US2023241227A1PendingUtilityA1
Bi-functional compounds and methods for targeted ubiquitination of androgen receptor
Est. expiryJan 30, 2039(~12.5 yrs left)· nominal 20-yr term from priority
A61K 47/55A61P 35/00C07D 417/14C07D 417/12C07D 403/12C07D 401/04
65
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Claims
Abstract
The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a chemical structure ARB-L-E3LB, wherein ARB is an AR binding moiety that does not bind to a ligand binding domain, E3LB is an E3 ligase binding moiety, and L or Link is a linker coupling the AR binding moiety to the E3 ligase binding moiety.
2 . The compound of claim 1 , wherein the AR binding moiety binds to one more of AR splice variants V1 to V15, for example, to AR splice variant V7 (AR-V7).
3 . The compound of claim 1 , wherein the AR binding moiety is selected from:
wherein:
A is 3-7 membered alicyclic with 0-4 heteroatoms (e.g., morpholinyl) or aryl, heteroaryl independently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, NR 2 R 3 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CH 2 F, CHF 2 , CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, or C 2-6 alkynyl;
B is aryl (e.g., phenyl), heteroaryl (e.g., imidazolyl) independently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, NR 2 R 3 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, or C 2-6 alkynyl, wherein the linker L is attached to B; and
R 1 is each independently H, OH, CONH 2 , CONR 2 R 3 , SONH 2 , SONR 2 R 3 , SO 2 NH 2 , SO 2 NR 2 R 3 , NHCO—C 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 COC 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 SO 2 C 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 SOC 1-3 alkyl (optionally substituted by 1 or more halo), CN, C═CH, NH 2 , NR 2 R 3 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CHF 2 , CH 2 F, CF 3 , halo, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl) or, if applicable, taken together with an R 1 on an adjacent bonded atom, together with the atoms they are attached to, form a 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2 heteroatoms, and R 2 , R 3 is independently H, halo, C 1-6 alkyl (optionally substituted by 1 or more F) or taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms.
4 . The compound of claim 3 , wherein A is:
wherein X is CH or N.
5 . The compound of claim 3 , wherein B is:
6 . The compound of claim 1 , wherein the E3 ligase binding moiety comprises a structure selected from the group consisting of:
wherein “ ” in the above structures, represents a bond that may be stereospecific ((R) or (S)), or non-stereospecific, and wherein:
R 1 is each independently H, OH, CONH 2 , CONR 2 R 3 , SONH 2 , SONR 2 R 3 , SO 2 NH 2 , SO 2 NR 2 R 3 , NHCO—C 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 COC 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 SO 2 C 1-3 alkyl (optionally substituted by 1 or more halo), NR 2 SOC 1-3 alkyl (optionally substituted by 1 or more halo), CN, C═CH, NH 2 , NR 2 R 3 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CHF 2 , CH 2 F, CF 3 , halo, C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl) or, if applicable, taken together with an R 1 on an adjacent bonded atom, together with the atoms they are attached to, form a 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2 heteroatoms, and R 2 , R 3 are each independently H, halo, C 1-6 alkyl (optionally substituted by 1 or more F) or taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; and
R 4 is selected from H, alkyl (linear, branched, optionally substituted with R 5 ), OH, R 5 OCOOR 6 , R 5 OCONR 5 R 7 , CH 2 -heterocyclyl optionally substituted with R 5 , or benzyl optionally substituted with R 5 ;
R 5 and R 7 are each independently a bond, H, alkyl (linear, branched), cycloalkyl, aryl, hetaryl heterocyclyl, or —C(═O)R 6 each of which is optionally substitute; and
R 6 is selected from CONR 5 R 7 , OR 5 , NR 5 R 7 , SR 5 , SO 2 R 5 , SO 2 NR 5 R 7 , CR 5 R 7 , CR 5 NR 5 R 7 , aryl, hetaryl, alkyl (linear, branched, optionally substituted), cycloalkyl, heterocyclyl, P(O)(OR 5 )R 7 , P(O)R 5 R 7 , OP(O)(OR 5 )R 7 , OP(O)R 5 R 7 , Cl, F, Br, I, CF 3 , CHF 2 , CH 2 F, CN, NR 5 SO 2 NR 5 R 7 , NR 5 CONR 5 R 7 , CONR 5 COR 7 , NR 5 C(═N—CN)NR 5 R 7 , C(═N—CN)NR 5 R 7 , NR 5 C(—N═CN)R 7 , NR 5 C(═C—NO 2 )NR 5 R 7 , SO 2 NR 5 COR 7 , NO 2 , CO 2 R 5 , C(C═N—OR 5 )R 7 , CR 5 , CR 5 R 7 , CCR 5 , S(C═O)(C═N—R 5 )R 7 , SF 5 , R 5 NR 5 R 7 , (R 5 O) n R 7 , or OCF 3 , where n is an integer from 1 to 10.
