# US 11,999,747 B2 · Furoquinolinediones as inhibitors of TDP2

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- Number: US 11,999,747 B2
- Document ID: US11999747B2
- Status: Granted
- Kind: B2
- Application number: 17/146,327
- Filed: 2021-01-11
- Published: 2021-05-13
- Granted: 2024-06-04
- Earliest claimed: 2015-01-08
- Assignees: The United States of America, as represented by the Secretary, Dept. of Health and Human Services
- Applicants: The United States of America, AS Represented By the Secretary, Department of Health
- Inventors: Linkun An; Christophe Marchand; Yves Pommier
- Web page: https://patentgrep.com/patent/US11999747B2

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4741: condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 221/08: Aza-anthracenes
- C07D 307/92: Naphthofurans; Hydrogenated naphthofurans
- C07D 471/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

Compounds of Formula I and the pharmaceutically acceptable salts thereof are disclosed The variables X1, X2, and R1-4 are disclosed herein. The compounds are useful for treating cancer and related proliferative diseases. Pharmaceutical compositions containing compounds of Formula I and methods of treatment comprising administering compounds of Formula I are also disclosed.

## Claims

### Claim 1

A compound or pharmaceutically acceptable salt thereof of Formula I:
wherein
X1 is N or CR5;
X2 is N or CR6; and
at least one of X1 or X2 is N;
R1 is hydroxyl or C1-C6alkoxy, where one or more methylene units in the alkoxy portion of R1 is optionally and independently replaced with —O— or —N(R7)—, and R1 other than hydroxyl is substituted by 0-3 substituents independently chosen at each occurrence from halogen, hydroxyl, cyano, ═N, ═NOR7, —CO2H, —(CO)—O—C1-C6alkyl, —C(O)NR7R8, and —W—P(O)YR9ZR10;
Y1 is O, NH, or S;
Y2 is N or C—R2;
R2 is halogen, C1-C6alykyl, C1-C6haloalkyl, C1-C6haloalkoxy, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)NR7R8, or phenyl, each R2 other than halogen being substituted with 0 to 3 groups chosen independently at each occurrence from halogen, C1-C6haloalkyl, and C1-C6haloalkoxy; or
R2 is a group -J-Q, where J is a 1 to 4 carbon alkylene linker in which any —CH2— group is optionally replaced by —C(O)O—, —C(O)NH—, —C(O)NR11, or —C(O)—;
Q is C1-C6alkyl, C1-C6alkylamino, aryl, or heteroaryl, each of which is unsubstituted or substituted with one or more groups independently chosen from halogen, hydroxyl, amino, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy;
W, Y, and Z are independently at each occurrence a bond or O;
R3, R4, R5, and R6, are chosen independently at each occurrence from hydrogen, halogen, cyano, amino, C1-C6alkyl, —(C0-C6alkyl)cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy;
R7, R1, R9 and R10 are chosen independently at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, —(C0-C6alkyl)cycloalkyl, and C1-C6haloalkyl, and any R7 and R8 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered heterocyloalkyl group substituted with 0 to 2 substituents chosen from hydroxyl, halogen, C1-C4alkyl, C1-C4alkoxy, and C2-C4alkanoyl; and
R11 is C1-C6alkyl or C1-C6alkylamino-.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein Y2 is N.

### Claim 3 (depends on 1)

The compound or salt of claim 1 wherein
Y2 is N;
R1 is C1-C6alkoxy in which one or more methylene units in the alkoxy is optionally and independently replaced with —O— or —N(R7)—, and R1 is substituted by 0-3 substituents independently chosen at each occurrence from hydroxyl, halogen, cyano, —CO2H, —(CO)—O—C1-C6alkyl, and —W—P(O)YR9ZR10;
R2 is halogen, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, or phenyl, said phenyl being substituted with 0 to 3 groups chosen independently at each occurrence from halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy.

### Claim 4 (depends on 1)

The compound or salt of claim 1 wherein R2 is a groups -J-Q.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein Y1 is O and Y2 is N.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein R2 is
where n is 1, 2, 3, or 4;
J1 is O, NH, NR11;
Q1 is C1-C6alkyl, or C1-C6alkylamino-;
R12 is absent or 1 or more substituents independently chosen from hydroxyl, halogen, amino, or cyano;
R13 is absent or 1 or 2 substituents independently chosen from C1-C4alkyl, and mono- or di-C1-C6alkylamino.

### Claim 7 (depends on 1)

The compound or salt of claim 1 wherein
R1 is substituted with at least one —W—P(O)YR9ZR10 substituent; and
W is a bond; and Y and Z are both O.

### Claim 8 (depends on 1)

The compound or salt of claim 1 wherein Y2 is C—R2, R1 is C1-C6alkoxy and R2 is C1-C6haloalkyl.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein
R1 is alkoxy where one or more methylene units is replaced by —O— or —N(R7)— and R1 is substituted with 1 to 3 substituents independently chosen from hydroxyl and —WP(O)YR9ZR10; where W is a bond; and Y and Z are both O.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein the compound is

### Claim 11 (depends on 10)

The compound or salt of claim 10, wherein the compound is

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound or salt of claim 1, together with a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1)

A method of treating cancer by inhibiting tyrosyl-DNA phosphodiesterase 2, comprising administering a therapeutically effective amount of a compound or salt of claim 1, to a patient in need of such treatment.

### Claim 14 (depends on 1, 13)

The method of claim 13, additionally comprising administering the compound of claim 1 in combination with one or more additional compounds, wherein at least one of the additional compounds is an active agent known to be an inhibitor of topoisomerase 2, to a patient in need of such treatment.

### Claim 15 (depends on 1, 13)

The method of claim 13, additionally comprising administering a therapeutically effective amount of a compound or salt of claim 1, in combination with one or more additional compounds, wherein at least one additional compound is an active agent chosen from etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, and 3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone (HU-331), to a patient in need of such treatment.

### Claim 16 (depends on 13)

The method of claim 13, wherein the cancer is glioma, acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cervical cancer, rectal cancer, ovarian cancer, cholangiocarcinomas, chondrosarcoma, or colon cancer.