US2018228907A1PendingUtilityA1
Cereblon ligands and bifunctional compounds comprising the same
Est. expiryApr 14, 2034(~7.8 yrs left)· nominal 20-yr term from priority
Inventors:Andrew P. CrewCraig M. CrewsHanqing DongKeith R. HornbergerJing WangYimin QianKurt ZimmermannMichael BerlinLawrence B. Snyder
C07D 401/14A61K 31/497A61K 47/545A61K 31/496A61K 31/506A61K 31/501A61K 47/55C07D 401/04C07D 471/04A61K 31/437A61K 31/551A61P 35/00A61K 45/06
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A cereblon E3 ubiquitin ligase binding compound having a chemical structure selected from:
wherein:
W is selected from the group consisting of CH 2 , CHR, C═O, SO 2 , NH, N, optionally substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-alkyl;
W 3 is selected from C or N;
each X is independently selected from the group consisting of O, S, and H 2 ,
Y is selected from the group consisting of CH 2 , —C═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 2 ;
G and G′ are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R′OCOOR, R′OCONRR″, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q 1 , Q 2 , Q 3 , and Q 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 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O) 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 3 , —CN, —NR′SO 2 NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO 2 )NR′R″, —SO 2 NR′COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5 and —OCF 3 ;
R′ and R″ are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═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
(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
(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 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 1 , R 2 , R 3 , R 4 , R′, Q 1 , Q 2 , Q 3 , Q 4 , and Q 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:
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 L )q-
wherein:
(A L ) 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 L is independently selected from the group consisting of, a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 3-11 heteocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5 groups; and
R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 .
9 . The bifunctional compound according to any of claims 2 - 8 , wherein A L is selected from the group consisting of:
—N(R)—(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, —O—(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, —O—(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O—; —N(R)—(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O—; —(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O—; —(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;
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
where m of the linker can be 2, 3, 4, 5;
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 L is selected from the group consisting of:
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 L is selected from the group consisting of:
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 L is selected from the group consisting of:
13 . The bifunctional compound according to any of claims 2 - 8 , wherein A L is selected from:
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) 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:
wherein:
W L1 and W L2 are each independently absent, a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with R Q , each R Q is independently a H, halo, OH, CN, CF 3 , C 1 -C 6 alkyl (linear, branched, optionally substituted), C 1 -C 6 alkoxy (linear, branched, optionally substituted), or 2 R Q groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, C 1 -C 6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; or C 1 -C 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:
wherein:
W L1 and W L2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl and optionally one or more C atoms are replaced with O, C 1-6 alkene and optionally one or more C atoms are replaced with O, C 1-6 alkyne and optionally one or more C atoms are replaced with O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with R Q , each R Q is independently a H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -C 6 alkyl (linear, branched, optionally substituted), C 1 -C 6 alkoxy (linear, branched, optionally substituted), OC 1-3 alkyl (optionally substituted by 1 or more —F), OH, NH 2 , NR Y1 R Y2 , CN, or 2 R Q groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C═O, C═S, SO, SO 2 , C 1 -C 6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; C 1 -C 6 alkoxy (linear, branched, optionally substituted);
Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R Q , each R Q is independently H, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), or 2 R Q groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
R YL1 , R YL2 are each independently H, OH, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), or R 1 , R 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:
wherein:
X PTM is O or C═O;
each of X PTM1 and X PTM2 is independently selected from N or CH;
R PTM1 is independently selected from OH, O(CO)R P , O-lower alkyl, wherein R PTM is an alkyl or aryl group in the ester;
R PTM2 and R PTM4 are independently selected from H, OH, halogen, CN, CF 3 , SO 2 -alkyl, O-lower alkyl;
R PTM3 and R PTM5 are independently selected from H, halogen;
PTM-I has at least one R PTM2 and at least one R 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:
wherein:
each X 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 PTM1 is independently OH, halogen, alkoxy, methoxy, ethoxy, O(CO)R PTM , wherein the substitution can be a mono-, di- or tri-substitution and the R PTM is alkyl or cycloalkyl group with 1 to 6 carbons or aryl groups;
each R PTM2 is independently H, halogen, CN, CF 3 , liner or branched alkyl, alkoxy, methoxy, ethoxy, wherein the substitution can be mono- or di-substitution;
each R PTM3 is independently H, halogen, wherein the substitution can be mono- or di-substitution; and
R 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:
wherein:
W 1 is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently substituted by 1 or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 alkyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 ;
Y 1 , Y 2 are each independently NR Y1 , O, S, SO2, heteroaryl, or aryl;
Y 3 , Y 4 , Y 5 are each independently a bond, O, NR Y2 , CR Y1 R Y2 , C═O, C═S, SO, SO 2 , heteroaryl, or aryl;
Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6 R Q , each R Q , is independently H, C 1-6 alkyl (linear, branched, optionally substituted, for example, optionally substituted by 1 or more halo, C 1-6 alkoxyl), halogen, C 1-6 alkoxy, or 2 R Q groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
R 1 , R 2 , R a , R b , R Y1 , R Y2 are each independently H, C 1-6 alkyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo, C 1-6 alkoxyl), halogen, C 1-6 alkoxy, cyclic, heterocyclic or R 1 , R 2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
W 2 is a bond, C 1-6 alkyl, C 1-6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each optionally substituted by 1-10 R W2 ;
each R W2 is independently H, halo, C 1-6 alkyl (linear or branched optionally substituted; for example, optionally substituted by 1 or more F), —OR W2A , C 3-6 cycloalkyl, C 4-6 cycloheteroalkyl, C 1-6 alkyl (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic hereoaryl or aryl, OC 1-3 alkyl (optionally substituted; for example, optionally substituted by 1 or more —F), OH, NH 2 , NR Y1 R Y2 , CN;
R W2A is H, C 1-6 alkyl (linear, branched), or C 1-6 heteroalkyl (linear, branched), each optionally substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or OC 1-3 alkyl; 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:
wherein:
Y 1 , Y 2 and Y 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:
wherein:
double dotted bonds are aromaric bonds;
V PTM , W PTM , X PTM , Y PTM , Z 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 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 PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
each of R PTM5 and R PTM22 is independently selected from the group consisting of
X PTM1 , X PTM2 , X PTM3 , X PTM4 , X PTM5 , X PTM6 , X PTM7 , X PTM8 , X PTM9 , X PTM10 , X PTM11 , X PTM12 , X PTM13 , X PTM14 , X PTM15 , X PTM16 , X PTM17 , X PTM18 , X PTM19 , X PTM20 , X PTM21 , X PTM22 , X PTM23 , X PTM24 , X PTM25 , X PTM26 , X PTM27 , X PTM28 , X PTM29 , X PTM30 , X PTM31 , X PTM32 , X PTM33 , X PTM34 , X PTM35 , X PTM36 , X PTM37 , X PTM38 are independently selected from CH or N;
R 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,
—NHC(O)R PTM5 ;
R PTM6a and R PTM6b are each independently selected from hydrogen, halogen, or C 1 -C 6 alkyl (linear, branched, optionally substituted);
R PTM6 is either of the following groups: absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle.
R PTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle.
R PTM8 , R PTM9 or R PTM10 are independently selected from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2 in which Ml, wherein CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 are independently Selected from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM20 is a small group containing less than four non-hydrogen atoms;
R 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 3 , NHCH 3 , dimethylamino or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R PTM25a and R PTM25b are each independently selected from hydrogen, halogen, or C 1 -C 6 alkyl (linear, branched, optionally substituted);
R PTM23 , R PTM24 , R PTM28 , R PTM29 , R PTM30 , R PTM31 , R 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 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 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 PTM25 is selected from absent, hydrogen, halogen, C 1 -C 6 alkyl (linear, branched, optionally substituted), OCH 3 , NHCH 3 or SCH 3 ;
R PTM26 is selected from absent, hydrogen, halogen, C 1 -C 6 alkyl (linear, branched, optionally substituted), OCH3, NHCH 3 or SCH 3 ;
R PTM27 is selected from the group consisting of absent, hydrogen, halogen, C 1 -C 6 alkyl (linear, branched, optionally substituted), OCH 3 , NHCH 3 or SCH 3 ; and
at least one of R PTM8 , R PTM9 or R PTM10 , R PTM12 , R PTM13 , R PTM16 , R PTM24 , R PTM29 , and R 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 PTM9 is the covalently joined position, R PTM7 and R PTM8 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM7 and R PTM8 are attached; or when R PTM8 is the covalently joined position, R PTM9 and R PTM10 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM9 and R 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 PTM12 is the covalently joined position, R PTM13 and R PTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM13 and R PTM14 are attached, and/or R PTM15 and R PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM15 and R PTM16 are attached; or when R PTM13 is the covalently joined position, R PTM12 and R PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM12 and R PTM16 are attached, and/or R PTM15 and R PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM15 and R PTM16 are attached; or when R PTM16 is the covalently joined position, R PTM12 and R PTM13 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM12 and R PTM13 are attached, and/or R PTM13 and R PTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM13 and R PTM14 are attached; or when R PTM24 is the covalently joined position, R PTM31 and R PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM31 and R PTM32 are attached, or R PTM29 and R PTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM29 and R PTM30 are attached; or when R PTM29 is the covalently joined position, R PTM24 and R PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM24 and R PTM32 are attached, and/or R PTM31 and R PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM31 and R PTM32 are attached; or when R PTM32 is the covalently joined position, R PTM24 and R PTM29 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM24 and R PTM29 are attached, and/or R PTM29 and R PTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM29 and R 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:
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-Barrésyndrome, 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 Alström 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-Dubé 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 (Alström syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-Zweymüller 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 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 2 acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) 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.Cited by (0)
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