# US 2019/0375731 A1 · Prodigiosin Analogs And Methods Of Use

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- Number: US 2019/0375731 A1
- Document ID: US20190375731A1
- Status: Published application
- Kind: A1
- Application number: 16/396,669
- Filed: 2019-04-27
- Published: 2019-12-12
- Earliest claimed: 2016-04-08
- Assignees: Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center
- Applicants: Institute For Cancer Research d/b/a The Research Institute Of Fox Chase Cancer Center
- Inventors: Wafik S. El-Deiry; Xiaobing Tian
- Web page: https://patentgrep.com/patent/US20190375731A1

## 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 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;
or an isomer, tautomer, or solvate thereof, or a pharmaceutically acceptable salt thereof;
provided that:
if n is 0, then R3 is not an optionally substituted pyrrolyl; and
if n is 2, then the compound is not

### Claim 2 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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 compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, wherein each R7 is, independently, H, halogen, or C1-C6alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, wherein R1 is —OCH3 and R2 is H.

### Claim 5 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted heteroaryl.

### Claim 6 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted heteroaryl 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 compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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 compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 3.

### Claim 9 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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;
provided that:
if n is 2, then the compound is not

### Claim 10 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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;
provided that:
if n is 2, then the compound is not

### Claim 11 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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;
provided that:
if n is 2, then the compound is not

### Claim 12 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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 consisting 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;
provided that:
if n is 2, then the compound is not

### Claim 13 (depends on 1)

The compound according to claim 1, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, 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;
provided that:
the compound is not

### Claim 14 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1, or an isomer, tautomer, or solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 14)

The pharmaceutical composition according to claim 14, further comprising an anti-cancer agent.

### Claim 16 (depends on 1)

A method of treating cancer in a subject comprising administering to the subject in need thereof the compound, or isomer, tautomer, or solvate thereof, or pharmaceutically acceptable salt thereof, according to claim 1.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the cancer is a colorectal cancer, a head and neck cancer, a pancreatic cancer, a breast cancer, a colon cancer, a lung cancer, or a glioblastoma cancer.

### Claim 18 (depends on 16)

The method according to claim 16, further comprising administering to the subject another anti-cancer therapy.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the another anti-cancer therapy is radiation therapy, chemotherapy, or immunotherapy, or any combination thereof.

### Claim 20

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.