ASH1L inhibitors and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-10632209-B2
Application number	US-201816186018-A
Country	US
Kind code	B2
Filing date	Nov 9, 2018
Priority date	Nov 10, 2017
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Provided herein are small molecules that bind to ASH1L and inhibit ASH1L activity, and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

First claim

The invention claimed is:

1. A compound comprising the structure of:

wherein X is CH or N:
wherein R 1 is selected from H, alkyl, substituted alkyl, branched alkyl, a substituted branched alkyl, alkoxy, amine, substituted amine, thioalkyl, ketone, amide, a substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, s substituted carobocyclic 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, Cl, F, Br, I, 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, branched alkyl, a 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, s substituted carobocyclic 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;
or a salt thereof.

2. The compound of claim 1 , wherein said compound is selected from:

or any of the preceding compound having benzothioamide-benzene or benzoamide-benzene ring connectivity in place of benzothioamide-pyrole or benzoamide-pyrole ring connectivity.

3. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and X, are selected from the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and X, groups of

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 inhibiting ASH1L, comprising contacting ASH1L with an effective amount of a compound of claim 1 .

8. The method of claim 7 , wherein ASH1L activity is inhibited by binding of the compound or pharmaceutical composition to ASH1L.

9. A method of treating a disease, comprising administering to a subject the pharmaceutical composition of claim 4 in an amount effective to inhibit the activity of ASH1L, wherein the disease is selected from leukemia, hematologic malignancy, and solid tumor cancer.

10. The method of claim 9 , wherein the disease is a solid tumor cancer selected from breast cancer, prostate cancer, ovarian cancer, liver cancer and thyroid cancer.

11. The method of claim 9 , wherein the disease is a leukemia selected from acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), Mixed Lineage Leukemia or a leukemia with Partial Tandem Duplication of MLL.

12. A method of treating a disorder mediated by chromosomal rearrangement on chromosome 11q23 in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 4 , wherein the disorder is selected from leukemia, hematologic malignancy, and solid tumor cancer.

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

14. The method of claim 12 , 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:

wherein R 12 , when present is

wherein o=0-4;
wherein R 13 , when present, is selected from H, linear (—CH 2 ) 0-8 CH 3 , branched (—CH 2 ) 0-8 CH 3 , —NH—(CH 2 ) 0-8 CH 3 , (—CH 2 ) 0-8 (O) 0-1 (CH 2 ) 0-8 CH 3 , and —NH—(—CH 2 ) 0-8 (O) 0-1 (CH 2 ) 0-8 CH 3 ;
wherein R 14 , whe

Assignees

• Univ Michigan Regents

Inventors

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

Classifications

• A61K38/45

  Transferases (2) · CPC title

• C12Y203/02

  Aminoacyltransferases (2.3.2) · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/454 Primary

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