# US 10,500,197 B2 · Use of oligopyridylamides to inhibit mutant p53 amyloid formation and restore its tumor suppressor function

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- Number: US 10,500,197 B2
- Document ID: US10500197B2
- Status: Granted
- Kind: B2
- Application number: 16/038,734
- Filed: 2018-07-18
- Published: 2019-01-24
- Granted: 2019-12-10
- Earliest claimed: 2017-07-18
- Assignees: New York University; New York University in Abu Dhabi Corporation
- Applicants: New York University; New York University in Abu Dhabi Corporation
- Inventors: Sunil Kumar; Andrew D. Hamilton; Mazin Magzoub; Sarah Hassan
- Web page: https://patentgrep.com/patent/US10500197B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61P 35/00: Antineoplastic agents
- 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

The invention relates to oligopyridylamide alpha-helix mimetic compounds and their use to inhibit p53 aggregation and restore its tumor suppressor function for treating diseases, e.g., cancers, associated with p53 mutations, e.g., R248W p53 mutation.

## Claims

### Claim 1

A method of inhibiting aggregation of a p53 protein comprising contacting said p53 protein with an effective amount of a compound of formula (I):
wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; and —N(R*)2;
X is independently at each occurrence selected from —O—; —S—; —NH—; —NR*—; and C(R*)2;
Y is independently at each occurrence selected from —O—; —S—; —NH—; and —NR*—;
R1 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
R2 is independently at each occurrence selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
R3 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
A is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2; C1-C8 perfluorocarbon; an aliphatic C1-C12 hydrocarbon; an aromatic C1-C12 hydrocarbon; and a C1-C12 heteroaryl;
B is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2; C1-C8 perfluorocarbon; an aliphatic C1-C12 hydrocarbon; an aromatic C1-C12 hydrocarbon; and a C1-C12 heteroaryl;
R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and
n is an integer from 0 to 2;
with the proviso that (i) when n is 0, and Y is O, R1 and R3 are not both —CH2CO2H; (ii) when n is 1, Y is O, and R1 and R3 are both —CH2CO2H, R2 is not —CH2CO2H or a straight chained, branched or cyclic aliphatic or aryl C1-C12 hydrocarbon, or R2 does not have the structure —C(CH2CO2H)3; (iii) when n is 1, and Y is O, R1 through R3 are not each an unsubstituted C1-C8 hydrocarbon; and (iv) when n is 2, and Y is O, R1 through R3 are not —CH2CO2H at all occurrences,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the p53 protein comprises one or more mutations.

### Claim 3 (depends on 2)

The method of claim 2, wherein the p53 protein comprises R248W mutation.

### Claim 4 (depends on 1)

The method of claim 1, wherein the p53 protein is in a cell.

### Claim 5 (depends on 4)

The method of claim 4, wherein the cell is in a subject.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound has the structure according to formula (II):
wherein R1′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
R2′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
R3′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
A′ is selected from —NO2; —NH2; —NHR*; —N(R*)—(C═O)—R*, —N(R*)2, where R* is hydrogen or an aliphatic C1-C12 hydrocarbon; and
B′ is selected from —(C═O)—R*; —CO2H; —CO2R*, where R* is hydrogen or an aliphatic C1-C12 hydrocarbon;
R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;
with the proviso that (i) when R1 and R3 are both —CH2CO2H, R2 is not —CH2CO2H or a straight chained, branched or cyclic aliphatic C1-C12 hydrocarbon, or R2 does not have the structure —C[CH2CO2H]3; and (ii) R1 through R3 are not each an unsubstituted C1-C8 hydrocarbon,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 13

A method of treating a cancer associated with aggregation of a p53 protein in a subject in need of such treatment, wherein the cancer is associated with one or more p53 mutations, comprising administering to said subject an effective amount of a compound of formula (I):
wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; and —N(R*)2;
X is independently at each occurrence selected from —O—; —S—; —NH—; —NR*—; and —C(R*)2;
Y is independently at each occurrence selected from —O—; —S—; —NH—; and —NR*—;
R1 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
R2 is independently at each occurrence selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
R3 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F; —Cl; —Br; —I; —OH, —OR*; —NO;
—NO2; —NO3; —O—NO; —N3; —NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*;
—S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2 and combinations thereof;
A is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3;
—NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2; C1-C8 perfluorocarbon; an aliphatic C1-C12 hydrocarbon; an aromatic C1-C12 hydrocarbon; and a C1-C12 heteroaryl;
B is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NO; —NO2; —NO3; —O—NO; —N3;
—NH2; —NHR*; —N(R*)2; —N(R*)3+; —N(R*)—OH; —O—N(R*)2; —N(R*)—O—R*; —CN; —NC; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH2; —(C═O)—N(R*)2; —(C═O)—NHNH2; —O—(C═O)—NHNH2; —(C═S)—NH2; —(C═S)—N(R*)2; —N(R*)—CHO; —N(R*)—(C═O)—R*; —SCN; —NCS; —NSO; —SSR*; —SO2R*; —SO2—N(R*)2; —S(═O)—OR*; —S(═O)—R*; —Si(R*)3; —CF3; —O—CF3; —P(R*)2; —O—P(═O)(OR*)2; —P(═O)(OR*)2; C1-C8 perfluorocarbon; an aliphatic C1-C12 hydrocarbon; an aromatic C1-C12 hydrocarbon; and a C1-C12 heteroaryl;
R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and
n is an integer from 0 to 2;
with the proviso that (i) when n is 0, and Y is O, R1 and R3 are not both —CH2CO2H; (ii) when n is 1, Y is O, and R1 and R3 are both —CH2CO2H, R2 is not —CH2CO2H or a straight chained, branched or cyclic aliphatic or aryl C1-C12 hydrocarbon, or R2 does not have the structure —C(CH2CO2H)3; (iii) when n is 1, and Y is O, R1 through R3 are not each an unsubstituted C1-C8 hydrocarbon; and (iv) when n is 2, and Y is O, R1 through R3 are not —CH2CO2H at all occurrences,
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the effective amount inhibits aggregation of the p53 protein.

### Claim 15 (depends on 13)

The method of claim 13, wherein the one or more p53 mutations comprise R248W mutation.

### Claim 16 (depends on 13)

The method of claim 13, wherein the subject is human.

### Claim 17 (depends on 13)

The method of claim 13, wherein the compound has the structure according to formula (II):
wherein R1′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
R2′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
R3′ is selected from a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon; an aromatic C6-C20 hydrocarbon; a heteroaromatic C1-C20 hydrocarbon; an aryl C6-C20 hydrocarbon; a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —NH2; —NHR*; —N(R*)2; —N(R*)3+; —(C═O)—R*; —CHO; —CO2H; —CO2R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; and combinations thereof;
A′ is selected from —NO2; —NH2; —NHR*; —N(R*)—(C═O)—R*, —N(R*)2, where R* is hydrogen or an aliphatic C1-C12 hydrocarbon; and
B′ is selected from —(C═O)—R*; —CO2H; —CO2R*, where R* is hydrogen or an aliphatic C1-C12 hydrocarbon;
R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;
with the proviso that (i) when R1 and R3 are both —CH2CO2H, R2 is not —CH2CO2H or a straight chained, branched or cyclic aliphatic C1-C12 hydrocarbon, or R2 does not have the structure —C[CH2CO2H]3; and (ii) R1 through R3 are not each an unsubstituted C1-C8 hydrocarbon,
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 13)

The method of claim 13, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 13)

The method of claim 13, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 13)

The method of claim 13, wherein the compound has the structure according to the following formula:
or a pharmaceutically acceptable salt thereof.