# US 11,993,585 B2 · Poly-ADP ribose polymerase (PARP) inhibitors

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- Number: US 11,993,585 B2
- Document ID: US11993585B2
- Status: Granted
- Kind: B2
- Application number: 17/342,873
- Filed: 2021-06-09
- Published: 2022-02-03
- Granted: 2024-05-28
- Earliest claimed: 2016-12-30
- Assignees: Mitobridge, Inc.
- Applicants: Mitobridge, Inc.
- Inventors: Taisuke Takahashi; Arthur Kluge; Bharat Lagu; Nan Ji
- Web page: https://patentgrep.com/patent/US11993585B2

## CPC

- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- C07D 401/14: containing three or more hetero rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/08: linked by a carbon chain containing alicyclic rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/08: linked by a carbon chain containing alicyclic rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/14: containing three or more hetero rings
- C07D 417/08: linked by a carbon chain containing alicyclic rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is related to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: The present invention is also related a method of treating a subject with a disease which can be ameliorated by inhibition of poly(ADP-ribose)polymerase (PARP). The definitions of the variables are provided herein.

## Claims

### Claim 1

A method of treating cell death in a subject after surgery, comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and wherein said compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, —C(═O)Rb, halo(C1-C5)alkyl and (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted one or two groups selected from —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, and —C(═O)Ra;
each Ra and each Rb are independently selected from —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
Rc is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
i is 0, 1, or 2;
Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R3;
is absent or a bond;
E is N or CH when is absent or E is C when is a bond;
is optionally substituted with (C1-C5)alkyl or hydroxy (C1-C5)alkyl;
each R3 is independently selected from the group consisting of -halogen, —CN, —NO2, —ORd, —S(O)iRe, —C(═NRe)NReRf, —NReS(O)iRf, —S(O)iNReRf, —C(═O)ORe, —OC(═O)ORe, —C(═S)ORe, —O(C═S)Re, —C(═O)NReRf, —NReC(═O)Rf, —C(═S)NReRf, —NReC(═S)Rf, —NRe(C═O)ORf, —O(C═O)NReRf, —NRe(C═S)ORf, —O(C═S)NReRf, —NRe(C═O)NReRf, —NRe(C═S)NReRf, —C(═S)Re, —C(═O)Re, halo(C1-C5)alkyl, and (C1-C5)alkyl, wherein the (C1-C5)alkyl represented by R3 is optionally substituted with —CN, —NO2, —ORe, —NReRf, —S(O)iRe, —NReS(O)iRf, —S(O)iNReRf, —C(═O)ORe, —OC(═O)ORe, —C(═S)ORe, —O(C═S)Re, —C(═O)NReRf, —NReC(═O)Rf, —C(═S)NReRf, —NReC(═S)Rf, —NRe(C═O)ORf, —O(C═O)NReRf, —NRe(C═S)ORf, —O(C═S)NReRf, —NRe(C═O)NReRf, —NRe(C═S)NReRf, —C(═S)Re, or —C(═O)Re;
Rd is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
each Re is independently selected from the group consisting of —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
each Rf is independently selected from the group consisting of —H, (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy, (C3-C6)cycloalkyl optionally substituted with (C1-C2) alkyl, and 4-6 membered oxygen-containing heterocyclyl optionally substituted with (C1-C2) alkyl; or
—NReRf taken together is a 4-6 membered heterocyclyl optionally substituted with (C1-C2) alkyl; or
—C(═NRe)NReRf taken together is a 4-6 membered heterocyclyl optionally substituted with Re;
R5 is —H or (C1-C5)alkyl; and
i is 0, 1, or 2,
wherein 5-6 membered heteroaryl refers to a monocyclic aromatic ring group having five or six ring atoms selected from carbon and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; and
5-6 membered heterocyclyl refers to a monocyclic non-aromatic ring radical containing 5-6 ring atoms selected from carbon atom and 1 or 2 heteroatoms, each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (NO), oxygen, sulfur, sulfoxide and sulfone.

### Claim 2 (depends on 1)

The method of claim 1, wherein said compound, said pharmaceutically acceptable salt thereof, or said pharmaceutical composition is administered orally.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, —C(═O)Rb, halo(C1-C5)alkyl and (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted one or two groups selected from —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, and —C(═O)Ra;
each Ra and each Rb are independently selected from —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
Re is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
i is 0, 1, or 2;
Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R3;
is absent or a bond;
E is N or CH when is absent or E is C when is a bond;
is optionally substituted with (C1-C5)alkyl or hydroxy (C1-C5)alkyl;
each R3 is independently selected from the group consisting of -halogen, —CN, —NO2, —ORd, —S(O)iRe, —C(═NRe)NReRf, —NReS(O)iRf, —S(O)iNReRf, —C(═O)ORe, —OC(═O)ORe, —C(═S)ORe, —O(C═S)Re, —C(═O)NReRf, —NReC(═O)Rf, —C(═S)NReRf, —NReC(═S)Rf, —NRe(C═O)ORf, —O(C═O)NReRf, —NRe(C═S)ORf, —O(C═S)NReRf, —NRe(C═O)NReRf, —NRe(C═S)NReRf, —C(═S)Re, —C(═O)Re, halo(C1-C5)alkyl and (C1-C5)alkyl, wherein the (C1-C5)alkyl represented by R3 is optionally substituted with —CN, —NO2, —ORe, —NReRf, —S(O)iRe, —NReS(O)iRf, —S(O)iNReRf, —C(═O)ORe, —OC(═O)ORe, —C(═S)ORe, —O(C═S)Re, —C(═O)NReRf, —NReC(═O)Rf, —C(═S)NReRf, —NReC(═S)Rf, —NRe(C═O)ORf, —O(C═O)NReRf, —NRe(C═S)ORf, —O(C═S)NReRf, —NRe(C═O)NReRf, —NRe(C═S)NReRf, —C(═S)Re, or —C(═O)Re;
Rd is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
each Re is independently selected from the group consisting of —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
each Rf is independently selected from the group consisting of —H, (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy, (C3-C6)cycloalkyl optionally substituted with (C1-C2) alkyl, and 4-6 membered oxygen-containing heterocyclyl optionally substituted with (C1-C2) alkyl; or
—NReRf taken together is a 4-6 membered heterocyclyl optionally substituted with (C1-C2) alkyl; or
C(═NRe)NReRf taken together is a 4-6 membered heterocyclyl optionally substituted with Re; and
i is 0, 1, or 2.

