white
solid. LC/MS (ESI) m/z: 359.2 [M+1].sup.+; .sup.1H-NMR (400 MHz,
MeOD) .delta.: 6.72 (s, 1H), 6.60 (s, 1H), 5.08-5.04 (m, 1H),
4.36-4.35 (m, 2H), 3.92 (s, 3H), 3.66-3.65 (m, 5H), 3.38-3.35 (m,
4H), 2.89-2.78 (m, 1H), 2.77-2.67 (m, 1H), 2.45-2.42 (m, 1H),
2.14-2.14 (m, 1H).
Step 12: Preparation of
3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1--
yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol--
2-yl}piperidine-2,6-dione (Exemplary Compound 2)
##STR00305##
[0814] To a mixture of
3-(7-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione
hydrochloride (89 mg, 0.23 mmol) in methyl alcohol (5 mL) and
dichloromethane (1 mL) was added sodium acetate (102 mg, 1.25 mmol,
5 eq) in one portion at 20.degree. C. The mixture was stirred at
20.degree. C. for 1 h, then
5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal
(100 mg, 0.25 mmol, 1 eq) was added to the reaction mixture and
stirred for 1 h. Sodium cyanoborohydride (31 mg, 0.50 mmol, 2 eq)
and acetic acid (0.05 mL) was added to the reaction mixture. The
resulting solution was stirred at 20.degree. C. for 5 h. LC/MS
showed the reaction was completed and desired product was formed.
The reaction mixture was concentrated under reduced pressure to
remove solvent. The residue was purified by preparative HPLC
(column: Phenomenex Synergi C18 150.times.25.times.10 um; mobile
phase: [water(0.05% HCl)-acetonitrile]; B %: 35%-55%, 7.8 min).
3-[5-[4-[5-[4-[(1R,2S)-6-Hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pen-
tyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione
(109.9 mg, 0.14 mmol, 56% yield, 100% purity, HCl salt) was
obtained as a white solid. LC/MS (ESI) m/z: 743.7 [M+1].sup.+;
.sup.1H-NMR (400 MHz, DMSO-d6) .delta. 10.93 (s, 1H), 10.56-10.43
(m, 1H), 9.18-9.13 (m, 1H), 7.16-7.13 (m, 3H), 6.84-6.83 (d, J=6.4
Hz, 2H), 6.69 (s, 1H), 6.62-6.61 (m, 2H), 6.55-6.52 (m, 3H),
6.28-6.26 (d, J=8.4 Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25 (m, 1H),
4.23-4.18 (m, 1H), 4.17-4.15 (m, 1H), 4.06-4.00 (m, 2H), 3.85-3.83
(m, 5H), 3.56-3.53 (m, 1H), 3.34-3.33 (m, 4H), 3.10-3.02 (m, 4H),
3.00-2.85 (m, 2H), 2.60-2.58 (m, 3H), 2.16-2.08 (m, 1H), 1.91-1.88
(m, 1H), 1.76-1.69 (m, 5H), 1.43-1.41 (m, 2H).
Exemplary Synthesis of Exemplary Compound 3:
3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]pi-
perazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione
Step 1: Preparation of 5-bromo-4-iodo-3H-isobenzofuran-1-one
##STR00306##
[0816] To a solution of 5-bromo-3H-isobenzofuran-1-one (50 g,
234.71 mmol, 1 eq) in trifluoromethanesulfonic acid (680 g, 4.53
mol, 400 mL, 19.30 eq) was added 1-iodopyrrolidine-2,5-dione (55.45
g, 246.45 mmol, 1.05 eq) at 0.degree. C. in portions. The mixture
was allowed to warm to 15.degree. C. and held for 16 h. TLC
(petroleum ether:ethyl acetate=5:1) showed no starting material
remained and two new spots (R.sub.f=0.4, 0.5) formed. The reaction
mixture was poured into ice-water (1 L) and yellow solid
precipitated. The mixture was filtered and the filter cake was
washed with water. The filter cake was dissolved in ethyl acetate
(500 mL) and the resulting orange solution was dried over sodium
sulfate. The mixture was filtered and the filtrate was concentrated
to afford a yellow solid. The residue was triturated with ethyl
acetate (50 mL), filtered and washed with ethyl acetate (10
mL.times.2). 5-Bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02
mmol, 50% yield) was obtained as a yellow solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.83 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz,
1H), 5.10 (s, 2H).
Step 2: Preparation of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one
##STR00307##
[0818] To a mixture of 5-bromo-4-iodo-3H-isobenzofuran-1-one (40 g,
118.02 mmol, 1 eq), sodium hydroxide (23.60 g, 590.10 mmol, 5 eq)
in water (400 mL) and N,N-dimethylacetamide (200 mL) was added
cuprous oxide (3.38 g, 23.60 mmol, 2.4 mL, 0.2 eq). The reaction
mixture was heated to 80.degree. C. and held for 16 h. TLC
(petroleum ether:ethyl acetate=1:1, R.sub.f=0.3) showed the
reaction was completed. The reaction mixture was poured into 1N
hydrochloride solution (400 mL) and extracted with ethyl acetate
(400 mL.times.2). The combined organic layers were concentrated and
dissolved in ethyl acetate (500 mL), washed with saturated aqueous
sodium bicarbonate (150 mL), brine (150 mL) and then dried over
sodium sulfate. The mixture was filtered and the filtrate was
concentrated to afford a residue. The residue was triturated with
ethyl acetate (20 mL), filtered and washed with ethyl acetate (10
mL) to give a solid. The filtrate was further concentrated and
triturated with ethyl acetate.
5-Bromo-4-hydroxy-3H-isobenzofuran-1-one (14.5 g, 60.15 mmol, 50%
yield, 95% purity) was obtained as a white solid. .sup.1H NMR (400
MHz, DMSO) .delta. 10.90 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.23 (d,
J=8.0 Hz, 1H), 5.35 (s, 2H).
Step 3: Preparation of 5-bromo-4-methoxy-3H-isobenzofuran-1-one
##STR00308##
[0820] To a mixture of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (3
g, 13.10 mmol, 1 eq) in acetone (20 mL) was added iodomethane (17.5
g, 123.29 mmol, 7.7 mL, 9.41 eq) and potassium carbonate (5.43 g,
39.30 mmol, 3 eq). The mixture was stirred at 20.degree. C. for 15
h. TLC (ethyl acetate:petroleum ether=1:3, R.sub.f=0.37) indicated
reaction was completed. The reaction mixture was quenched by
addition of water (10 mL), and then extracted with ethyl acetate
(20 mL.times.2). The combined organic layers were washed with
saturated sodium bicarbonate (10 mL.times.2), dried over sodium
sulfate, filtered and concentrated under reduced pressure.
5-Bromo-4-methoxy-3H-isobenzofuran-1-one (2.9 g, 11.93 mmol, 91%
yield) was obtained as a yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.72 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H),
5.44 (s, 2H), 4.00 (s, 3H).
Step 4: Preparation of tert-butyl
4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)
piperazine-1-carboxylate
##STR00309##
[0822] A vial was charged with
5-bromo-4-methoxy-3H-isobenzofuran-1-one (500 mg, 2.06 mmol, 1 eq),
tert-butyl piperazine-1-carboxylate (383 mg, 2.06 mmol, 1 eq),
tris(dibenzylideneacetone)dipalladium(0) (188 mg, 0.20 mmol, 0.1
eq), XantPhos (119 mg, 0.20 mmol, 0.1 eq), potassium phosphate (873
mg, 4.11 mmol, 2 eq) and dioxane (5 mL). The mixture was purged
with nitrogen and heated to 100.degree. C. for 16 h. TLC (ethyl
acetate:petroleum ether=1:3) showed reaction was complete. The
mixture was diluted with ethyl acetate (30 mL) and washed with
water (30 mL). The aqueous layer was extracted with ethyl acetate
(15 mL.times.3). The organic layer was washed with brine (30 mL)
and dried over sodium sulfate. The crude was purified by silica gel
chromatography (ethyl acetate:petroleum ether=1:20 to 1:6).
Tert-butyl
4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate
(700 mg, 2.01 mmol, 97% yield) was obtained as a yellow solid.
LC/MS (ESI) m/z: 349.2 [M+1].sup.+.
Step 5: Preparation of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxylmethyl)-3-methoxy-benz-
oic acid
##STR00310##
[0824] To a solution of tert-butyl
4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate
(700 mg, 2.01 mmol, 1 eq) in tetrahydrofuran (4 mL) and water (4
mL) was added sodium hydroxide (401 mg, 10.05 mmol, 5 eq). The
mixture was stirred at 20.degree. C. for 16 h. TLC (ethyl
acetate:petroleum ether=1:2) showed reaction was complete. The
mixture was adjusted to pH=4 with aqueous hydrochloric acid (1 M)
and extracted with ethyl acetate (10 ml.times.3). The organic layer
was washed with brine (20 mL) and dried over sodium sulfate. The
crude material was not further purified.
4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzo-
ic acid (700 mg, crude) was obtained as a yellow solid.
Step 6: Preparation of
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic
acid
##STR00311##
[0826] To a solution of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzo-
ic acid (700 mg, 1.91 mmol, 1 eq) in dichloromethane (10 mL) was
added manganese dioxide (2.49 g, 28.66 mmol, 15 eq). The mixture
was stirred at 20.degree. C. for 1 h. TLC
(dichloromethane:methanol=20:1) showed reaction was complete. The
mixture was diluted with dichloromethane (10 mL) and filtered
through a pad of Celite. The filtrate was concentrated in vacuum.
The crude product was purified by silica gel column chromatography
(dichloromethane:methanol=100:1 to 60:1).
4-(4-(Tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic
acid (300 mg, 0.82 mmol, 43% yield) was obtained as a pale yellow
solid.
Step 7: Preparation of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]-
methyl]-3-methoxy-benzoic acid
##STR00312##
[0828] To a mixture of 3-aminopiperidine-2,6-dione (135 mg, 0.82
mmol, 1 eq, HCl salt) in methanol (2 mL) and dichloromethane (4 mL)
was added sodium acetate (270 mg, 3.29 mmol, 4 eq). The mixture was
stirred at 20.degree. C. for 10 min, then
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-3-methoxy-benzoic
acid (300 mg, 0.82 mmol, 1 eq) was added and the mixture was
stirred for 10 min. Sodium cyanoborohydride (103 mg, 1.65 mmol, 2
eq) was added and the mixture was further stirred for 40 min. LCMS
showed reaction was complete. The mixture was adjusted to pH=4-5
with aqueous hydrochloric acid solution (1 M) and extracted with
ethyl acetate (10 mL.times.3). The organic layer was dried over
sodium sulfate. The crude product was not further purified.
4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]-
methyl]-3-methoxy-benzoic acid (400 mg, crude) was obtained as a
white solid. LC/MS (ESI) m/z: 477.1 [M+1].sup.+.
Step 8: Preparation of tert-butyl
4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-
-carboxylate
##STR00313##
[0830] To a solution of
4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]
methyl]-3-methoxy-benzoic acid (400 mg, 0.84 mmol, 1 eq) in
dimethylformamide (5 mL) was added
o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (383 mg, 1.01 mmol, 1.2 eq). The solution was
stirred for 10 min, then N,N-diisopropylethylamine (325 mg, 2.52
mmol, 3 eq) was added. The solution was stirred at 20.degree. C.
for 20 min. LCMS showed reaction was complete. The solution was
diluted with ethyl acetate (40 mL) and washed with water (30
mL.times.5) and brine (40 mL). The organic layer was dried over
sodium sulfate. Tert-butyl
4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]
piperazine-1-carbo xylate (400 mg, crude) was obtained as a pale
yellow solid. LC/MS (ESI) m/z: 459.1 [M+1].sup.+.
Step 9: Preparation of
3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)
piperidine-2,6-dione
##STR00314##
[0832] To a mixture of tert-butyl
4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]
piperazine-1-carboxylate (400 mg, 0.87 mmol, 1 eq) in dioxane (2
mL) was added hydrochloric acid in dioxane (4 M, 4 mL, 18.34 eq).
The mixture was stirred at 20.degree. C. for 10 min and solvent was
removed under vacuum.
3-(4-Methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione
(350 mg, crude, HCl salt) was obtained as a white solid. LC/MS
(ESI) m/z: 359.1 [M+1].sup.+.
Step 10: Preparation of
3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]
phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-
-2,6-dione (Exemplary Compound 3)
##STR00315##
[0834] To a mixture of
3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione
(100 mg, 0.25 mmol, 1 eq, HCl salt) in dichloromethane (4 mL) and
methanol (1 mL) was added sodium acetate (83 mg, 1.01 mmol, 4 eq).
The mixture was stirred at 20.degree. C. for 10 min. Then
5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal
(101 mg, 0.25 mmol, 1.00 eq) was added and the mixture was stirred
for 10 min. Sodium cyanoborohydride (31 mg, 0.51 mmol, 2 eq) was
added to the mixture and stifling was kept for 40 min. LCMS and TLC
(dichloromethane:methanol=10:1) showed reaction was complete.
Solvent was removed under vacuum. The crude product was purified by
prep-TLC (dichloromethane:methanol=10:1).
3-[5-[4-[5-[4-[(1R,2S)-6-Hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]pi-
perazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione
(55 mg, 0.07 mmol, 29% yield, 99% purity) was obtained as a white
solid. LC/MS (ESI) m/z: 743.3 [M+1].sup.+; .sup.1H-NMR (400 MHz,
DMSO-d6) .delta. 10.96 (s, 1H), 9.12 (s, 1H), 7.39 (d, J=8.0 Hz,
1H), 7.25-6.98 (m, 4H), 6.83 (d, J=6.8 Hz, 2H), 6.72-6.43 (m, 5H),
6.26 (d, J=8.6 Hz, 2H), 5.06 (dd, J=5.0, 13.2 Hz, 1H), 4.56-4.11
(m, 3H), 3.94-3.70 (m, 5H), 3.30-3.25 (m, 1H), 3.21-2.77 (m, 8H),
2.64-2.55 (m, 5H), 2.46-2.26 (m, 2H), 2.16-1.94 (m, 2H), 1.80-1.22
(m, 7H).
B. Exemplary Synthetic Schemes for Exemplary Androgen Receptor
Binding Moiety Based Compounds
General Synthetic Scheme B-1
##STR00316## ##STR00317##
[0835] General Synthetic Scheme B-2
##STR00318##
[0836] Exemplary Synthetic Scheme for Exemplary Compound 32
##STR00319##
[0837] 1. Synthesis of 5-bromo-3-methoxybenzene-1,2-dicarboxylic
acid
[0838] Into a 100-mL round-bottom flask, was placed
4-bromo-2-methoxy-6-methylbenzonitrile (800 mg, 3.54 mmol, 1.00
equiv), water (10 mL), sodium hydroxide (708 mg, 17.70 mmol, 5.00
equiv), KMnO.sub.4 (1.12 g, 7.09 mmol, 2.00 equiv). The resulting
solution was stirred for 16 h at 100.degree. C. in an oil bath. The
solids were filtered out. The pH value of the solution was adjusted
to 3 with hydrogen chloride (2 mol/L). The resulting solution was
extracted with dichloromethane (15 mL.times.3) and the aqueous
layers combined. The resulting solution was extracted with ethyl
acetate/methanol=10:1 (15 mL.times.3) and the organic layers
combined and dried in an oven under reduced pressure, concentrated
under vacuum. This resulted in 330 mg (34%) of
5-bromo-3-methoxybenzene-1,2-dicarboxylic acid as a white
solid.
2. Synthesis of 1,2-dimethyl
5-bromo-3-methoxybenzene-1,2-dicarboxylate
[0839] Into a 100-mL round-bottom flask, was placed
5-bromo-3-methoxybenzene-1,2-dicarboxylic acid (330 mg, 1.20 mmol,
1.00 equiv), methanol (20 mL), sulfuric acid (5 mL). The resulting
solution was stirred for 16 h at 70.degree. C. in an oil bath. The
resulting solution was diluted with water (40 mL). The pH value of
the solution was adjusted to 8 with sodium carbonate. The resulting
solution was extracted with ethyl acetate (30 mL.times.3) and the
organic layers combined and dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:10). This resulted
in 340 mg (93%) of 1,2-dimethyl
5-bromo-3-methoxybenzene-1,2-dicarboxylate as a white solid.
[0840] LC-MS (ES+): m/z 302.85 [MH+], t.sub.R=0.906 min (2.0 minute
run).
3. Synthesis of
1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-
-1,2-dicarboxylate
[0841] Into a 100-mL round-bottom flask, was placed 1,2-dimethyl
5-bromo-3-methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00
equiv), tert-butyl piperazine-1-carboxylate (277 mg, 1.49 mmol,
1.50 equiv), RuphosPd (39 mg, 0.05 mmol, 0.05 equiv),
Cs.sub.2CO.sub.3 (978 mg, 3.00 mmol, 3.00 equiv), toluene (15 mL).
The resulting solution was stirred for 12 h at 100.degree. C. in an
oil bath. The resulting solution was diluted with water (30 mL).
The resulting solution was extracted with ethyl acetate (30
mL.times.3) and the organic layers combined and dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was applied onto a silica gel column with dichloromethane/ethyl
acetate (10:1). This resulted in 340 mg (84%) of 1,2-dimethyl
5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarbox-
ylate as light yellow oil.
[0842] LC-MS (ES+): m/z 409.05 [MH+], t.sub.R=0.963 min (2.0 minute
run).
4. Synthesis of
5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarbox-
ylic acid
[0843] Into a 100-mL round-bottom flask, was placed 1,2-dimethyl
5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarbox-
ylate (340 mg, 0.83 mmol, 1.00 equiv), methanol/H.sub.2O/THF (8
mL), sodiumol (100 mg, 2.50 mmol, 3.00 equiv). The resulting
solution was stirred for 12 h at 25.degree. C. The resulting
solution was diluted with water (30 mL). The pH value of the
solution was adjusted to 8 with hydrogen chloride (2 mol/L). citric
acid monohydrate was employed to adjust the pH to 3. The resulting
solution was extracted with ethyl acetate (30 mL.times.3) and the
organic layers combined and dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 300 mg (95%) of
5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarbox-
ylic acid as colorless oil.
[0844] LC-MS (ES+): m/z 306.95 [MH+], t.sub.R=0.853 min (2.0 minute
run).
5. Synthesis of
tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-
-1H-isoindol-5-yl]piperazine-1-carboxylate
[0845] Into a 100-mL round-bottom flask, was placed tert-butyl
4-(7-methoxy-1,3-dioxo-1,3-dihydro-2-benzofuran-5-yl)piperazine-1-carboxy-
late (260 mg, 0.72 mmol, 1.00 equiv), 3-aminopiperidine-2,6-dione
hydrochloride (153.6 mg, 0.93 mmol, 1.30 equiv), pyridine (10 mL).
The resulting solution was stirred for 4 h at 120.degree. C. in an
oil bath. The resulting solution was diluted with water (30 mL).
The resulting solution was extracted with ethyl acetate (30
mL.times.3) and the organic layers combined and dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was applied onto a silica gel column with dichloromethane/methanol
(100:1). This resulted in 280 mg (83%) of tert-butyl
4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindo-
l-5-yl]piperazine-1-carboxylate as a yellow solid.
[0846] LC-MS (ES+): m/z 417.05 [MH+], t.sub.R=0.852 min (2.0 minute
run).
6. Synthesis of
2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-d-
ione
[0847] Into a 50-mL round-bottom flask, was placed tert-butyl
4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindo-
l-5-yl]piperazine-1-carboxylate (270 mg, 0.57 mmol, 1 equiv),
dichloromethane (6 mL, 0.07 mmol, 0.124 equiv), TFA (2 mL, 0.02
mmol, 0.031 equiv). The resulting solution was stirred for 2 hr at
25.degree. C. The resulting mixture was concentrated to give
2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-d-
ione as a brown oil.
[0848] LC-MS (ES+): m/z 373.05 [MH+], t.sub.R=0.155 min (2.0 minute
run).
7. Synthesis of
6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H--
isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-
-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide
[0849] Into a 100-mL round-bottom flask, was placed
2,2,2-trifluoroacetaldehyde;
2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)-2,3-dihydro-1H-i-
soindole-1,3-dione (130 mg, 0.28 mmol, 1.078 equiv),
dichloromethane (10 mL, 0.12 mmol),
6-(4-formylpiperidin-1-yl)-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohex-
yl]pyridazine-3-carboxamide (120 mg, 0.26 mmol, 1 equiv),
NaBH(OAc).sub.3 (163.4 mg, 0.77 mmol, 3.006 equiv). The resulting
solution was stirred for 2 hr at 25.degree. C. The resulting
solution was diluted with dichloromethane (30 mL). The resulting
mixture was washed with H.sub.2O (30 mL.times.3). The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The resulting mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with dichloromethane/ethyl
acetate (3:1). The crude product was purified by Prep-HPLC with the
following conditions: Column, XBridge Prep C18 OBD Column, 5
um,19*150 mm; mobile phase, Water (10 mmol/L NH.sub.4HCO.sub.3) and
acetonitrile (43% Phase B up to 65% in 8 min); Detector, uv. This
resulted in 70 mg (33.11%) of
6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H--
isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-
-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide as a yellow
solid.
[0850] 1H NMR (400 MHz, DMSO-d6) .delta. 11.04 (s, 1H), 8.57 (d,
J=8.4 Hz, 1H), 7.87-7.79 (m, 2H), 7.39-7.32 (m, 2H), 7.15-7.12 (m,
1H), 6.96 (s, 1H), 6.68 (s, 1H), 5.04-4.98 (m, 1H), 4.50-4.47 (m,
3H), 4.93-3.85 (m, 4H), 3.35-3.33 (m, 5H), 3.07-2.81 (m, 3H), 2.51
(s, 3H), 2.27-22.1 (m, 2H), 2.09-2.01 (m, 2H), 2.00-1.49 (m, 11H),
1.23-1.11 (m, 3H); LC-MS (ES+): m/z 824.25/826.25 [MH+],
t.sub.R=182 min (3.0 minute run).
[0851] Chemical Formula: C.sub.42H.sub.46ClN.sub.9O.sub.7
[823.32/825.32]
[0852] Total H count from HNMR data: 46.
Exemplary Synthesis of Exemplary Compound 34
##STR00320##
[0853]
rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo-
butyl)-4-(4-((4-(2'-(2,6-dioxopiperidin-3-yl)-3'-oxospiro[cyclopropane-1,1-
'-isoindolin]-6'-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide
Synthetic Scheme
##STR00321## ##STR00322##
[0854] Step 1: Synthesis of dimethyl 2-bromopentanedioate
##STR00323##
[0856] To a solution of glutaric acid (30 g, 227.07 mmol, 1 eq) in
chloroform (90 mL) was added thionyl chloride (59 g, 499.56 mmol,
36 mL, 2.2 eq). The mixture was stirred at 70.degree. C. for 1 h.
Liquid bromine (36.29 g, 227.07 mmol, 1 eq) was added into the
mixture dropwise. The mixture was stirred at 70.degree. C. for 12
h. The mixture was cooled to 0.degree. C. and methanol (58 g, 1.82
mol, 73 mL, 8 eq) was added into the mixture drop wise at 0.degree.
C. LCMS detected the desired product. The mixture was extracted
with ethyl acetate (150 mL.times.3) and washed with saturated
aqueous sodium bicarbonate (200 mL). The organic layer was dried
over anhydrous sodium sulfate and concentrated. The residue was
purified with Flash C18 column chromatography
(acetonitrile:water=1:0 to 1:1). Dimethyl 2-bromopentanedioate (4
g+20 g (crude), 16.73 mmol, 7% yield) was obtained as a yellow
oil.
[0857] LCMS: MS (ESI) m/z: 241.0 [M+1].sup.+.
[0858] Chemical Formula: C.sub.7H.sub.11BrO.sub.4, Molecular
Weight: 239.06
[0859] .sup.1H NMR: (400 MHz, DCCl.sub.3) .delta.: 4.39-4.36 (m,
1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.56-2.49 (m, 2H), 2.44-2.34 (m,
1H), 2.33-2.23 (m, 1H).
[0860] Total H count from HNMR data: 11.
Step 2: Synthesis of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)
phenyl)piperazine-1-carboxylate
##STR00324##
[0862] To a solution of methyl 2-cyano-4-fluoro-benzoate (10 g,
55.82 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (12.48 g,
66.98 mmol, 1.2 eq) in dimethylsulfoxide (100 mL) was added
diisopropylethylamine (28.86 g, 223.28 mmol, 4 eq). The reaction
mixture was stirred at 120.degree. C. for 12 h. Thin layer
chromatography (petroleum ether:Ethyl acetate=3:1) showed methyl
2-cyano-4-fluoro-benzoate was consumed, and desired product was
detected. The mixture was poured into water (50 mL), and filtered.
The filtrate was dried under vacuum. The residue was purified with
silica gel column chromatography (petroleum ether:ethyl
acetate=10:1 to 3:1). Tert-butyl
4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (18 g,
52.11 mmol, 93% yield) was obtained as a yellow solid.
[0863] Chemical Formula: C.sub.18H.sub.23N.sub.3O.sub.4, Molecular
Weight: 345.39
Step 3: Synthesis of tert-butyl
4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxyl-
ate
##STR00325##
[0865] To a solution of tert-butyl
4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (18 g,
52.11 mmol, 1 eq) in tetrahydrofuran (200 mL) was added
tetraisopropyl titanate (17.77 g, 62.54 mmol, 1.2 eq) and a
solution of ethyl magnesium bromide in tetrahydrofuran (2 M, 52.11
mL, 2 eq) at 0.degree. C. The mixture was stirred at 25.degree. C.
for 1 h. Thin layer chromatography (petroleum ether:ethyl
acetate=1:1) showed tert-butyl 4-(3-cyano-4-methoxycarbony
1-phenyl)piperazine-1-carboxylate was consumed, and desired product
was detected. The mixture was added into saturated aqueous ammonium
chloride (150 mL). The mixture was extracted with ethyl acetate
(100 mL.times.3). The organic layer was dried over sodium sulfate
and concentrated. The residue was triturated with ethyl acetate (30
mL) and filtered. Tert-butyl
4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxyl-
ate (6 g, 17.47 mmol, 33% yield) was obtained as a yellow
solid.
[0866] Chemical Formula: C.sub.19H.sub.25O.sub.3N.sub.3, Molecular
Weight: 343.42
[0867] .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta.: 7.75-7.73 (d,
J=8.8 Hz, 1H), 6.97-6.95 (d, J=8.8 Hz, 1H), 6.94-6.85 (m, 1H), 6.41
(s, 1H), 3.61-3.58 (t, J=4.8 Hz, 4H), 3.28-3.25 (t, J=4.8 Hz, 4H),
1.56 (s, 2H), 1.49 (s, 9H), 1.38-1.36 (m, 2H).
[0868] Total H count from HNMR data: 25.
Step 4: Synthesis of dimethyl
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1-
'-isoindoline]-2'-yl]pentanedioate
##STR00326##
[0870] 20 batches in parallel:
[0871] To a solution of tert-butyl
4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxyl-
ate (100 mg, 0.29 mmol, 1 eq) and dimethyl 2-bromopentanedioate
(104 mg, 0.44 mmol, 1.5 eq) in dimethylformamide (2 mL) was added
sodium hydride (35 mg, 0.88 mmol, 60% in mineral oil, 3 eq). The
mixture was stirred at 30.degree. C. for 12 h. Thin layer
cromatography (petroleum ether:ethyl acetate=1:1) showed 30% of the
tert-butyl
4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxyl-
ate was consumed. The 20 reaction mixtures were poured into 50 mL
of brine, and extracted with ethyl acetate (30 mL.times.2), the
combined organic layers were dried over anhydrous sodium sulfate,
filtered and concentrated in vacuum. The residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate=3/1
to 1/1). Dimethyl
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1-
'-isoindoline]-2'-yl]pentanedioate (200 mg, 0.40 mmol, 10% yield
corrected for recovered starting material) was obtained as a yellow
oil. Also isolated was tert-butyl
4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxyl-
ate (675 mg).
[0872] Chemical Formula: C.sub.26H.sub.35N.sub.3O.sub.7, Molecular
Weight: 501.57
Step 5: Synthesis of
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1-
'-isoindoline]-2'-yl]pentanedioic acid
##STR00327##
[0874] To a solution of dimethyl
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro
[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioate (800 mg, 1.59
mmol, 1 eq) in tetrahydrofuran (5 mL) and methanol (5 mL) was added
a solution of sodium hydroxide (255 mg, 6.38 mmol, 4 eq) in water
(3 mL). The mixture was stirred at 25.degree. C. for 2 hr. LCMS
showed the reaction was completed and desired MS was detected. The
mixture together with the other batch was poured into 20 mL water,
and adjusted the pH to 3.0 with 2.0 N hydrochloride acid, then
extracted with ethyl acetate (30 mL.times.3). The combined organic
layers were dried over anhydrous sodium sulfate, then concentrated
in vacuum.
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1-
'-isoindoline]-2'-yl]pentanedioic acid (740 mg, 1.56 mmol, 97%
yield) as an off-white solid was obtained, which was directly used
for the next step without further purification.
