# US 12,109,207 B2 · Methods of using 4(1H)-quinolone derivatives

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- Number: US 12,109,207 B2
- Document ID: US12109207B2
- Status: Granted
- Kind: B2
- Application number: 18/184,364
- Filed: 2023-03-15
- Published: 2023-07-27
- Granted: 2024-10-08
- Earliest claimed: 2019-04-19
- Assignees: Academia Sinica
- Applicants: Academia Sinica
- Inventors: Rong-Jie Chein; Pan-Chyr Yang; Chi-Huey Wong; Ming-Shiu Lin; Ting-Jen Cheng; Ting-Hung Rachel Chou
- Web page: https://patentgrep.com/patent/US12109207B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 215/233: only one oxygen atom which is attached in position 4
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are compounds of Formula (I). The disclosure provides new compounds, compositions, and methods for treating, delaying, and/or preventing the adverse effects of proliferative diseases, such as cancers including, for example, lung cancer, breast cancer, ovarian cancer, prostate cancer, head cancer, neck cancer, head and neck cancer, or leukemia (e.g., cancer resistant to treatment by one or more microtubule-targeting agents (e.g., cancer resistant to multiple drugs associated with P-glycoprotein (P-gp) overexpression)). Provided are methods of inhibiting polymerization of a cancer cell microtubule in a subject in need thereof or a cell, tissue, or biological sample, binding β-tubulin, inhibiting microtubule assembly and, inducing apoptosis in a cancer cell resistant to multiple drugs in a tissue, biological sample, or subject. Also provided in the present disclosure are pharmaceutical compositions, kits, and methods of using the compounds for treating any of the target diseases described herein.

## Claims

### Claim 1

A method of treating one or more cancers of breast cancer, ovarian cancer, prostate cancer, colon cancer, head cancer, neck cancer, and head and neck cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt, co-crystal, tautomer, or stereoisomer thereof, wherein:
each instance of R1 is independently halogen, —C(═O)(unsubstituted alkyl), unsubstituted or substituted alkyl by halogen, unsubstituted or substituted alkenyl by halogen, unsubstituted or substituted alkynyl by halogen, unsubstituted or substituted carbocyclyl by halogen, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
each instance of R2 is independently halogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —(CH2)xORaa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1; and at least one R2 is —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —(CH2)xORaa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa or —CN;
R3 is hydrogen, unsubstituted alkyl, or a nitrogen protecting group;
each instance of R4 is independently halogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
RD1 is hydrogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each occurrence of RD1a is hydrogen, —C(═O)Raa—CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group; or optionally-two instances of RD1a are taken together with their intervening atoms to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring;
Raa is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom;
each occurrence of Rbb is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom;
R2c is hydrogen;
m is 0, 1, 2, 3, 4, or 5;
n is 1, 2, 3, or 4;
x is 1, 2, 3, 4, 5, or 6;
z is 1, 2, 3, 4, 5, or 6; and
p is 0 or 1.

### Claim 2 (depends on 1)

The method of claim 1, wherein m is 0.

### Claim 3 (depends on 1)

The method of claim 1, wherein m is 1.

### Claim 4 (depends on 1)

The method of claim 1, wherein at least one instance of R1 is halogen.

### Claim 5 (depends on 1)

The method of claim 1, wherein at least one instance of R1 is fluoro or bromo.

### Claim 6 (depends on 1)

The method of claim 1, wherein at least one instance of R1 is alkyl substituted with halogen.

### Claim 7 (depends on 6)

The method of claim 6, wherein at least one instance of R1 is —CF3.

### Claim 8 (depends on 1)

The method of claim 1, wherein at least one instance of R1 is —ORD1, and RD1 is hydrogen or unsubstituted alkyl, unsubstituted alkenyl or unsubstituted alkynyl.

### Claim 9 (depends on 8)

The method of claim 8, wherein at least one instance of R1 is —OH, —OMe, or of formula:

### Claim 10 (depends on 1)

The method of claim 1, wherein R3 is hydrogen.

### Claim 11 (depends on 1)

The method of claim 1, wherein n is 1.

### Claim 12

A method of treating one or more cancers of lung cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, head cancer, neck cancer, head and neck cancer and leukemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formulae (IA), (IB), or (IC):
or a pharmaceutically acceptable salt, co-crystal, tautomer, or stereoisomer thereof, wherein:
each instance of R1 is independently halogen, —C(═O)(-unsubstituted alkyl), unsubstituted or substituted alkyl by halogen, unsubstituted or substituted alkenyl by halogen, unsubstituted or substituted alkynyl by halogen, unsubstituted or substituted carbocyclyl by halogen, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
R2 of the formula (IA) is independently —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —(CH2)xORaa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, or —N(RD1a)2; R2 of the formula (IB) is independently halogen, —C(═O)Raa—CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —(CH2)xORaa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —C(═NR bb)Raa—C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, -unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1; and R2 of the formula (IC) is independently halogen, —C(═O)OR2a, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —(CH2)xORaa, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
R3 is hydrogen, unsubstituted alkyl, or a nitrogen protecting group;
each instance of R4 is independently halogen, —C(═O)Raa—CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
RD1 is hydrogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, -unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each occurrence of RD1a is hydrogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group; or two instances of RD1a are taken together with their intervening atoms to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring;
R2a is unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom;
Raa is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom;
each occurrence of Rbb is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom;
R2c is hydrogen;
m is 0, 1, 2, 3, 4, or 5;
x is 1, 2, 3, 4, 5, or 6;
z is 1, 2, 3, 4, 5, or 6; and
p is 0 or 1.

