P62-ZZ small molecule modulators
View Patent ↗A compound, or a pharmaceutically acceptable salt thereof, having a formula I of: wherein Ar is an arylene or heteroarylene; R 1 has a structure of: wherein W is an alkanediyl, alkenediyl, a carbonyl, or a combination thereof; X is —NR 5 —, wherein R 5 is H or an alkyl, or —O—; and Y is optionally-substituted cycloalkyl, optionally-substituted cycloalkyl-substituted alkyl, optionally-substituted heterocycloalkyl, or optionally-substituted heterocycloalkyl-substituted alkyl; each R 2 is the same or different and has a structure of: wherein Z is —NR 6 —, wherein R 6 is H or an alkyl, —O—, —S—, or —CH 2 —; Z 1 is (—CH 2 -) m wherein m is 0 to 5, or an alkenediyl having 2 to 6 carbon atoms; Cy is a 3-8-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and each R 4 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and each R 3 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a nitro, wherein a is 2 to 5, and b is 0 to 3.
1. A method for treating multiple myeloma in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a formula I of:
wherein Ar is benzenetriyl;
R 1 has a structure of:
—CH 2 —X—(CH 2 ) m —R 11 , wherein X is NH or O, m is 0 to 6, and R 11 is optionally-substituted cycloalkyl;
each R 2 is the same or different and has a structure of:
wherein Z is —O;
Z 1 is (—CH 2 -) m wherein m is 0 to 5;
Cy is phenyl; and
each R 4 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and
each R 3 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a nitro,
wherein a is 2 to 5, and b is 0 to 3.
2. The method of claim 1 , wherein a is 2; and b is 0.
3. The method of claim 1 , wherein a first R 2 group is in a meta position on the Ar ring relative to the R 1 group, and a second R 2 group is in a para position on the Ar ring relative to the R 1 group.
4. The method of claim 1 , wherein R 4 is —F, —Cl, —OCH 3 , —OH, —CH 3 or —NH 2 .
5. The method of claim 1 , wherein c is 1 and R 4 is 4-fluoro, or 4-methyl.
6. The method of claim 1 , wherein c is 2 and R 4 is 2, 4-difluoro.
7. The method of claim 1 , wherein R 11 is
8. The method of claim 1 , wherein each R 2 group has the same structure.
9. The method of claim 1 , wherein the compound has a structure of:
wherein each of R 7 , R 8 , and R 9 are the same or different and are selected from —F, —Cl, —OCH 3 , —OH, —CH 3 , or —NH 2 ; d is 0 to 3; e is 0 to 5; and f is 0 to 5; m is 0 or 1; and R 11 is optionally-substituted cycloalkyl.
10. The method of claim 1 , wherein the compound has a structure of:
wherein each of R 7 , R 8 , and R 9 are the same or different and are selected from —F, —Cl, —OCH 3 , —OH, —CH 3 , or —NH 2 ; d is 0 to 3; e is 0 to 5; and f is 0 to 5; m is 0 or 1; and R 11 is optionally-substituted cycloalkyl.
11. The method of claim 9 , wherein R 1 is
12. The method of claim 10 , wherein R 11 is
13. The method of claim 1 , wherein the multiple myeloma is drug-resistant multiple myeloma.
14. The method of claim 1 , further comprising co-administering the compound with at least one anti-cancer agent, wherein the anti-cancer agent is, arsenic sulfide, adriamycin, cisplatin, carboplatin, cimetidine, caminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine, lomustine, lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, raltitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, enediynes, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethasone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxygenated paclitaxel, TL-139, 5′-nor-anhydrovinblastine, camptothecin, irinotecan, topotecan, BAY 38-3441, exatecan, lurtotecan, gimatecan, homocamptothecins diflomotecan and SN-38, ST 1481, karanitecin, indolocarbazoles, protoberberines, intoplicines, idenoisoquinolones, benzo-phenazines or NB-506.
15. The method of claim 1 , wherein the compound is selected from: