# US 11,110,177 B2 · ASH1L degraders and methods of treatment therewith

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- Number: US 11,110,177 B2
- Document ID: US11110177B2
- Status: Granted
- Kind: B2
- Application number: 16/186,012
- Filed: 2018-11-09
- Published: 2019-05-16
- Granted: 2021-09-07
- Earliest claimed: 2017-11-10
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of the University of Michigan
- Inventors: Jolanta Grembecka; Szymon Klossowski; Jing Deng; Tomasz Cierpicki; Hao Li; Hongzhi Miao; Trupta Purohit; EunGi Kim; Dong Chen
- Web page: https://patentgrep.com/patent/US11110177B2

## CPC

- A61K 47/64: 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)
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 38/45: Transferases (2)
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/556: {enzyme catalyzed therapeutic agent [ECTA]}
- A61P 35/02: specific for leukemia
- C07D 209/24: with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
- C07D 471/04: Ortho-condensed systems
- C12Y 203/02: Aminoacyltransferases (2.3.2)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Y: ENZYMES

## 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.

## Claims

### Claim 1

A compound having a structure of:
wherein R1 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 R2, R3, R4, R5, and R7, when present, are independently selected from H, halogen, CH3, OH, SH, NH2, CN, CF3, CCl3, —CH2—CH3, —CH2—OH, —CH2NH2, CH3SH, CH2Cl, CH2Br, CH2F, CHF2, CH2CN, CH2CF3, CH2Cl3, alkyl, haloalkyl, and alcohol; and
wherein R6 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 CH2, and
wherein X and Y are independently N or CH, and wherein Z is O, NH, or CH2;
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 CH2, 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound of claim 1, wherein X, Z, A, the Linker, the Ligase Ligand, and R1-R7, when present are selected from the X, Z, A, the Linker, the Ligase Ligand, and R1-R7 groups of compounds 1-91, in any combination.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 4)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 4)

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.

### Claim 11 (depends on 10)

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.

### Claim 12 (depends on 11)

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

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 10)

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

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of:
wherein R9 and R10, when present, are selected from H, CH3, F, CFH2, CF2H, CF3, and OH;
wherein R8, when present is selected from
and wherein R11, when present is selected from

### Claim 16 (depends on 1)

The compound of claim 1, wherein R6 is selected from the group consisting of:
wherein R12, when present is
wherein o=0-4;
wherein R13, when present, is selected from H, linear (—CH2)0-8CH3, branched (—CH2)0-8CH3, —NH—(CH2)0-8CH3, (—CH2)0-8(O)0-1(CH2)0-8CH3, and —NH—(—CH2)0-8(O)0-1(CH2)0-8CH3;
wherein R14, when present, is selected from
wherein X, Y, Z, and F, when present, are independently C, S, N, or O
wherein G, when present, is C or N;
wherein E, when present, is any 5-member heterocycle;
wherein l, when present, is 0-4;
wherein R15, when present, is selected from H, linear (—CH2)0-8CH3, branched (—CH2)0-8CH3; —NH—(CH2)0-8CH3, (—CH2)0-8(O)0-1(CH2)0-8CH3, and —NH—(—CH2)0-8(O)0-1(CH2)0-8CH3,
wherein R16, when present, is (—CH2)0-8CH3,
wherein R17, when present, is selected from
wherein R18, when present, is selected from H, linear (—CH2)0-8CH3, branched (—CH2)0-8CH3, and (—CH2)0-8(O)0-1(CH2)0-8CH3;
wherein i, when present, is 0-4;
wherein R19, when present, is selected from H, —CH3,
wherein R20, when present, is selected from H, linear (—CH2)0-8CH3, branched (—CH2)0-8CH3, —NH—(CH2)0-8CH3, —NH—(—CH2)0-8(O)0-1(CH2)0-8CH3, and (—CH2)0-8(O)0-1(CH2)0-8CH3; and
wherein R21, when present, is selected from H, linear (—CH2)0-8CH3, branched (—CH2)0-8CH3, and (—CH2)0-8(O)0-1(CH2)0-8CH3,
wherein l, when present, is 0-4;
wherein E, when present, is any 5-member heterocycle.