[0875] LCMS: MS (ESI) m/z: 474.3[M+1].sup.+.
[0876] Chemical Formula: C.sub.24H.sub.31N.sub.3O.sub.7, Molecular
Weight: 473.52
Step 6: Synthesis of
5-amino-4-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopro-
pane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid;
5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopro-
pane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid and tert-butyl
4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-
-5'-yl]piperazine-1-carboxylate
##STR00328##
[0878] A mixture of
2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1-
'-isoindoline]-2'-yl]pentanedioic acid (400 mg, 0.85 mmol, 1 eq)
and urea (253 mg, 4.22 mmol, 5 eq) in 1-methyl-2-pyrrolidinone (4
mL) was heated to 160.degree. C. and stirred at 160.degree. C. for
2 hours. LCMS showed two peaks with desired MS signals. The mixture
together with the other batch was filtered. The filtrate was
further purified by Semi-preparative reverse phase HPLC (column:
Boston Green ODS 150*30 5 um; mobile phase: [water (0.225% formic
acid)-acetonitrile]; B %: 35%-45%, 10 min). 2 isomeric mono-amides
5-amino-4-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopro-
pane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid and
5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopro-
pane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid were obtained
(170 mg, 0.36 mmol, 42% yield and 90 mg, 0.19 mmol, 22% yield
respectively. It was not conclusively established which of the 2
isomeres corresponds to which structure.) Also isolated was
tert-butyl
4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-
-5'-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 23% yield) as an
off-white solid.
[0879] LCMS: mono-amide product 1: MS (ESI) m/z: 473.1[M+1].sup.+,
Mono-amide product 2: MS (ESI) m/z: 473.1[M+1].sup.+, Imide product
3: MS (ESI) m/z: 455.1[M+1].sup.+.
[0880] Chemical Formula mono-amide product 1:
C.sub.24H.sub.32N.sub.4O.sub.6, Molecular Weight: 472.53.
[0881] Chemical Formula mono-amide product 2:
C.sub.24H.sub.32N.sub.4O.sub.6, Molecular Weight: 472.53.
[0882] Chemical Formula Imide product:
C.sub.24H.sub.30N.sub.4O.sub.5, Molecular Weight: 454.52.
Step 7a: Synthesis of
3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)pi-
peridine-2,6-dione from the mono-amide product 1 of step 6
##STR00329##
[0884] To a mixture of
5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro
[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid (190
mg, 0.40 mmol, 1 eq, the first eluting mono-amide product from
above) in acetonitrile (15 mL) was added benzenesulfonic acid (114
mg, 0.72 mmol, 1.80 eq) in one portion at 25.degree. C. under
nitrogen atmosphere. The mixture was stirred at 90.degree. C. for 3
hours. LCMS showed the product was the main peak. The mixture was
concentrated in vacuum. The residue was purified by
Semi-preparative reverse phase HPLC (column: Boston Green ODS
150*30 5 um; mobile phase: [water (0.225% formic
acid)-acetonitrile]; B %: 1%-27%, 10 min). The product
3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)pi-
peridine-2,6-dione (55 mg, 0.14 mmol, 34% yield, benzene sulfonate)
was obtained as a brown solid.
[0885] LCMS: EW4875-628-P1B, MS (ESI) m/z: 355.1[M+1].sup.+.
[0886] Chemical Formula: C.sub.19H.sub.22N.sub.4O.sub.3, Molecular
Weight: 354.40.
Step 7b: Synthesis of
3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)pi-
peridine-2,6-dione from the imide product of step 6
##STR00330##
[0888] To a mixture of tert-butyl
4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-
-5'-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 1 eq) in
dichloromethane (5 mL) was added hydrochloric acid (4 M in dioxane,
2.5 mL, 50 eq) in one portion at 25.degree. C. The mixture was
stirred at 25.degree. C. for 1 hour. LCMS showed the product was
the main peak. The mixture was concentrated in vacuum. The crude
solid The product
3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)pi-
peridine-2,6-dione (70 mg, 0.18 mmol, 90% yield, hydrochloride) was
obtained as a brown solid, which was directly used into the next
step without further purification.
[0889] LCMS: MS (ESI) m/z: 355.1[M+1].sup.+.
[0890] Chemical Formula: C.sub.19H.sub.22N.sub.4O.sub.3, Molecular
Weight: 354.40
Step 8: Synthesis of
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-[[4--
[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-
-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide
##STR00331##
[0892] To a solution of
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-form-
yl-1-piperidyl)benzamide (63 mg, 0.12 mmol, 1 eq) in
1,2-dichloroethane (3 mL) was added triethylamine (38 mg, 0.38
mmol, 3 eq) and
3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)pi-
peridine-2,6-dione (50 mg, 0.12 mmol, 1 eq, hydrochloride). The
mixture was stirred at 30.degree. C. for 30 min. Sodium
triacetoxyborohydride (54 mg, 0.25 mmol, 2 eq) was added, then the
mixture was stirred at 30.degree. C. for 12 hours. LCMS showed the
reaction was completed and desired MS can be detected. The reaction
mixture was concentrated under reduced pressure to remove solution.
The residue was purified by Semi-preparative reverse phase HPLC
(column: Phenomenex Synergi C18 150*25*10 um; mobile phase:
[water(0.225% FA)-ACN]; B %: 40%-70%, 10 min) to give
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-
-[4-[[4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindo-
line]-5'-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide (17.8 mg,
0.02 mmol, 16% yield, 98% purity) as a white solid.
[0893] LCMS: MS (ESI) m/z: 932.3 [M+1].sup.+.
[0894] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.: 10.88 (s, 1H),
8.22 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H),
7.53-7.45 (m, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.99 (dd, J=9.2, 17.6
Hz, 4H), 6.73 (s, 1H), 4.33 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.86
(d, J=12.4 Hz, 3H), 3.32-3.29 (m, 9H), 2.80 (t, J=12.0 Hz, 3H),
2.59-2.54 (m, 4H), 2.22 (d, J=6.8 Hz, 2H), 1.81 (d, J=10.3 Hz, 4H),
1.55-1.47 (m, 2H), 1.45-1.31 (m, 2H), 1.25-1.17 (s, 8H), 1.13 (s,
6H).
[0895] Chemical Formula: C.sub.47H.sub.54ClN.sub.7O.sub.5,
Molecular Weight: 832.43.
[0896] Total H count from HNMR data: 54.
C. Exemplary Synthetic Schemes for Exemplary Androgen Receptor
Binding Moiety Based Compounds that are Imide Isosteres
General Synthetic Scheme C-1
Synthesis of Building Block
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide
##STR00332##
[0897] Synthetic Scheme
##STR00333##
[0898] Step 1: Synthesis of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid
##STR00334##
[0900] 6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in
N,N-dimethylacetamide (15 mL), and tert-butyl
piperazine-1-carboxylate (1.9 g, 10.0 mmol) and
ethyldiisopropylamine (2.6 g, 20 mmol) were added thereto, followed
by stirring at 130.degree. C. overnight. The reaction mixture was
concentrated under reduced pressure, and to the obtained residue
was added a 1 M aqueous NaOH solution (10 mL), followed by washing
with CHCl.sub.3 (50 mL). The pH of the aqueous layer was adjusted
to around 6 to 7 by the addition of 1 M hydrochloric acid, followed
by extraction with CHCl.sub.3 (50 mL.times.3). The organic layer
was dried over anhydrous sodium sulfate and the solvent was
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography
(CH.sub.2Cl.sub.2/MeOH=10/1) to give
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 65%
yield) as a white solid.
[0901] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min). Purity is 83.17%, Rt=1.312 min; MS Calcd.:
307.15; MS Found: 308.2 [M+H].sup.+.
[0902] Chemical Formula: C.sub.15H.sub.21N.sub.3O.sub.4, Molecular
Weight: 307.34.
[0903] Step 2: Synthesis of tert-butyl
4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylca-
rbamoyl)pyridin-2-yl)piperazine-1-carboxylate
##STR00335##
[0904] A mixture of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (614 mg,
2.0 mmol),
4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile
hydrochloride (630 mg, 2.0 mmol),
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (1.1 g, 3.0 mmol) and ethyldiisopropylamine
(516 mg, 4.0 mmol) in dichloromethane (20 mL) was stirred at room
temperature overnight. Water (50 mL) was added and extracted with
dichloromethane (50 mL.times.3). Combined organic layers were
washed by brine (50 mL.times.2), dried over anhydrous sodium
sulfate. The solvent was concentrated to give the residue, which
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate=1/1) to give tert-butyl
4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylca-
rbamoyl)pyridin-2-yl)piperazine-1-carboxylate (977 mg, 86% yield)
as a white solid.
[0905] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min). Purity is 88.26%, Rt=2.161 min; MS Calcd.:
567.26; MS Found: 568.3 [M+H].sup.+.
[0906] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.1.12 (6H, s),
1.22 (6H, s), 1.43 (9H, s), 3.42-3.44 (4H, m), 3.60-3.63 (4H, m),
4.02-4.07 (1H, m), 4.31 (1H, s), 6.88 (1H, d, J=8.8 Hz), 7.00 (1H,
dd, J=8.4, 2.4 Hz), 7.21 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=9.2 Hz),
7.91 (1H, d, J=8.8 Hz), 7.99 (1H, dd, J=8.8, 2.4 Hz), 8.64 (1H, d,
J=2.4 Hz).
[0907] Chemical Formula: C.sub.30H.sub.38ClN.sub.5O.sub.4,
Molecular Weight: 568.11.
[0908] Total H count from HNMR data: 38.
Step 3: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide hydrochloride
##STR00336##
[0910] A mixture of tert-butyl
4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl
carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (405 mg, 0.7 mmol)
in HCl/1,4-dioxane (10 mL) was stirred at room temperature for 4 h.
The solvent was removed in vacuum to give
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide hydrochloride (353 mg, 100% yield) as a
white solid.
[0911] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min). Rt=1.791 min; MS Calcd.:467.21; MS Found:
468.3 [M+H].sup.+.
[0912] Chemical Formula: C.sub.25H.sub.31Cl.sub.2N.sub.5O.sub.2,
Molecular Weight: 504.45
General Synthetic Scheme C-2
Synthesis of Building Block tert-butyl
4-(4-formylpiperidin-1-yl)benzoate
##STR00337##
[0913] Synthetic Scheme
##STR00338##
[0914] Step 1: Synthesis of tert-butyl
4-(4-(hydroxymethyl)piperidin-1-yl)benzoate
##STR00339##
[0916] To a solution of tert-butyl 4-fluorobenzoate (23 g, 0.12
mmol) in DMSO (100 mL) was added piperidin-4-ylmethanol (40.5 g,
0.35 mmol). The mixture was heated to 120.degree. C. overnight
under nitrogen. After cooling to room temperature, water (50 mL)
was added to the reaction mixture, and extracted with ethyl acetate
(20 mL.times.3). The organic layer was washed with brine (15
mL.times.3). The combined organic phases were dried over anhydrous
sodium sulfate and concentrated in vacuo, and purified by CC
(PE/EA=10:1) to give compound tert-butyl
4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (31 g, 91.2%) as a
white solid.
[0917] LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 90%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] to 10%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 90%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 1.6
min, then under this condition for 2.4 min, finally changed to 90%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10%
[(total 10 mM AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 0.1
min and under this condition for 0.7 min). Purity is 99.57%,
Rt=2.035 min.; MS Calcd.: 291.2; MS Found: 292.2 [M+H]+.
[0918] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 10 min, then under this
condition for 5 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 5 min). Purity is 93.27%, Rt=9.542 min.
[0919] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.29-1.40 (2H, m),
1.49 (1H, d, J=5.4 Hz), 1.57 (9H, s), 1.70-1.75 (1H, m), 1.82 (2H,
d, J=12.8 Hz), 2.80-2.87 (2H, m), 3.53 (2H, t, J=5.8 Hz), 3.87-3.90
(2H, m), 6.85 (2H, d, J=9.2 Hz), 7.84 (2H, d, J=9.2 Hz).
[0920] Chemical Formula: C.sub.17H.sub.25NO.sub.3, Molecular
Weight: 291.39.
[0921] Total H count from HNMR data: 25.
Step 2: Synthesis of tert-butyl
4-(4-formylpiperidin-1-yl)benzoate
##STR00340##
[0923] To a solution of tert-butyl
4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (300 mg, 1.03 mmol) in
dichloromethane (20 mL) was added Dess-Martin periodinane (1.31 g,
3.09 mmol) slowly at 0.degree. C. The reaction mixture was stirred
at room temperature for 1 h. Then filtered, and concentrated in
vacuo to give compound tert-butyl
4-(4-formylpiperidin-1-yl)benzoate (240 mg, 81%) as a pale yellow
solid.
Exemplary Synthesis of Exemplary Compound 46
##STR00341##
[0924]
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty-
l)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinol-
in-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide
Synthetic Scheme
##STR00342## ##STR00343##
[0925] Step 1: Synthesis of methyl 2-bromo-4-methoxybenzoate
##STR00344##
[0927] To a solution of 2-bromo-4-methoxybenzoic acid (5.0 g, 21.7
mmol) in methanol (50 mL) was added 98% sulfuric acid (0.5 ml). The
reaction mixture was heated to 90.degree. C. for 16 h under
nitrogen gas, and concentraction under reduced pressure. After
cooling to room temperature, sodium bicarbonate (2.0 M) was added
to adjust PH=8. Thus was extracted with ethyl acetate (50
mL.times.3). The organic layer was washed with brine (30 mL). The
combined organic phases were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give
2-bromo-4-methoxybenzoate (4.8 g, 91%) as yellow oil.
[0928] Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] to 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 1.6 min, then under
this condition for 2.4 min, finally changed to 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 0.1 min and under
this condition for 0.7 min. Purity is 98.94%, Rt=2.609 min; MS
Calcd.: 243.97; MS Found: 245.0 [M+H].sup.+.
Step 2: Synthesis of methyl 2-allyl-4-methoxybenzoate
##STR00345##
[0930] To a solution of methyl 2-bromo-4-methoxybenzoate (3.0 g,
12.3 mmol), cesium carbonate (12.0 g, 36.9 mmol),
2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.98 g, 18.5 mmol)
in N,N-dimethylformamide/water (30.0 mL/3.0 mL) was added
tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) under
nitrogen atmosphere. The reaction mixture was heated to 100.degree.
C. and stirred for 4 h. The resulting reaction was concentrated
under reduced pressure, and then water (10 mL) was added. The
mixture was extracted with ethyl acetate (50 mL.times.3). The
combined organic phase was washed with brine (20 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by silica gel chromatography column (petroether/ethyl
acetate=4:1) to give the methyl 2-allyl-4-methoxybenzoate (2.6 g,
100%) as yellow oil.
[0931] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water+0.05% TFA]
and 5% [CH.sub.3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100%
[CH.sub.3CN+0.05% TFA] in 1.5 min, then under this condition for
0.5 min, finally changed to 95% [water+0.05% TFA] and 5%
[CH.sub.3CN+0.05% TFA] in 0.1 min and under this condition for 0.5
min. Purity is 96.85%, Rt=1.293 min; MS Calcd.: 206.09; MS
Found:207.3 [M+H].sup.+.
Step 3: Synthesis of methyl 4-methoxy-2-(2-oxoethyl)benzoate
##STR00346##
[0933] To a solution of methyl 2-allyl-4-methoxybenzoate (1.20 g,
5.83 mmol) and osmium tetraoxide (5 mg) in acetonitrile, acetone,
and water (v:v:v=10 mL:10 mL:10 mL) was added sodium periodate
(4.99 g, 23.3 mmol) at 0.degree. C. The mixture was stirred at room
temperature for 4 h. The mixture was filtered through a pad of
celite and extracted with ethyl acetate (20.times.3 mL). The
organic layer was separated, washed with water and brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by prep-TLC (petroether/ethyl acetate=4:1) to
give compound methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg, 35%)
as yellow oil.
[0934] LC-MS (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95%
[water+0.05% TFA] and 5% [CH.sub.3CN+0.05% TFA] to 0% [water+0.05%
TFA] and 100% [CH.sub.3CN+0.05% TFA] in 1.5 min, then under this
condition for 0.5 min, finally changed to 95% [water+0.05% TFA] and
5% [CH.sub.3CN+0.05% TFA] in 0.1 min and under this condition for
0.5 min.). Purity is 96.26%, Rt=1.007 min; MS Calcd.: 208.1; MS
Found: 209.3 [M+H].sup.+.
Step 4: Synthesis of
3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
##STR00347##
[0936] To a solution of methyl 4-methoxy-2-(2-oxoethyl)benzoate
(420 mg, 2.02 mmol) in methanol (6 mL) was added a solution of
3-aminopiperidine-2,6-dione hydrochloride (397 mg, 2.42 mmol) and
triethylamine (245 mg, 2.24 mmol) in methanol (2 mL). The reaction
mixture was stirred at room temperature for 1 h, then sodium
cyanoborohydride (254 mg, 4.04 mmol) was added at 0.degree. C. The
reaction was stirred at room temperature overnight, water (10 mL)
was added, and extracted with ethyl acetate (20 mL.times.3), washed
with water and brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by prep-TLC
(dichloromethane/methanol=20:1) to give
3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
(340 mg, 59%) as a pale yellow solid.
[0937] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm.times.3 mm.times.2.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] to
5% [water+10 mM NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN+10 mM
NH.sub.4HCO.sub.3] in 1.5 min, then under this condition for 0.5
min, finally changed to 95% [water+10 mM NH.sub.4HCO.sub.3] and 5%
[CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] in 0.1 min and under this
condition for 0.5 min.). Purity is 80.84%, Rt=0.924 min; MS Calcd.:
288.1; MS Found: 289.1 [M+H].sup.+.
Step 5: Synthesis of
3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
##STR00348##
[0939] To a solution of
3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
(220 mg, 0.76 mmol) in dichloromethane (10 mL) was added boron
tribromide (0.5 mL) in dichloromethane (2 mL) dropwise at
-78.degree. C. and stirred overnight at room temperature. The
reaction mixture was added to water (10 mL) and sodium bicarbonate
(20 mL), then extracted with dichloromethane/methanol (30
mL.times.5). The organic layer was washed with brine (10 mL). The
combined organic phases were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
prep-TLC (dichloromethane/methanol=10:1) to give compound
3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
(80 mg, 38%) as a yellow solid.
[0940] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm.times.3 mm.times.2.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] to
5% [water+10 mM NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN+10 mM
NH.sub.4HCO.sub.3] in 1.5 min, then under this condition for 0.5
min, finally changed to 95% [water+10 mM NH.sub.4HCO.sub.3] and 5%
[CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] in 0.1 min and under this
condition for 0.5 min.). Purity is 96.22%, Rt=0.736 min; MS Calcd.:
274.1; MS Found: 275.1 [M+H].sup.+.
Step 6: Synthesis of
3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-
-2,6-dione
##STR00349##
[0942] To a solution of
3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione
(80 mg, 0.292 mmol) in N,N-dimethylformamide (5.0 mL) was added
5-chloropentyl 4-methylbenzenesulfonate (64.5 mg, 0.234 mmol) and
potassium carbonate (121 mg, 0.876 mmol). The mixture was heated to
40.degree. C. overnight. After cooling to rt., the reaction mixture
was added to water (10 mL), and extracted with ethyl acetate (20
mL.times.3). The organic layer was washed with brine (10
mL.times.3). The combined organic phases were dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by prep-TLC (dichloromethane/methanol=10:1) to give
3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-
-2,6-dione (25 mg, 23%) as a yellow solid.
[0943] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm.times.3 mm.times.2.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] to
5% [water+10 mM NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN+10 mM
NH.sub.4HCO.sub.3] in 1.5 min, then under this condition for 0.5
min, finally changed to 95% [water+10 mM NH.sub.4HCO.sub.3] and 5%
[CH.sub.3CN+10 mM NH.sub.4HCO.sub.3] in 0.1 min and under this
condition for 0.5 min.). Purity is 93.68%, Rt=1.263 min; MS Calcd.:
378.1; MS Found: 379.1 [M+H].sup.+.
Step 7: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl-
oxy)pentyl)piperazin-1-yl)nicotinamide
##STR00350##
[0945] A solution of
3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-
-2,6-dione (25 mg, 0.066 mmol) was dissolved in acetonitrile (2
mL),
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide (31 mg, 0.066 mmol),
ethyldiisopropylamine (17 mg, 0.132 mmol), potassium iodide (2 mg)
was added to the solution. The mixture was heated to 100.degree. C.
for 16 h under sealed tube. After cooling to rt., the reaction
mixture was added to water (10 mL), and extracted with ethyl
acetate (10 mL.times.3). The organic layer was washed with brine
(10 mL.times.3). The combined organic phases were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo, then
purified by prep-HPLC to give compound
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl-
oxy)pentyl)piperazin-1-yl)nicotinamide (4.1 mg, 8%) as a white
solid.
[0946] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 3.0 min, then under
this condition for 1.0 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.). Purity is 87.84%, Rt=2.923 min; MS Calcd.:
809.4; MS Found: 810.3 [M+H].sup.+.
[0947] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 10 min, then under this
condition for 5 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 5 min). Purity is 84.56%, Rt=10.161 min.
[0948] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.12 (6H, s),
1.21 (6H, s), 1.43-1.54 (4H, m), 1.74-1.78 (2H, m), 1.88-1.91 (1H,
m), 2.30-2.44 (8H, m), 2.90-2.97 (3H, m), 3.42-3.59 (7H, m),
4.03-4.07 (3H, m), 4.30 (1H, s), 6.86-6.91 (3H, m), 6.99-7.02 (1H,
m), 7.22 (1H, d, J=2.4 Hz), 7.64 (1H, d, J=8.8 Hz), 7.79 (1H, d,
J=8.8 Hz), 7.90-7.97 (2H, m), 8.62 (1H, d, J=2.0 Hz), 10.90 (1H,
s).
[0949] Chemical Formula: C.sub.44H.sub.52ClN.sub.7O.sub.6,
Molecular Weight: 810.38.
[0950] Total H count from HNMR data: 52.
Exemplary Synthesis of Exemplary Compound 47
##STR00351##
[0951]
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty-
l)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoqu-
inolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide
Synthetic Scheme
##STR00352## ##STR00353##
[0952] Step 1: Synthesis of 2-(carboxymethyl)-4-methoxybenzoic
acid
##STR00354##
[0954] To a solution of of 4-methoxy-2-methylbenzoic acid (5.0 g,
30.1 mmol) in dry tetrahydrofuran (50 mL) was added lithium
diisopropylamide in tetrahydrofuran (1.0 mol/L)(66.3 mL, 66.3 mmol)
at -78.degree. C. under nitrogen gas. The mixture was left to stir
for 1 hour at that temperature and then dimethyl carbonate (2.98 g,
33.1 mmol) was added. The reaction mixture was left to stir
overnight. Water (200 mL) and ethyl acetate (100 mL) was added. The
aqueous layer was separated, extracted with ethyl acetate (50
mL.times.2) and neutralized with hydrochloric acid (1 N) until
pH<4. The mixture was extracted with ethyl acetate (100
mL.times.2). The combined organic layers were washed with saturated
brine (50.0 mL.times.2), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was dissolved in
dimethyl sulfoxide (40 mL) and lithium hydroxide hydrate (5.06 g,
120.4 mmol) was added. The mixture was stirred at 120.degree. C.
for 2 hour, cooled down to room temperature and poured into
ice-water (200 mL). Hydrochloric acid (1 N) was added until
pH<4. The mixture was extracted with ethyl acetate (100
mL.times.2). The combined organic layers were washed with saturated
brine (50.0 mL.times.2), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give
2-(carboxymethyl)-4-methoxybenzoic acid (4.6 g, 73% two steps) as a
yellow solid.
[0955] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 1.5 mL/min; Mobile Phase: from 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] to 0% [water+0.1% TFA] and 100%
[CH.sub.3CN+0.1% TFA] in 0.5 min, then under this condition for 1.5
min, finally changed to 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] in 0.1 min and under this condition for 0.5
min). Purity is 94.6%, Rt=0.774 min; MS Calcd.: 210.1; MS Found:
233.1 [M+23].sup.+.
Step 2: Synthesis of methyl
4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate
##STR00355##
[0957] To a solution of (2-(carboxymethyl)-4-methoxybenzoic acid
(1.2 g, 5.7 mmol) in methanol (10.0 mL) was added thionyl chloride
(1.7 g, 14.3 mmol) dropwise. The mixture was refluxed for 2 hour.
The mixture was cooled down to room temperature and then the
solvent was removed in vacuo to give crude product which was
purified by column chromatography on silica gel (ethyl
acetate/petroleum ether=1:1) to give
4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (900 mg, 66%) as a white
solid.
Step 3: Synthesis of 2-(carboxymethyl)-4-hydroxybenzoic acid
##STR00356##
[0959] To a solution of 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate
(0.9 g, 3.78 mmol) in dichloromethane (30 mL) was added boron
tribromide (4.7 g, 18.9 mmol) dropwise under ice-water bath. The
resulting mixture was allowed to warm to room temperature and
stirred overnight. Water (100 mL) was added. The organic layer was
separated, washed with brine (50 mL.times.2), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give a
mixture. The mixture was dissolved in methanol (30 mL) and sodium
hydroxide (0.76 g, 18.9 mmol) in water (4.0 mL) was added. The
mixture was refluxed for 5 hour. The solvent was removed. The
residue was dissolved in water (30 mL). Hydrochloric acid (1 N) was
added until pH<4. The mixture was extracted with ethyl acetate
(50 mL.times.2). The combined organic layers were washed with
saturated brine (20.0 mL.times.2), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to give
2-(carboxymethyl)-4-hydroxybenzoic acid (0.45 g, 61% two steps) as
a yellow solid.
[0960] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 1.5 mL/min; Mobile Phase: from 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] to 0% [water+0.1% TFA] and 100%
[CH.sub.3CN+0.1% TFA] in 0.5 min, then under this condition for 1.5
min, finally changed to 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] in 0.1 min and under this condition for 0.5
min). Purity is 95.2%, Rt=0.570 min; MS Calcd.: 196.0; MS Found:
197.2 [M+H].sup.+.
Step 4: Synthesis of
2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid
##STR00357##
[0962] The mixture of 2-(carboxymethyl)-4-hydroxybenzoic acid (120
mg, 0.61 mmol), potassium carbonate (253 mg, 1.83 mmol) and
5-chloropentyl 4-methylbenzenesulfonate (506 mg, 1.83 mmol) in
dimethyl sulfoxide (5 mL) was stirred at 70.degree. C. overnight.
The resulting mixture was allowed to cooled down to room
temperature and stirred overnight. Water (20 mL) and ethyl acetate
(20 mL) was added. The organic layer was separated, washed with
brine (50 mL.times.2), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give a mixture. The mixture
was dissolved in methanol (30 mL) and lithium hydroxide hydrate
(128 mg, 3.05 mmol) was added. The mixture was stirred at room
temperature overnight. The solvent was removed. The residue was
dissolved in water (30 mL). Hydrochloric acid (1 N) was added until
pH<4. The mixture was extracted with ethyl acetate (20
mL.times.2). The combined organic layers were washed with saturated
brine (10 mL.times.2), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give
2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85
mg, 44% two steps) as yellow oil.
[0963] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] to 5% [water+10 mM
NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN] in 0.5 min, then under this
condition for 1.5 min, finally changed to 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] in 0.1 min and under this
condition for 0.5 min.). Purity is 69.9%, Rt=0.829 min; MS Calcd.:
314.1; MS Found: 315.1 [M+H].sup.+.
Step 5: Synthesis of methyl
4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate
##STR00358##
[0965] To a solution of
2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85
mg, 0.27 mmol) in methanol (2 mL) was added thionyl chloride (48.3
mg, 0.41 mmol) dropwise. The mixture was refluxed for 2 hour. The
mixture was cooled down to room temperature and then the solvent
was removed in vacuo to give crude product which was purified by
prep-TLC (ethyl acetate/petroleum ether=1:1) to give methyl
4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 62%)
as yellow oil.
[0966] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] to 5% [water+10 mM
NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN] in 0.5 min, then under this
condition for 1.5 min, finally changed to 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] in 0.1 min and under this
condition for 0.5 min.). Purity is 72.9%, Rt=1.208 min; MS Calcd.:
328.1; MS Found: 329.2 [M+H].sup.+.
Step 6: Synthesis of methyl
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoate
##STR00359##
[0968] The mixture of methyl
4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 0.17
mmol), ethyldiisopropylamine (65.8 mg, 0.51 mmol), potassium iodide
(28.2 mg, 0.17 mmol) and
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide (78.5 mg, 0.17 mmol) in dimethyl
sulfoxide (2 mL) was stirred at 70.degree. C. overnight. The
resulting mixture was allowed to cooled down to room temperature
and stirred overnight. Water (20 mL) and ethyl acetate (20 mL) was
added. The organic layer was separated, washed with brine (50
mL.times.2), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to give the crude product which was purified
by column and flash chromatography (ethyl acetate/petroleum
ether=1:1) to give methyl
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoate (53 mg, 41%) as a white solid.
