# US 10,870,640 B2 · Prodigiosin analogs and methods of use

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- Number: US 10,870,640 B2
- Document ID: US10870640B2
- Status: Granted
- Kind: B2
- Application number: 16/396,669
- Filed: 2019-04-27
- Published: 2019-12-12
- Granted: 2020-12-22
- Earliest claimed: 2016-04-08
- Assignees: Institute For Cancer Research
- Applicants: Institute for Cancer Research
- Inventors: Wafik S. El-Deiry; Xiaobing Tian
- Web page: https://patentgrep.com/patent/US10870640B2

## CPC

- C07D 403/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Prodigiosin analogs which reactivate the p53 pathway are provided, as well as compositions of these compounds, and methods for reactivation of the p53 pathway using these compounds are provided. The prodigiosin analogs may be used to treat cancer in which p53 mutation plays a role, including prostate cancer, breast cancer, kidney cancer, ovarian cancer, lymphoma, leukemia, and glioblastoma, among others.

## Claims

### Claim 1

A method of preparing a compound of Formula XIV:
wherein:
R1 and R2 are, independently, selected from the group consisting of H, OH, halogen, —C1-6alkyl, —C1-6fluoroalkyl, —CN, —NO2, —OR7, —SR7, —S(═O)R7, —S(═O)2R7, —NHS(═O)2R7, —C(═O)R7, —OC(═O)R7, —CO2R7, —OCO2R7, —CH(R7)2, —N(R7)2, —C(═O)N(R7)2, —NHC(═O)NHR7,—NHC(═O)R7, —NHC(═O)OR7, —C(OH)(R7)2, and —C(NH2)(R7)2;
each R7 is, independently, H, halogen, or C1-C6alkyl, wherein the alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halogen, OH, CN, and NO2;
R3 is an optionally substituted aryl or an optionally substituted heteroaryl;
R4, R5, and R6 are, independently, —OH, —C1-10alkyl, —OC1-10alkyl, or —SC1-10alkyl, wherein each alkyl group is, independently, optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halogen, OH, CN, and NO2; and
n is an integer from 0 to 5;
wherein the method comprises:
admixing a solvent, an acid, a compound of Formula XII
and a compound of Formula XIII
at a temperature sufficient to result in the formation of the compound of Formula XIV;
the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, acetic acid, phosphoric acid, toluenesulfonic acid, sulfuric acid, and nitric acid; and
the temperature is about from about 0° C. to about 100° C.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 and R2 are, independently, selected from the group consisting of H, halogen, —C1-6alkyl, —C1-6fluoroalkyl, —OR7, —SR7, —S(═O)R7, —C(═O)R7, —OC(═O)R7, —CO2R7, —OCO2R7, —CH(R7)2, —C(═O)N(R7)2, —C(OH)(R7)2, and —C(NH2)(R7)2.

### Claim 3 (depends on 1)

The method of claim 1, wherein each R7 is, independently, H, halogen, or C1-C6alkyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein R1 is —OCH3 and R2 is H.

### Claim 5 (depends on 1)

The method of claim 1, wherein R3 is an optionally substituted heteroaryl.

### Claim 6 (depends on 5)

The method of claim 5, wherein the optionally substituted heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, pyrazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, isothiazolyl, purinyl, carbazolyl, isoxazolyl, indolinyl, pyranyl, pyrazolyl, triazolyl, oxadiazolyl, thianthrenyl, indolizinyl, isoindolyl, pyrrolyl, and xanthenyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein R4, R5, and R6 are, independently, OH, —C1-6alkyl or —OC1-10alkyl, wherein each alkyl group is, independently, optionally substituted by 1, 2, or 3 substituents independently selected from halogen, OH, CN, and NO2.

### Claim 8 (depends on 1)

The method of claim 1, wherein n is an integer from 1 to 3.

### Claim 9 (depends on 1)

The method of claim 1, wherein:
R1 and R2 are, independently, selected from the group consisting of H, halogen, —C1-6alkyl, —C1-6fluoroalkyl, —OR7, —SR7, —S(═O)R7, —C(═O)R7, —OC(═O)R7, —CO2R7, —OCO2R7, —CH(R7)2, —C(═O)N(R7)2, —C(OH)(R7)2, and —C(NH2)(R7)2;
each R7 is, independently, H, halogen, or C1-C6alkyl;
R3 is an optionally substituted heteroaryl;
R4, R5, and R6 are, independently, OH, —C1-6alkyl or —OC1-10alkyl, wherein each alkyl group is, independently, optionally substituted by 1, 2, or 3 substituents independently selected from halogen, OH, CN, and NO2; and
n is an integer from 1 to 3.