7 . The compound of claim 1 , wherein the E3 ligase binding moiety comprises a structure selected from:
wherein in each moiety:
R 8 is H, a straight chain or branched C 1-8 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C 3-6 cycloalkyl (e.g., cyclopropyl), halo, CFH 2 , CF 2 H, or CF 3 ;
R 9 is a H, halo, 4-methylthiazol-5-ylm, or oxazol-5-yl;
R 10 are independently optionally substituted alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), optionally substituted cycloalkyl (e.g., cyclopropyl), optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, (CH 2 ) v COR 14 , CH 2 CHR 15 COR 16 or CH 2 R 17 , where v=1 to 3;
R 14 and R 16 are independently selected from OH, NR 18 R 19 , or —OR 20 (as defined hereinbelow);
R 15 is —NR 18 R 19 ;
R 17 is optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen;
R 18 is hydrogen or optionally substituted alkyl;
R 19 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, —CH 2 (OCH 2 CH 2 O) n CH 3 , or a polyamine chain, where w=1 to 8;
each R 11 is independently optionally substituted alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), optionally substituted cycloalkyl (e.g., cyclopropyl), optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl wherein the substituents are alkyl, halogen, or OH.
8 . The compound of claim 1 , wherein the E3 ligase binding moiety comprises a structure selected from the group consisting of:
wherein:
R 10 and R 11 are each as defined in Compound 1.9;
R 12 and R 13 are independently hydrogen, optionally substituted alkyl (e.g., methyl), or optionally substituted cycloalkyl;
X is CH 2 , NR 2 , or O;
Y is S or O;
D is a bond (direct bond between X and L) or a ring which may be aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, NR 2 R 3 , OCH 3 , OC 1-3 alkyl (optionally substituted by 1 or more halo), CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxyl), C 1-6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF 3 , C 1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6 alkoxy), C 1-6 alkoxy (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, or C 2-6 alkynyl;
R 2 , R 3 are each independently H, halo, C 1-6 alkyl (optionally substituted by 1 or more F) or taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; and
R 20 is selected from the group consisting of:
wherein A is a C 4-8 aliphatic ring, and B is an aryl (e.g., phenyl) or N-containing heteroaryl (e.g., pyridyl) and each is optionally substituted by alkyl or haloalkyl.
9 . The compound of claim 1 , wherein the E3 ligase binding moiety is:
wherein:
R 22 is aryl (e.g. phenyl) or heteroaryl (e.g., pyridyl) optionally substituted by halogen (e.g., F or Cl), e.g., mono-, di or tri-substituted independently by halogen;
R 21 is aryl (e.g. phenyl) or heteroaryl (e.g., pyridyl), optionally substituted by halogen (e.g., F or Cl), e.g., mono-, di- or tri-substituted by halogen, CN, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, other C 1-6 alkyl, other C 1-6 alkenyl and C 1-6 alkynyl;
R 23 is selected from alkyl (e.g., methyl, ethyl, isopropyl, propyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, isoamyl, neopentyl, n-hexyl), substituted alkyl, alkenyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted cycloalkenyl;
R 24 is H, alkyl (e.g., methyl), aryl, substituted alkyl, cycloalkyl, aryl substituted cycloalkyl and alkoxy substituted cycloalkyl; and
E is para-substituted (1,4-disubstituted) aryl (e.g., phenyl), single or multiple N containing heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), each optionally further substituted by —OCH 3 , —OCH 2 CH 3 and halogen.
10 . The compound of claim 1 , wherein the AR binding moiety is:
11 . The compound of claim 1 , wherein the E3 ligase binding moiety is selected from:
wherein the substituents are as defined herein.
12 . The compound of claim 1 , wherein the E3 ligase binding moiety is selected from the group consisting of:
13 . The compound of claim 1 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-12;
Wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 2-4;
wherein m is from 0-12;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein m is from 0-10;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 0-10.
14 . The compound of claim 1 , wherein the AR binding moiety is selected from:
and
wherein the E3 ligase binding moiety is selected from the group consisting of
and
wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 2-4;
wherein m is from 0-12;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein m is from 0-10;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 0-10.
15 . The compound of claim 1 , wherein the compound is effective in causing or promoting the degradation of the androgen receptor (AR) in a cell, or of causing or promoting apoptosis in a cell, e.g., a cancer cell.
16 . A compound selected from the group consisting of:
17 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, additive and/or excipient.
18 . A method of treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease or condition, said method comprising administering an effective amount of a compound according to claim 1 , to a patient in need thereof.
19 . A method of degrading an androgen receptor in a cell, e.g., a mutated AR such as any AR-V1 to AR-V15 splice variant, e.g., the AR-V7 splice variant, said method comprising administering an effective amount of a compound according to claim 1 , to such cell, e.g., a cancer cell.
20 . A method of inducing apoptosis in a cell, e.g., a cancer cell, said method comprising administering an effective amount of a compound according to claim 1 , to such cell.Join the waitlist — get patent alerts
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