Step 7: Synthesis of
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoic acid
##STR00360##
[0970] The mixture of methyl
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoate (53 mg, 0.07 mmol) was dissolved in methanol (2 mL) and
lithium hydroxide hydrate (14.7 mg, 0.35 mmol) was added. The
mixture was stirred at room temperature for 3 hour. The solvent was
removed. The residue was dissolved in water (15 mL). Hydrochloric
acid (1 N) was added until pH<4. The mixture was extracted with
ethyl acetate (15 mL.times.2). The combined organic layers were
washed with saturated brine (10 mL.times.2), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoic acid (42 mg, 81%) as a white solid.
[0971] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] to 5% [water+10 mM
NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN] in 0.5 min, then under this
condition for 1.5 min, finally changed to 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] in 0.1 min and under this
condition for 0.5 min.). Purity is 75.4%, Rt=1.041 min; MS Calcd.:
745.3; MS Found: 746.2 [M+H].sup.+.
Step 8: Synthesis of methyl
2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyc-
lobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperi-
din-3-ylcarbamoyl)phenyl)acetate
##STR00361##
[0973] A solution of
4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob-
utylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoeth-
yl)benzoic acid (42 mg, 0.056 mmol), HATU (25.5 mg, 0.067 mmol) and
ethyldiisopropylamine (29.7 mg, 0.23 mmol) in N,
N-dimethylformamide (2 mL) was stirred for 30 min, and then
3-aminopiperidine-2,6-dione hydrochloride (9.2 mg, 0.056 mmol) was
added. The mixture was stirred at room temperature overnight and
water (10 mL) was added. The mixture was extracted by ethyl acetate
(20 mL.times.3). The combined organic layers were washed with brine
(10 mL.times.3), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by prep-TLC
(dichloromethane/methanol=10:1) to give methyl
2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyc-
lobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperi-
din-3-ylcarbamoyl)phenyl)acetate (45 mg, 94%) as a white solid.
[0974] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(30 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] to 5% [water+10 mM
NH.sub.4HCO.sub.3] and 95% [CH.sub.3CN] in 0.5 min, then under this
condition for 1.5 min, finally changed to 90% [water+10 mM
NH.sub.4HCO.sub.3] and 10% [CH.sub.3CN] in 0.1 min and under this
condition for 0.5 min.). Purity is 77.7%, Rt=1.213 min; MS Calcd.:
855.4; MS Found: 856.3 [M+H].sup.+.
Step 9: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin--
6-yloxy)pentyl)piperazin-1-yl)nicotinamide
##STR00362##
[0976] A solution of methyl
2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyc-
lobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperi-
din-3-ylcarbamoyl)phenyl)acetate (45 mg, 0.053 mmol) in dimethyl
sulfoxide (2 mL) was added sodium hydroxide in water (2.5 moL/L, 2
drops). The mixture was stirred at room temperature for 5 min.
Water (20 mL) and ethyl acetate (20 mL) was added. The organic
layer was separated, washed with brine (10 mL.times.2), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo to
give the crude product which was purified by prep-HPLC to give
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin--
6-yloxy)pentyl)piperazin-1-yl)nicotinamide (18.5 mg, 42%) as a
white solid.
[0977] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] to 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] in 1.6 min, then under this
condition for 2.4 min, finally changed to 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 0.1 min and under
this condition for 0.7 min). Purity is 100.0%, Rt=2.988 min; MS
Calcd.:823.4; MS Found:824.3 [M+H].sup.+.
[0978] HPLC (Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6
mm*5.0 .mu.m); Column Temperature: 40.degree. C.; Flow Rate: 1.0
mL/min; Mobile Phase: from 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] to 0% [water+0.1% TFA] and 100%
[CH.sub.3CN+0.1% TFA] in 10 min, then under this condition for 5
min, finally changed to 95% [water+0.1% TFA] and 5%
[CH.sub.3CN+0.1% TFA] in 0.1 min and under this condition for 5
min). Purity is 95.2%, Rt=8.168 min.
[0979] .sup.1H NMR (400 MHz, DMSO-d.sup.6) .delta. 1.12 (6H, s),
1.21 (6H, s), 1.37-1.58 (4H, m), 1.73-1.81 (2H, m), 1.86-1.91 (1H,
m), 2.30-2.37 (2H, m), 2.40-2.46 (2H, m), 2.82-2.91 (1H, m),
3.30-3.35 (4H, m), 3.55-3.65 (4H, m), 4.03-4.30 (6H, m), 5.54-5.63
(1H, m), 6.87 (1H, d, J=9.6 Hz), 6.96-7.07 (3H, m), 7.21 (1H, d,
J=2.4 Hz), 7.63 (1H, d, J=9.6 Hz), 7.90-8.04 (3H, m), 8.62 (1H, d,
J=2.4 Hz), 10.93 (1H, s).
[0980] Chemical Formula: C.sub.44H.sub.50ClN.sub.7O.sub.7,
Molecular Weight: 824.36.
[0981] Total H count from HNMR data: 50.
Exemplary Synthesis of Exemplary Compound 48
##STR00363##
[0982]
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty-
l)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo-
[4,3-a]pyridin-7-yl)oxy)pentyl)piperazin-1-yl)nicotinamide
Synthetic Scheme
##STR00364##
[0983] Step 1: Synthesis of
4-(5-(benzyloxy)pentyloxy)-2-chloropyridine
##STR00365##
[0985] To a solution of 2-chloropyridin-4-ol (1.3 g, 10.0 mmol) in
DMF (15 mL) was added sodium hydride (60% dispersed in mineral oil,
482 mg, 12.0 mmol) at 0.degree. C., and the mixture was stirred at
room temperature for 30 min. Then ((5-bromopentyloxy)methyl)benzene
(3.1 g, 12.0 mmol) was added to the reaction and the resulted
mixture was stirred at 50.degree. C. overnight. When the reaction
was completed (monitored by TLC), water (30 mL) was added. The
resultant mixture was extracted by ethyl acetate (10 mL.times.3)
and the combined organic layers were washed by brine (20
mL.times.3), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by column chromatography on
silica (petroleum/ethyl acetate=1/4) to give
4-(5-(benzyloxy)pentyloxy)-2-chloropyridine (2.4 g, 78% yield) as a
brown solid.
[0986] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.47-1.53 (2H, m),
1.59-1.64 (2H, m), 1.71-1.76 (2H, m), 3.42 (2H, t, J=6.4 Hz), 3.91
(2H, t, J=6.4 Hz), 4.44 (2H, s), 7.07-7.15 (2H, m), 7.23-7.28 (5H,
m), 7.96 (1H, d, J=3.2 Hz).
Step 2: Synthesis of
4-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine
##STR00366##
[0988] To a microwave glass vial was added
4-(5-(benzyloxy)pentyloxy)-2-chloropyridine (2.0 g, 6.5 mmol),
hydrazine monohydrate (10 mL) and EtOH (10 mL), and the mixture was
stirred under microwave conditions at 120.degree. C. for 8 h. When
it was cooled to room temperature, water (20 mL) was added to the
reaction. The resultant mixture was extracted by ethyl acetate (10
mL.times.3) and the combined organic layers were washed by brine
(15 mL.times.3), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue (1.6 g, 83% yield) was directly
used to the next step without further purification as brown
oil.
Step 3: Synthesis of
7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
##STR00367##
[0990] To a solution of 5-ethoxy-2-hydrazinylpyridine (1.6 g, 5.4
mmol) in acetonitrile (25 mL) was added CDI (1.3 g, 8.2 mmol), and
the mixture was stirred at 80.degree. C. for 2 h. When it was
cooled to room temperature, water (20 mL) was added to the
reaction. The resultant mixture was extracted by ethyl acetate (10
mL.times.3) and the combined organic layers were washed by brine
(15 mL.times.3), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica (DCM/MeOH=20/1) to give
7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
(360 mg, 20% yield) as a white solid.
[0991] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 96.77%, Rt=1.716 min. MS Calcd.:
327.16; MS Found: 328.2 [M+H].sup.+.
Step 4: Synthesis of
3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y-
l)piperidine-2,6-dione
##STR00368##
[0993] The solution of
7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
(300 mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol)
and K.sub.2CO.sub.3 (253 mg, 1.8 mmol) in acetonitrale (10 mL) was
stirred at 80.degree. C. overnight. When it was cooled to room
temperature, water (10 mL) was added. The resultant mixture was
extracted by ethyl acetate (10 mL.times.3) and the combined organic
layers were washed by brine (10 mL.times.3), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by Prep-TLC (DCM/MeOH=20/1) to give
3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(-
3H)-yl)piperidine-2,6-dione (157 mg, 39% yield) as a white
solid.
[0994] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 99.45%, Rt=1.836 min. MS Calcd.:
438.19; MS Found: 439.3 [M+H].sup.+.
Step 5: Synthesis of
3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione
##STR00369##
[0996] To a solution of
3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y-
l)piperidine-2,6-dione (157 mg, 0.4 mmol) in CHCl.sub.3 (5 mL) was
added TMSI (143 mg, 0.7 mmol), and the mixture was stirred at room
temperature overnight. Then the mixture was washed by sat.
NaHSO.sub.3 (5 mL.times.2), washed by brine (5 mL.times.2), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by Prep-TLC (DCM/MeOH=15/1) to give
3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione (130 mg, 79% yield) as a white solid.
[0997] LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 100%, Rt=1.754 min. MS Calcd.:
458.05; MS Found: 459.1 [M+H].sup.+.
Step 6: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]-
pyridin-7-yloxy)pentyl)piperazin-1-yl)nicotinamide
##STR00370##
[0999] A solution of
3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione (85 mg, 0.2 mmol),
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide (87 mg, 0.2 mmol), and
ethyldiisopropylamine (72 mg, 0.6 mmol) in acetonitrile (5 mL) was
stirred at 80.degree. C. overnight. When it was cooled to room
temperature, water (5 mL) was added and the mixture was extracted
by ethyl acetate (5 mL.times.3) and the combined organic layers
were washed by brine (5 mL.times.3), dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
Prep-HPLC to give
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]-
pyridin-7-yloxy)pentyl)piperazin-1-yl)nicotinamide (50 mg, 34%
yield) as a white solid.
[1000] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 3.0 min, then under
this condition for 1.0 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 100%, Rt=2.877 min; MS Calcd.:
797.34; MS Found: 798.3 [M+H].sup.+.
[1001] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 10 min, then under this
condition for 5 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 5 min.) Purity is 93.85%, Rt=9.967 min.
[1002] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.12 (6H, s),
1.21 (6H, s), 1.43-1.47 (2H, m), 1.49-1.53 (2H, m), 1.73-1.78 (2H,
m), 2.13-2.17 (1H, m), 2.32 (2H, t, J=7.2 Hz), 2.43-2.47 (5H, m),
2.61-2.62 (1H, m), 2.87-2.93 (1H, m), 3.59 (4H, s), 4.01-4.07 (3H,
m), 4.30 (1H, s), 5.28 (1H, dd, J=12.4, 5.2 Hz), 6.35 (1H, dd,
J=8.0, 2.4 Hz), 6.52 (1H, d, J=1.6 Hz), 6.86 (1H, d, J=8.8 Hz),
7.00 (1H, dd, J=8.8, 2.4 Hz), 7.21 (1H, d, J=2.4 Hz), 7.63 (1H, d,
J=9.2 Hz), 7.80 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.8 Hz), 7.95
(1H, dd, J=9.2, 2.4 Hz), 8.62 (1H, d, J=2.4 Hz), 11.09 (1H, s).
[1003] Chemical Formula: C.sub.41H.sub.48ClN.sub.9O.sub.6,
Molecular Weight: 798.33.
[1004] Total H count from HNMR data: 48.
Exemplary Synthesis of Exemplary Compound 49
##STR00371##
[1005] N-((1
r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5--
((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyri-
din-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide
Synthetic Scheme
##STR00372##
[1006] Step 1: Synthesis of
5-(5-(benzyloxy)pentyloxy)-2-chloropyridine
##STR00373##
[1008] To a solution of 6-chloropyridin-3-ol (1.0 g, 7.7 mmol) in
DMF (10 mL) was added sodium hydride (60% dispersed in mineral oil,
371 mg, 9.3 mmol) at 0.degree. C., and the mixture was stirred at
room temperature for 30 min. Then ((5-bromopentyloxy)methyl)benzene
(2.0 g, 7.7 mmol) was added to the reaction and the resulted
mixture was stirred at room temperature for 2 h. When the reaction
was completed (monitored by TLC), water (30 mL) was added. The
resultant mixture was extracted by ethyl acetate (10 mL.times.3)
and the combined organic layers were washed by brine (10
mL.times.3), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue (1.6 g, 68% yield) was directly used to
the next step without further purification as a brown solid.
Step 2: Synthesis of
5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine
##STR00374##
[1010] To a microwave glass vial was added
5-(5-(benzyloxy)pentyloxy)-2-chloropyridine (1.6 g, 5.2 mmol) and
hydrazine monohydrate (20 mL), and the mixture was stirred under
microwave conditions at 170.degree. C. for 18 h. When it was cooled
to room temperature, water (20 mL) was added to the reaction. The
resultant mixture was extracted by ethyl acetate (10 mL.times.3)
and the combined organic layers were washed by brine (15
mL.times.3), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue (1.3 g, 82% yield) was directly
used to the next step without further purification as brown
oil.
Step 3: Synthesis of
6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
##STR00375##
[1012] To a solution of
5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine (1.3 g, 4.4 mmol)
in acetonitrile (30 mL) was added CDI (1.1 g, 6.7 mmol), and the
mixture was stirred at 80.degree. C. for 2 h. When it was cooled to
room temperature, water (20 mL) was added to the reaction. The
resultant mixture was extracted by ethyl acetate (10 mL.times.3)
and the combined organic layers were washed by brine (15
mL.times.3), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica (DCM/MeOH=20/1) to give
6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
(280 mg, 19% yield) as a white solid.
[1013] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 98.98%, Rt=1.728 min. MS Calcd.:
327.16; MS Found: 328.1 [M+H].sup.+.
Step 4: Synthesis of
3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y-
l)piperidine-2,6-dione
##STR00376##
[1015] The solution of
6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
(280 mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol)
and K.sub.2CO.sub.3 (253 mg, 1.8 mmol) in acetonitrile (10 mL) was
stirred at 80.degree. C. overnight. When it was cooled to room
temperature, water (10 mL) was added. The resultant mixture was
extracted by ethyl acetate (10 mL.times.3) and the combined organic
layers were washed by brine (10 mL.times.3), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by Prep-TLC (DCM/MeOH=20/1) to give
3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(-
3H)-yl)piperidine-2,6-dione (155 mg, 41% yield) as a white
solid.
[1016] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 85.76%, Rt=1.675 min. MS Calcd.:
438.19; MS Found: 439.2 [M+H].sup.+.
Step 5: Synthesis of
3-(6-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione
##STR00377##
[1018] To a solution of
3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y-
l)piperidine-2,6-dione (155 mg, 0.4 mmol) in CHCl.sub.3 (5 mL) was
added TMSI (143 mg, 0.7 mmol), and the mixture was stirred at room
temperature overnight. Then the mixture was washed by sat.
NaHSO.sub.3 (5 mL.times.2), washed by brine (5 mL.times.2), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by Prep-TLC (DCM/MeOH=15/1) to give
3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione (130 mg, 79% yield) as a white solid.
[1019] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 1.6 min, then under
this condition for 1.4 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 95.44%, Rt=1.706 min. MS Calcd.:
458.05; MS Found: 459.1 [M+H].sup.+.
Step 6: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]-
pyridin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide
##STR00378##
[1021] A solution of
3-(6-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piper-
idine-2,6-dione (85 mg, 0.2 mmol),
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
piperazin-1-yl)nicotinamide (87 mg, 0.2 mmol), and
ethyldiisopropylamine (72 mg, 0.6 mmol) in acetonitrile (5 mL) was
stirred at 80.degree. C. overnight. When it was cooled to room
temperature, water (5 mL) was added and the mixture was extracted
by ethyl acetate (5 mL.times.3) and the combined organic layers
were washed by brine (5 mL.times.3), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
Prep-HPLC to give
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(-
4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]-
pyridin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide (58 mg, 39%
yield) as a white solid.
[1022] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature:
40.degree. C.; Flow Rate: 2.0 mL/min; Mobile Phase: from 95%
[water+10 mM NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10
mM NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 3.0 min, then under
this condition for 1.0 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min.) Purity is 100%, Rt=2.890 min; MS Calcd.:
797.34; MS Found: 798.3 [M+H].sup.+.
[1023] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150
mm.times.4.6 mm.times.3.5 .mu.m); Column Temperature: 40.degree.
C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 10 min, then under this
condition for 5 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 5 min.) Purity is 93.46%, Rt=10.027 min.
[1024] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.12 (6H, s),
1.21 (6H, s), 1.44-1.48 (2H, m), 1.52-1.58 (2H, m), 1.74-1.79 (2H,
m), 2.15-2.19 (1H, m), 2.30 (2H, t, J=7.2 Hz), 2.43-2.50 (4H, m),
2.51-2.67 (2H, m), 2.86-2.95 (1H, m), 3.60 (4H, s), 3.97 (2H, t,
J=6.4 Hz), 4.05 (1H, d, J=9.2 Hz), 4.30 (1H, s), 5.38 (1H, dd,
J=5.2, 12.8 Hz), 6.86 (1H, d, J=9.2 Hz), 7.00 (1H, dd, J=8.4, 2.4
Hz), 7.10 (1H, dd, J=10.0, 2.0 Hz), 7.21 (1H, d, J=2.4 Hz), 7.25
(1H, d, J=10.0 Hz), 7.36 (1H, s), 7.62 (1H, d, J=9.2 Hz), 7.90 (1H,
d, J=8.8 Hz), 7.95 (1H, dd, J=9.2, 2.4 Hz), 8.62 (1H, d, J=2.4 Hz),
11.10 (1H, s).
[1025] Chemical Formula: C.sub.41H.sub.48ClN.sub.9O.sub.6,
Molecular Weight: 798.33.
[1026] Total H count from HNMR data: 48.
Exemplary Synthesis of Exemplary Compound 50
##STR00379##
[1027]
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty-
l)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo-
[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide
Synthetic Scheme
##STR00380## ##STR00381##
[1028] Step 1: Synthesis of tert-butyl
4-(2-chloropyridin-4-yl)piperazine-1-carboxylate
##STR00382##
[1030] To a solution of 4-bromo-2-chloropyridine (5.8 g, 30.2 mmol)
in dry toluene (150 mL) was added sodium tert-butoxide (4.3 g, 45.0
mmol), Pd.sub.2(dba).sub.3 (0.55 g, 0.60 mmol), Xantphos (1.0 g,
1.80 mmol) and tert-butyl piperazine-1-carboxylate (5.6 g, 30.2
mmol). The reaction mixture was stirred at 100.degree. C. for 3 h
under nitrogen and then cooled to rt. The organic layer was washed
with water and brine and then dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by silica gel
chromatography column (PE/EA=8:1) to give tert-butyl
4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (3.6 g, 46%) as a
yellow solid.
[1031] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.42 (9H, s),
3.38-3.41 (8H, m), 6.83-6.86 (2H, m), 7.96 (1H, d, J=6.0 Hz).
[1032] Chemical Formula: C.sub.14H.sub.20ClN.sub.3O.sub.2,
Molecular Weight: 297.78.
[1033] Total H count from HNMR data: 20.
Step 2: Synthesis of tert-butyl
4-(2-hydrazinylpyridin-4-yl)piperazine-1-carboxylate
##STR00383##
[1035] To a solution of tert-butyl
4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (5.0 g, 16.8 mmol)
in hydrazine monohydrate (98%, 40 mL), was stirred at 120.degree.
C. for 48 h under nitrogen. Water (100 mL) was added to the
mixture. The resultant mixture was extracted by ethyl acetate (50
mL.times.3), washed by brine (100 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue (4.8 g,
30% purity) was directly used to the next step without further
purification as a brown solid.
Step 3: Synthesis of tert-butyl
4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carb-
oxylate
##STR00384##
[1037] To a solution of tert-butyl
4-(2-hydrazinylpyridin-4-yl)piperazine-1-carboxylate (4.8 g, 30%
purity, 4.9 mmol) in acetonitrile (100 mL) was added CDI (1.6 g,
9.8 mmol), and the mixture stirred at 100.degree. C. for 16 h. When
it was cooled to room temperature, water (100 mL) was added to the
reaction. The resultant mixture was extracted by ethyl acetate (100
mL.times.3), washed by brine (150 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica (DCM/MeOH=20/1) to give
tert-butyl
4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carb-
oxylate (1.2 g, 22% yield for two steps) as a yellow solid.
[1038] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] to 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] in 1.6 min, then under this
condition for 2.4 min, finally changed to 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 0.1 min and under
this condition for 0.7 min). Purity is 99.11%, Rt=1.418 min; MS
Calcd.: 319.7; MS Found: 320.2 [M+H].sup.+.
[1039] .sup.1H NMR (400 MHz, DMSO-d.sup.6) .delta. 1.42 (9H, s),
3.21-3.23 (4H, m), 3.42-3.43 (4H, m), 6.13 (1H, d, J=1.6 Hz), 6.60
(1H, dd, J=8.0, 2.0 Hz), 7.65 (1H, d, J=8.0 Hz), 11.90 (1H, s).
[1040] Chemical Formula: C.sub.15H.sub.21N.sub.5O.sub.3, Molecular
Weight: 319.36
[1041] Total H count from HNMR data: 21.
Step 4: Synthesis of tert-butyl
4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]py-
ridin-7-yl)piperazine-1-carboxylate
##STR00385##
[1043] The solution of tert-butyl
4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carb-
oxylate (320 mg, 1.0 mmol), 3-bromopiperidine-2,6-dione (390 mg,
2.0 mmol) and sodium tert-butoxide (120 mg, 1.2 mmol) in
acetonitrale (20 mL) was stirred at 100.degree. C. overnight. When
it was cooled to room temperature, water (20 mL) was added. The
resultant mixture was extracted by ethyl acetate (20 mL.times.3),
washed by brine (30 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by Prep-TLC
(DCM/MeOH=20/1) to give tert-butyl
4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]py-
ridin-7-yl)piperazine-1-carboxylate (100 mg, 23% yield) as a yellow
solid.
[1044] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.47 (9H, s),
2.16-2.20 (1H, m), 2.47-2.50 (1H, m), 2.66-2.70 (1H, m), 2.90-2.99
(1H, m), 3.31-3.33 (4H, m), 3.47-3.49 (4H, m), 5.27-5.31 (1H, m),
6.20 (1H, d, J=1.2 Hz), 6.73 (1H, dd, J=7.6, 2.0 Hz), 7.80 (1H, d,
J=8.0 Hz), 11.11 (1H, s).
[1045] Chemical Formula: C.sub.20H.sub.26N.sub.6O.sub.5, Molecular
Weight: 430.46.
[1046] Total H count from HNMR data: 26.
Step 5: Synthesis of
3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperi-
dine-2,6-dione
##STR00386##
[1048] To a solution of tert-butyl
4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]py-
ridin-7-yl)piperazine-1-carboxylate (0.40 g, 0.93 mmol) in
dichloromethane (20 mL) was added TFA (8 mL), then stirred at room
temperature for 2 h and concentrated in vacuo to give
3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperi-
dine-2,6-dione (0.30 g, 98%) as a yellow solid, which was used to
the next step without further purification.
Step 6: Synthesis of tert-butyl
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate
##STR00387##
[1050] To a solution of
3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperi-
dine-2,6-dione (0.30 g, 0.91 mmol) in dry
methanol/1,2-dichloroethane/HOAc (20 mL/4 mL/0.1 mL) was added
tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (0.26 g, 0.91 mmol).
The mixture was left to stir for 30 min under N.sub.2 gas. Then
sodium cyanoborohydride (0.11 g, 1.82 mmol) was added and the
reaction mixture was left to stir for 16 h at room temperature. The
solvent was removed and the residue partitioned between
dichloromethane and water, washed with brine, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give crude
product. The residue was purified by prep-TLC to give compound
tert-butyl
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate
(0.20 g, 36%) as a yellow solid.
[1051] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] to 10% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=900/100 (v/v)] and 90% [(total 10 mM AcONH.sub.4)
water/CH.sub.3CN=100/900 (v/v)] in 1.6 min, then under this
condition for 2.4 min, finally changed to 90% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=900/100 (v/v)] and 10% [(total 10 mM
AcONH.sub.4) water/CH.sub.3CN=100/900 (v/v)] in 0.1 min and under
this condition for 0.7 min). Purity is 87.07%, Rt=2.195 min.; MS
Calcd.: 603.3; MS Found: 604.4 [M+H].sup.+.
Step 7: Synthesis of
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic
acid
##STR00388##
[1053] To a solution of tert-butyl
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate
(0.10 g, 0.16 mmol) in dichloromethane (10 mL) was added TFA (5
mL), then stirred at room temperature for 2 h, then concentrated in
vacuo to give
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid
(0.075 g, 83%) as a yellow solid, which was used to the next step
without further purification.
Step 8: Synthesis of
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(-
4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a-
]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide
##STR00389##
[1055] A solution of
4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4-
,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid
(75 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) (39 mg, 0.21 mmol), 1-hydroxybenzotriazole
hydrate (HOBt) (28 mg, 0.21 mmol) and ethyldiisopropylamine (88 mg,
0.69 mmol) in DMF (5 mL) was stirred for 30 min, and then
4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile
(38 mg, 0.14 mmol) was added. The mixture was stirred at room
temperature overnight and water (10 mL) was added. The aqueous
layer was extracted by dichloromethane (20 mL.times.2). The
combined organic layer was washed by brine (10 mL.times.2), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The residue was purified by prep-HPLC to give
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(-
4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a-
]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (57
mg, 52%) as a white solid.
[1056] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18
(50 mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow
Rate: 2.0 mL/min; Mobile Phase: from 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] to 0% [water+10 mM
NH.sub.4HCO.sub.3] and 100% [CH.sub.3CN] in 3.0 min, then under
this condition for 1.0 min, finally changed to 95% [water+10 mM
NH.sub.4HCO.sub.3] and 5% [CH.sub.3CN] in 0.1 min and under this
condition for 0.7 min). Purity is 98.22%, Rt=3.022 min; MS Calcd.:
807.4; MS Found: 808.3 [M+H].sup.+.
[1057] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150
mm*4.6 mm*3.5 .mu.m); Column Temperature: 40.degree. C.; Flow Rate:
1.0 mL/min; Mobile Phase: from 95% [water+10 mM NH.sub.4HCO.sub.3]
and 5% [CH.sub.3CN] to 0% [water+10 mM NH.sub.4HCO.sub.3] and 100%
[CH.sub.3CN] in 10 min, then under this condition for 5 min,
finally changed to 95% [water+10 mM NH.sub.4HCO.sub.3] and 5%
[CH.sub.3CN] in 0.1 min and under this condition for 5 min). Purity
is 99.00%, Rt=10.305 min.
[1058] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.13 (6H, s),
1.22 (6H, s), 1.79-1.81 (3H, m), 2.09-2.15 (1H, m), 2.19-2.21 (2H,
m), 2.49-2.50 (7H, m), 2.60-2.67 (1H, m), 2.76-2.92 (3H, m),
3.22-3.26 (4H, m), 3.86 (2H, d, J=12.8 Hz), 4.05 (1H, d, J=9.2 Hz),
4.32 (1H, s), 5.23 (1H, dd, J=12.4, 5.2 Hz), 6.12 (1H, s), 6.70
(1H, dd, J=8.0, 1.6 Hz), 6.95 (2H, d, J=9.2 Hz), 7.00 (1H, dd,
J=8.8, 2.4 Hz), 7.21 (1H, d, J=2.4 Hz), 7.48 (1H, d, J=8.8 Hz),
7.72 (3H, t, J=8.4 Hz), 7.91 (1H, d, J=8.8 Hz), 11.04 (1H, s).
[1059] Chemical Formula: C.sub.43H.sub.50ClN.sub.9O.sub.5,
Molecular Weight: 808.37.
[1060] Total H count from HNMR data: 50.
General Synthetic Scheme C-3
Synthesis of Building Block
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(-
4-formylpiperidin-1-yl)benzamide
##STR00390##
[1061] Synthetic Scheme
##STR00391##
[1062] Step 1: Synthesis of Ethyl
4-(4-(hydroxymethyl)piperidin-1-yl)benzoate
##STR00392##
[1064] To a solution of ethyl 4-fluorobenzoate (27 g, 0.16 mol) in
DMSO (500 mL) was added K.sub.2CO.sub.3 (44 g, 0.32 mol) and
piperidin-4-ylmethanol (32 g, 0.19 mol) at 25.degree. C. The
resulting solution was stirred at 100.degree. C. for 12 h. The
reaction was diluted with H.sub.2O (600 mL). The resulting mixture
was extracted with EtOAc (200 mL.times.3). The combined organic
layers were dried over anhydrous sodium sulfate and concentration.
The crude product was slurry in PE/MTBE=1:1 to afford ethyl
4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (30 g, 71% yield) as a
white solid, which was used into next step without further
purification.
[1065] Chemical Formula: C.sub.15H.sub.21NO.sub.3; Molecular
Weight: 263.34.
[1066] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.91 (d, J=8.8
Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.30-4.35 (m, 2H), 3.90 (d, J=12.8
Hz, 2H), 3.54 (d, J=6.4 Hz, 2H), 2.82-2.89 (m, 2H), 1.85 (d, J=12.8
Hz, 2H), 1.71-1.77 (m, 1H), 1.35-1.54 (m, 6H).
[1067] Total H count from .sup.1H NMR data: 21
Step 2: Synthesis of 4-(4-(Hydroxymethyl)piperidin-1-yl)benzoic
acid
##STR00393##
[1069] To a solution of ethyl
4-[4-(hydroxymethyl)-1-piperidyl]benzoate (52 g, 197.47 mmol, 1 eq)
in tetrahydrofuran (250 mL), methanol (250 mL) and water (250 mL)
was added sodium hydroxide (31.6 g, 0.79 mmol, 4 eq). The mixture
was stirred at 30.degree. C. for 12 hours. Thin layer
chromatography (petroleum ether:ethyl acetate=1:1) showed the
reaction was completed. The mixture was adjusted to pH 3.about.4
with hydrochloric acid (2 M) and filtered. The filter cake was
dried in vacuum. The residue was triturated with ethyl acetate (500
mL) to give 4-[4-(hydroxymethyl)-1-piperidyl]benzoic acid (35 g,
148.76 mmol, 75% yield) as a white solid.
[1070] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.: 12.19 (s, 1H),
7.74 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.48 (br t, J=5.2
Hz, 1H), 3.90 (d, J=12.8 Hz, 2H), 3.27 (br t, J=5.2 Hz, 2H),
2.86-2.72 (m, 2H), 1.72 (d, J=12.8 Hz, 2H), 1.66-1.51 (m, 1H), 1.17
(dq, J=4.0, 12.0 Hz, 2H)
[1071] Chemical Formula: C.sub.13H.sub.17NO.sub.3, Molecular
Weight: 235.28.
[1072] Total H count from HNMR data: 17.
Step 3: Synthesis of
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hyd-
roxymethyl)-1-piperidyl]benzamide
##STR00394##
[1074] To a solution of 4-[4-(hydroxymethyl)-1-piperidyl]benzoic
acid (38 g, 161.51 mmol, 1 eq) and
4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile
(50.9 g, 161.51 mmol, 1 eq, hydrochloride) in dimethylformamide
(800 mL) was added diisopropylethylamine (83.5 g, 646.04 mmol, 112
mL, 4 eq). The mixture was stirred at 30.degree. C. for 10 min, and
then o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium
hexafluorophosphate (64.48 g, 169.59 mmol, 1.05 eq) was added. The
mixture was stirred at 30.degree. C. for 1 hour. LCMS showed the
reaction was completed and desired MS can be detected. The mixture
was poured into water (4 L) and filtered. The filter cake was
concentrated and triturated with methanol (500 mL.times.2) to give
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hyd-
roxymethyl)-1-piperidyl]benzamide (72 g, 137.89 mmol, 85% yield,
95% purity) as a white solid.
[1075] LCMS: MS (ESI) m/z: 496.1 [M+1].sup.+
[1076] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.: 7.90 (d, J=8.8
Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H), 7.20 (d,
J=2.4 Hz, 1H), 7.00 (dd, J=2.4, 8.8 Hz, 1H), 6.95 (d, J=8.8 Hz,
2H), 4.48 (t, J=5.2 Hz, 1H), 4.31 (s, 1H), 4.05 (d, J=9.2 Hz, 1H),
3.86 (d, J=12.8 Hz, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.80-2.70 (m, 2H),
1.73 (d, J=11.2 Hz, 2H), 1.63-1.52 (m, 1H), 1.27-1.15 (m, 8H), 1.12
(s, 6H).
[1077] Chemical Formula: C.sub.28H.sub.34ClN.sub.3O.sub.3,
Molecular Weight: 496.04.
[1078] Total H count from HNMR data: 34.
Step 4: Synthesis of
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-form-
yl-1-piperidyl)benzamide
##STR00395##
[1080] To a solution of
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hyd-
roxymethyl)-1-piperidyl]benzamide (65 g, 131.04 mmol, 1 eq) in
dichloromethane (700 mL) was added Dess-Martin reagent (76.70 g,
180.83 mmol, 1.38 eq). The mixture was stirred at 30.degree. C. for
2 hours. Thin layer chromatography (dichloromethane:methanol=1:1)
showed the reaction was completed. The reaction was adjusted to pH
8.about.9 with saturated sodium bicarbonate. The mixture was
diluted with water (3 L) and extracted with dichloromethane (1.5
L.times.3). The combined organic phase was washed with saturated
brine (1.5 L.times.2), dried with anhydrous sodium sulfate,
filtered and concentrated in vacuum. The residue was purified by
silica gel chromatography (dichloromethane:methanol=100:0 to 50:1)
to give
N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-form-
yl-1-piperidyl)benzamide (34.6 g, 67.94 mmol, 51% yield, 97%
purity) as a white solid.
[1081] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.: 9.63 (s, 1H),
7.90 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz,
1H), 7.20 (d, J=2.4 Hz, 1H), 7.03-6.94 (m, 3H), 4.32 (s, 1H), 4.05
(d, J=9.2 Hz, 1H), 3.76 (td, J=3.6, 12.8 Hz, 2H), 3.01-2.92 (m,
2H), 2.62-2.55 (m, 1H), 2.62-2.55 (m, 1H), 1.92 (dd, J=3.6, 12.8
Hz, 2H), 1.62-1.48 (m, 2H), 1.21 (s, 6H), 1.12 (s, 6H).
[1082] Chemical Formula: C.sub.28H.sub.32ClN.sub.3O.sub.3,
Molecular Weight: 494.02.
[1083] Total H count from HNMR data: 32.
General Synthetic Scheme C-4
Synthesis of Building Block
N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(-
4-(2-oxoethyl)piperidin-1-yl)benzamide
##STR00396##
[1084] Synthetic Scheme
##STR00397##
[1085] Step 1: Synthesis of benzyl
4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate
##STR00398##
[1087] Into a 100-mL round-bottom flask, was placed benzyl
4-fluorobenzoate (2.3 g, 10.0 mmol, 1.0 equiv),
N,N-dimethylformamide (30.0 mL), 2-(piperidin-4-yl)ethan-1-ol (1.3
g, 10.0 mmol, 1.0 equiv), N,N-Diisopropylethylamine (3.87 g, 29.9
mmol, 4.0 equiv). The resulting solution was stirred for 12 h at
90.degree. C. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1/1). This resulted in 2.1 g (62%) of
benzyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate as a yellow
solid.
[1088] LC-MS (ES.sup.+): 340.25 m/z [MH.sup.+], t.sub.R=1.20 min,
(1.90 minute run).
Step 2: Synthesis of 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic
acid
##STR00399##
[1090] To a solution of benzyl
4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate (500 mg, 1.47 mmol,
1.00 equiv) in 20.0 mL methyl alcohol (30.0 mL) was added Pd/C
(10%, 300 mg) under nitrogen atmosphere in a 100.0 mL round bottom
flask. The flask was then vacuumed and flushed with hydrogen. The
reaction mixture was hydrogenated at room temperature for 12 hours
under hydrogen atmosphere using a hydrogen balloon, then filtered
through a Celite pad and concentrated under reduced pressure. This
resulted in 300.0 m g (82.0%) of
4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic acid as a yellow
solid.
[1091] LC-MS (ES.sup.+): 250.00 m/z [MH.sup.+], t.sub.R=0.74 min,
(2.00 minute run).
Step 3: Synthesis of
4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenox-
y)-2,2,4,4-tetramethylcyclobutyl]benzamide
##STR00400##
[1093] Into a 100-mL round-bottom flask, was placed
4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic acid (300.0 mg, 1.2
mmol, 2.0 equiv), N,N-dimethylformamide (10.0 g, 136.8 mmol, 227.0
equiv), N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophospate (686 mg, 1.8 mmol, 3.0 equiv),
2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile
hydrochloride (190.0 mg, 0.6 mmol, 1.0 equiv),
N,N-Diisopropylethylamine (466.0 mg, 3.6 mmol, 6.0 equiv). The
resulting solution was stirred for 1 h at room temperature. The
reaction was then quenched by the addition of 60 mL of water. The
resulting solution was extracted with 3.times.30 mL of ethyl
acetate and the organic layers combined and dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:1). This resulted in 250.0 mg (81%) of
4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenox-
y)-2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.
[1094] LC-MS (ES.sup.+): 510.25 m/z [MH.sup.+], t.sub.R=1.35 min,
(1.90 minute run).
Step 4: Synthesis of
4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-
,2,4,4-tetramethylcyclobutyl]benzamide
##STR00401##
[1096] Into a 100-mL round-bottom flask, was placed
4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenox-
y)-2,2,4,4-tetramethylcyclobutyl]benzamide (200.0 mg, 0.4 mmol, 1.0
equiv), dichloromethane (20.0 mL), Dess-Martin (249.0 mg, 0.60
mmol, 1.5 equiv). The resulting solution was stirred for 4 h at
room temperature. The resulting solution was extracted with of
ethyl acetate and the organic layers combined and concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:1). This resulted in 80.0 mg (40%)
of
4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-
,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.
[1097] LC-MS (ES.sup.+): 508.20 m/z [MH.sup.+], t.sub.R=1.19 min,
(2.00 minute run).
Exemplary Synthesis of Exemplary Compound 51
##STR00402##
[1098]
rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo-
butyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-py-
rrolo[3,4-c]pyridin-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide
Synthetic scheme
##STR00403##
[1099] Step 1: Synthesis of 3,4-dimethyl
6-chloropyridine-3,4-dicarboxylate
##STR00404##
[1101] Into a 100-mL round-bottom flask, was placed
6-chloropyridine-3,4-dicarboxylic acid (200.0 mg, 1.0 mmol, 1.0
equiv), methanol (5.0 mL), acetonitrile (5.0 mL), TMSCHN2 (2.0 mL),
N,N-Diisopropylethylamine (516.0 mg, 4.0 mmol, 4.0 equiv). The
resulting solution was stirred for 2 h at room temperature. The
reaction was then quenched by the addition of water (30 mL). The
resulting solution was extracted with ethyl acetate (20.0
mL.times.3) and the organic layers combined and concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1). The resulting mixture was
concentrated under vacuum. This resulted in 220 mg (96%) of
3,4-dimethyl 6-chloropyridine-3,4-dicarboxylate as a yellow
solid.
[1102] LC-MS (ES.sup.+): 230.10 m/z [MH.sup.+], t.sub.R=1.01 min,
(1.90 minute run).
Step 2: Synthesis of 3,4-dimethyl
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate
##STR00405##
[1104] Into a 100-mL round-bottom flask, was placed 3,4-dimethyl
6-chloropyridine-3,4-dicarboxylate (200.0 mg, 0.9 mmol, 1.0 equiv),
N,N-dimethylformamide (5.0 mL), tert-butyl piperazine-1-carboxylate
(325.0 mg, 1.7 mmol, 2.0 equiv), N,N-Diisopropylethylamine (450.0
mg, 3.5 mmol, 4.0 equiv). The resulting solution was stirred for 2
h at 100.degree. C. The reaction was then quenched by the addition
of water(80 mL). The resulting solution was extracted with ethyl
acetate (30.0 mL.times.3) and the organic layers combined and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:3). This resulted
in 320.0 mg (97%) of 3,4-dimethyl
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate
as a yellow solid.
[1105] LC-MS (ES.sup.+): 380.10 m/z [MH.sup.+], t.sub.R=1.19 min,
(2.0 minute run).
Step 3: Synthesis of
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylic
acid
##STR00406##
[1107] Into a 100-mL round-bottom flask, was placed 3,4-dimethyl
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate
(320.0 mg, 0.8 mmol, 1.0 equiv), methanol (10.0 mL), water(5 mL),
lithium hydroxide (96 mg, 4 mmol, 5 equiv). The resulting solution
was stirred for 5 h at room temperature. The resulting mixture was
concentrated under vacuum. This resulted in 300.0 mg (101%) of
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylic
acid as a white solid.
[1108] LC-MS (ES.sup.+): 296.20 m/z [MH.sup.+], t.sub.R=0.52 min,
(1.90 minute run).
Step 4: Synthesis of
3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piper-
idine-2,6-dione
##STR00407##
[1110] Into a 100-mL round-bottom flask, was placed
6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylic
acid (300.0 mg, 0.8 mmol, 1.0 equiv), acetic acid (20.0 mL),
3-aminopiperidine-2,6-dione (218 mg, 1.7 mmol, 2.0 equiv). The
resulting solution was stirred for 2 h at 130.degree. C. The
reaction was then quenched by the addition of water (30 mL). The
resulting solution was extracted with ethyl acetate (30 mL.times.3)
and the organic layers combined and dried in an oven under reduced
pressure. and concentrated under vacuum. The residue was applied
onto a silica gel column with dichloromethane/methanol (3:1). This
resulted in 60.0 mg (20%) of
3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piper-
idine-2,6-dione as a yellow solid.
[1111] LC-MS (ES.sup.+): 344.20 m/z [MH.sup.+], t.sub.R=0.66 min,
(1.90 minute run).
Step 5: Synthesis of
4-[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1H,2H,3H-pyrrolo[3,4-c]-
pyridin-6-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-
-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide
##STR00408##
[1113] Into a 100-mL round-bottom flask, was placed
3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piper-
idine-2,6-dione hydrochloride (60.0 mg, 0.2 mmol, 1.0 equiv),
dichloromethane (10 mL),
4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-
,2,4,4-tetramethylcyclobutyl]benzamide (80.0 mg, 0.1 mmol, 1.0
equiv), Sodium triacetoxyborohydride (110.0 mg, 3.0 equiv). The
resulting solution was stirred for 4 h at room temperature. The
reaction was then quenched by the addition of 40 mL of water. The
resulting solution was extracted with dichloromethane (20
mL.times.3) and the organic layers combined and concentrated under
vacuum. The crude product (4.0 mL) was purified by Prep-HPLC with
the following conditions: Column, Sunfire Prep C18 OBD Column, 10
um, 19*250 mm; mobile phase, Water(0.1% formic acid) and
acetonitrile (30.0% acetonitrile up to 52.0% in 8 min); Detector,
UV 254 nm. 5.0 mL product was obtained. This resulted in 50.5 mg
(38.2%) of
4-[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1H,2H,3H-pyrrolo[3,4-c]-
pyridin-6-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-
-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow
solid.
[1114] 1H NMR (300 MHz, DMSO-d6) .delta. 11.07 (s, 1H), 8.57 (s,
1H), 7.87 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.44 (d, J=9.1
Hz, 1H), 7.29 (s, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.02-6.87 (m, 3H),
5.07 (dd, J=12.8, 5.3 Hz, 1H), 4.29 (s, 1H), 4.02 (d, J=9.1 Hz,
1H), 3.28 (s, 5H), 2.59-2.41 (m, 9H), 2.00 (t, J=11.3 Hz, 1H), 1.73
(d, J=12.8 Hz, 2H), 1.45 (s, 3H), 1.14 (d, J=27.2 Hz, 14H).
[1115] LC-MS (ES.sup.+): 835.25 m/z [MH.sup.+], t.sub.R=2.56 min,
(4.80 minute run).
Exemplary Synthesis of Exemplary Compound 52
##STR00409##
[1116]
(rac)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyc-
lobutyl)-4-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H--
pyrrolo[3,4-d]pyrimidin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide
Synthetic Scheme
##STR00410##
[1117] Step 1: Synthesis of tert-butyl
4-carbamimidoylpiperazine-1-carboxylate
##STR00411##
[1119] Into a 250-mL round-bottom flask, was placed tert-butyl
piperazine-1-carboxylate (10 g, 53.69 mmol, 1.00 equiv), i-propanol
(150 mL), (methylsulfanyl)methanimidamide (7.4 g, 82.09 mmol, 1.00
equiv), DIEA (25 mL, 3.00 equiv). The resulting solution was
stirred for 24 h at 100.degree. C. in an oil bath. The resulting
mixture was concentrated under vacuum. The resulting solution was
diluted with acetonitrile (150 mL), then stirred for 30 min. The
solids were collected by filtration. This resulted in 11.5 g (94%)
of tert-butyl 4-carbamimidoylpiperazine-1-carboxylate as a white
solid.
Step 2: Synthesis of 1,4-diethyl
(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate
##STR00412##
[1121] Into a 250-mL round-bottom flask, was placed 1,4-diethyl
2-oxobutanedioate (10 g, 53.14 mmol, 1.00 equiv), DMFDMA (12.65 g,
106.30 mmol, 2.00 equiv) at 0.degree. C. The resulting solution was
stirred for 2 h at room temperature. The residue was applied onto a
silica gel column with ethyl acetate/petroleum ether (7/3). This
resulted in 2.79 g (22%) of 1,4-diethyl
(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate as yellow
oil.
[1122] LC-MS (ES.sup.+): m/z 243.95 [MH.sup.+], t.sub.R=0.64 min,
(1.90 minute run).
Step 3: Synthesis of 4,5-diethyl
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate
##STR00413##
[1124] Into a 250-mL round-bottom flask, was placed tert-butyl
4-carbamimidoylpiperazine-1-carboxylate (1.0 g, 4.38 mmol, 1.00
equiv), ethanol (20 mL), 1,4-diethyl
(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate (1.065 g,
4.38 mmol, 1.00 equiv), EtONa (596 mg, 8.76 mmol, 1.00 equiv). The
resulting solution was stirred for 2 h at 75.degree. C. in an oil
bath. The resulting mixture was concentrated under vacuum. The
resulting solution was extracted with ethyl acetate (100 mL) and
the organic layers combined. The resulting mixture was washed with
brine (100 mL). The mixture was dried over anhydrous sodium
sulfate. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1/5). This resulted in 873.0 mg
(49%) of 4,5-diethyl
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate
as light yellow oil.
[1125] LC-MS (ES.sup.+): m/z 409.20 [MH.sup.+], t.sub.R=1.19 min,
(1.90 minute run).
Step 4: Synthesis of
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylic
acid
##STR00414##
[1127] Into a 100-mL round-bottom flask, was placed 4,5-diethyl
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate
(873.0 mg, 2.14 mmol, 1.00 equiv), ethanol/water(5/2) (14 mL),
lithium hydroxide (256.7 mg, 10.72 mmol, 5.00 equiv). The resulting
solution was stirred for 8 h at room temperature. The resulting
mixture was concentrated under vacuum. This resulted in 1.02 g
(crude) of
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylic
acid as a white solid.
[1128] LC-MS (ES.sup.+): m/z 352.45 [MH.sup.+], t.sub.R=0.73 min,
(1.90 minute run).
Step 5: Synthesis of tert-butyl
4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-
-2-yl]piperazine-1-carboxylate
##STR00415##
[1130] Into a 100-mL round-bottom flask, was placed
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylic
acid (735.0 mg, 2.09 mmol, 1.00 equiv). This was followed by the
addition of acetic anhydride (10 mL), after stirred 2 h at
130.degree. C., concentrated under vacuum. To this was added
pyridine (10 mL), 3-aminopiperidine-2,6-dione hydrochloride (445.0
mg, 2.70 mmol, 1.30 equiv). The resulting solution was stirred
overnight at 120.degree. C. in an oil bath. The resulting mixture
was concentrated under vacuum. The resulting solution was diluted
with dichloromethane (100 mL). The solids were filtered out. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (7/3). This resulted in 243.0 mg (26%) of
tert-butyl
4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-
-2-yl]piperazine-1-carboxylate as brown oil.
[1131] LC-MS (ES.sup.+): m/z 467.10 [M Na.sup.+], t.sub.R=1.10 min,
(2.00 minute run).
Step 6: Synthesis of
3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]pip-
eridine-2,6-dione
##STR00416##
[1133] Into a 50-mL round-bottom flask, was placed tert-butyl
4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-
-2-yl]piperazine-1-carboxylate (243.0 mg, 0.55 mmol, 1.00 equiv),
dichloromethane (5.0 mL), trifluoroacetic acid (2.0 mL). The
resulting solution was stirred for 2 h at room temperature. The
resulting mixture was concentrated under vacuum. This resulted in
320.0 mg (crude) of
3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]pip-
eridine-2,6-dione as brown oil.
[1134] LC-MS (ES.sup.+): m/z 345.25 [MH.sup.+], t.sub.R=0.61 min,
(1.90 minute run).
Step 7: Synthesis of
4-[4-(2-[4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]-
pyrimidin-2-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-
-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide
##STR00417##
[1136] Into a 100-mL round-bottom flask, was placed
4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-
,2,4,4-tetramethylcyclobutyl]benzamide (90 mg, 0.18 mmol, 1.00
equiv), dichloromethane (10 mL),
3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]pip-
eridine-2,6-dione (61.24 mg, 0.18 mmol, 1.00 equiv). This was
followed by the addition of DIEA (0.5 mL), after stirred at
30.degree. C. for 1 h. To this was added NaBH(OAc).sub.3 (122.89
mg, 0.58 mmol, 3.00 equiv). The resulting solution was stirred for
5 h at 30.degree. C. in an oil bath. The resulting solution was
extracted with dichloromethane (150 mL) and the organic layers
combined. The resulting mixture was washed with brine (50 mL). The
mixture was dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude product was purified by Prep-HPLC with the
following conditions: Column, XBridge Prep C18 OBD Column, Sum,
19*150 mm; mobile phase, water (10 mmol/L bicarbonate amine) and
acetonitrile (30.0% acetonitrile up to 51.0% in 8 min); Detector,
UV 254 nm. This resulted in 50 mg (34%) of
4-[4-(2-[4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]-
pyrimidin-2-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-
-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide as a
yellow solid.
[1137] .sup.1H NMR (400 MHz, d6-DMSO): .delta.11.12 (s, 1H), 8.90
(s, 1H), 7.91-7.89 (d, J=8.4 Hz, 1H), 7.74-7.72 (d, J=7.6 Hz, 2H),
7.49-7.47 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 6.99-6.94 (m, 3H),
5.16-5.13 (m, 1H), 4.32 (s, 1H), 4.06-3.83 (m, 7H), 2.88-2.57 (m,
5H), 2.39-2.33 (m, 2H), 2.07-2.01 (m, 1H), 1.78-1.75 (m, 2H),
1.54-1.35 (m, 3H), 1.21 (m, 8H), 1.12 (s, 6H); LC-MS (ES.sup.+):
m/z 836.45/838.45 [MH.sup.+], t.sub.R=2.17 min, (2.95 minute
run).
[1138] Chemical formula: C.sub.44H.sub.50ClN.sub.9O.sub.6
[835.36/837.36].
[1139] Total H count from HNMR data: 50.
D. Exemplary Synthetic Schemes for Exemplary BRaf Targeting Moiety
Based Compounds
General Synthetic Approach
[1140] The synthetic realization and optimization of the
bifunctional molecules as described herein may be approached in a
step-wise or modular fashion. For example, identification of
compounds that bind to the target molecules can involve high or
medium throughput screening campaigns if no suitable ligands are
immediately available. It is not unusual for initial ligands to
require iterative design and optimization cycles to improve
suboptimal aspects as identified by data from suitable in vitro and
pharmacological and/or ADMET assays. Part of the optimization/SAR
campaign would be to probe positions of the ligand that are
tolerant of substitution and that might be suitable places on which
to attach the linker chemistry previously referred to herein. Where
crystallographic or NMR structural data are available, these can be
used to focus such a synthetic effort.
[1141] In a very analogous way one can identify and optimize
ligands for an E3 Ligase, i.e. ULMs/ILMs/VLMs/CLMs/ILMs.
[1142] With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in
hand, one skilled in the art can use known synthetic methods for
their combination with or without a linker moiety. Linker moieties
can be synthesized with a range of compositions, lengths and
flexibility and functionalized such that the PTM and ULM groups can
be attached sequentially to distal ends of the linker. Thus a
library of bifunctional molecules can be realized and profiled in
in vitro and in vivo pharmacological and ADMET/PK studies. As with
the PTM and ULM groups, the final bifunctional molecules can be
subject to iterative design and optimization cycles in order to
identify molecules with desirable properties.
[1143] In some instances, protecting group strategies and/or
functional group interconversions (FGIs) may be required to
facilitate the preparation of the desired materials. Such chemical
processes are well known to the synthetic organic chemist and many
of these may be found in texts such as "Greene's Protective Groups
in Organic Synthesis" Peter G. M. Wuts and Theodora W. Greene
(Wiley), and "Organic Synthesis: The Disconnection Approach" Stuart
Warren and Paul Wyatt (Wiley).
General Synthetic Scheme D-1
##STR00418##
[1145] A compound of formula XVI may be reacted with a reagent II'
(commercially available or readily prepared using standard reaction
techniques known to one skilled in the art) under Chan-Lam
cross-coupling conditions, e.g. copper (II) acetate, pyridine or
diethylamine or triethylamine, 100.degree. C., to produce a
compound of formula XVII. M' represents a boronic acid or boronic
ester; Ar represents an aromatic or heteroaromatic ring system; L
represents an optional linker, represents a primary or secondary
amine, optionally cyclized into a 4 to 8 membered heterocyclic
ring, wherein PG represents a suitable protecting group, including
but not limited to t-butoxycarbonyl or benzyl. Compounds of formula
XVII may be may be reacted with a reagent XVIII under
palladium-catalyzed cross-coupling conditions, e.g.
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium,
tri-tert-butylphosphine tetrafluoroborate, cesium fluoride,
1,4-dioxane, 90.degree. C., to produce a compound of formula XIX. M
represents a functional group capable of undergoing
palladium-catalyzed transmetallation, e.g. a boronic acid, boronic
ester, or trialkylstannane and Ar' represents an aromatic or
heteroaromatic ring system with optional substituents. A compound
of formula XIX may then be converted to a compound of formula XX by
treatment with a reagent suitable for the removal of PG, e.g.
hydrogen chloride in 1,4-dioxane or methanol when PG is t-butyl. A
compound of formula XX may also be reacted with a compound of
formula VII to provide compounds of formula XXI, wherein X is a
suitable leaving group such as fluorine or chlorine, Y is C.dbd.O,
the aromatic ring of VII may have further optional substituents,
and reaction conditions are those for a nucleophilic aromatic
substitution, e.g. triethylamine, DMSO, 80.degree. C. In cases
where the group Ar' contains optional substituents, e.g. a ketone,
these may undergo further functionalization, e.g. by treatment with
hydroxylamine hydrochloride and pyridine at room temperature, to
provide further compounds of formula XXI.
General Synthetic Scheme D-2
##STR00419##
[1147] Alternatively, a compound of formula XVII may be converted
to a compound of formula XXII by using conditions analogous to
those for the conversion of XIX to XX in Scheme 5. A compound of
formula XXII may then be treated with a compound of formula VII as
defined in Scheme 5 to produce a compound of formula XXIII The
compound of formula XXIII may then be treated with a reagent XVIII
as defined in Scheme 5 to produce a compound of formula XXI. In
cases where the group Ar' contains optional substituents, e.g. a
ketone, these may undergo further functionalization, e.g. by
treatment with hydroxylamine hydrochloride and pyridine at room
temperature, to provide further compounds of formula XXI.
Exemplary Synthesis of Exemplary Compound 42
(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1-
H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-me-
thylisoindoline-1,3-dione
##STR00420##
[1148] Step A:
2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-ind-
en-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin-
e-1,3-dione
##STR00421##
[1150] To a solution of
4-chloro-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-ind-
en-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin-
e-1,3-dione (100 mg, 0.14 mmol) in 1,4-dioxane 10 mL and H.sub.2O 1
mL were added methylboronic acid (33.6 mg, 0.56 mmol),
Pd(aMPhos)Cl.sub.2 (9.9 mg, 0.014 mmol), and CsF (85.12 mg, 0.56
mmol). The resulting solution was irradiated at 90.degree. C. with
MW for 2 h. After cooling to rt, it was diluted with EA (50 mL),
and the mixture was washed with brine (3.times.20 mL). The organic
phase was dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by prep-TLC to
afford
2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-ind-
en-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin-
e-1,3-dione (70 mg, 72.1% yield). LCMS (ES.sup.+): m/z 706.3
[M+H].sup.+.
Step B: (E)-2-(2,6-dioxopiperidin-3-yl)-5 (4 (4 (4 (1
(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-y-
l)phenyl)piperazin-1-yl)-4-methylisoindoline-1,3-dione
##STR00422##
[1152] To a solution of
2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-ind-
en-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin-
e-1,3-dione (70 mg, 0.10 mmol) in acetonitrile 3 mL and pyridine 3
mL was added hydroxylamine hydrochloride (69.5 mg, 1.0 mmol). The
mixture was stirred at 40.degree. C. for 20 min. Then it was
diluted with DCM (20 mL), and the mixture was washed with brine (10
mL). The organic phase was concentrated and purified by prep-TLC to
afford
(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro--
1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-m-
ethylisoindoline-1,3-dione (19.6 mg, 27.8% yield) as yellow
solid.
