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US 2026/0035360 A1Published application
Inhibitors of myc and uses thereof
AssigneeNorthwestern University
InventorsGary E. Schiltz, Sarki Abba Abdulkadir
Life of this patent
Estimating the term…
Abstract
Disclosed are substituted heterocyclic compounds and proteolysis-targeting chimeric molecules (PROTACs). The substituted heterocycles disclosed herein are shown to be useful in inhibiting c-MYC. The disclosed PROTACs are shown to induce degradation of c-MYC protein. The substituted heterocyclic compounds and proteolysis-targeting chimeric molecules (PROTACs) disclosed, herein may be utilized as therapeutics for treating cancer and cell proliferative disorders.
Claims20
A compound having a formula I:
- wherein
- W is CR8 or N;
- Y is CH or N;
- Q is CR2 or N;
- Z is C(Alk2)q(X)p(Alk1)nR1 or N;
- R1 is hydrogen, halo, alkyl, aryl, benzyl, heteroaryl, cycloalkyl, alkoxy, or cycloheteroalkyl, wherein R1 is optionally substituted at one or more positions with one or more of alkyl, alkoxy, cycloalkyl, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, carboxyl, —(CH2)—NH—R9, —(((CH2)2)m—R15, or —OR11;
- Alk1 is straight-chain or branched alkylenyl, or a cycloalkylenyl;
- n is 0, 1, or 2;
- p is 0 or 1;
- Alk2 is straight-chain or branched alkylenyl;
- q is 0 or 1;
- r is 0 or 1;
- m is an integer selected from 1 to 20;
- X is O or NR13;
- R2 is hydrogen or halo;
- R3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, —O—C(O)-alkyl, or halo;
- R4 is hydrogen, halo, amino, alkyl, or haloalkyl;
- or R4 is aryl or benzyl optionally substituted at one or more ring positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, carboxyl, aryloxy, and alkylaryloxy;
- or R4 is alkyl optionally substituted with halo-substituted aryloxy;
- or R4 together with R1 form a cycloheteroalkyl fused to ring A, wherein the cycloheteroalkyl fused to ring A is optionally substituted with aryl or alkylaryl optionally substituted with halogen;
- R5 is hydrogen, halo, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R5 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, carboxy, aryloxy, and heteroaryloxy;
- R6 is hydrogen, halo, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R6 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, carboxy, aryloxy, and heteroaryloxy;
- R7 is alkyl;
- R8 is hydrogen, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, benzyl, hydroxyl, halo, amido, and carboxyl;
- R9 is alkyl optionally substituted with one or more of —P(O)(OR1)2;
- R10 is hydrogen or alkyl;
- R11 is alkyl optionally substituted with one or more of —P(O)(OR12)2;
- R12 is hydrogen or alkyl;
- R13 is hydrogen, alkyl, or —C(O)R14;
- R14 is aryl optionally substituted at one or more ring positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, and carboxyl;
- R15 is OR16, —OS(O)2—R16, or NR17R18;
- R16 is alkyl or aryl, wherein R16 is optionally substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, and carboxyl;
- and
- R17 and R18 are independently hydrogen or alkyl,
- with the proviso that the compound is not 4′-chloro-6-((4-chlorobenzyl)oxy)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol.
32 more elements
A compound having a formula II:
- wherein
- R1 is hydrogen, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, benzyl, hydroxyl, halo, amido, and carboxyl;
- R2 is alkyl;
- R3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, —O—C(O)-alkyl, or halo;
- R4 is hydrogen, halo, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R4 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, carboxy, aryloxy, and heteroaryloxy;
- X is O or NR5;
- R5 is hydrogen, alkyl, or —C(O)R6;
- R6 is aryl optionally substituted at one or more ring positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, and carboxyl;
- Y is alkylenyl, arylenyl, benzylenyl, heteroarylenyl, cycloalkylenyl, or cycloheteroalkylenyl;
- L is a bond, or a linker selected from the group consisting of —(O(CH2)2)a—, —(O(CH2)2)a—NH—C(O)-Alk3-, —(O(CH2)2)a—C(O)—NH—(CH2)2—O)b-Alk3-, —(O(CH2)2)a—C(O)—NH-Alk3-C(O)—, —(((CH2)2)a—C(O)—NH—((CH2)2—O)b—, —(O(CH2)2)a—C(O)—NH—((CH2)2—O)b-Alk3-C(O)—, —(((CH2)2)a—C(O)—NH-Alk3-NH—C(O)—CH2—, and —(O(CH2)2)a—C(O)—NH-Alk3-;
- a is an integer selected from 1-20;
- b is an integer selected from 1-20;
- Alk3 is straight-chain or branched alkylenyl;
- ME3 is selected from the group consisting of
- R11 is hydrogen or alkyl.
12 more elements
Dependencies are inferred from the claim text.