### Claim 10 (depends on 1)

The method of claim 1, wherein:
R1 and R2 are, independently, selected from the group consisting of H, halogen, —C1-6alkyl, —OR7, —SR7, —S(═O)R7, —C(═O)R7, —OC(═O)R7, —CO2R7, —OCO2R7, —CH(R7)2, and —C(OH)(R7)2;
each R7 is, independently, H, halogen, or C1-C3alkyl;
R3 is an optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, pyrazolyl, isoxazolyl, indazolyl, isothiazolyl, purinyl, carbazolyl, isoxazolyl, indolinyl, pyranyl, pyrazolyl, oxadiazolyl, and pyrrolyl;
R4, R5, and R6 are, independently, OH, —C1-6alkyl or —OC1-8alkyl, wherein each alkyl group is, independently, optionally substituted by 1 or 2 substituents independently selected from halogen and OH; and
n is an integer from 1 to 3.

### Claim 11 (depends on 1)

The method of claim 1, wherein:
R1 and R2 are, independently, selected from the group consisting of H, —C1-6alkyl, —OR7, —C(═O)R7, and —OC(═O)R7;
each R7 is, independently, halogen or C1-C3alkyl;
R3 is an optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, furyl, thienyl, imidazolyl, indolyl, pyrryl, purinyl, pyranyl, pyrazolyl, oxadiazolyl, and pyrrolyl;
R4 and R6 are, independently, —C1-3alkyl, and R5 is OH or —OC1-8alkyl, wherein each alkyl group is, independently, optionally substituted by 1 or 2 halogens; and
n is 2 or 3.

### Claim 12 (depends on 1)

The method of claim 1, wherein:
R1 and R2 are, independently, selected from the group consisting of H, —C1-6alkyl, and —OR7;
each R7 is, independently, halogen or C1-C3alkyl;
R3 is an optionally substituted heteroaryl selected from the group conisisting of pyridyl, pyrimidinyl, pyridinyl, imidazolyl, indolyl, pyrryl, purinyl, pyranyl, and pyrrolyl;
R4 and R6 are, independently, —C1-3alkyl;
R5 is OH or —OC6-8alkyl; and
n is 2 or 3.

### Claim 13 (depends on 1)

The method of claim 1, wherein:
R1 is —OR7, wherein R7 is halogen or C1-C3alkyl;
R2 is H;
R3 is an optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridinyl, pyrryl, and pyrrolyl;
R4 and R6 are, independently, —C1-3alkyl;
R5 is —OC6-8alkyl; and
n is 2.

### Claim 14 (depends on 1)

The method of claim 1, wherein the solvent is a protic solvent.

### Claim 15 (depends on 1)

The method of claim 1, wherein the solvent is an aprotic solvent.

### Claim 16 (depends on 1)

The method of claim 1, further comprising alkylating the compound of Formula XIII, when R5 is OH, prior to reacting with the compound of Formula XII, by admixing the compound of Formula XIII with an alkylating agent, a base, a nucleophilic catalyst salt, and a solvent at a temperature from about 0° C. to about 100° C. thereby resulting in the formation of the compound of Formula XIV.

### Claim 17 (depends on 16)

The method of claim 16, wherein:
the alkylating agent is selected from the group consisting of a linear —C1-6haloalkyl, a linear —C1-20haloalkyl, a branched —C1-6haloalkyl, and a branched —C1-20haloalkyl;
the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, and calcium carbonate; and
the nucleophilic catalyst salt is selected from the group consisting of potassium iodide, sodium iodide, calcium iodide, and tetra-n-butyl ammonium iodide.

### Claim 18 (depends on 1)

The method of claim 1, further comprising alkylating the compound of Formula XIV, when R5 is OH, after reacting the compound of Formula XIII with the compound of Formula XII, by admixing the compound of Formula XIV with an alkylating agent, a base, a nucleophilic catalyst salt, and a solvent at a temperature from about 0° C. to about 100° C. thereby resulting in the formation of the compound of Formula XIV.

### Claim 19 (depends on 18)

The method of claim 18, wherein:
the alkylating agent is selected from the group consisting of a linear —C1-6haloalkyl, a linear —C1-20haloalkyl, a branched —C1-6haloalkyl, and a branched —C1-20haloalkyl;
the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, and calcium carbonate; and
the nucleophilic catalyst salt is selected from the group consisting of potassium iodide, sodium iodide, calcium iodide, and tetra-n-butyl ammonium iodide.