ASH1L degraders and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11110177-B2
Application number	US-201816186012-A
Country	US
Kind code	B2
Filing date	Nov 9, 2018
Priority date	Nov 10, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

Provided herein are small molecules comprising a first domain that binds to ASH1L and a second domain that facilitates ASH1L degradation. In particular, ASH1L-targeting proteolysis targeting chimeras (PROTACs) and methods of use thereof for the treatment of disease (e.g., acute leukemia, solid cancers and other diseases dependent on activity of ASH1L) are provided.

First claim

The invention claimed is:

1. A compound having a structure of:

wherein R 1 is selected from H, alkyl, substituted alkyl, halogen substituted alkyl, branched alkyl, a substituted brached alkyl halogen substituted branched alkyl, alkoxy, amine, substituted amine, thioalkyl, ketone, amide, a substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, a substituted carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
wherein R 2 , R 3 , R 4 , R 5 , and R 7 , when present, are independently selected from H, halogen, CH 3 , OH, SH, NH 2 , CN, CF 3 , CCl 3 , —CH 2 —CH 3 , —CH 2 —OH, —CH 2 NH 2 , CH 3 SH, CH 2 Cl, CH 2 Br, CH 2 F, CHF 2 , CH 2 CN, CH 2 CF 3 , CH 2 Cl 3 , alkyl, haloalkyl, and alcohol; and
wherein R 6 is selected from H, alkyl, substituted alkyl, halogen substituted alkyl, branched alkyl, a substituted brached alkyl halogen substituted branched alkyl hydroxy, alkoxy, amine, substituted amine, alkylamine, substituted alkylamine, thioalkyl, alkylthioalkyl, halogen, ketone, amide, a substituted amide, alkylamide, substituted alkylamide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, substituted carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
wherein X is CH or N;
wherein Z is O or S;
wherein A is a covalent bond or is selected from

wherein one of X and Y is

or

and the other is H,

wherein X and Y are independently CH or N,

wherein erein X and Y are O, NH, or CH 2 , and

wherein X and Y are independently N or CH, and wherein Z is O, NH, or CH 2 ;
wherein n, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; wherein m, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or ranges therebetween; wherein the Linker is selected from:

wherein X, Y, and Z groups, when present are independently O, NH, or CH 2 , and do not need to be the same group when present in the same linker;
wherein n, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15;
wherein m, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or ranges therebetween;
wherein k, when present is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
wherein l, when present is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein the Ligase Ligand is selected from:

or a salt thereof.

2. The compound of claim 1 , wherein the compound is selected from Compounds 1-182.

3. The compound of claim 1 , wherein X, Z, A, the Linker, the Ligase Ligand, and R 1 -R 7 , when present are selected from the X, Z, A, the Linker, the Ligase Ligand, and R 1 -R 7 groups of compounds 1-91, in any combination.

4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is formulated for oral administration.

6. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is formulated for injection.

7. A method of degrading ASH1L, comprising contacting ASH1L with an effective amount of a compound of claim 1 or a pharmaceutical composition thereof.

8. A method of inhibiting the activity of ASH1L, comprising contacting ASH1L with an effective amount of a compound of claim 1 or a pharmaceutical composition thereof.

9. The method of claim 8 , wherein ASH1L activity is inhibited by any combination of binding of the compound or pharmaceutical composition to ASH1L and/or facilitating degradation of ASH1L by the compound or pharmaceutical composition.

10. A method of treating cancer, comprising administering to a subject pharmaceutical composition of claim 4 in an amount effective to inhibit the activity of ASH1L and/or facilitate degradation of ASH1L.

11. The methods of claim 10 , wherein the cancer comprises leukemia, hematologic malignancy, solid tumor cancer, breast cancer, prostate cancer, ovarian cancer, liver cancer or thyroid cancer.

12. The method of claim 11 , wherein the cancer comprises AML, ALL, Mixed Lineage Leukemia or a leukemia with Partial Tandem Duplication of MLL.

13. The method of claim 12 , wherein the pharmaceutical composition is co-administered with an additional therapeutic.

14. The method of claim 10 , wherein the subject is a human.

15. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

wherein R 9 and R 10 , when present, are selected from H, CH 3 , F, CFH 2 , CF 2 H, CF 3 , and OH;
wherein R 8 , when present is selected from

and wherein R 11 , when present is selected from

16. The compound of claim 1 , wherein R 6 is selected from the group consisting of:

Assignees

• Univ Michigan Regents

Inventors

• Grembecka Jolanta
• Klossowski Szymon
• Deng Jing
• Cierpicki Tomasz
• Li Hao
• Miao Hongzhi
• Purohit Trupta
• Kim Eungi
• Chen Dong

Classifications

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• C12Y203/02

  Aminoacyltransferases (2.3.2) · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title