[1153] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.09 (s, 1H),
10.89 (s, 1H), 8.72 (s, 1H), 8.58-8.57 (m, 2H), 7.83 (d, J=8.0 Hz,
2H), 7.73 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.50-7.41 (m,
4H), 7.23-7.17 (m, 3H), 5.13-5.09 (m, 1H), 3.61-3.42 (m, 8H),
3.04-2.97 (m, 2H), 2.93-2.82 (m, 3H), 2.62-2.56 (m, 5H), 2.08-2.00
(m, 1H); LCMS (ES.sup.+): m/z 721.3 [M+H].sup.+.
[1154] Exemplary Compound 41 may be prepared by a procedure
analogous to that described for Examplary Compound 42.
E. Exemplary Synthetic Schemes for Exemplary BRD4 Binding Moiety
Based Compounds
Exemplar Synthesis of Exemplary Compound 45:
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)--
2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-
phenyl)acetamide
##STR00423##
[1155] Step 1: Preparation of 2-amino-4-hydroxybenzoic acid
[1156] A mixture of 2-amino-4-methoxybenzoic acid (1.0 g, 5.98
mmol), red phosphorus (556 mg, 17.94 mmol) and 55% hydroiodic acid
(10 mL) was heated at 100.degree. C. for 14 h in a sealed tube. The
reaction mixture was poured into ice water. The pH of the solution
was adjusted to 6-7 by sodium carbonate. The solution was extracted
with ethyl acetate (20 mL.times.3). The combined organic phases
were dried over anhydrous sodium sulfate, filtered and concentrated
in vacuum to afford crude 2-amino-4-hydroxybenzoic acid (400 mg,
44% yield) which was used in the next step without further
purification. .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 7.53-7.55
(m, 1H), 6.12 (s, 1H), 5.99-6.02 (m, 1H).
Step 2: Preparation of 2-acetamido-4-acetoxybenzoic acid
[1157] To a mixture of 2-amino-4-hydroxybenzoic acid (400 mg, 2.61
mmol) and imidazole (888 mg, 10.06 mmol) in acetonitrile (20 mL)
was added acetyl chloride (789 mg, 10.06 mmol) dropwise at
0.degree. C. The solution was stirred at rt for 10 h and then
quenched by water (40 mL). The mixture was extracted with ethyl
acetate (20 mL.times.3). The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate and filtered.
Volatiles were evaporated in vacuum and the residue was purified by
column chromatography (ethyl acetate/petroleum ether=2:1) to afford
2-acetamido-4-acetoxybenzoic acid (350 mg, 57% yield). .sup.1HNMR
(400 MHz, DMSO-d.sub.6): .delta. 11.19 (s, 1H), 8.30 (s, 1H),
8.01-8.03 (m, 1H), 6.92-6.95 (m, 1H), 2.30 (s, 3H), 2.15 (s,
3H).
Step 3: Preparation of
3-(7-hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
[1158] To a mixture of 2-acetamido-4-acetoxybenzoic acid (400 mg,
1.69 mmol), 3-aminopiperidine-2,6-dione hydrochloride (333 mg, 2.02
mmol), triphenyl phosphite (2.0 mL) in acetonitrile (10 mL) was
added imidazole (383 mg, 5.63 mmol). The reaction solution was
heated to reflux for 10 h. The solution was evaporated under
reduced pressure and the residue was re-crystallized (20% ethyl
acetate in hexane) to afford
3-(7-Hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
(110 mg, 19% yield). .sup.1HNMR (400 MHz, DMSO-d.sup.6): .delta.
10.94 (s, 1H), 10.51 (s, 1H), 7.84-7.86 (m, 1H), 6.92-6.94 (m, 1H),
6.85 (s, 1H), 5.16-5.20 (m, 1H), 2.73-2.85 (m, 1H), 2.58-2.63 (m,
5H), 2.13-2.15 (m, 1H).
Step 4: Preparation of tert-butyl
(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroqu-
inazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate
[1159] To a mixture of
3-(7-hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
(161 mg, 0.348 mmol) and
2-(2-(2-(2-(4-((tert-butoxycarbonyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)et-
hyl methanesulfonate (100 mg, 0.348 mmol, prepared according to
procedures of similar intermediate described in US 2015/0291562) in
DMF (5.0 mL) was added sodium carbonate (74 mg, 0.696 mmol). The
mixture was stirred at 80.degree. C. for 6 h. The resulting mixture
was cooled to rt. Ethyl acetate (30 mL) was added and the organic
layer was washed with water and brine. The organic layer was dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purification by preparative TLC
to afford tert-butyl
(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroqu-
inazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate
(55.4 mg, 24% yield). .sup.1HNMR (400 MHz, DMSO-d.sup.6): .delta.
10.98 (s, 1H), 9.08 (s, 1H), 7.91-7.93 (m, 1H), 7.32-7.34 (m, 2H),
7.07-7.09 (m, 2H), 6.82-6.84 (m, 2H), 5.20-5.24 (m, 1H), 4.24 (s,
2H), 3.99 (m, 2H), 3.79 (m, 2H), 3.70-3.71 (m, 2H), 3.56-3.60 (m,
8H), 2.79-2.87 (m, 1H), 2.57-2.70 (m, 5H), 2.17-2.18 (m, 1H), 1.47
(s, 9H). LC-MS: (ES.sup.+): m/z 655.3 [M+H].sup.+.
Step 5: Preparation of
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)--
2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-
phenyl)acetamide (Exemplary Compound 45)
[1160] To a pre-mixed solution containing
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)acetic acid (6.11 mg, 0.01525 mmol) in
DMF (2.00 ml), TBTU (7.34 mg, 0.02287 mmol) and DIPEA (7.96 .mu.L,
0.04575 mmol) was added
3-(7-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-
-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (8.46 mg,
0.01525 mmol, prepared by treating the product from step 4 with HCl
in dioxane) and the mixture was left to stir for 2 h. The mixture
was diluted with ethyl acetate and water. The organic layer was
washed with sodium bicarbonate, water (3.times.) and brine. The
resulting solution was filtered through a thin pad of silica gel
and then concentrated in vacuo to give a crude solid. This material
was purified by silica gel chromatography on a Teledyne Combiflash
ISCO eluting with MeOH/DCM (0:100 to 7:93) to yield
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(24(3-(2,6-dioxopiperidin-3-yl)-2-
-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)p-
henyl)acetamide (10.1 mg, 0.01077 mmol, 71.1% yield). .sup.1H NMR
(400 MHz, methanol-d.sub.4) .quadrature. 8.55 (s, 1H), 7.96-8.00
(m, 1H), 7.36-7.50 (m, 6H), 7.03-7.09 (m, 2H), 6.87 (dd, J=3.03,
9.10 Hz, 2H), 5.22 (td, J=5.40, 10.91 Hz, 1H), 4.70-4.74 (m, 1H),
4.22 (d, J=3.33 Hz, 2H), 4.10 (d, J=4.30 Hz, 2H), 3.85-3.91 (m,
2H), 3.79-3.84 (m, 2H), 3.64-3.71 (m, 7H), 3.55-3.64 (m, 2H),
3.42-3.50 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=3.33 Hz, 2H), 2.44 (d,
J=3.33 Hz, 3H), 1.89 (s, 3H), 1.68 (d, J=3.33 Hz, 2H), 1.29 (br.
s., 3H). LC/MS (ES.sup.+): m/z 937.19/939.19 [M+H].sup.+.
Exemplar Synthesis of Exemplary Compound 44:
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)--
2-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-
phenyl)acetamide
##STR00424##
[1162] This molecule was synthesized using the same method as
described in Example 1. The key intermediate was prepared according
the scheme listed above. .sup.1H NMR (400 MHz, methanol-d.sub.4)
.quadrature. 8.55 (s, 1H), 7.96-8.00 (m, 1H), 7.36-7.50 (m, 6H),
7.03-7.09 (m, 2H), 6.87 (dd, J=3.03, 9.10 Hz, 2H), 5.22 (td,
J=5.40, 10.91 Hz, 1H), 4.70-4.74 (m, 1H), 4.22 (d, J=3.33 Hz, 2H),
4.10 (d, J=4.30 Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.84 (m, 2H),
3.64-3.71 (m, 7H), 3.55-3.64 (m, 2H), 3.42-3.50 (m, 2H), 2.71 (s,
3H), 2.66 (d, J=3.33 Hz, 2H), 2.44 (d, J=3.33 Hz, 3H), 1.89 (s,
3H), 1.68 (d, J=3.33 Hz, 2H), 1.29 (br. s., 3H). LCMS (ES.sup.+):
m/z 937.19/939.19 [M+H].sup.+.
Exemplary Synthesis of Exemplar Compound 43:
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-
[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((1-oxo-2-((S)-6-oxopiperidin--
3-yl)isoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
##STR00425##
[1164] The key intermediate for the preparation of this compound
was synthesized according the scheme listed above. The final step
of amide coupling was carried out under the same condition as
described in Example 1. .sup.1H NMR (400 MHz, CDCl.sub.3) d 9.03
(s, 1H), 7.45 (dd, J=8.71, 13.21 Hz, 4H), 7.31-7.37 (m, 3H), 7.24
(d, J=7.24 Hz, 1H), 6.84 (d, J=9.00 Hz, 2H), 6.78 (d, J=8.02 Hz,
1H), 6.75 (br. s., 1H), 4.66-4.73 (m, 2H), 4.20 (d, J=2.74 Hz, 1H),
4.07-4.12 (m, 2H), 3.80-3.90 (m, 3H), 3.64-3.77 (m, 10H), 3.52-3.58
(m, 1H), 3.35-3.42 (m, 3H), 2.68 (br. s., 3H), 2.52-2.59 (m, 2H),
2.41 (s, 3H), 2.02-2.08 (m, 2H), 1.69 (s, 3H), 1.26 (s, 3H). LC-MS
(ES.sup.+): m/z 895.22/897.22 [M+H].sup.+.
[1165] Protein Level Control
[1166] This description also provides methods for the control of
protein levels with a cell. This is based on the use of compounds
as described herein, which are known to interact with a specific
target protein such that degradation of a target protein in vivo
will result in the control of the amount of protein in a biological
system, preferably to a particular therapeutic benefit.
[1167] The following examples are used to assist in describing the
present invention, but should not be seen as limiting the present
invention in any way.
Exemplary Embodiments of the Present Disclosure
[1168] The present disclosure encompasses the following specific
embodiments. These following embodiments may include all of the
features recited in a proceeding embodiment, as specified. Where
applicable, the following embodiments may also include the features
recited in any proceeding embodiment inclusively or in the
alternative.
[1169] An aspect of the present disclosure provides a cereblon E3
ubiquitin ligase binding compound having a chemical structure
selected from:
##STR00426## ##STR00427##
wherein: [1170] W is selected from the group consisting of
CH.sub.2, CHR, C.dbd.O, SO.sub.2, NH, N, optionally substituted
cyclopropyl group, optionally substituted cyclobutyl group, and
N-alkyl; W.sub.3 is selected from C or N; [1171] each X is
independently selected from the group consisting of O, S, and
H.sub.2, [1172] Y is selected from the group consisting of
CH.sub.2, --C.dbd.CR', NH, N-alkyl, N-aryl, N-hetaryl,
N-cycloalkyl, N-heterocyclyl, O, and S; [1173] Z is selected from
the group consisting of O, S, and H.sub.2; [1174] G and G' are
independently selected from the group consisting of H, alkyl
(linear, branched, optionally substituted), OH, R'OCOOR,
R'OCONRR'', CH.sub.2-heterocyclyl optionally substituted with R',
and benzyl optionally substituted with R'; [1175] Q.sub.1, Q.sub.2,
Q.sub.3, and Q.sub.4 represent a carbon C substituted with a group
independently selected from R', N or N-oxide; [1176] A is
independently selected from the group H, alkyl (linear, branched,
optionally substituted), cycloalkyl, Cl and F; [1177] R comprises
--CONR'R'', --OR', --NR'R'', --SR', --SO.sub.2R', --SO.sub.2NR'R'',
--CR'R''--, --CR'NR'R''--, (--CR'O).sub.n'R'', -aryl, -hetaryl,
-alkyl (linear, branched, optionally substituted), -cycloalkyl,
-heterocyclyl, --P(O)(OR')R'', --P(O)R'R'', --OP(O)(OR')R'',
--OP(O)R'R'', --Cl, --F, --Br, --I, --CF.sub.3, --CN,
--NR'SO.sub.2NR'R'', --NR'CONR'R'', --CONR'COR'',
--NR'C(.dbd.N--CN)NR'R'', --C(.dbd.N--CN)NR'R'',
--NR'C(.dbd.N--CN)R'', --NR'C(.dbd.C--NO.sub.2)NR'R'',
--SO.sub.2NR'COR'', --NO.sub.2, --CO.sub.2R', --C(C.dbd.N--OR')R'',
--CR'.dbd.CR'R'', --CCR', --S(C.dbd.O)(C.dbd.N--R')R'', --SF.sub.5
and --OCF.sub.3; [1178] R' and R'' are independently selected from
the group consisting of a bond, H, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclic, --C(.dbd.O)R, heterocyclyl, each of which
is optionally substituted; [1179] n' integer from 1-10; [1180]
represents a single bond or a double bond; [1181] represents a bond
that may be stereospecific ((R) or (S)) or non-stereospecific; and
[1182] Rn comprises 1-4 independent functional groups, optionally
substituted linear or branched alkyl (e.g., a C1-C6 linear or
branched alkyl optionally substituted with one or more halogen,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted aryl (e.g., an optionally substituted C5-C7
aryl), optionally substituted alkyl-aryl (e.g., an alkyl-aryl
comprising at least one of an optionally substituted C1-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof),
optionally substituted alkoxyl group (e.g., a methoxy, ethoxy,
butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl may be
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
[1182] ##STR00428## (e.g., optionally substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
##STR00429## (e.g., optionally substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6
cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and [1183] each
of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6, [1184] n
is an integer from 1-10 (e.g., 1-4).
[1185] Another aspect of the present disclosure provides a
bifunctional compound having the chemical structure:
CLM-L-PTM,
[1186] or a pharmaceutically acceptable salt, enantiomer,
stereoisomer, solvate, polymorph or prodrug thereof,
[1187] wherein: [1188] the PTM is a small molecule comprising a
protein targeting moiety; [1189] the L is a bond or a chemical
linking moiety covalently coupling the CLM and the PTM; and [1190]
the CLM is a small molecule cereblon E3 ubiquitin ligase binding
moiety of claim 1, wherein when n is 2, 3, or 4, then at least one
of R.sub.n or W is modified to be covalently joined to the linker
group (L) or a PTM.
[1191] In any aspect or embodiment described herein, the CLM is
linked to the PTM, the chemical linker group (L), or a combination
thereof via W, X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R', Q.sub.1,
Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5.
[1192] In any aspect or embodiment described herein, the PTM is a
moiety that binds BRD4, BRaf, Estrogen Receptor (ER), or Androgen
Receptor (AR).
[1193] In any aspect or embodiment described herein, the compound
may further comprise a second E3 ubiquitin ligase binding moiety
coupled through a linker group.
[1194] In any aspect or embodiment described herein, the second E3
ubiquitin ligase binding moiety binds or targets an E3 ubiquitin
ligase selected from the group consisting of Von Hippel-Lindau
(VLM), cereblon (CLM), mouse double-minute homolog 2 (MLM), and
inhibitors of apoptosis proteins (ILM).
[1195] In any aspect or embodiment described herein, the CLM is
represented by a chemical structure selected from the group
consisting of:
##STR00430## ##STR00431## ##STR00432##
[1196] In any aspect or embodiment described herein, the linker (L)
comprises a chemical structural unit represented by the
formula:
-(A.sup.L)q-
wherein: [1197] (A.sup.L).sub.q is a group which is connected to at
least one of the CLM, the PTM, or a combination thereof; [1198] q
is an integer greater than or equal to 1; [1199] each A.sup.L is
independently selected from the group consisting of, a bond,
CR.sup.L1R.sup.L2, O, S, SO, SO.sub.2, NR.sup.L3,
SO.sub.2NR.sup.L3, SONR.sup.L3, CONR.sup.L3, NR.sup.L3CONR.sup.L4,
NR.sup.L3SO.sub.2NR.sup.L4, CO, CR.sup.L1.dbd.CR.sup.L2, C.ident.C,
SiR.sup.L1R.sup.L2, P(O)R.sup.L1, P(O)OR.sup.L1,
NR.sup.L3C(.dbd.NCN)NR.sup.L4, NR.sup.L3C(.dbd.NCN),
NR.sup.L3C(.dbd.CNO.sub.2)NR.sup.L4, C.sub.3-11cycloalkyl
optionally substituted with 0-6 R.sup.L1 and/or R.sup.L2 groups,
C.sub.3-11heteocyclyl optionally substituted with 0-6 R.sup.L1
and/or R.sup.L2 groups, aryl optionally substituted with 0-6
R.sup.L1 and/or R.sup.L2 groups, heteroaryl optionally substituted
with 0-6 R.sup.L1 and/or R.sup.L2 groups, where R.sup.L1 or
R.sup.L2, each independently are optionally linked to other groups
to form cycloalkyl and/or heterocyclyl moiety, optionally
substituted with 0-4 R.sup.L5 groups; and [1200] R.sup.L1,
R.sup.L2, R.sup.L3, R.sup.L4 and R.sup.L5 are, each independently,
H, halo, C.sub.1-8alkyl, OC.sub.1-8alkyl, SC.sub.1-8alkyl,
NHC.sub.1-8alkyl, N(C.sub.1-8alkyl).sub.2, C.sub.3-11cycloalkyl,
aryl, heteroaryl, C.sub.3-11heterocyclyl, OC.sub.1-8cycloalkyl,
SC.sub.1-8cycloalkyl, NHC.sub.1-8cycloalkyl,
N(C.sub.1-8cycloalkyl).sub.2,
N(C.sub.1-8cycloalkyl)(C.sub.1-8alkyl), OH, NH.sub.2, SH,
SO.sub.2C.sub.1-8alkyl, P(O)(OC.sub.1-8alkyl)(C.sub.1-8alkyl),
P(O)(OC.sub.1-8alkyl).sub.2, CC--C.sub.1-8alkyl, CCH,
CH.dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.CH(C.sub.1-8alkyl),
C(C.sub.1-8alkyl).dbd.C(C.sub.1-8alkyl).sub.2, Si(OH).sub.3,
Si(C.sub.1-8alkyl).sub.3, Si(OH)(C.sub.1-8alkyl).sub.2,
COC.sub.1-8alkyl, CO.sub.2H, halogen, CN, CF.sub.3, CHF.sub.2,
CH.sub.2F, NO.sub.2, SF.sub.5, SO.sub.2NHC.sub.1-8alkyl,
SO.sub.2N(C.sub.1-8alkyl).sub.2, SONHC.sub.1-8alkyl,
SON(C.sub.1-8alkyl).sub.2, CONHC.sub.1-8alkyl,
CON(C.sub.1-8alkyl).sub.2, N(C.sub.1-8alkyl)CONH(C.sub.1-8alkyl),
N(C.sub.1-8alkyl)CON(C.sub.1-8alkyl).sub.2, NHCONH(C.sub.1-8alkyl),
NHCON(C.sub.1-8alkyl).sub.2, NHCONH.sub.2,
N(C.sub.1-8alkyl)SO.sub.2NH(C.sub.1-8alkyl), N(C.sub.1-8alkyl)
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH(C.sub.1-8alkyl), NH
SO.sub.2N(C.sub.1-8alkyl).sub.2, NH SO.sub.2NH.sub.2.
[1201] In any aspect or embodiment described herein, the A.sup.L is
selected from the group consisting of: [1202]
--N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O-
(CH2).sub.r-OCH2-, [1203]
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH-
2).sub.r-OCH2-, [1204]
--O--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH-
2).sub.r-O--; [1205]
--N(R)--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O-
(CH2).sub.r-O--; [1206]
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH2).-
sub.r-O--; [1207]
--(CH2).sub.m-O(CH2).sub.n-O(CH2).sub.o-O(CH2).sub.p-O(CH2).sub.q-O(CH2).-
sub.r-OCH2-;
##STR00433## ##STR00434## ##STR00435##
[1207] wherein [1208] m, n, o, p, q, and r of the linker are
independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20; [1209] when the number is zero, there is no
N--O or O--O bond [1210] R of the linker is H, methyl and ethyl;
[1211] X of the linker is H and F
[1211] ##STR00436## [1212] where m of the linker can be 2, 3, 4,
5;
[1212] ##STR00437## ##STR00438## ##STR00439## ##STR00440##
##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445##
##STR00446## ##STR00447## ##STR00448## ##STR00449## [1213] where
each n and m of the linker can independently be 0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
[1214] In any aspect or embodiment described herein, the A.sup.L is
selected from the group consisting of:
##STR00450## ##STR00451## ##STR00452## ##STR00453##
##STR00454##
wherein each m and n is independently selected from 0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
[1215] In any aspect or embodiment described herein, the A.sup.L is
selected from the group consisting of:
##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459##
##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464##
##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469##
##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474##
##STR00475## ##STR00476## ##STR00477## ##STR00478##
##STR00479##
##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484##
##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489##
##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494##
##STR00495## ##STR00496##
wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[1216] In any aspect or embodiment described herein, the A.sup.L is
selected from the group consisting of:
##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501##
##STR00502##
##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507##
##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512##
##STR00513## ##STR00514## ##STR00515## ##STR00516##
##STR00517##
[1217] In any aspect or embodiment described herein, the A.sup.L is
selected from:
##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522##
##STR00523## ##STR00524## ##STR00525##
wherein: [1218] `X" in above structures can be linear chain with
atoms ranging from 2 to 14, and the mentioned chain can contain
heteroatoms such as oxygen; and [1219] "Y" in above structures can
be O, N, S(O).sub.n (n=0, 1, 2).
[1220] In any aspect or embodiment described herein, the linker (L)
comprises a structure selected from:
##STR00526##
wherein: [1221] W.sup.L1 and W.sup.L2 are each independently
absent, a 4-8 membered ring with 0-4 heteroatoms, optionally
substituted with R.sup.Q, each R.sup.Q is independently a H, halo,
OH, CN, CF.sub.3, C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted), C.sub.1-C.sub.6 alkoxy (linear, branched,
optionally substituted), or 2 R.sup.Q groups taken together with
the atom they are attached to, form a 4-8 membered ring system
containing 0-4 heteroatoms; [1222] Y.sup.L1 is each independently a
bond, C.sub.1-C.sub.6 alkyl (linear, branched, optionally
substituted) and optionally one or more C atoms are replaced with
O; or C.sub.1-C.sub.6 alkoxy (linear, branched, optionally
substituted); [1223] n is 0-10; and [1224] a dashed line indicates
the attachment point to the PTM or CLM moieties.
[1225] In any aspect or embodiment described herein, the linker
comprises a structure selected from:
##STR00527##
wherein: [1226] W.sup.L1 and W.sup.L2 are each independently
absent, aryl, heteroaryl, cyclic, heterocyclic, C.sub.1-6 alkyl and
optionally one or more C atoms are replaced with O, C.sub.1-6
alkene and optionally one or more C atoms are replaced with O,
C.sub.1-6 alkyne and optionally one or more C atoms are replaced
with O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each
optionally substituted with R.sup.Q, each R.sup.Q is independently
a H, halo, OH, CN, CF.sub.3, hydroxyl, nitro, C.ident.CH, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkyl (linear,
branched, optionally substituted), C.sub.1-C.sub.6 alkoxy (linear,
branched, optionally substituted), OC.sub.1-3alkyl (optionally
substituted by 1 or more --F), OH, NH.sub.2, NR.sup.Y1R.sup.Y2, CN,
or 2 R.sup.Q groups taken together with the atom they are attached
to, form a 4-8 membered ring system containing 0-4 heteroatoms;
[1227] Y.sup.L1 is each independently a bond, NR.sup.YL1, O, S,
NR.sup.YL2, CR.sup.YL1R.sup.YL2, C.dbd.O, C.dbd.S, SO, SO.sub.2,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted)
and optionally one or more C atoms are replaced with O;
C.sub.1-C.sub.6 alkoxy (linear, branched, optionally substituted);
[1228] Q.sup.L is a 3-6 membered alicyclic or aromatic ring with
0-4 heteroatoms, optionally bridged, optionally substituted with
0-6 R.sup.Q, each R.sup.Q is independently H, C.sub.1-6 alkyl
(linear, branched, optionally substituted by 1 or more halo,
C.sub.1-6 alkoxyl), or 2 R.sup.Q groups taken together with the
atom they are attached to, form a 3-8 membered ring system
containing 0-2 heteroatoms); [1229] R.sup.YL1, R.sup.YL2 are each
independently H, OH, C.sub.1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), or R.sup.1,
R.sup.2 together with the atom they are attached to, form a 3-8
membered ring system containing 0-2 heteroatoms); [1230] n is 0-10;
and [1231] a dashed line indicates the attachment point to the PTM
or CLM moieties.
[1232] In any aspect or embodiment described herein, the linker (L)
is a polyethylenoxy group optionally substituted with aryl or
phenyl comprising from 1 to 10 ethylene glycol units.
[1233] In any aspect or embodiment described herein, the PTM is an
estrogen receptor (ER) binding moiety represented by the chemical
structure:
##STR00528##
wherein: [1234] X.sub.PTM is O or C=0; [1235] each of X.sub.PTM1
and X.sub.PTM2 is independently selected from N or CH; [1236]
R.sub.PTM1 is independently selected from OH, O(CO)R.sub.PTM,
O-lower alkyl, wherein R.sub.PTM is an alkyl or aryl group in the
ester; [1237] R.sub.PTM2 and R.sub.PTM4 are independently selected
from H, OH, halogen, CN, CF.sub.3, SO.sub.2-alkyl, O-lower alkyl;
[1238] R.sub.PTM3 and R.sub.PTM5 are independently selected from H,
halogen; [1239] PTM-I has at least one R.sub.PTM2 and at least one
R.sub.PTM3 on each respective rings; and the indicates the site of
attachment of at least one of the linker, the CLM, a CLM', or a
combination thereof.
[1240] In any aspect or embodiment described herein, the PTM is an
estrogen receptor (ER) binding moiety represented by the chemical
structure:
##STR00529##
wherein: [1241] each X.sub.PTM is independently CH, N; [1242]
indicates the site of attachment of at least one of the linker (L),
the CLM, a CLM', ULM, an ILM, a VLM, MLM, a ULM', a ILM', a VLM', a
MLM', or a combination thereof; [1243] each R.sub.PTM1 is
independently OH, halogen, alkoxy, methoxy, ethoxy, O(CO)R.sub.PTM,
wherein the substitution can be a mono-, di- or tri-substitution
and the R.sub.PTM is alkyl or cycloalkyl group with 1 to 6 carbons
or aryl groups; [1244] each R.sub.PTM2 is independently H, halogen,
CN, CF.sub.3, liner or branched alkyl, alkoxy, methoxy, ethoxy,
wherein the substitution can be mono- or di-substitution; [1245]
each R.sub.PTM3 is independently H, halogen, wherein the
substitution can be mono- or di-substitution; and [1246] R.sub.PTM4
is a H, alkyl, methyl, ethyl.
[1247] In any aspect or embodiment described herein, the PTM is an
androgen receptor (AR) binding moiety (ABM) represented by a
structure selected from the group consisting of:
##STR00530##
wherein: [1248] W.sup.1 is aryl, heteroaryl, bicyclic, or
biheterocyclic, each independently substituted by 1 or more H,
halo, hydroxyl, nitro, CN, C.ident.CH, C.sub.1-6 alkyl (linear,
branched, optionally substituted; for example, optionally
substituted by 1 or more halo, C.sub.1-6 alkoxyl), C.sub.1-6
alkoxyl (linear, branched, optionally substituted; for example,
optionally substituted by 1 or more halo), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or CF.sub.3; [1249] Y.sup.1, Y.sup.2 are each
independently NR.sup.Y1, O, S, SO2, heteroaryl, or aryl; [1250]
Y.sup.3, Y.sup.4, Y.sup.5 are each independently a bond, O,
NR.sup.Y2, CR.sup.Y1R.sup.Y2, C.dbd.O, C.dbd.S, SO, SO.sub.2,
heteroaryl, or aryl; [1251] Q is a 3-6 membered ring with 0-4
heteroatoms, optionally substituted with 0-6 R.sup.Q, each R.sup.Q,
is independently H, C.sub.1-6 alkyl (linear, branched, optionally
substituted, for example, optionally substituted by 1 or more halo,
C.sub.1-6 alkoxyl), halogen, C.sub.1-6 alkoxy, or 2 R.sup.Q groups
taken together with the atom they are attached to, form a 3-8
membered ring system containing 0-2 heteroatoms); [1252] R.sup.1,
R.sup.2, R.sup.a, R.sup.b, R.sup.Y1, R.sup.Y2 are each
independently H, C.sub.1-6 alkyl (linear, branched, optionally
substituted; for example, optionally substituted by 1 or more halo,
C.sub.1-6 alkoxyl), halogen, C.sub.1-6 alkoxy, cyclic, heterocyclic
or R.sup.1, R.sup.2 together with the atom they are attached to,
form a 3-8 membered ring system containing 0-2 heteroatoms); [1253]
W.sup.2 is a bond, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, O, aryl,
heteroaryl, alicyclic, heterocyclic, biheterocyclic, biaryl, or
biheteroaryl, each optionally substituted by 1-10 R.sup.W2; [1254]
each R.sup.W2 is independently H, halo, C.sub.1-6 alkyl (linear or
branched optionally substituted; for example, optionally
substituted by 1 or more F), --OR.sup.W2A, C.sub.3-6 cycloalkyl,
C.sub.4-6 cycloheteroalkyl, C.sub.1-6 alkyl (optionally
substituted), heterocyclic (optionally substituted), aryl
(optionally substituted), or heteroaryl (optionally substituted),
bicyclic hereoaryl or aryl, OC.sub.1-3alkyl (optionally
substituted; for example, optionally substituted by 1 or more --F),
OH, NH.sub.2, NR.sup.Y1R.sup.Y2, CN; [1255] R.sup.W2A is H,
C.sub.1-6 alkyl (linear, branched), or C.sub.1-6 heteroalkyl
(linear, branched), each optionally substituted by a cycloalkyl,
cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or
OC.sub.1-3alkyl; and [1256] the dashed line indicates the site of
attachment of at least one of the linker, the CLM, a CLM', or a
combination thereof.
