# US 10,501,467 B2 · Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors

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- Number: US 10,501,467 B2
- Document ID: US10501467B2
- Status: Granted
- Kind: B2
- Application number: 16/135,512
- Filed: 2018-09-19
- Published: 2019-01-17
- Granted: 2019-12-10
- Earliest claimed: 2016-01-05
- Assignees: BeiGene, Ltd.
- Applicants: BeiGene, Ltd.
- Inventors: Changyou Zhou; Bo Ren; Hexiang Wang
- Web page: https://patentgrep.com/patent/US10501467B2

## CPC

- C07D 487/06: Peri-condensed systems
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 471/16: Peri-condensed systems
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 487/14: 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

Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

## Claims

### Claim 1

An oral dosage form comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit PARP:
wherein:
RN is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
X is selected from C, N, O, or S;
m and n, which may be the same or different, are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R1, at each occurrence, is independently selected from halogen, CN, NO2, OR9, NR9R10, NR9COR10, NR9SO2R10, CONR9R10, COOR9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R2 is selected from hydrogen, COR9, CONR9R10, CO2R9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R3, R4, R5, R6, R7 and R8, which may be the same or different, are each independently selected from hydrogen, halogen, —NR9R10, —OR9, oxo, —COR9, —CO2R9, —CONR9R10, —NR9CONR10R11, —NR9CO2R10, —NR9SO2R10, —SO2R9, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is independently optionally substituted with at least one substituent R12;
or (R3 and R4), and/or (R4 and R5), and/or (R5 and R6), and/or (R6 and R7), and/or (R7 and R8), together with the atom(s) they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR13—, —O—, —S—, —SO— or —SO2-, and said ring is optionally substituted with at least one substituent R12;
provided that
when X is O, R5 and R6 are absent,
when X is N, R6 is absent,
when X is S, R5 and R6 are absent, or at least one of R5 and R6 is oxo,
when one of R3 and R4 is oxo, the other is absent,
when one of R7 and R8 is oxo, the other is absent, and
when X is C and one of R5 and R6 is oxo, the other is absent;
R9, R10, and R11, which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with at least one substituent R12;
R12 is selected from CN, halogen, haloalkyl, NO2, —NR′R″, —OR′, oxo, —COR′, —CO2R′, —CONR′R″, —NR′CONR″R′″, —NR′CO2R″, —NR′SO2R″, —SO2R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected from —NR13—, —O—, —S—, —SO— or —SO2-; and
R13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,
wherein the cycloalkyl is a hydrocarbon group selected from saturated or partially unsaturated cyclic hydrocarbon groups, comprising monocyclic, bicyclic or tricyclic groups, and comprising from 3 to 12 carbon atoms;
wherein the heteroaryl is a group selected from:
5- to 7-membered aromatic, monocyclic rings comprising at least one heteroatom selected from N, O, or S, with the remaining ring atoms being carbon;
8- to 12-membered bicyclic rings comprising at least one heteroatom selected from N, O, or S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
11- to 14-membered tricyclic rings comprising at least one heteroatom selected from N, O, or S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and
wherein the heterocyclyl is a ring selected from 4- to 12-membered monocyclic, bicyclic or tricyclic, saturated or partially unsaturated rings, comprising at least one carbon atoms in addition to at least one heteroatom selected from oxygen, sulfur, or nitrogen;
and a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The oral dosage form of claim 1, wherein RN is hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C1-C12 alkoxyl.

### Claim 3 (depends on 1)

The oral dosage form of claim 1, wherein X is C or N.

### Claim 4 (depends on 1)

The oral dosage form of claim 1, wherein m and n are each 1 or 2.

### Claim 5 (depends on 1)

The oral dosage form of claim 1, wherein t is 0 or 1.

### Claim 6 (depends on 1)

The oral dosage form of claim 1, wherein R2 is hydrogen or alkyl.

### Claim 7 (depends on 1)

The oral dosage form of claim 1, wherein R3, R4, R5, R6, R7 and R8, which may be the same or different, are each independently selected from hydrogen, —OR9, —COR9, —CO2R9, alkyl, cycloalkyl, or aryl.

### Claim 8 (depends on 1)

The oral dosage form of claim 1, wherein the compound is a compound of Formula (II):
or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
RN is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
m and n, which may be the same or different, are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R1, at each occurrence, is independently selected from halogen, CN, NO2, OR9, NR9R10, NR9COR10, NR9SO2R10, CONR9R10, COOR9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R2 is selected from hydrogen, COR9, CONR9R10, CO2R9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R3, R4, R5, R6, R7 and R8, which may be the same or different, are each independently selected from hydrogen, halogen, —NR9R10, —OR9, oxo, —COR9, —CO2R9, —CONR9R10, —NR9CONR10R11, —NR9CO2R10, —NR9SO2R10, —SO2R9, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is independently optionally substituted with at least one substituent R12, or (R3 and R4), and/or (R4 and R5), and/or (R5 and R6), and/or (R6 and R7), and/or (R7 and R8), together with the atom(s) to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR13—, —O—, —S—, —SO— or —SO2-, and said ring is optionally substituted with at least one substituent R12, provided that
when one of R3 and R4 is oxo, the other is absent,
when one of R7 and R8 is oxo, the other is absent, and
when one of R5 and R6 is oxo, the other is absent;
R9, R10, and R11, which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with at least one substituent R12;
R12 is selected from CN, halogen, haloalkyl, NO2, —NR′R″, —OR′, oxo, —COR′, —CO2R′, —CONR′R″, —NR′CONR″R′″, —NR′CO2R″, —NR′SO2R″, —SO2R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected from —NR13—, —O—, —S—, —SO— or —SO2-; and
R13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

### Claim 9 (depends on 8)

The oral dosage form of claim 8, wherein:
RN is selected from hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C1-C12 alkoxyl;
m and n are each 1 or 2;
t is 0 or 1;
R1, at each occurrence, is independently selected from halogen, CN, NO2, OR9, NR9R10, NR9COR10, NR9SO2R10, CONR9R10, COOR9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R2 is selected from hydrogen, COR9, CONR9R10, CO2R9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R3, R4, R5, R6, R7 and R8, which may be the same or different, are each independently selected from hydrogen, —OR9, —COR9, —CO2R9, alkyl, cycloalkyl, or aryl,
or (R3 and R4), and/or (R4 and R5), and/or (R5 and R6), and/or (R6 and R7), and/or (R7 and R8), together with the atom(s) to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR13-, —O—, —S—, —SO— or —SO2-;
R9 and R10, which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

### Claim 10 (depends on 1)

The oral dosage form of claim 1, wherein the compound is a compound of Formula (III):
or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
RN is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
m and n, which may be the same or different, are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R1, at each occurrence, is independently selected from halogen, CN, NO2, OR9, NR9R10, NR9COR10, NR9SO2R10, CONR9R10, COOR9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R2 is selected from hydrogen, COR9, CONR9R10, CO2R9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R3, R4, R5, R7 and R8, which may be the same or different, are each independently selected from hydrogen, halogen, —NR9R10, —OR9, oxo, —COR9, —CO2R9, —CONR9R10, —NR9CONR10R11, —NR9CO2R10, —NR9SO2R10, —SO2R9, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently optionally substituted with at least one substituent R12, or (R3 and R4), and/or (R4 and R5), and/or (R5 and R7), and/or (R7 and R8), together with the atom(s) they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR13—, —O—, —S—, —SO—, or —SO2-, and said ring is optionally substituted with at least one substituent R12,
provided that
when one of R3 and R4 is oxo, the other is absent, and
when one of R7 and R8 is oxo, the other is absent;
R9, R10, and R11, which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R12;
R12 is selected from CN, halogen, haloalkyl, NO2, —NR′R″, —OR′, oxo, —COR′, —CO2R′, —CONR′R″, —NR′CONR″R′″, —NR′CO2R″, —NR′SO2R″, —SO2R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected from —NR13—, —O—, —S—, —SO— or —SO2-; and
R13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

### Claim 11 (depends on 10)

The oral dosage form of claim 10, wherein:
RN is hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C1-C12 alkoxyl;
X is C or N;
m and n are each 1 or 2;
t is 0 or 1;
R1, at each occurrence, is independently selected from halogen, CN, NO2, OR9, NR9R10, NR9COR10, NR9SO2R10, CONR9R10, COOR9, SO2R9, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R2 is hydrogen or alkyl;
R3, R4, R5, R7 and R8, which may be the same or different, are each independently selected from hydrogen, —OR9, —COR9, —CO2R9, alkyl, cycloalkyl, or aryl,
or (R3 and R4), and/or (R4 and R5), and/or (R5 and R7), and/or (R7 and R8), together with the atom(s) they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR13-, —O—, —S—, —SO—, or —SO2-;
R9 and R10, which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

### Claim 12 (depends on 1)

The oral dosage form of claim 1, wherein the compound is
or a stereoisomer or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The oral dosage form of claim 1, wherein the compound is selected from the group consisting of:
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The oral dosage form of claim 1, wherein the dosage form is a tablet or a capsule.

### Claim 15 (depends on 1)

The oral dosage form of claim 1, wherein the compound is
or a stereoisomer or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 14)

The oral dosage form of claim 14, wherein the dosage form comprises about 10 mg to about 500 mg of the compound.

### Claim 17 (depends on 15)

The oral dosage form of claim 15, wherein the dosage form comprises about 10 mg to about 500 mg of the compound.