# US 11,028,061 B2 · Modulators of myocyte lipid accumulation and insulin resistance and methods of use thereof

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- Number: US 11,028,061 B2
- Document ID: US11028061B2
- Status: Granted
- Kind: B2
- Application number: 15/748,515
- Filed: 2016-07-27
- Published: 2018-08-09
- Granted: 2021-06-08
- Earliest claimed: 2015-07-27
- Assignees: Sanford Burnham Prebys Medical Discovery Institute
- Applicants: Sanford Burnham Prebys Medical Discovery Institute
- Inventors: Daniel Kelly; Richard Vega; Hampton Sessions; Teresa Leone; Byungyong Ahn; Satyamaheshwar Peddibhotla
- Web page: https://patentgrep.com/patent/US11028061B2

## CPC

- C07D 277/46: by carboxylic acids, or sulfur or nitrogen analogues thereof
- A61K 31/426: 1,3-Thiazoles
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 277/82: Nitrogen atoms
- C07D 295/185: from aliphatic carboxylic acids
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Formulations and methods for reducing blood glucose and/or increasing insulin signaling in a subject have been developed. The formulations include SBI-477 and compounds based on SBI-477 i.e., SBI-477 analogs (collectively, SBI-477 compounds) and/or Mondo family inhibitors, in an effective amount to inhibit intracellular lipid accumulation and/or increase cellular glucose uptake when compared to levels in a control subject not administered the composition. Also disclosed are methods of reducing intracellular lipid accumulation and/or increase glucose uptake in a subject in need thereof. The method includes administering to the subject an effective amount of SBI-477 compounds and/or Mondo family inhibitor to reducing intracellular lipid accumulation and/or increase glucose uptake in the subject. Also disclosed are method for treating one or more Myc-driven cancers, including neuroblastoma, lung squamous cell carcinoma/lung adenocarcinoma, liver hepatocellular carcinoma, colon adenocarcinoma, acute myeloid leukemia, and breast invasive carcinoma.

## Claims

### Claim 1

A compound represented by the general Formula II:
wherein A is
Z is O or —NH—;
L1 is —C(O)NR′—, —NR′C(O)—, —C(O)O—, —OC(O)—, —O—, a bond, substituted alkyl, unsubstituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, substituted alkylthio, or unsubstituted alkylthio;
L2 is —C(O)NR′—, —NR′C(O)—, —C(O)O—, —OC(O)—, —O—, absent, a bond, substituted alkyl, unsubstituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, substituted alkylthio, or unsubstituted alkylthio;
R1′, R2′, R3′, R4′ and R5′ are independently hydrogen, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C3-C30 cycloalkyl, unsubstituted C3-C30 cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, amide, substituted amide, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, substituted alkylthio, unsubstituted alkylthio, halogen (F, Cl, Br, I), hydroxyl, nitro, or cyano, or any two adjacent R1′, R2′, R3′, R4′ and R5′ fuse to form substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C3-C30 cycloalkyl, unsubstituted C3-C30 cycloalkyl, substituted heterocyclyl, or unsubstituted heterocyclyl, and
X and Y are, as valence permits, independently C, O, N, S, CR6′R7′, or NR8′,
wherein R6′, R7′, and R8′ are independently hydrogen, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C3-C30 cycloalkyl, unsubstituted C3-C30 cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, substituted alkylthio, or unsubstituted alkylthio.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound of Formula II is represented by the general Formula IV:
wherein R16′, R17′, R19′, and R20′, are independently hydrogen, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C3-C30 cycloalkyl, unsubstituted C3-C30 cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, amide, substituted amide, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, substituted alkylthio, unsubstituted alkylthio, halogen (F, Cl, Br, I), hydroxyl, nitro, or cyano,
R18′ is
and
Z is —O— or —NH—.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound of Formula IV is represented by the general Formula VIII:
wherein
L1 is —NR′C(O)—, —C(O)NR′—, or substituted amino,
R19′ are independently hydrogen, substituted alkoxy, unsubstituted alkoxy, substituted amino, or unsubstituted amino,
R18′ is
and
Z is —O— or —NH—.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound of Formula II is represented by the general Formula IX:
wherein
R1′, R2′ and R3′ are independently hydrogen, substituted heterocyclyl, unsubstituted heterocyclyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, amide, substituted amide, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, substituted alkylthio, unsubstituted alkylthio, halogen (F, Cl, Br, I), hydroxyl, nitro, cyano, R1′ and R2′, or R2′ and R3′ combine to form substituted heterocyclyl or unsubstituted heterocyclyl,
A is
and
Z is O or —NH—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is not SBI-993.

### Claim 6

A compound represented by the Formula:

### Claim 7 (depends on 1)

The compound of claim 1 in a pharmaceutical carrier, said carrier further comprising a Mondo inhibitor.