[1257] In any aspect or embodiment described herein, the PTM is a
BET/BRD4 targeting moiety comprising a group according to the
chemical structure PTM-a:
##STR00531##
wherein: [1258] Y.sub.1, Y.sub.2 and Y.sub.3 are independently
selected from the group of carbon, nitrogen or oxygen and together
with the atoms to form an aromatic fused ring. [1259] A and B are
independently selected from the group of a 5-membered aromatic
ring, a 6-membered aromatic ring, a heteroaromatic ring, a
carbocyclic, a thiophene a pyrrole ring, a pyridine, a pyrimidine,
a pyrazine, a pyrazole ring each optionally substituted with alkyl,
alkoxy, halogen, an aromatic and a heteroaromatic ring; wherein
ring A is fused to the central azepine (Y1=C) or diazepine (Y1=N)
moiety; and [1260] Z1 is selected from the group of methyl or
analkyl group, and [1261] wherein the dashed line indicates the
site of attachment of at least one of the linker, the CLM, a CLM',
or a combination thereof.
[1262] In any aspect or embodiment described herein, the PTM is a
BRaf targeting moiety that is represented by at least one of
chemical structures PTM-Ia, PTM-Ib, PTM-IIa, PTM-IIb, PTM-IIIa,
PTM-IIIb, PTM-IVa, PTM-IVb:
##STR00532## ##STR00533##
wherein: [1263] double dotted bonds are aromaric bonds; [1264]
V.sub.PTM, W.sub.PTM, X.sub.PTM, Y.sub.PTM, Z.sub.PTM is one of the
following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C,
CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N,
CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C,
N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N,
N, C; [1265] R.sub.PTM1 is covalently joined to a ULM, a chemical
linker group (L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a
ILM', a VLM', a MLM', or combination thereof; [1266] R.sub.PTM2 is
hydrogen, halogen, aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [1267]
R.sub.PTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl,
cyclic alkyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle; [1268] R.sub.PTM4 is hydrogen, halogen,
aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [1269] each
of R.sub.PTM5 and R.sub.PTM22 is independently selected from the
group consisting of
[1269] ##STR00534## [1270] X.sub.PTM1, X.sub.PTM2, X.sub.PTM3,
X.sub.PTM4, X.sub.PTM5, X.sub.PTM6, X.sub.PTM7, X.sub.PTM8,
X.sub.PTM9, X.sub.PTM10, X.sub.PTM11, X.sub.PTM12, X.sub.PTM13,
X.sub.PTM14, X.sub.PTM15, X.sub.PTM16, X.sub.PTM17, X.sub.PTM18,
X.sub.PTM19, X.sub.PTM20, X.sub.PTM21, X.sub.PTM22, X.sub.PTM23,
X.sub.PTM24, X.sub.PTM25, X.sub.PTM26, X.sub.PTM27, X.sub.PTM28,
X.sub.PTM29, X.sub.PTM30, X.sub.PTM31, X.sub.PTM32, X.sub.PTM33,
X.sub.PTM34, X.sub.PTM35, X.sub.PTM36, X.sub.PTM37, X.sub.PTM38 are
independently selected from CH or N; [1271] R.sub.PTM5a is selected
from the group consisting of: H, optionally substituted amide
(e.g., optionally substituted with an alkyl, methyl, ethyl, propyl,
or butyl group), optionally substituted amine,
##STR00535##
[1271] --NHC(O)R.sub.PTM5;
[1272] R.sub.PTM6a and R.sub.PTM6b are each independently selected
from hydrogen, halogen, or C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted); [1273] R.sub.PTM6 is either of the
following groups: absent, hydrogen, halogen, aryl, methyl, ethyl,
OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is
CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or heterocycle. [1274] R.sub.PTM7 is absent, hydrogen, halogen,
aryl, methyl, ethyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle. [1275]
R.sub.PTM8, R.sub.PTM9 or R.sub.PTM10 are independently selected
from the group consisting of absent, hydrogen, halogen, aryl,
heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl,
OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2, wherein M1 is
CH.sub.2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or heterocycle; [1276] R.sub.PTM11 is absent, hydrogen, halogen,
methyl, ethyl, OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2 in
which Ml, wherein CH.sub.2, O and NH, and M2 is hydrogen, alkyl,
cyclic alkyl, aryl or heterocycle; [1277] R.sub.PTM12, R.sub.PTM13,
R.sub.PTM14, R.sub.PTM15, R.sub.PTM16, R.sub.PTM17, R.sub.PTM18,
R.sub.PTM19 are independently Selected from the group consisting of
absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl,
heterocycle, methyl, ethyl, other alkyl, OCH.sub.3, NHCH.sub.3 or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O and NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [1278]
R.sub.PTM20 is a small group containing less than four non-hydrogen
atoms; [1279] R.sub.PTM21 is selected from the group consisting of
trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl,
isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, OCH.sub.3, NHCH.sub.3, dimethylamino or
M1-CH.sub.2--CH.sub.2-M2, wherein M1 is CH.sub.2, O or NH, and M2
is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; [1280]
R.sub.PTM25a and R.sub.PTM25b are each independently selected from
hydrogen, halogen, or C.sub.1-C.sub.6 alkyl (linear, branched,
optionally substituted); [1281] R.sub.PTM23, R.sub.PTM24,
R.sub.PTM28, R.sub.PTM29, R.sub.PTM30, R.sub.PTM31, R.sub.PTM32 are
independently selected from the group consisting of absent, bond,
hydrogen, halogen, aryl (optionally substituted), heteroaryl
(optionally substituted), cycloalkyl (optionally substituted),
heterocycle (optionally substituted), methyl, ethyl (optionally
substituted), other alkyl (linear, branched, optionally
substituted), OCH.sub.3, NHCH.sub.3 or M1-CH.sub.2--CH.sub.2-M2,
wherein M1 is CH.sub.2, O and NH, and M2 is hydrogen, alkyl
(linear, branched, optionally substituted), cyclic alkyl
(optionally substituted), aryl (optionally substituted) or
heterocycle (optionally substituted); [1282] R.sub.PTM25 is
selected from absent, hydrogen, halogen, C.sub.1-C.sub.6 alkyl
(linear, branched, optionally substituted), OCH.sub.3, NHCH.sub.3
or SCH.sub.3; [1283] R.sub.PTM26 is selected from absent, hydrogen,
halogen, C.sub.1-C.sub.6 alkyl (linear, branched, optionally
substituted), OCH3, NHCH.sub.3 or SCH.sub.3; [1284] R.sub.PTM27 is
selected from the group consisting of absent, hydrogen, halogen,
C.sub.1-C.sub.6 alkyl (linear, branched, optionally substituted),
OCH.sub.3, NHCH.sub.3 or SCH.sub.3; and [1285] at least one of
R.sub.PTM8, R.sub.PTM9 or R.sub.PTM10, R.sub.PTM12, R.sub.PTM13,
R.sub.PTM16, R.sub.PTM24, R.sub.PTM29, and R.sub.PTM32 is modified
to be covalently joined to a ULM, a chemical linker group (L), a
CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM', a VLM', a MLM', or
combination thereof.
[1286] In any aspect or embodiment described herein, when
R.sub.PTM9 is the covalently joined position, R.sub.PTM7 and
R.sub.PTM8 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM7 and
R.sub.PTM8 are attached.
[1287] In any aspect or embodiment described herein, when
R.sub.PTM8 is the covalently joined position, R.sub.PTM9 and
R.sub.PTM10 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM9 and
R.sub.PTM10 are attached.
[1288] In any aspect or embodiment described herein, when RPTM10 is
the covalently joined position, RPTM8 and RPTM9 are connected
together via a covalent bond in a way to form a bicyclic group with
the ring to which RPTM8 and RPTM9 are attached.
[1289] In any aspect or embodiment described herein, when
R.sub.PTM12 is the covalently joined position, R.sub.PTM13 and
R.sub.PTM14 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM13 and
R.sub.PTM14 are attached, and/or R.sub.PTM15 and R.sub.PTM16 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM15 and R.sub.PTM16 are
attached.
[1290] In any aspect or embodiment described herein, when
R.sub.PTM13 is the covalently joined position, R.sub.PTM12 and
R.sub.PTM16 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM12 and
R.sub.PTM16 are attached, and/or R.sub.PTM15 and R.sub.PTM16 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM15 and R.sub.PTM16 are
attached.
[1291] In any aspect or embodiment described herein, when
R.sub.PTM16 is the covalently joined position, R.sub.PTM12 and
R.sub.PTM13 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM12 and
R.sub.PTM13 are attached, and/or R.sub.PTM13 and R.sub.PTM14 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM13 and R.sub.PTM14 are
attached.
[1292] In any aspect or embodiment described herein, when
R.sub.PTM24 is the covalently joined position, R.sub.PTM31 and
R.sub.PTM32 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM31 and
R.sub.PTM32 are attached, or R.sub.PTM29 and R.sub.PTM30 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM29 and R.sub.PTM30 are
attached.
[1293] In any aspect or embodiment described herein, when
R.sub.PTM29 is the covalently joined position, R.sub.PTM24 and
R.sub.PTM32 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM24 and
R.sub.PTM32 are attached, and/or R.sub.PTM31 and R.sub.PTM32 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM31 and R.sub.PTM32 are
attached.
[1294] In any aspect or embodiment described herein, when
R.sub.PTM32 is the covalently joined position, R.sub.PTM24 and
R.sub.PTM29 are connected together via a covalent bond in a way to
form a bicyclic group with the ring to which R.sub.PTM24 and
R.sub.PTM29 are attached, and/or R.sub.PTM29 and R.sub.PTM30 are
connected together via a covalent bond in a way to form a bicyclic
group with the ring to which R.sub.PTM29 and R.sub.PTM30 are
attached.
[1295] In any aspect or embodiment described herein, the PTM has a
structure selected from the group consisting of:
##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540##
##STR00541## ##STR00542## ##STR00543## ##STR00544##
##STR00545##
wherein: [1296] R is H, a lower alkyl, a bond, or a chemical moiety
coupling the CLM to the PTM; and [1297] Linker is a bond or a
chemical linker moiety coupling the CLM to the PTM, including
pharmaceutically acceptable salt forms thereof.
[1298] In any aspect or embodiment described herein, the compound
is selected from the group consisting of compounds 1-52.
[1299] A further aspect of the present disclosure provides a
composition comprising an effective amount of a bifunctional
compound of the present disclosure, and a pharmaceutically
acceptable carrier.
[1300] In any aspect or embodiment described herein, the
composition further comprises at least one of additional bioactive
agent or another bifunctional compound of the present
disclosure.
[1301] In any aspect or embodiment described herein, the additional
bioactive agent is anti-cancer agent, an anti-neurodegenerative
agent, an antimicrobial agent, an antiviral agent, an anti-HIV
agent, or an antifungal agent.
[1302] An additional aspect of the present disclosure provides a
composition comprising an effective amount of at least one compound
of the present disclosure and a pharmaceutically acceptable
carrier, additive, and/or excipient for treating a disease or
disorder in a subject, the method comprising administering the
composition to a subject in need thereof, wherein the compound is
effective in treating or ameliorating at least one symptom of the
disease or disorder.
[1303] In any aspect or embodiment described herein, the disease or
disorder is associated with the accumulation and/or aggregation of
the target protein.
[1304] In any aspect or embodiment described herein, the disease or
disorder is selected from the group consisting of asthma,
autoimmune diseases such as multiple sclerosis, various cancers,
ciliopathies, cleft palate, diabetes, heart disease, hypertension,
inflammatory bowel disease, mental retardation, mood disorder,
obesity, refractive error, infertility, Angelman syndrome, Canavan
disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic
fibrosis, Duchenne muscular dystrophy, Haemochromatosis,
Haemophilia, Klinefelter's syndrome, Neurofibromatosis,
Phenylketonuria, Polycystic kidney disease, (PKD1) or 4 (PKD2)
Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease,
Turner syndrome.
[1305] In any aspect or embodiment described herein, the disease or
disorder is selected from the group consisting of Alzheimer's
disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease),
Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention
deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic
fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's
disease, Coronary heart disease, Dementia, Depression, Diabetes
mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre
syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome,
Multiple sclerosis, Myocardial infarction, Obesity,
Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,
Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia,
Stroke, Thromboangiitis obliterans, Tourette syndrome,
Vasculitis.
[1306] In any aspect or embodiment described herein, the disease or
disorder is selected from the group consisting of
aceruloplasminemia, Achondrogenesis type II, achondroplasia,
Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,
Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase
deficiency, adenylosuccinate lyase deficiency, Adrenogenital
syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase
deficiency, Alkaptonuria, Alexander disease, Alkaptonuric
ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase
inhibitor, emphysema, amyotrophic lateral sclerosis Alstrom
syndrome, Alexander disease, Amelogenesis imperfecta, ALA
dehydratase deficiency, Anderson-Fabry disease, androgen
insensitivity syndrome, Anemia Angiokeratoma Corporis Diffusum,
Angiomatosis retinae (von Hippel-Lindau disease) Apert syndrome,
Arachnodactyly (Marfan syndrome), Stickler syndrome, Arthrochalasis
multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type)
ataxia telangiectasia, Rett syndrome, primary pulmonary
hypertension, Sandhoff disease, neurofibromatosis type II,
Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,
familial, Benjamin syndrome, beta-thalassemia, Bilateral Acoustic
Neurofibromatosis (neurofibromatosis type II), factor V Leiden
thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti),
Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich
syndrome (Turner syndrome), Bourneville disease (tuberous
sclerosis), prion disease, Birt-Hogg-Dube syndrome, Brittle bone
disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome
(Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis
(hemochromatosis), Bulbospinal muscular atrophy (Kennedy's
disease), Burger-Grutz syndrome (lipoprotein lipase deficiency),
CGD Chronic granulomatous disorder, Campomelic dysplasia,
biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du
chat, CAVD (congenital absence of the vas deferens), Caylor
cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic
porphyria), cystic fibrosis, congenital hypothyroidism,
Chondrodystrophy syndrome (achondroplasia),
otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome,
galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia,
Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous
polyposis), Congenital erythropoietic porphyria, Congenital heart
disease, Methemoglobinemia/Congenital methaemoglobinaemia,
achondroplasia, X-linked sideroblastic anemia, Connective tissue
disease, Conotruncal anomaly face syndrome, Cooley's Anemia
(beta-thalassemia), Copper storage disease (Wilson's disease),
Copper transport disease (Menkes disease), hereditary
coproporphyria, Cowden syndrome, Craniofacial dysarthrosis (Crouzon
syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne
syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome
(myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome,
primary hyperoxaluria, spondyloepimetaphyseal dysplasia (Strudwick
type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher
syndrome, Degenerative nerve diseases including de Grouchy syndrome
and Dejerine-Sottas syndrome, developmental disabilities, distal
spinal muscular atrophy, type V, androgen insensitivity syndrome,
Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's
syndrome, Dihydrotestosterone receptor deficiency, androgen
insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic
protoporphyria Erythroid 5-aminolevulinate synthetase deficiency,
Erythropoietic porphyria, erythropoietic protoporphyria,
erythropoietic uroporphyria, Friedreich's ataxia, familial
paroxysmal polyserositis, porphyria cutanea tarda, familial
pressure sensitive neuropathy, primary pulmonary hypertension
(PPH), Fibrocystic disease of the pancreas, fragile X syndrome,
galactosemia, genetic brain disorders, Giant cell hepatitis
(Neonatal hemochromatosis), Gronblad-Strandberg syndrome
(pseudoxanthoma elasticum), Gunther disease (congenital
erythropoietic porphyria), haemochromatosis, Hallgren syndrome,
sickle cell anemia, hemophilia, hepatoerythropoietic porphyria
(HEP), Hippel-Lindau disease (von Hippel-Lindau disease),
Huntington's disease, Hutchinson-Gilford progeria syndrome
(progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic
anemia, Immune system disorders, including X-linked severe combined
immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome,
Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome,
Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,
Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,
Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch
syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease,
Metabolic disorders, including Kniest dysplasia, Marfan syndrome,
Movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke
syndrome, Multiple neurofibromatosis, Nance-Insley syndrome,
Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack
syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease,
Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic
fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers
syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary
hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary
hypertension, primary senile degenerative dementia, prion disease,
progeria (Hutchinson Gilford Progeria Syndrome), progressive
chorea, chronic hereditary (Huntington) (Huntington's disease),
progressive muscular atrophy, spinal muscular atrophy, propionic
acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary
arterial hypertension, PXE (pseudoxanthoma elasticum), Rb
(retinoblastoma), Recklinghausen disease (neurofibromatosis type
I), Recurrent polyserositis, Retinal disorders, Retinoblastoma,
Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome,
Roussy-Levy syndrome, severe achondroplasia with developmental
delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome,
sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome,
sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital
(spondyloepiphyseal dysplasia congenita), SED Strudwick
(spondyloepimetaphyseal dysplasia, Strudwick type), SEDc
(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type
(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen
syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome,
South-African genetic porphyria (variegate porphyria),
infantile-onset ascending hereditary spastic paralysis, Speech and
communication disorders, sphingolipidosis, Tay-Sachs disease,
spinocerebellar ataxia, Stickler syndrome, stroke, androgen
insensitivity syndrome, tetrahydrobiopterin deficiency,
beta-thalassemia, Thyroid disease, Tomaculous neuropathy
(hereditary neuropathy with liability to pressure palsies),
Treacher Collins syndrome, Triplo X syndrome (triple X syndrome),
Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von
Hippel-Lindau disease), Vision impairment and blindness (Alstrom
syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo
Fledelius Syndrome, Weissenbacher-Zweymuller syndrome,
Wolf-Hirschhorn syndrome, Wolff Periodic disease,
Weissenbacher-Zweymuller syndrome and Xeroderma pigmentosum.
[1307] In any aspect or embodiment described herein, the
composition further comprises an additional bioactive agent.
[1308] In any aspect or embodiment described herein, the additional
bioactive agent is at least one of an anti-cancer agent, an
anti-neurodegenerative agent, an antimicrobial agent, an antiviral
agent, an anti-HIV agent, an antifungal agent, or a combination
thereof.
[1309] In any aspect or embodiment described herein, the anticancer
agent is selected from the group consisting of everolimus,
trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,
GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,
TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197,
MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a
VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor,
a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET
inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor,
an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase
inhibitors, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STAT
inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase
inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap
antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib,
panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171,
batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine,
rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab,
gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,
cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR.sub.1
KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx
102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380,
sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,
doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine,
vincristine, temozolomide, ZK-304709, seliciclib; PD0325901,
AZD-6244, capecitabine, L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane,
letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated
estrogen, bevacizumab, IMC-1C11, CHIR-258);
3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone,
vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6,
Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu
t)-Leu-Arg-Pro-Azgly-NH.sub.2 acetate
[C.sub.59H.sub.84N.sub.18Oi.sub.4-(C.sub.2H.sub.4O.sub.2).sub.x
where x=1 to 2.4], goserelin acetate, leuprolide acetate,
triptorelin pamoate, medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;
TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF
antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib,
BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide
hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,
sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,
L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine,
chlorambucil, cisplatin, cladribine, clodronate, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin, fludarabine, fludrocortisone,
fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,
methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin,
porfimer, procarbazine, raltitrexed, rituximab, streptozocin,
teniposide, testosterone, thalidomide, thioguanine, thiotepa,
tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard,
uracil mustard, estramustine, altretamine, floxuridine,
5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine,
vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat,
BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, droloxifene,
idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,
denileukin diftitox, gefitinib, bortezimib, paclitaxel,
cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550,
BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,
ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene,
idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK
222584, VX-745, PD 184352, rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,
wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,
erythropoietin, granulocyte colony-stimulating factor,
zolendronate, prednisone, cetuximab, granulocyte macrophage
colony-stimulating factor, histrelin, pegylated interferon alfa-2a,
interferon alfa-2a, pegylated interferon alfa-2b, interferon
alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,
all-transretinoic acid, ketoconazole, interleukin-2, megestrol,
immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab
tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab, arsenic trioxide, cortisone, editronate, mitotane,
cyclosporine, liposomal daunorubicin, Edwina-asparaginase,
strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,
palonosetron, aprepitant, diphenhydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol,
dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim,
erythropoietin, epoetin alfa, darbepoetin alfa and mixtures
thereof.
[1310] An additional aspect of the present disclosure provides a
method for inducing degradation of a target protein in a cell
comprising administering an effective amount of a compound of the
present disclosure to the cell, wherein the compound effectuates
degradation of the target protein.
[1311] Another aspect of the present disclosure provides a
composition comprising an effective amount of a compound of the
present disclosure for use in a method for treating cancer, said
method comprising administering the composition to a patient in
need thereof, wherein the composition is effectuates for the
treatment or alleviation of at least one symptom of cancer in the
patient.
[1312] In any aspect or embodiment described herein, the cancer is
squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,
hepatocellular carcinomas, and renal cell carcinomas, cancer of the
bladder, bowel, breast, cervix, colon, esophagus, head, kidney,
liver, lung, neck, ovary, pancreas, prostate, and stomach;
leukemias; benign and malignant lymphomas, particularly Burkitt's
lymphoma and Non-Hodgkin's lymphoma; benign and malignant
melanomas; myeloproliferative diseases; multiple myeloma, sarcomas,
including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma,
liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial
sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas,
gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,
medulloblastomas, pineal cell tumors, meningiomas, meningeal
sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast
cancer, prostate cancer, cervical cancer, uterine cancer, lung
cancer, ovarian cancer, testicular cancer, thyroid cancer,
astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer,
liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's
disease, Wilms' tumor or teratocarcinomas, T-lineage Acute
lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma
(T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B
ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma,
B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia
chromosome positive CML.
[1313] While preferred embodiments of the invention have been shown
and described herein, it will be understood that such embodiments
are provided by way of example only. Numerous variations, changes
and substitutions will occur to those skilled in the art without
departing from the spirit of the invention. Accordingly, it is
intended that the appended claims cover all such variations as fall
within the spirit and scope of the invention.
EXAMPLES
[1314] A. Protein Degradation Bioassays:
[1315] The following bioassays evaluate the level of protein
degradation observed in various cell types using representative
compounds disclosed herein.
[1316] In each bioassay, cells were treated with varying amounts of
compounds encompassed by the present disclosure. The degradation of
the following proteins may be evaluated: estrogen receptor .alpha.
(ER.alpha.), bromodomain-containing protein 4 (BRD4), androgen
receptor (AR), and BRaf protein.
[1317] 1. ERE Luciferase Assay for Compounds in Table 5.
[1318] T47D-KBlue cells (ATCC.RTM. #CRL_2865, T47D human breast
cancer cells stably transfected with estrogen responsive
element/promoter/luciferase reporter gene) were seeded into 96-well
white opaque plates in RPMI growth medium supplemented with 10%
fetal bovine serum (FBS) and allowed to adhere overnight in a
37.degree. C. humidified incubator. The following day, cells were
treated with PROTACs in a 12-point concentration curve (top final
concentration of 300 nM with subsequent concentrations being 3-fold
less with 2 pM being the lowest concentration in the assay). Each
PROTAC was tested independently in two experiments on 96-well
plates. After 24 hours, media was removed and lysis buffer was
added to the wells. Following lysis, Bright-Glo.TM. Luciferase
Assay Substrate (Promega, Madison Wis.) was added and the
luciferase activity was measured using a Cytation 3 plate reader
(BioTek.TM., Winooski, Vt.). Each compound was assayed in duplicate
and the activity was calculated as IC50 using GraphPad. Prism
software (San Diego, Calif.).
[1319] 2. Estrogen Receptor-Alpha (ER.alpha.) Degradation Assay in
MCF-7 Cells Using Western Blot Method for Table 5.
[1320] The exemplary novel ER.alpha. degraders were assessed for
their activity in degrading ER.alpha. in MCF-7 cells via western
blot. The assay was carried out in the presence of 10% FBS or high
percentage of human or mouse serum. Protocols of the western blot
assay are described below.
[1321] MCF7 cells were grown in DMEM/F12 with 10% FBS and seeded at
24,000 cells per well in 100 .mu.l into 96-well clear tissue
culture plates. The following day, the cells were treated with
PROTACs in a 7-point concentration curve with 100 nM being the top
concentration and serial dilutions to make the other concentrations
(30 nM, 10 nM, 3 nM, 1 nM, and 0.3 nM). At all concentrations,
0.01% DMSO is the final concentration in the well. The following
day, the plates are aspirated, washed with 50 .mu.l of cold PBS.
The cells are lysed with 50 .mu.l/well 4.degree. C. Cell Lysis
Buffer (Catalog#9803; Cell Signaling Technology, Danvers, Mass.)
(20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na.sub.2EDTA, 1 mM
EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM
B-glycerophosphate, 1 mM sodium vanadate, 1 ug/ml leupeptin).
Lysates were clarified at 16,000.times.g for 10 minutes, and 2
.mu.g of protein was subjected to SDS-PAGE analysis and followed by
immunoblotting according to standard protocols. The antibodies used
were ER.alpha. (Cell Signaling Technologies Catalog #8644), and
Tubulin (Sigma Catalog #T9026; St. Louis, Mo.). Detection reagents
were Clarity Western ECL substrate (Bio-Rad Catalog #170-5060;
Hercules, Calif.).
[1322] Alternatively, MCF7 cells were grown in DMEM/F12 with 10%
PBS and seeded at 24,000 cells per well in 500 .mu.l in 24-well
clear tissue culture plates. The following day, the cells were
treated with PROTACs in a 5-point concentration curve (100 nM, 33
nM, 11 nM, 3.7 nM, and 1.2 nM) in the presence of 0.01% DMSO. After
72 hours, the wells are aspirated and washed with 500 .mu.l of PBS.
The cells are lysed with 100 .mu.l/well 4.degree. C. Cell Lysis
Buffer (Catalog#9803; Cell Signaling Technology, Danvers, Mass.)
(20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na.sub.2EDTA, 1 mM
EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM
B-glycerophosphate, 1 mM sodium vanadate, 1 ug/ml leupeptin).
Lysates were clarified at 16,000.times.g for 10 minutes, and 2
.mu.g of protein was subjected to SDS-PAGE analysis and followed by
immunoblotting according to standard protocols. The antibodies used
were ER.alpha. (Cell Signaling Technologies Catalog #8644), and
Tubulin (Sigma Catalog #T9026; St. Louis, Mo.). Detection reagents
were Clarity Western ECL substrate (Bio-Rad Catalog #170-5060;
Hercules, Calif.).
[1323] 3. Estrogen Receptor-Alpha (ER.alpha.) Degradation Assay
Using in-Cell Western.TM. Assay for Table 5.
[1324] Degradation of ER.alpha. by claimed compounds were
determined in MCF7 cells using an In-Cell Western.TM. assay.
Briefly, MCF7 cells were plated in 96-well plates (2000 cells per
well in 100 .mu.l media) and incubated at 37.degree. C. under an
atmosphere of 5% CO.sub.2 in a humidified incubator overnight.
