# US 11,299,469 B2 · Naphthofuran derivatives, preparation, and methods of use thereof

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- Number: US 11,299,469 B2
- Document ID: US11299469B2
- Status: Granted
- Kind: B2
- Application number: 16/464,413
- Filed: 2017-11-29
- Published: 2021-04-15
- Granted: 2022-04-12
- Earliest claimed: 2016-11-29
- Assignees: Sumitomo Dainippon Pharma Oncology, Inc.
- Applicants: Sumitomo Dainippon Pharma Oncology, Inc.
- Inventors: Jeevanandam Arumugasamy; Wei Li
- Web page: https://patentgrep.com/patent/US11299469B2

## CPC

- C07D 307/92: Naphthofurans; Hydrogenated naphthofurans
- C07C 249/02: of compounds containing imino groups
- C07C 251/24: having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Provided herein are methods of preparation of I by reacting i with acid where R1 and R2 are each independently a leaving group. Intermediates to make i are also claimed.

## Claims

### Claim 1

A method of making a compound having formula (I):
or a prodrug, a pharmaceutically acceptable salt, or a solvate thereof;
comprising reacting a compound having formula (i):
or a salt or solvate thereof, with an acid;
wherein R1 and R2 each independently is a leaving group.

### Claim 2 (depends on 1)

The method of claim 1, wherein
R1 is chosen from halides, ORa, and NRbRc; where Ra is chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, alkenyl groups, substituted alkenyl groups, cycloalkenyl groups, substituted cycloalkenyl groups, alkynyl groups, substituted alkynyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and
Rb and Rc each is independently chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups, or
Rb and Rc together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group.

### Claim 3 (depends on 1)

The method of claim 1, wherein R1 is NRbH, where Rb is phenyl or substituted phenyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein R2 is chosen from halides, carboxylates, alkoxycarboxylates, and aryloxycarboxylates.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2 is chosen from Cl, Br, —COOH, —COO—, methoxycarboxylate, ethoxycarboxylate, isopropoxycarboxylate, and tert-butoxycarboxylate.

### Claim 6 (depends on 1)

The method of claim 1, wherein R2 is tert-butoxycarboxylate.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound having formula (i) has formula (i-a):
or a salt or solvate thereof.

### Claim 8 (depends on 1)

The method of claim 1, further comprising reacting a compound having formula (ii):
or a salt or solvate thereof;
wherein
X is O or N—R4, and
R3 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups;
R4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)Rg, S(═O)2Re, P(═O)2Re, C(═O)ORe, C(═O)NRbRc, S(═O)2NRbRc, and P(═O)2NRbRc;
wherein Rb and Rc each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups,
or Rb and Rc together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group;
Rc is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and
Rg is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups;
with a compound having formula (iii):
wherein R2 and R5 each independently is a leaving group.

### Claim 9 (depends on 8)

The method of claim 8, wherein the compound having formula (ii) has the formula (ii-b)
wherein R4 is chosen from methyl, ethyl, isopropyl, tert- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, and pyrrolyl.

### Claim 10 (depends on 8)

The method of claim 8, wherein R4 is phenyl.

### Claim 11 (depends on 8)

The method of claim 8, wherein the compound having formula (ii) has formula (ii-c):
or a salt or solvate thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound having formula (iii) has the formula (iii-a):

### Claim 13 (depends on 8)

The method of claim 8, further comprising converting a 2-hydroxynaphthalene-1,4-dione having formula (iv):
or a salt or solvate thereof, to the compound having formula (ii).

### Claim 14 (depends on 1)

The method of claim 1, wherein the acid comprises an acid chosen from sulfuric acid (H2SO4), phosphoric acid (H3PO4), nitric acid (HNO3), perchloric acid (HClO4), hydrofluoric acid (HF), hydrochloric acid (HCl), hydrobromic acid (HBr), and hydroiodic acid (HI).

### Claim 15 (depends on 1)

The method of claim 1, wherein the acid is sulfuric acid (H2SO4), phosphoric acid (H3PO4), or hydrochloric acid (HCl).

### Claim 16 (depends on 1)

The method of claim 1, wherein the acid is chosen from formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, chloroacetic acid, and chloroacetic anhydride.

### Claim 17 (depends on 1)

The method of claim 1, wherein the acid comprises an acid chosen from sulfuric acid (H2SO4), acetic acid, and acetic anhydride.

### Claim 18 (depends on 1)

The method of claim 1, comprising reacting a solution of the compound having formula (i) with the acid.

### Claim 19 (depends on 18)

The method of claim 18, wherein the solution comprises a solvent chosen from isopropyl acetate, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dimethylimidazolidinone (DMI).

### Claim 20 (depends on 8)

The method of claim 8, comprising reacting the compound having formula (ii) in the presence of a base chosen from NaHCO3, KHCO3, Na3PO4, Na2HPO4, K3PO4, K2HPO4, LiOCH2CH3, NaOCH2CH3, KOCH2CH3, LiOC(CH3)3, NaOC(CH3)3, KOC(CH3)3, triethylamine (TEA), diisopropylethylamine (DIPEA), and triethanolamine.

### Claim 21 (depends on 13)

The method of claim 13, comprising reacting the 2-hydroxynaphthalene-1,4-dione having formula (iv) with a compound of formula (v):
wherein R4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)Rg, S(═O)2Re, P(═O)2Re, C(═O)ORe, C(═O)NRbRc, S(═O)2NRbRc, and P(═O)2NRbRc;
wherein Rb and Rc each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups,
or Rb and Rc together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group;
Re is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and
Rf and Rg each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups.

### Claim 22 (depends on 21)

The method of claim 21, wherein Rf is chosen from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.