# US 12,180,159 B2 · Activators of the unfolded protein response

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- Number: US 12,180,159 B2
- Document ID: US12180159B2
- Status: Granted
- Kind: B2
- Application number: 17/254,771
- Filed: 2019-07-01
- Published: 2021-09-09
- Granted: 2024-12-31
- Earliest claimed: 2018-07-03
- Assignees: The Board of Trustees of the University of Illinois
- Applicants: The Board of Trustees of the University of Illinois
- Inventors: David J. Shapiro; Paul J. Hergenrother; Matthew W. Boudreau
- Web page: https://patentgrep.com/patent/US12180159B2

## CPC

- C07D 209/34: in position 2
- A61P 35/00: Antineoplastic agents
- 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

A set of small molecules ERα biomodulators that kill therapy-resistant ERα positive breast, ovarian, and endometrial cancer cells. These small molecules have increased therapeutic potential because of an increased ability to kill therapy-resistant breast cancer cells compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen and fulvestrant/ICI). The new compounds do not only inhibit proliferation of the cancer cells but actually kills them, which prevents reactivation of tumors years later.

## Claims

### Claim 1

A compound of Formula I:
or a salt or solvate thereof;
wherein
R1 is —ORA, —SRA, —N(RA)2, alkyl, cycloalkyl, or aryl;
R2, R3 and R4 are each independently H, halo, —ORA, —SRA, —N(RA)2, alkyl, cycloalkyl, or aryl;
A1, A2, A3 and A4 are each independently H, halo, or alkyl;
G1 is —ORB wherein RB is CF3, CHF2, CH2CF3, CF2CH3, or CF2CF3;
G2 is halo, —ORC, —SRC, —S(═O)2RC, or alkyl;
X and Z are each independently O, S, or —NRD; and
RA, R′ and RD are each independently H or alkyl;
wherein each alkyl, cycloalkyl, or aryl is optionally substituted with one or more halo substituents.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the compound is the (S)-enantiomer.

### Claim 3 (depends on 1)

The compound of claim 1 wherein the compound is the (R)-enantiomer.

### Claim 4 (depends on 1)

The compound of claim 1 wherein RA, RC and RD are each independently H or —(C1-C6)alkyl, and R2, R3 and R4 are each independently H, halo, or —(C1-C6)alkyl.

### Claim 5 (depends on 1)

The compound of claim 1 wherein A1, A2, A3 and A4 are each independently H or halo.

### Claim 6 (depends on 1)

The compound of claim 1 wherein X is —NRD and Z is O.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R1 is CH3, CH2CH3, CF3, CHF2, CH2CF3, CF2CH3, or CF2CF3.

### Claim 8 (depends on 1)

The compound of claim 1 wherein the compound is a compound of Formula II or Formula III:

### Claim 9 (depends on 1)

The compound of claim 1 wherein the compound is a compound of Formula IV:
wherein R1 is alkyl or cycloalkyl, wherein the alkyl is substituted with one or more halo groups.

### Claim 10 (depends on 1)

The compound of claim 1 wherein one or more hydrogen atoms is deuterium or tritium, one or more carbon atoms is a carbon isotope, or a combination thereof.

### Claim 11 (depends on 1)

The compound of claim 1 wherein the compound is any one of compounds (S)- or (R)-2, 4, 6, 8 or 105:

### Claim 12 (depends on 11)

The compound of claim 11 wherein the compound is levorotatory.

### Claim 13 (depends on 11)

The compound of claim 11 wherein the compound is dextrorotatory.

### Claim 14 (depends on 11)

The compound of claim 11 wherein the compound is (R)-105 or (S)-105.

### Claim 15 (depends on 14)

The compound of claim 14 wherein the compound is (R)-105.

### Claim 16 (depends on 11)

The compound of claim 11 wherein the compound has a binding affinity for the alpha estrogen receptor (ERα), and the IC50 of the binding affinity is less than about 500 nM.

### Claim 17 (depends on 1)

A composition comprising the compound of claim 1 and an anticancer drug.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable diluent, carrier, excipient, or buffer.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18 wherein the compound is a racemic mixture of (R)-105 and (S)-105:

### Claim 20 (depends on 1)

A method of treating a cancer comprising administering to an ERα positive cancer subject in need thereof a therapeutically effective amount of the compound of claim 1, thereby treating the cancer in the subject, wherein the ERα positive cancer is a breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, or endometrial cancer.

### Claim 21 (depends on 20)

The method of claim 20 wherein the compound kills or inhibits growth of ERα positive cancer by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum.

### Claim 22 (depends on 20)

The method of claim 20 wherein the compound is a racemic mixture of (R)-105 and (S)-105:

### Claim 23 (depends on 20)

The method of claim 20 wherein the ERα positive cancer is a breast cancer or ovarian cancer.

### Claim 24 (depends on 20)

The method of claim 20 wherein the compound is administered orally or by injection.