One-hundred (100) .mu.l of media containing test compound (at
2.times. concentration) was added to the appropriate wells to
provide 11 serially decreasing concentrations (top final
concentration, 1 .mu.M then 3-fold less for the next 10
concentrations); a vehicle control (DMSO) was also added for each
compound. For each experiment, all compounds were assayed in
duplicate plates. Cells were then incubated for 3 or 5 days in the
above-mentioned environment. The assay was terminated by removal of
media, a single wash with ice-cold PBS and the addition of 50 .mu.l
paraformaldehyde (PFA: 4% in PBS). After 15 minutes in PFA at room
temperature, the cells were permeabilized in
Tris-phosphate-buffered saline with Tween (0.1%) (TBST)
supplemented with Triton X-100 (0.5%) for 15 minutes. Cells were
then blocked in BSA (TBST with BSA, 3%) for one hour. Primary
antibodies for the detection of ER.alpha. (rabbit monoclonal,
1:1000, Cell Signaling Technology Catalog #8644) and tubulin (mouse
monoclonal, 1:5000, Sigma Catalog #T6074) in TBST with BSA (3%)
were added. The cells were incubated overnight at 4.degree. C. The
cells were then washed thrice with TBST at room temperature and
then incubated with anti-rabbit and anti-mouse
fluorescently-labelled secondary antibodies (IRDye.RTM.; LI-COR;
Lincoln, Nebr.) in LI-COR blocking buffer (Catalog #927-50000) for
one hour at room temperature. Following 3 washes with TBST, the
buffer was removed and the plates were read on an Odyssey.RTM.
infrared imaging system (LI-COR.RTM.; Lincoln, Nebr.) at 700 nm and
800 nm. Using commercial software (ImageStudio.TM.; LI-COR,
Lincoln, Nebr.), the staining intensity for ER.alpha. and tubulin
in each well was quantified and exported for analysis. For each
data point, ER.alpha. intensity was normalized to tubulin intensity
and for each compound all normalized intensity values were
normalized to the vehicle control. DC.sub.50 and D.sub.max values
were determined following a 4-parameter IC.sub.50 curve fit using
ACAS dose response module (McNeil & Co Inc.).
[1325] 4. AR ELISA Assay Protocol for Table 6
[1326] Compounds were evaluated in this assay in LNCaP and/or VCaP
cells utilizing similar protocols. The protocols used with VCaP
cells are described below. The androgen receptor ELISA assay was
performed using PathScan AR Sandwich ELISA (Cell Signaling
Catalog#12850) according to the following assay steps:
[1327] VCaP cells were seeded at 40,000 cells/well at a volume of
100 .mu.L/well in VCaP assay medium [Phenol red free RPMI (Gibco
Cat#11835-030); 5% Charcoal Stripped (Dextran treated) FBS (Omega
Scientific, Cat#FB-04); 1% penstrep (Life Technologies, Gibco Cat#:
10378-016)] in Corning 3904 plates. The cells were incubated for a
minimum of 3 days. Cells were dosed with PROTACs diluted in 0.01%
DMSO and the drug treatment was allowed for 5 hours.
[1328] AR ELISA (Cell Signaling) was performed as follows. 1.times.
Cell Signaling Cell lysis buffer was made (Catalogue #9803; comes
with the kit). Media from the treated wells is aspirated, and 100
.mu.L 1.times. cell lysis buffer/well is added. The cells were
placed on a shaker for 10 minutes at 4.degree. C. Twenty
microliters of lysate was transferred to 100 .mu.l of Diluent in
ELISA plate (0.15 .mu.g/ml-0.075 .mu.g/ml). The lysate-diluent
mixture was shaken for 30 minutes at 37.degree. C. Allow mouse AR
antibody, anti-mouse antibody, TMB, and STOP solution to come to
room temperature. The 1.times.ELISA buffer included in kit was made
and loaded in the reservoir. Media from the plates was discarded,
the ELISA plate tapped hard on paper towel, and washed 4.times.200
.mu.l ELISA wash buffer using a plate washer.
[1329] One-hundred (100) .mu.L/well of mouse AR detection Ab was
added; the plates were covered and shaken at 37.degree. C. for 1
hour; media was discarded from the plates, the plates were tapped
on a paper towel, washed 4.times. with 200 .mu.L ELISA wash buffer
with a plate washer.
[1330] One-hundred (100) .mu.L/well of anti-mouse-HRP conjugated Ab
(comes with the kit) was added; the plates were covered and shaken
at 37.degree. C. for 30 minutes; the TMB reagent was allowed to
come to room temperature; the media was discard from the plate, the
plates were tapped on paper towl, washed 4.times. with 200 .mu.L of
ELISA wash buffer; the plates were tapped the plates on paper towl.
One-hundred (100) .mu.L of TMB was added and the plates shaken for
2 minutes--while watching for color development. One-hundred (100)
.mu.L Stop solution was added when light blue color developed.
Plates were shaken and read at 450 nM.
[1331] Progression of prostate cancer in patients treated with
anti-androgen therapy usually involves one of several mechanisms of
enhanced Androgen Receptor (AR) signaling, including increased
intratumoral androgen synthesis, increased AR expression and AR
mutations. PROTACs (PROteolysis TArgeting Chimera), which use
bi-functional molecules that simultaneously bind a target of choice
and an E3 ligase, cause ubiquitination via induced proximity and
degradation of the targeted, pathological protein. As opposed to
traditional target inhibition, which is a competitive process,
degradation is a progressive process. As such, it is less
susceptible to increases in endogenous ligand, target expression,
or mutations in the target. Thus, this technology appears to be
ideal for addressing the mechanisms of AR resistance in patients
with prostate cancer. Data was analyzed and plotted using GraphPad
Prism software.
[1332] 5. BRaf Protein In Vitro Degradation Assay (A375 Cells) of
Table 7
[1333] A375 cells were cultured in ATCC DMEM+10% FBS in 12 well
plates, and treated with indicated compound from Tables 1-41 or
0.1% DMSO vehicle control for 16 hours. Cells were harvested in
Cell Signaling lysis buffer (Cat#9803) with the addition of Roche
protease inhibitor tablets (Cat#11873580001), and lysates clarified
by microcentrifugation. Proteins were separated by SDS-PAGE, and
transferred onto nitrocellulose membranes using an Invitrogen iBlot
system. Immunoblotting was performed for BRaf (Santa Cruz
Cat#9002), CRAF (BD Cat#610151), and pErk (Cell Signaling
Cat#9106). GAPDH (Cell Signaling Cat#2118) was used as a loading
control. Quantification was carried out using the BioRad Image Lab
5 software.
[1334] 6. BRaf in-Cell Western Cellular Degradation Assay (A375
Cells) of Table 7
[1335] A375 cells were cultured in ATCC DMEM+10% FBS in 96-well
plates, and treated with indicated compounds from Tables-43 or 0.1%
DMSO vehicle control for 72 hours. Cells were washed with PBS
1.times., and affixed to plate using 4% PFA in phosphate buffered
saline for 15 minutes; washed 1.times. and permeabilized using 0.1%
Triton-X-100 in PBS for 5 minutes; washed 1.times. and blocked with
LICOR blocker (Cat.#927-50000) for 1 hour. Cells were then
incubated with B-Raf antibody (Santa Cruz Cat#9002, Santa Cruz
Cat#528) and tubulin antibody (Sigma #T6074) in LICOR blocker for
18 hours. Cells were washed 3.times. prior to adding secondary
antibodies (LICOR cat #926-32210 and 926-68071) and incubated for 1
hour. Cells were washed 3.times. and imaged using LICOR Odyssey
Software.
[1336] 7. BRD4 Western Protocol for Table 8
[1337] 22Rv-1 or VCaP cells were purchased from ATCC and cultured
in Dulbecco's Modified Eagle's Medium (ATCC), supplemented with 10%
FBS (ATCC) and Penicillin/Streptomycin (Life Technologies). DMSO
control and compound treatments (0.003 .mu.M, 0.01 .mu.M, 0.03
.mu.M and 0.1 .mu.M) were performed in 12-well plates for 16 hours.
Cells were harvested, and lysed in RIPA buffer (50 mM Tris pH8, 150
mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate)
supplemented with protease and phosphatase inhibitors. Lysates were
clarified at 16,000 g for 10 minutes, and protein concentration was
determined. Equal amount of protein (20 .mu.g) was subjected to
SDS-PAGE analysis and followed by immunoblotting according to
standard protocols. The antibodies used were BRD4 (Cell Signaling
#13440), and Actin (Sigma #5441). Detection reagents were Clarity
Western ECL substrate (Bio-rad #170-5060).
TABLE-US-00001 TABLE 1 Exemplary Estrogen Receptor PROTACs General
Ex. Synthetic # Chemical Structure Name Method 1 ##STR00546##
3-{5-[4-(5-{4-[(1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-
tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-
1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-
yl}piperidine-2,6-dione A-2, A-8 2 ##STR00547##
3-(5-(4-(5-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-
tetrahydronaphthalen-1-yl)phenoxy)pentyl)piperazin-
1-yl)-7-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione A-2, A-8
Exp. Procedure included 3 ##STR00548##
3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]pi-
perazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione
A-4, A-8 Exp. Procedure included 4 ##STR00549##
3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]pi-
perazin-1-yl]-4-[2-(2- methoxyethoxy)ethoxy]-1-oxo-isoindolin-2-
yl]piperidine-2,6-dione A-4, A-5, A-8 5 ##STR00550##
3-(5-{4-[(l-{4-[(1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-
tetrahydronaphthalen-1-yl]phenyl}piperidin-4-
yl)methyl]piperazin-1-yl}-4-[2-(2-
methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H-
isoindol-2-yl)piperidine-2,6-dione A-4, A-5, A-12 6 ##STR00551##
3-(5-{4-[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-l-
-yl]phenyl}piperidin-4- yl)methyl]piperazin-1-yl}-4-[2-(2-
methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H-
isoindol-2-yl)piperidine-2,6-dione A-4, A-5, A-12 7 ##STR00552##
(3S)-3-(5-{2-[4-(4-{4-[(1S,2R)-6-hydroxy-2-
phenyl-1,2,3,4-tetrahydronaphthalen-1-
yl]phenoxy}butyl)-1,4-diazepan-1-yl]ethyl}-4-[2-(2-
methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H-
isoindol-2-yl)piperidine-2,6-dione A-5, A-9 8 ##STR00553##
(3S)-3-[5-[2-[4-(4-[4-[(1R,2S)-6-hydroxy-2-phenyl-
tetralin-1-yl]phenoxy]butyl]-1,4-diazepan-1-
yl]ethyl]-4-[2-(2-methoxyethoxy)ethoxy]-1-oxo-
isoindolin-2-yl]piperidine-2,6-dione A-5, A-9 9 ##STR00554##
3-(5-{4-[2-(1-{4-[(1S,2R)-6-hydroxy-2-phenyl-
1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-
4-yl)ethyl]piperazin-1-yl}-7-methoxy-1-oxo-2,3-
dihydro-1H-isoindol-2-yl)piperidine-2,6-dione A-2, A-13 10
##STR00555## 3-[5-[4-[2-[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-
tetralin-1-yl]phenyl]-4-piperidyl]ethyl]piperazin-
1-yl]-7-methoxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-2,
A-13 11 ##STR00556##
3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-
1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-4-
(2-methoxyethoxy)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-4,
A-12 12 ##STR00557##
3-[5-[4-[4,4-difluoro-5-[4-[(1R,2S)-6-hydroxy-2-
phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-
1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2,
A-10 13 ##STR00558##
(3R)-3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-
tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-7-
methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-8 14
##STR00559## (3S)-3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-
tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-7-
methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-8 15
##STR00560## 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl -tetralin-
1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindoli-
n-2-yl]piperidine-2,6-dione A-2, A-12 16 ##STR00561##
3-[5-[4-[5-[4-[(1R,2S)-2-(4-fluorophenyl)-6-hydroxy-tetralin-1-yl]phenoxy-
]-1,2,3,3a,4,5,6,6a-
octahydropentalen-2-yl]piperazin-l-yl]-7-methoxy-1-oxo-isoindolin-2-yl]pi-
peridine-2,6-dione A-2, A-11 17 ##STR00562##
3-[5-[4-[[6-[[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]methyl]-
-2-pyridyl]methyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidi-
ne- 2,6-dione A-16 18 ##STR00563##
3-(5-{4-[(1-{2,6-difluoro-4-[(1S,2R)-6-hydroxy-2-
phenyl-1,2,3,4-tetrahydronaphthalen-1-
yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-
7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione
A-1, A-2 19 ##STR00564##
3-(5-(4-((1-(2,6-difluoro-4-((1R,2S)-6-hydroxy-2-
phenyl-1,2,3,4-tetrahydronaphthalen-1-
yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-7-
methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione A-1, A-2, A-8 20
##STR00565## 3-[7-(difluoromethoxy)-5-[4-[5-[4-[(1R,2S)-6-
hydroxy-2-phenyl-tetralin-1-
yl]phenoxy]pentyl]piperazin-1-yl]-1-oxo-
isoindolin-2-yl]piperidine-2,6-dione A-3, A-8 21 ##STR00566##
3-[5-[4-[4,4-difluoro-5-[4-[(1R,2S)-6-hydroxy-2-
phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-
1-yl]-7-(difluoromethoxy)-1-oxo-isoindolin-2-
yl]piperidine-2,6-dione A-6, A-10 22 ##STR00567##
3-[7-(difluoromethoxy)-5-[4-[2-[1-[4-[(1R,2S) -6-
hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-
piperidyl]ethyl]piperazin-1-yl]-1-oxo-isoindolin-
2-yl]piperidine-2,6-dione A-2, A-13 23 ##STR00568##
3-[7-(difluoromethoxy)-5-[4-[2-[3-[4-[(1R,2S)-6-
hydroxy-2-phenyl-tetralin-1-
yl]phenoxy]cyclobutyl]ethyl]piperazin-1-
yl]-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-3, A-14 24
##STR00569## 3-[5-[4-[2-[1-[2-fluoro-4-[(1R,2S)-6-hydroxy-2-
phenyl-tetralin-1-yl]phenyl]-4- piperidyl]ethyl]piperazin-1-
yl]-7-methoxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-2, A-12
25 ##STR00570## 3-{7-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-
tetrahydronaphthalen-1- yl]phenoxy}pentyl)piperazin-1-yl]-3-oxo-
2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}piperidine-2,6-dione A-7,
A-8 26 ##STR00571## 3-[5-[4-[2-[3-[4-[(1R,2S)-6-hydroxy-2-phenyl-
tetralin-1-yl]phenoxy]cyclobutyl]-2-
oxo-ethyl]piperazin-1-yl]-7-methoxy-1-oxo-
isoindolin-2-yl]piperidine-2,6-dione A-17 27 ##STR00572##
3-[7-(difluoromethoxy)-5-[4-[2-[1-hydroxy-3-[4-
[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-
yl]phenoxy]cyclobutyl]ethyl]piperazin-1-yl]-1-
oxo-isoindolin-2-yl]piperidine-2,6-dione A-3, A-15 28 ##STR00573##
3-[5-[4-[2-[1-hydroxy-3-[4-[(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-
yl]phenoxy]cyclobutyl]ethyl]piperazin-1-
yl]-7-methoxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-2, A-15
29 ##STR00574##
3-(6'-{4-[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-
tetrahydronaphthalen-1-yl]phenyl}piperidin-4-
yl)methyl]piperazin-1-yl}-3'-oxo-2',3'-
dihydrospiro[cyclopropane-1,1'-isoindole]-2'-
yl)piperidine-2,6-dione A-6, A-12 30 ##STR00575##
3-[6'-[4-[[1-[2-fluoro-4-[(1R,2S)-6-hydroxy-2-
phenyl-tetralin-1-yl]phenyl]-4-
piperidyl]methyl]piperazin-1-yl]-3'-oxo-
spiro[cyclopropane-1,1'-isoindoline]-2'- yl]piperidine-2,6-dione
A-6, A-12 31 ##STR00576## A-1, A-2
TABLE-US-00002 TABLE 2 Exemplary Androgen Receptor PROTACs Ex.
General # Chemical Structure Name Method 32 ##STR00577##
rac-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-
6-(4-((4-(2-(2,6- dioxopiperidin-3-yl)-7- methoxy-1,3-
dioxoisoindolin-5- yl)piperazin-1- yl)methyl)piperidin-1-
yl)pyridazine-3-carboxamide Exp. procedure provided 33 ##STR00578##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-2-(4- ((4-(2-(2,6-dioxopiperidin-3-
yl)-7-methoxy-1,3- dioxoisoindolin-5- yl)piperazin-1-
yl)methyl)piperidin-1- yl)pyrimidine-5- carboxamide B-1, B-2 34
##STR00579## rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-4-(4- ((4-(2'-(2,6-dioxopiperidin- 3-yl)-3'-
oxospiro[cyclopropane-1,1- isoindolin]-6'-yl)piperazin-1-
yl)methyl)piperidin-1- yl)benzamide Synthesis described in detail
35 ##STR00580## rac-N-((1r,4r)-4-(3-chloro-4-
cyanophenoxy)cyclohexyl)- 5-(4-((((1r,3r)-3-((2'-(2,6-
dioxopiperidin-3-yl)-3'- oxospiro[cyclopropane-1,1'-
isoindolin]-5'- yl)oxy)cyclobutyl)(isopropyl)
amino)methyl)piperidin- 1-yl)pyrazine-2-carboxamide Synthesized
following the route described for Ex. Comp. 34 36 ##STR00581##
rac-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-
5-(4-((((1r,3r)-3-((2'-(2,6- dioxopiperidin-3-yl)-3'-
oxospiro[cyclopropane-1,1'- isoindolin]-6'-
yl)oxy)cyclobutyl)(isopropyl) amino)methyl)piperidin-
1-yl)pyrazine-2-carboxamide Synthesized following the route
described for Ex. Comp. 34 37 ##STR00582##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-5-(4- ((((1r,3r)-3-((2'-(2,6-
dioxopiperidin-3-yl)-3'- oxospiro[cyclopropane-1,1'-
isoindolin]-5'- yl)oxy)cyclobutyl)(isopropyl)
amino)methyl)piperidin- 1-yl)pyrazine-2-carboxamide Synthesized
following the route described for Ex. Comp. 34 38 ##STR00583##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-5-(4- ((((1r,3r)-3-((2'-(2,6-
dioxopiperidin-3-yl)-3'- oxospiro[cyclopropanc-1,1'-
isoindolin]-6'- yl)oxy)cyclobutyl)(isopropyl)
amino)methyl)piperidin- 1-yl)pyrazine-2-carboxamide Synthesized
following the route described for Ex. Comp. 34 46 ##STR00584##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-
yl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-6-
yl)oxy)pentyl)piperazin-1- yl)nicotinamide C-1 and Exp. procedure
provided as well 47 ##STR00585## rac-N-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-6-(4-
(5-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxo-1,2,3,4-
tetrahydroisoquinolin-6- yl)oxy)pentyl)piperazin-1- yl)nicotinamide
C-1 and Exp. procedure provided as well 48 ##STR00586##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-
yl)-3-oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridin-
7-yl)oxy)pentyl)piperazin-1- yl)nicotinamide Exp procedure provided
49 ##STR00587## rac-N-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-6-(4-
(5-((2-(2,6-dioxopiperidin-3- yl)-3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin- 6-yl)oxy)pentyl)piperazin-1-
yl)nicotinamide Exp procedure provided 50 ##STR00588##
rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-4-(4- ((4-(2-(2,6-dioxopiperidin-3-
yl)-3-oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridin-
7-yl)piperazin-1- yl)methyl)piperidin-1- yl)benzamide Exp procedure
provided 51 ##STR00589## N-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-
(2-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-
1H-pyrrolo[3,4-c]pyridin-6- yl)piperazin-1- yl)ethyl)piperidin-1-
yl)benzamide C-3, C-4 and Exp procedure provided 52 ##STR00590##
N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)-4-(4- (2-(4-(6-(2,6-dioxopiperidin-
3-yl)-5,7-dioxo-6,7-dihydro- 5H-pyrrolo[3,4-d]pyrimidin-
2-yl)piperazin-1- yl)ethyl)piperidin-1- yl)benzamide C-3, c-4 and
Exp procedure provided
TABLE-US-00003 TABLE 3 Exemplary BRaf PROTACs Ex. Synthetic #
Chemical Structure Name Scheme 39 ##STR00591##
(E)-2-(2,6-dioxopiperidin- 3-yl)-6-(4-(4-(4-(1- (hydroxyimino)-2,3-
dihydro-1H-inden-5-yl)- 3-(pyridin-4-yl)-1H- pyrazol-1-
yl)phenyl)piperazin-1-yl)- 4-phenylisoindoline- 1,3-dione D-1 40
##STR00592## (E)-2-(2,6-dioxopiperidin- 3-yl)-5-(4-(4-(4-(1-
(hydroxyimino)-2,3- dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-
1H-pyrazol-1- yl)phenyl)pipeiazin-1-yl)- 6-methylisoindoline-
1,3-dione D-1 41 ##STR00593## (E)-2-(2,6-dioxopiperidin-
3-yl)-5-(4-(4-(4-(1- (hydroxyimino)-2,3- dihydro-1H-inden-5-yl)-3-
(pyridin-4-yl)-1H- pyrazol-1- yl)phenyl)piperazin- 1-yl)-4-
phenylisoindoline- 1,3-dione Custom synthesis provided 42
##STR00594## (E)-2-(2,6-dioxopiperidin- 3-yl)-5-(4-(4-(4-(1-
(hydroxyimino)-2,3- dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-1H-
pyrazol-1- yl)phenyl)piperazin- 1-yl)-4- methylisoindoline-
1,3-dione Custom synthesis provided
TABLE-US-00004 TABLE 4 Exemplary BRD4 PROTACs Ex. # Chemical
Structure Name 43 ##STR00595## 2-((R)-4-(4-chlorophenyl)-2,3,9-
trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-
a][1,4]diazepin-6-yl)-N-(4-(2-(2- (2-(2-((1-oxo-2-((R)-6-
oxopiperidin-3-yl)isoindolin-4-
yl)amino)ethoxy)ethoxy)ethoxy)ethoxy) phenyl)acelamide 44
##STR00596## 2-((R)-4-(4-chlorophenyl)-2,3,9-
trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-
a][1,4]diazepin-6-yl)-N-(4-(2-(2-
(2-(2-((3-(2,6-dioxopiperidin-3-yl)- 2-methyl-4-oxo-3,4-
dihydroquinazolin-8- yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)
phenyl)acetamide 45 ##STR00597## 2-((R)-4-(4-chlorophenyl)-2,3,9-
trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-
a][1,4]diazepin-6-yl)-N-(4-(2-(2-
(2-(2-((3-(2,6-dioxopiperidin-3-yl)- 2-methyl-4-oxo-3,4-
dihydroquinazolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)
phenyl)acetamide
TABLE-US-00005 TABLE 5 Characterization of Exemplary Estrogen
Receptor PROTACs Target Ex. Observed Engagement ER ER # [M + H]/Z
IC.sub.50 (nM) DC.sub.50* D.sub.max* NMR 1 743.58 58.2 C B 2 743.58
0.79 B A .delta. 10.93 (s, 1H), 10.56-10.43 (m, 1H), 9.18-9.13 (m,
1H), 7.16-7.13 (m, 3H), 6.84-6.83 (d, J = 6.4 Hz, 2H), 6.69 (s,
1H), 6.62-6.61 (m, 2H), 6.55- 6.52 (m, 3H), 6.28-6.26 (d, J = 8.4
Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25 (m, 1H), 4.23-4.18 (m, 1H),
4.17-4.15 (m, 1H), 4.06-4.00 (m, 2H), 3.85- 3.83 (m, 5H), 3.56-3.53
(m, 1H), 3.34-3.33 (m, 4H), 3.10-3.02 (m, 4H), 3.00-2.85 (m, 2H),
2.60-2.58 (m, 3H), 2.16-2.08 (m, 1H), 1.91-1.88 (m, 1H), 1.76-1.69
(m, 5H), 1.43-1.41 (m, 2H). (DMSO-d6, 400 MHz) 3 743.57 1.35 A A
.delta.: 10.96 (s, 1H), 9.12 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H),
7.25-6.98 (m, 4H), 6.83 (d, J = 6.8 Hz, 2H), 6.72-6.43 (m, 5H),
6.26 (d, J = 8.6 Hz, 2H), 5.06 (dd, J = 5.0, 13.2 Hz, 1H),
4.56-4.11 (m, 3H), 3.94-3.70 (m, 5H), 3.30- 3.25 (m, 1H), 3.21-2.77
(m, 8H), 2.64-2.55 (m, 5H), 2.46-2.26 (m, 2H), 2.16-1.94 (m, 2H),
1.80-1.22 (m, 7H). (DMSO-d6, 400 MHz) 4 831.65 1.42 A A .delta.
10.98 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.40 (d, J = 8.8 Hz,
1H), 7.17- 7.07 (m, 4H), 6.83-6.82 (m, 2H), 6.65-6.60 (m, 2H),
6.54-6.47 (m, 3H), 6.27-6.29 (m, 2H), 5.07 (dd, J = 5.2, 13.2 Hz,
1H), 4.44-4.40 (m, 1H), 4.29-4.17 (m, 4H), 3.81 (t, J = 6.4 Hz,
2H), 3.62-3.60 (m, 3H), 3.53- 3.51 (m, 3H), 3.43-3.41 (m, 4H),
3.24-3.17 (m, 6H), 2.97-2.88 (m, 4H), 2.78-2.74 (m, 3H), 2.61-2.56
(m, 2H), 2.44-2.37 (m, 2H), 2.10- 1.97 (m, 2H), 1.71-1.53 (m, 5H),
1.41-1.38 (m, 2H). (DMSO-d6, 400 MHz) 5 842.66 >300 C 6 842.67
2.18 C 7 859.68 102 D B 8 859.68 0.34 B B .delta. 10.99 (s, 1H),
9.12 (s, 1H), 8.16 (s, 1H), 7.36 (s, 2H), 7.17-7.10 (m, 3H), 6.83
(d, J = 6.8 Hz, 2H), 6.66-6.59 (m, 2H), 6.52 (d, J = 8.8 Hz, 2H),
6.50-6.46 (m, 1H), 6.26 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 5.2,
13.2 Hz, 1H), 4.59 (d, J = 17.2 Hz, 1H), 4.41 (d, J = 17.2 Hz, 1H),
4.22-4.16 (m, 3H), 3.82 (t, J = 6.0 Hz, 2H), 3.73-3.67 (m, 2H),
3.60-3.55 (m, 2H), 3.48-3.42 (m, 2H), 3.37-3.35 (m, 2H), 3.22 (s,
3H), 3.03-2.82 (m, 6H), 2.82-2.69 (m, 10H), 2.63-2.61 (m, 1H),
2.42-2.36 (m, 1H), 2.15-2.04 (m, 1H), 2.03- 1.95 (m, 1H), 1.81-1.69
(m, 3H), 1.66-1.60 (m, 2H), 1.58-1.50 (m, 2H). (DMSO-d6, 400 MHz) 9
768.61 >300 D B 10 768.61 0.86 B A .delta. 10.90 (s, 1H), 8.28
(s, 1H), 7.19-7.07 (m, 3H), 6.83 (d, J = 6.4 Hz, 2H), 6.64 (d, J =
8.4 Hz, 1H), 6.59 (s, 2H), 6.52 (d, J = 8.8 Hz, 2H), 6.49-6.44 (m,
2H), 6.19 (d, J = 8.8 Hz, 2H), 5.02-4.91 (m, 1H), 4.96 (dd, J =
5.2, 13.2 Hz, 1H), 4.26-4.19 (m, 1H), 4.14-4.06 (m, 2H), 3.82 (s,
3H), 3.55-3.45 (m, 2H), 3.30-3.10 (m, 12H), 2.98-2.85 (m, 3H),
2.59-2.53 (m, 1H), 2.44-2.41 (m, 1H), 2.38-2.35 (m, 2H), 2.13-2.03
(m, 1H), 1.95-1.87 (m, 1H), 1.75-1.65 (m, 3H), 1.48-1.33 (m, 3H),
1.26-1.12 (m, 2H). (DMSO-d6, 400 MHz) 11 798.63 2 B B .delta. 10.95
(s, 1H), 9.09 (s, 1H), 7.38 (d, J = 8.03 Hz, 1H), 7.14 (m, 4H),
6.83 (d, J = 6.53 Hz, 2H), 6.64-6.59 (m, 2H), 6.56-6.45 (m, 3H),
6.19 (d, J = 8.66 Hz, 2H), 5.06 (dd, J = 12.99, 5.08 Hz, 1H),
4.36-4.27 (m, 1H), 4.19- 4.18 (m, 4H), 3.55-3.53 (m, 4H), 3.26 (s,
3H), 3.11 (s, 4H), 2.96 (d, J = 5.9 Hz, 2H), 2.69-2.57 (m, 1H),
2.32-2.31 (m, 1H), 2.19 (d, J = 6.65 Hz, 4H), 2.14-2.04 (m, 3H),
1.98-1.89 (m, 2H), 11.56 (m, 6H), 1.29-1.01 (m, 3H). (DMSO-d6, 400
MHz) 12 779.56 1 A A 10.91 (br s, 1H), 8.20 (s, 1H), 7.19-7.09 (m,
3H), 6.84 (br d, J = 6.9 Hz, 2H), 6.67-6.58 (m, 5H), 6.54-6.43 (m,
2H), 6.30 (d, J = 8.5 Hz, 2H), 4.97 (dd, J = 5.1, 13.2 Hz, 1H),
4.27-4.07 (m, 5H), 3.83 (s, 3H), 3.39-3.28 (m, 5H), 3.04-2.85 (m,
4H), 2.59 (br s, 3H), 2.43-2.22 (m, 4H), 2.15-1.88 (m, 4H),
1.82-1.56 (m, 4H). (DMSO-d6, 400 MHz) 13 743.58 0.37 A A .delta.