### Claim 13 (depends on 12)

The method of claim 12, wherein R2 of the formula (IA) is is —CO2Raa, —C(═O)N(Rbb)2, or —(CH2)xORaa or —C(═O)(OCH2CH2)zO(R2c), R2 of the formula (IB) is is —CO2Raa, —C(═O)N(Rbb)2, or —(CH2)xORaa or —C(═O)(OCH2CH2)zO(R2c), and R2 of the formula (IC) is —C(═O)OR2a, —C(═O)N(Rbb)2, or —(CH2)xORaa or —C(═O)(OCH2CH2)zO(R2c).

### Claim 14 (depends on 13)

The method of claim 13, wherein R2 of the formula (IA) is —CO2Raa or —C(═O)(OCH2CH2)zO(R2c), R2 of the formula (IB) is —CO2Raa or —C(═O)(OCH2CH2)zO(R2c), and R2 of the formula (IC) is —C(═O)OR2a or —C(═O)(OCH2CH2)zO(R2c), and R2a is unsubstituted C1-6 alkyl, Raa is hydrogen or unsubstituted C1-6 alkyl, R2c is hydrogen, and z is 1, 2, 3, 4, 5, or 6.

### Claim 15 (depends on 14)

The method of claim 14, wherein —CO2Raa is —C(═O)OH, —C(═O)OMe, —C(═O)OEt, or —C(═O)O(iPr), —C(═O)OR2a is —C(═O)OMe, —C(═O)OEt or —C(═O)O(iPr), and —C(═O)(OCH2CH2)zO(R2c) is —C(═O)(OCH2CH2)3OH, or —C(═O)(OCH2CH2)4OH.

### Claim 16 (depends on 13)

The method of claim 13, wherein R2 of the formulas (IA), (IB) and (IC) is —C(═O)NH(Rbb), and Rbb is unsubstituted C1-6 alkyl.

### Claim 17 (depends on 16)

The method of claim 16, wherein R2 of the formulas (IA), (IB) and (IC) is —C(═O)NH(Et).

### Claim 18 (depends on 13)

The method of claim 13, wherein R2 of the formulas (IA), (IB) and (IC) is —(CH2)xORaa, x is 1, 2, 3, 4, or 5, and Raa is unsubstituted C1-6 alkyl.

### Claim 19 (depends on 18)

The method of claim 18, wherein R2 of the formulas (IA), (IB) and (IC) is —(CH2)OEt.

### Claim 20 (depends on 1)

The method of claim 1, wherein p is 0.

### Claim 21 (depends on 13)

The method of claim 13, wherein the compound is of formula:
or a pharmaceutically acceptable salt, co-crystal, tautomer, or stereoisomer thereof.

### Claim 22 (depends on 12)

The method of claim 12, wherein the compound is of formula:
or a pharmaceutically acceptable salt, co-crystal, tautomer, or stereoisomer thereof.

### Claim 23 (depends on 22)

The method of claim 22, wherein the compound is of formula:

### Claim 24

A method of treating leukemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA)
or a pharmaceutically acceptable salt, co-crystal, tautomer, or stereoisomer thereof, wherein:
each instance of R1 is independently halogen, —C(═O)(-unsubstituted alkyl), unsubstituted or substituted alkyl by halogen, unsubstituted or substituted alkenyl by halogen, unsubstituted or substituted alkynyl by halogen, unsubstituted or substituted carbocyclyl by halogen, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
R2 is independently halogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═O)(OCH2CH2)zOR2c, —(CH2)xORaa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —C(═NRbb) Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
R3 is hydrogen, unsubstituted alkyl, or a nitrogen protecting group;
each instance of R4 is independently halogen, —C(═O)Raa—CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORD1, —N(RD1a)2, or —SRD1;
RD1 is hydrogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of RD1a is hydrogen, —C(═O)Raa, —CHO, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group; or two instances of RD1a are taken together with their intervening atoms to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring;
Raa is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom;
each occurrence of Rbb is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom;
R2c is hydrogen;
m is 0, 1, 2, 3, 4, or 5;
x is 1, 2, 3, 4, 5, or 6;
z is 1, 2, 3, 4, 5, or 6; and
p is 0 or 1.

### Claim 25 (depends on 12)

The method of claim 12, wherein the lung cancer is non-small cell lung cancer.

### Claim 26 (depends on 12)

The method of claim 12, wherein the breast cancer is triple-negative breast cancer.

### Claim 27 (depends on 12)

The method of claim 12, wherein the one or more cancers are resistant to treatment by one or more microtubule-targeting agents.

### Claim 28 (depends on 27)

The method of claim 27, wherein the one or more microtubule-targeting agents comprise a taxane or a vinca alkaloid.

### Claim 29 (depends on 28)

The method of claim 28, wherein the taxane is paclitaxel or ixabepilone.

### Claim 30 (depends on 28)

The method of claim 28, wherein the vinca alkaloid is vincristine or vinblastine.

### Claim 31 (depends on 27)

The method of claim 27, wherein the one or more microtubule-targeting agents comprise paclitaxel and vincristine.

### Claim 32 (depends on 12)

The method of claim 12, wherein the one or more cancers are resistant to multiple drugs.

### Claim 33 (depends on 32)

The method of claim 32, wherein the one or more cancers resistant to multiple drugs are associated with P-glycoprotein (P-gp) overexpression.

### Claim 34 (depends on 32)

The method of claim 32, wherein the one or more cancers resistant to multiple drugs are associated with β-tubulin mutations.