10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.18-7.07 (m, 3H), 6.82
(d, J = 6.8 Hz, 2H), 6.69-6.58 (m, 3H), 6.55-6.47 (m, 4H), 6.26 (d,
J = 8.8 Hz, 2H), 4.96 (dd, J = 5.2, 13.2 Hz, 1H), 4.29-4.06 (m,
3H), 3.85-3.78 (m, 5H), 3.30-3.28 (m, 4H), 3.04-2.80 (m, 3H),
2.60-2.52 (m, 6H), 2.45- 2.34(m, 3H), 2.17-1.99 (m, 1H), 1.97-1.82
(m, 1H), 1.76-1.58 (m, 3H), 1.56-1.45 (m, 2H), 1.43-1.29 (m, 2H).
(DMSO-d6, 400 MHz) 14 743.58 0.49 A A .delta. 10.91 (s, 1H), 9.13
(s, 1H), 8.14 (s, 1H), 7.18-7.08 (m, 3H), 6.82 (d, J = 6.8 Hz, 2H),
6.66-6.58 (m, 3H), 6.55-6.47 (m, 4H), 6.26 (d, J = 8.8 Hz, 2H),
4.96 (dd, J = 5.2, 13.2 Hz, 1H), 4.28-4.10 (m, 3H), 3.85-3.78 (m,
5H), 3.30-3.28 (m, 4H), 3.05-2.80 (m, 3H), 2.58-2.51 (m, 6H), 2.38-
2.33 (m, 2H), 2.32-2.24 (m, 1H), 2.18-2.00 (m, 1H), 1.97-1.86 (m,
1H), 1.74-1.58 (m, 3H), 1.55-1.44 (m, 2H), 1.43-1.34 (m, 2H).
(DMSO-d6, 400 MHz) 15 754.60 1.7 A A .delta. 10.91 (s, 1H), 8.23
(s, 2H), 7.17-7.09 (m, 3H), 6.83 (d, J = 6.8 Hz, 2H), 6.64 (d, J =
8.4 Hz, 1H), 6.59 (s, 2H), 6.53 (d, J = 8.8 Hz, 2H), 6.49-6.45 (m,
2H), 6.20 (d, J = 8.8 Hz, 2H), 4.96 (dd, J = 5.0, 13.2 Hz, 1H),
4.25-4.19 (m, 1H), 4.14-4.06 (m, 1H), 4.15-4.06 (m, 1H), 3.84-3.80
(m, 3H), 3.51 (d, J = 9.2 Hz, 7H), 3.28 (s, 4H), 2.98-2.83 (m, 1H),
3.03-2.82 (m, 2H), 2.58 (s, 1H), 2.32-2.26 (m, 1H), 2.22-2.04 (m,
4H), 1.94-1.87 (m, 1H), 1.80-1.55 (m, 5H), 1.21-1.11 (m, 2H).
(DMSO-d6, 400 MHz) 16 799.6 0.82 A B .delta. 10.90 (s, 1H), 9.13
(s, 1H), 8.14 (s, 1H), 7.01-6.92 (m, 2H), 6.87-6.79 (m, 2H), 6.65
(d, J = 8.4 Hz, 1H), 6.60 (s, 2H), 6.55 (d, J = 8.8 Hz, 2H), 6.51-
6.44 (m, 2H), 6.26 (d, J = 8.4 Hz, 2H), 4.96 (dd, J = 5.4, 13.4 Hz,
1H), 4.75 (t, J = 4.8 Hz, 1H), 4.27-4.06 (m, 3H), 3.85-3.80 (m,
3H), 3.29-3.25 (m, 6H), 2.99-2.84 (m, 3H), 2.54 (d, J = 4.4 Hz,
8H), 2.19-1.86 (m, 4H), 1.85- 1.58 (m, 5H), 1.24-1.07 (m, 2H).
(DMSO-d6, 400 MHz) 17 778.57 1.5 B B .delta. 10.91 (s, 1H), 9.14
(s, 1H), 7.85 (br s, 1H), 7.48-7.34 (m, 2H), 7.18- 7.10 (m, 3H),
6.83 (br d, J = 6.7 Hz, 2H), 6.69-6.60 (m, 5H), 6.54-6.47 (m, 2H),
6.30 (d, J = 8.5 Hz, 2H), 5.08-4.94 (m, 3H), 4.28-4.17 (m, 2H),
4.16-4.08 (m, 1H), 3.84 (s, 4H), 3.66 (br s, 1H), 3.04-2.83 (m,
4H), 2.82- 2.71 (m, 1H), 2.68 (br s, 1H), 2.63-2.54 (m, 2H),
2.48-2.26 (m, 2H), 2.15-2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.71 (br
d, J = 7.5 Hz, 1H). (DMSO-d6, 400 MHz) 18 790.59 17.5 B B 19 790.58
4.5 B A .delta. 10.89 (s, 1H), 8.19 (s, 1H), 7.22-7.16 (m, 3H),
6.90 (br d, J = 6.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.61 (br d,
J = 9.2 Hz, 2H), 6.54-6.50 (m, 1H), 6.47 (s, 1H), 5.87 (d, J = 11.2
Hz, 2H), 4.95 (dd, J = 5.2, 13.2 Hz, 1H), 4.25-4.20 (m, 2H),
4.13-4.07 (m, 1H), 3.82 (s, 3H), 3.27-3.25 (m, 6H), 3.03-2.83 (m,
9H), 2.19 (br d, J = 7.2 Hz, 3H), 2.07-1.89 (m, 3H), 1.76-1.58 (m,
5H), 1.16 (br d, J = 9.2 Hz, 2H). (DMSO-d6, 400 MHz) 20 779.6 1.2 B
B .delta. 10.96 (s, 1H), 8.20 (s, 1H), 7.62-7.20 (m, 1H), 7.18-7.05
(m, 3H), 6.94 (s, 1H), 6.82 (d, J = 6.4 Hz, 2H), 6.71 (s, 1H),
6.67-6.58 (m, 2H), 6.56- 6.43 (m, 3H), 6.26 (d, J = 8.8 Hz, 2H),
5.00 (dd, J = 5.2, 13.2 Hz, 1H), 4.37- 4.29 (m, 1H), 4.26-4.14 (m,
2H), 3.81 (t, J = 6.4 Hz, 2H), 3.31-3.27 (m, 5H), 3.04-2.82 (m,
3H), 2.64-2.52 (m, 2H), 2.48-2.42 (m, 3H), 2.41- 2.25 (m, 3H),
2.17-2.02 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.59 (m, 3H), 1.53-1.43
(m, 2H), 1.42-1.32 (m, 2H). (DMSO-d6, 400 MHz) 21 815.6 2.5 B B
.delta. 10.98 (s, 1H), 8.15 (s, 1H), 7.68-7.34 (m, 1H), 7.21-7.05
(m, 3H), 6.95 (s, 1H), 6.84 (d, J = 7.2 Hz, 2H), 6.73 (s, 1H),
6.68-6.58 (m, 4H), 6.50 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 8.4 Hz,
2H), 5.02 (dd, J = 4.8, 13.2 Hz, 1H), 4.42- 4.27 (m, 1H), 4.27-4.04
(m, 4H), 3.31 (s, 4H), 3.03-2.78 (m, 3H), 2.68- 2.55 (m, 1H), 2.48
(s, 6H), 2.41-2.32 (m, 3H), 2.16-1.90 (m, 4H), 1.72 (m, 1H), 1.63
(m, 2H). (DMSO-d6, 400 MHz) 22 804.6 4.4 B A .delta. 10.97 (s, 1H),
8.19 (s, 1H), 7.68-7.20 (m, 1H), 7.18-7.07 (m, 3H), 6.94 (s, 1H),
6.83 (d, J = 6.4 Hz, 2H), 6.71 (s, 1H), 6.66-6.57 (m, 2H), 6.55-
6.43 (m, 3H), 6.19 (d, J = 8.4 Hz, 2H), 5.00 (dd, J = 5.0, 13.2 Hz,
1H), 4.38- 4.28 (m, 1H), 4.26-4.17 (m, 1H), 4.12 (d, J = 4.6 Hz,
1H), 3.30 (s, 9H), 3.01-2.78 (m, 4H), 2.71-2.55 (m, 2H), 2.44-2.26
(m, 5H), 2.16-2.03 (m, 1H), 2.02-1.89 (m, 1H), 1.79-1.62 (m, 3H),
1.40 (m, 3H), 1.27- 1.06 (m, 2H). (DMSO-d6, 400 MHz) 23 791.6 1.8 B
B .delta. 10.96 (s, 1H), 9.12 (s, 1H), 8.16 (s, 1H), 7.63-7.20 (m,
1H), 7.18-7.06 (m, 3H), 6.94 (s, 1H), 6.81 (d, J = 6.4 Hz, 2H),
6.71 (s, 1H), 6.67-6.58 (m, 2H), 6.51-6.37 (m, 3H), 6.24 (d, J =
8.4 Hz, 2H), 5.00 (dd, J = 5.2, 13.2 Hz, 1H), 4.71-4.60 (m, 1H),
4.40-4.29 (m, 1H), 4.26-4.13 (m, 2H), 3.32- 3.27 (m, 9H), 3.04-2.80
(m, 3H), 2.63-2.54 (m, 2H), 2.42-2.31 (m, 1H), 2.30-2.19 (m, 3H),
2.13-2.03 (m, 4H), 2.02-1.91 (m, 1H), 1.74- 1.51 (m, 3H). (DMSO-d6,
400 MHz) 24 786.6 0.7 B A .delta. 10.89 (s, 1H), 9.17 (s, 1H), 8.32
(s, 1H), 7.21-7.10 (m, 3H), 6.86 (d, J = 6.4 Hz, 2H), 6.68-6.58 (m,
4H), 6.52-6.44 (m, 2H), 6.08 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 14.2
Hz, 1H), 4.95 (dd, J = 5.2, 13.2 Hz, 1H), 4.28-4.16 (m, 2H),
4.14-4.05 (m, 1H), 3.83 (s, 3H), 3.18 (s, 2H), 2.99-2.85 (m, 3H),
2.54-2.52 (m, 13H), 2.12-1.86 (m, 3H), 1.71 (d, J = 10.8 Hz, 3H),
1.48-1.19 (m, 6H). (DMSO-d6, 400 MHz) 25 715.6 0.5 C 26 769.6 0.7 A
A .delta. 10.90 (s, 1H), 9.16 (s, 1H), 7.19-7.09 (m, 3H), 6.82 (br
d, J = 6.6 Hz, 2H), 6.68-6.57 (m, 3H), 6.53-6.40 (m, 4H), 6.29-6.23
(m, 2H), 4.96 (dd, J = 5.1, 13.3 Hz, 1H), 4.53 (quin, J = 7.3 Hz,
1H), 4.31-4.01 (m, 3H), 3.83 (s, 3H), 3.63 (br s, 1H), 3.33-3.23
(m, 11H), 3.10 (td, J = 8.8, 17.4 Hz, 1H), 3.03-2.79 (m, 3H), 2.55
(br s, 2H), 2.46-2.25 (m, 2H), 2.16- 2.00 (m, 3H), 1.99-1.87 (m,
1H), 1.70 (br d, J = 6.0 Hz, 1H). (DMSO-d6, 400 MHz) 27 807.6 0.5 A
B .delta. 10.96 (s, 1H), 9.13 (br s, 1H), 8.20-7.39 (m, 1H),
7.22-7.08 (m, 3H), 6.97-6.93 (m, 1H), 6.81 (br d, J = 7.7 Hz, 2H),
6.73-6.69 (m, 1H), 6.67- 6.62 (m, 1H), 6.60 (d, J = 2.3 Hz, 1H),
6.50-6.38 (m, 3H), 6.27-6.21 (m, 2H), 5.00 (br dd, J = 5.1, 13.2
Hz, 1H), 4.65 (br t, J = 5.8 Hz, 1H), 4.37- 4.30 (m, 1H), 4.25-4.18
(m, 1H), 4.16 (br d, J = 4.9 Hz, 1H), 3.28-3.25 (m, 6H), 3.02-2.81
(m, 3H), 2.61-2.53 (m, 4H), 2.45-2.37 (m, 4H), 2.12-1.90 (m, 5H),
1.76-1.64 (m, 3H). (DMSO-d6, 400 MHz) 28 771.6 0.3 A A .delta.
10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.18-7.08 (m, 3H), 6.81
(br d, J = 7.7 Hz, 2H), 6.66-6.59 (m, 3H), 6.51-6.39 (m, 4H),
6.27-6.22 (m, 2H), 4.96 (br dd, J = 5.1, 12.9 Hz, 1H), 4.65 (br t,
J = 6.3 Hz, 1H), 4.26- 4.19 (m, 1H), 4.16 (br d, J = 4.6 Hz, 1H),
4.13-4.07 (m, 1H), 3.84-3.80 (m, 3H), 3.29-3.23 (m, 5H), 3.00-2.84
(m, 3H), 2.62-2.52 (m, 8H), 2.35 (br s, 2H), 2.09-1.88 (m, 4H),
1.78-1.66 (m, 3H). (DMSO-d6, 400 MHz)
29 750.6 2.4 C 30 768.6 2.1 B B .delta. 10.87 (s, 1H), 9.20 (s,
1H), 8.26 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.24- 7.07 (m, 3H),
6.99 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 6.8 Hz, 2H), 6.75-6.56 (m,
4H), 6.50 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 5.97 (d, J
= 14.4 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 3.89 (s, 1H), 3.35-3.23
(m, 8H), 3.19 (d, J = 6.8 Hz, 3H), 3.05-2.84 (m, 2H), 2.76-2.60 (m,
2H), 2.54 (s, 3H), 2.20 (d, J = 6.8 Hz, 2H), 2.06 (dd, J = 6.0,
12.0 Hz, 1H), 1.83 (s, 1H), 1.75 (d, J = 12.0 Hz, 3H), 1.62 (s,
1H), 1.54-1.44 (m, 2H), 1.44-1.29 (m, 2H), 1.21 (d, J = 10.0 Hz,
2H). (DMSO-d6, 400 MHz) 31 C *ER DC.sub.50 (nM) A < 1; 1 <= B
< 10; 10 <= C < 100; D >= 100 **ER D.sub.max(%) A >=
75; 50 <= B < 75; C < 50
TABLE-US-00006 TABLE 6 Characterization of Exemplary Androgen
Receptor PROTACs AR AR Ex. # m/z observed DC.sub.50* D.sub.max**
NMR 32 824.54 A 33 852.58 A 34 832.61 C 1H NMR (400 MHz, d6-DMSO):
.delta. 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.74
(d, J = 8.8 Hz, 2H), 7.53-7.45 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H),
6.99 (dd, J = 9.2, 17.6 Hz, 4H), 6.73 (s, 1H), 4.33 (s, 1H), 4.06
(d, J = 9.2 Hz, 1H), 3.86 (d, J = 12.4 Hz, 3H), 3.32-3.29 (m, 9H),
2.80 (t, J = 12.0 Hz, 3H), 2.59- 2.54 (m, 4H), 2.22 (d, J = 6.8 Hz,
2H), 1.81 (d, J = 10.3 Hz, 4H), 1.55-1.47 (m, 2H), 1.45-1.31 (m,
2H), 1.25-1.17 (s, 8H), 1.13 (s, 6H) 35 849.6 C 36 849.61 C 37
877.64 C 38 877.64 C 46 810.3 A A .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.12 (6H, s), 1.21 (6H, s), 1.43-1.54 (4H,
m), 1.74-1.78 (2H, m), 1.88-1.91 (1H, m), 2.30-2.44 (8H, m),
2.90-2.97 (3H, m), 3.42-3.59 (7H, m), 4.03-4.07 (3H, m), 4.30 (1H,
s), 6.86-6.91 (3H, m), 6.99- 7.02 (1H, m), 7.22 (1H, d, J = 2.4
Hz), 7.64 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.8 Hz), 7.90-7.97
(2H, m), 8.62 (1H, d, J = 2.0 Hz), 10.90 (1H, s). 47 824.3 B B
.sup.1H NMR (400 MHz, DMSO-d.sup.6) .delta. 1.12 (6H, s), 1.21 (6H,
s), 1.37-1.58 (4H, m), 1.73-1.81 (2H, m), 1.86-1.91 (1H, m),
2.30-2.37 (2H, m), 2.40-2.46 (2H, m), 2.82-2.91(1H, m), 3.30-3.35
(4H, m), 3.55-3.65 (4H, m), 4.03-4.30 (6H, m), 5.54-5.63 (1H, m),
6.87 (1H, d, J = 9.6 Hz), 6.96-7.07 (3H, m), 7.21 (1H, d, J = 2.4
Hz), 7.63 (1H, d, J = 9.6 Hz), 7.90-8.04 (3H, m), 8.62 (1H, d, J =
2.4 Hz), 10.93 (1H, s). 48 798.6 A B .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.12 (6H, s), 1.21 (6H, s), 1.43-1.47 (2H,
m), 1.49-1.53 (2H, m), 1.73-1.78 (2H, m), 2.13-2.17 (1H, m), 2.32
(2H, t, J = 7.2 Hz), 2.43-2.47 (5H, m), 2.61-2.62 (1H, m),
2.87-2.93 (1H, m), 3.59 (4H, s), 4.01-4.07 (3H, m), 4.30 (1H, s),
5.28 (1H, dd, J = 12.4, 5.2 Hz), 6.35 (1H, dd, J = 8.0, 2.4 Hz),
6.52 (1H, d, J = 1.6 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.00 (1H, dd, J
= 8.8, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.63 (1H, d, J = 9.2 Hz),
7.80 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.95 (1H, dd, J
= 9.2, 2.4 Hz), 8.62 (1H, d, J = 2.4 Hz), 11.09 (1H, s). 49 798.6 A
A .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.12 (6H, s), 1.21
(6H, s), 1.44-1.48 (2H, m), 1.52-1.58 (2H, m), 1.74-1.79 (2H, m),
2.15-2.19 (1H, m), 2.30 (2H, t, J = 7.2 Hz), 2.43-2.50 (4H, m),
2.51-2.67 (2H, m), 2.86-2.95 (1H, m), 3.60 (4H, s), 3.97 (2H, t, J
= 6.4 Hz), 4.05 (1H, d, J = 9.2 Hz), 4.30 (1H, s), 5.38 (1H, dd, J
= 5.2, 12.8 Hz), 6.86 (1H, d, J = 9.2 Hz), 7.00 (1H, dd, J = 8.4,
2.4 Hz), 7.10 (1H, dd, J = 10.0, 2.0 Hz), 7.21 (1H, d, J = 2.4 Hz),
7.25 (1H, d, J = 10.0 Hz), 7.36 (1H, s), 7.62 (1H, d, J = 9.2 Hz),
7.90 (1H, d, J = 8.8 Hz), 7.95 (1H, dd, J = 9.2, 2.4 Hz), 8.62 (1H,
d, J = 2.4 Hz), 11.10 (1H, s). 50 808.6 A A .sup.1H NMR (400 MHz,
DMSO-d.sup.6) .delta. 1.13 (6H, s), 1.22 (6H, s), 1.79-1.81 (3H,
m), 2.09-2.15 (1H, m), 2.19-2.21 (2H, m), 2.49-2.50 (7H, m),
2.60-2.67 (1H, m), 2.76-2.92 (3H, m), 3.22-3.26 (4H, m), 3.86 (2H,
d, J = 12.8 Hz), 4.05 (1H, d, J = 9.2 Hz), 4.32 (1H, s), 5.23 (1H,
dd, J = 12.4, 5.2 Hz), 6.12 (1H, s), 6.70 (1H, dd, J = 8.0, 1.6
Hz), 6.95 (2H, d, J = 9.2 Hz), 7.00 (1H, dd, J = 8.8, 2.4 Hz), 7.21
(1H, d, J = 2.4 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.72 (3H, t, J = 8.4
Hz), 7.91 (1H, d, J = 8.8 Hz), 11.04 (1H, s). 51 835.59 A A 1H NMR
(300 MHz, DMSO-d6) .delta. 11.07 (s, 1H), 8.57 (s, 1H), 7.87 (d, J
= 8.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 9.1 Hz, 1H),
7.29 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.02-6.87 (m, 3H), 5.07
(dd, J = 12.8, 5.3 Hz, 1H), 4.29 (s, 1H), 4.02 (d, J = 9.1 Hz, 1H),
3.88-3.70 (m, 5H), 3.29 (br s, 5H), 2.95-2.65 (m, 3H), 2.59-2.41
(m, 6H), 2.00 (m, 1H), 1.73 (d, J = 12.8 Hz, 2H), 1.45 (br, 3H),
1.17 (s, 6H), 1.09 (s, 6H) 52 836.59 A B .sup.1H NMR (400 MHz,
d6-DMSO): .delta. 11.12 (s, 1H), 8.90 (s, 1H), 7.91-7.89 (d, J =
8.4 Hz, 1H), 7.74-7.72 (d, J = 7.6 Hz, 2H), 7.49-7.47 (d, J = 8.8
Hz, 1H), 7.20 (s, 1H), 6.99-6.94 (m, 3H), 5.16-5.13 (m, 1H), 4.32
(s, 1H), 4.06-3.83 (m, 7H), 2.88-2.57 (m, 5H), 2.39-2.33 (m, 2H),
2.07-2.01 (m, 1H), 1.78-1.75 (m, 2H), 1.54-1.35 (m, 3H), 1.21 (m,
8H), 1.12 (s, 6H) *AR DC.sub.50 (nM) A < 1; 1 <= B < 10;
10 <= C < 100; D >= 100 **AR D.sub.max(%) A >= 75; 50
<= B < 75; C < 50
TABLE-US-00007 TABLE 7 Characterization of Exemplary BRaf PROTACs
BRaf BRaf Ex. # DC.sub.50* D.sub.max** MH+ NMR Transcript 39 C B
783.51 1H NMR (400 MHz, DMSO-d6): .delta. 11.03 (s, 1H), 10.87 (s,
1H), 8.72 (s, 1H), 8.57 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H),
7.62-7.60 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.50-7.41 (m, 6H),
7.22 (d, J = 8.0 Hz, 2H), 7.17-7.15(m, 3H), 5.07-5.03 (m, 1H), 3.73
(m, 8H), 3.01 (s, 2H), 2.83-2.81 (m, 3H), 2.67 (s, 2H), 2.03-2.00
(m, 1H) 40 C A 721.48 1H NMR (400 MHz, DMSO-d6): .delta. 11.15 (bs,
1H), 8.72 (s, 1H), 8.72 (s, 1H), 8.57 (d, J = 5.6 Hz, 2H), 7.83 (d,
J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.49-7.57 (m, 4H), 7.41 (s, 1H),
7.17-7.30 (m, 3H), 5.09-5.13 (m, 1H), 3.20-3.35 (m, 8H), 2.80-3.12
(m, 6H), 2.52-2.75 (m, 3H), 1.90- 2.12 (m, 2H) 41 C A 783.51 1H NMR
(400 MHz, DMSO-d6): .delta. 11.04 (s, 1H), 10.88 (s, 1H), 8.69 (s,
1H), 8.57 (d, J = 4.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.76 (d, J
= 8.8 Hz, 2H), 7.40-7.56 (m, 10H), 7.22 (d, J = 4.8 Hz, 1H), 7.03
(d, J = 9.2 Hz, 2H), 5.00-5.05 (m, 1H), 3.02 (m, 9H), 2.83 (t, J =
6.8 Hz, 2H), 1.99-2.01 (m, 3H) 42 C B 721.48 1H NMR (400 MHz,
DMSO-d6): .delta. 11.09 (s, 1H), 10.89 (s, 1H), 8.72 (s, 1H),
8.58-8.57 (m, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6 Hz,
1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.23-7.17 (m,
3H), 5.13-5.09 (m, 1H), 3.61-3.42 (m, 8H), 3.04-2.97 (m, 2H),
2.93-2.82 (m, 3H), 2.62-2.56 (m, 5H), 2.08-2.00 (m, 1H) *BRaf
DC.sub.50 (nM) A < 1; 1 <= B < 10; 10 <= C < 100; D
>= 100 **BRaf D.sub.max(%) A >= 75; 50 <= B < 75; C
< 50
TABLE-US-00008 TABLE 8 Characterization of Exemplary BRD4 PROTACs
Ex. BRD4 BRD4 Observed # DC.sub.50* D.sub.max** [M + H]+ NMR 43 D B
895.22 .sup.1H NMR (400 MHz, CHLOROFORM-d) d 9.03 (s, 1H), 7.45
(dd, J = 8.71, 13.21 Hz, 4H), 7.31-7.37 (m, 3H), 7.24 (d, J = 7.24
Hz, 1H), 6.84 (d, J = 9.00 Hz, 2H), 6.78 (d, J = 8.02 Hz, 1H), 6.75
(br. s., 1H), 4.66-4.73 (m, 2H), 4.20 (d, J = 2.74 Hz, 1H),
4.07-4.12 (m, 2H), 3.80-3.90 (m, 3H), 3.64-3.77 (m, 10H), 3.52-3.58
(m, 1H), 3.35-3.42 (m, 3H), 2.68 (br. s., 3H), 2.52-2.59 (m, 2H),
2.41 (s, 3H), 2.02-2.08 (m, 2H), 1.69 (s, 3H), 1.26 (s, 3H). 44 D C
937.19 1H NMR (400 MHz, METHANOL-d4) d 7.60-7.65 (m, 1H), 7.30-7.47
(m, 8H), 6.82- 6.87 (m, 2H), 5.24 (dd, J = 5.67, 10.76 Hz, 1H),
4.69 (ddd, J = 2.84, 5.62, 8.56 Hz, 1H), 4.26-4.31 (m, 2H),
4.02-4.07 (m, 2H), 3.91-3.96 (m, 2H), 3.77-3.81 (m, 2H), 3.70- 3.74
(m, 2H), 3.63-3.69 (m, 6H), 3.53-3.61 (m, 1H), 3.43-3.49 (m, 2H),
2.81 (dt, J = 4.60, 14.33 Hz, 2H), 2.70 (s, 6H), 2.43 (s, 3H),
2.13-2.20 (m, 1H), 1.68 (s, 2H), 1.26- 1.29 (m, 2H). 45 C A 937.19
.sup.1H NMR (400 MHz, METHANOL-d4) d 8.55 (s, 1H), 7.96-8.00 (m,
1H), 7.36-7.50 (m, 6H), 7.03-7.09 (m, 2H), 6.87 (dd, J = 3.03, 9.10
Hz, 2H), 5.22 (td, J = 5.40, 10.91 Hz, 1H), 4.70-4.74 (m, 1H), 4.22
(d, J = 3.33 Hz, 2H), 4.10 (d, J = 4.30 Hz, 2H), 3.85-3.91 (m, 2H),
3.79-3.84 (m, 2H), 3.64-3.71 (m, 7H), 3.55-3.64 (m, 2H), 3.42-3.50
(m, 2H), 2.71 (s, 3H), 2.66 (d, J = 3.33 Hz, 2H), 2.44 (d, J = 3.33
Hz, 3H), 1.89 (s, 3H), 1.68 (d, J = 3.33 Hz, 2H), 1.29 (br. s.,
3H). *BRD4 DC.sub.50 (nM) A < 1; 1 <= B < 10; 10 <= C
< 100; D >= 100 **BRD4 D.sub.max(%) A >= 75; 50 <= B
< 75; C < 50
5. INDUSTRIAL APPLICABILITY
[1338] A novel bifunctional molecule, which contains a BRD4 or an
androgen receptor recruiting moiety and an E3 Ligase Cereblon
recruiting moiety, through PROTAC technology is described. The
bifunctional molecules of the present disclosure actively degrades
BRD4, leading to significant and persistent downstream MYC
suppression and robust cellular proliferation suppression and
apoptosis induction. PROTAC mediated protein degradation provides a
promising strategy in targeting the "undruggable" pathological
proteins by traditional approaches.
[1339] The contents of all references, patents, pending patent
applications and published patents, cited throughout this
application are hereby expressly incorporated by reference.
[1340] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims. It is understood that the detailed examples and
embodiments described herein are given by way of example for
illustrative purposes only, and are in no way considered to be
limiting to the invention. Various modifications or changes in
light thereof will be suggested to persons skilled in the art and
are included within the spirit and purview of this application and
are considered within the scope of the appended claims. For
example, the relative quantities of the ingredients may be varied
to optimize the desired effects, additional ingredients may be
added, and/or similar ingredients may be substituted for one or
more of the ingredients described. Additional advantageous features
and functionalities associated with the systems, methods, and
processes of the present disclosure will be apparent from the
appended claims. Moreover, those skilled in the art will recognize,
or be able to ascertain using no more than routine experimentation,
many equivalents to the specific embodiments of the invention
described herein. Such equivalents are intended to be encompassed
by the following claims.
* * * * *