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO2, —ORe, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, —C(═O)Rb, halo(C1-C5)alkyl and (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted one or two groups selected from —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, and —C(═O)Ra;
each Ra and each Rb are independently selected from —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
Rc is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
i is 0, 1, or 2;
Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R3; and
is optionally substituted with (C1-C5)alkyl or hydroxy(C1-C5)alkyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is represented by a structural formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, wherein:
X1, X2, X3 and X4 are each independently selected from the group consisting of N and CH, provided no more than two of X1, X2, X3 and X4 is N;
X5 is NR2, O, or S;
Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R3;
is optionally substituted with (C1-C5)alkyl or hydroxy(C1-C5)alkyl;
each R1 is independently selected from the group consisting of -halogen, —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, —C(═O)Rb, halo(C1-C5)alkyl and (C1-C5)alkyl, wherein the (C1-C5)alkyl represented by R1 is optionally substituted with —CN, —NO2, —NRaRb, —S(O)iRa, —NRaS(O)iRb, —S(O)iNRaRb, —C(═O)ORa, —OC(═O)ORa, —C(═S)ORa, —O(C═S)Ra, —C(═O)NRaRb, —NRaC(═O)Rb, —C(═S)NRaRb, —NRaC(═S)Rb, —NRa(C═O)ORb, —O(C═O)NRaRb, —NRa(C═S)ORb, —O(C═S)NRaRb, —NRa(C═O)NRaRb, —NRa(C═S)NRaRb, —C(═S)Ra, or —C(═O)Ra;
R2 is —H, C1-5 alkyl, phenyl, —C(O)(C1-C5 alkyl), —C(O)(phenyl), —C(O)O(C1-5 alkyl), —C(O)O(phenyl), —S(O)2(C1-C5 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R2 independently is optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, phenyl, 5-6 membered heteroaryl, (C1-C5) alkoxy, and halo(C1-C5)alkoxy, and wherein each phenyl in the groups represented by R2 independently is optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, (C1-C5)alkyl, halo(C1-C5)alkyl, (C1-C5)alkoxy and halo(C1-C5)alkoxy;
each Ra and each Rb are independently selected from —H and (C1-C5)alkyl optionally substituted with hydroxyl or (C1-C3)alkoxy;
Rc is —H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy;
i is 0, 1, or 2; and
n is 0, 1 or 2.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is represented by a structural formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, wherein:
Ring B is aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, each optionally substituted with one or more substituents represented by R3; and
is optionally substituted with (C1-C5)alkyl or hydroxy(C1-C5)alkyl.

### Claim 7 (depends on 5)

The method of claim 5, wherein:
each R1 is independently halogen, (C1-C5)alkyl, halo(C1-C5)alkyl, (C1-C5)alkoxy, halo(C1-C5)alkoxy or cyano;
each R3 is independently selected from the group consisting of -halogen, —CN, —C(═NRe)NHRf, —S(O)iNReRf, —C(═O)NReRf, —C(═S)NReRf, —O(C═O)NReRf, —O(C═S)NReRf, —NRe(C═O)NReRf, —NRe(C═S)NReRf, and (C1-C5)alkyl.

### Claim 8 (depends on 7)

The method of claim 7, wherein:
each R1 is independently halogen or (C1-C5)alkyl;
each R3 is independently selected from the group consisting of -halogen, —CN, —C(═O)NReRf, —C(═NRe)NHRf and (C1-C5)alkyl.

### Claim 9 (depends on 8)

The method of claim 8, wherein:
each R1 is independently chloro, fluoro or methyl;
each R3 is independently selected from the group consisting of chloro, fluoro, —CN, —C(═NRe)NHRf, —C(═O)NReRf and methyl;
the
group is optionally substituted with methyl or hydroxymethyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein Ring B is selected from the group consisting of:
each R4 is —H, (C1-C5)alkyl, or hydroxy (C1-C5)alkyl;
each p is independently 0 or 1; and
each m is 0 or 1, or 2.

### Claim 11 (depends on 10)

The method of claim 10, wherein Ring B is selected from the group consisting of

### Claim 12 (depends on 7)

The method of claim 7, wherein each Re and each Rf are independently selected from the group consisting of —H and methyl; or Re is —H and Rf is —(C3-C6)cycloalkyl or 4-6 membered oxygen-containing heterocyclyl each optionally substituted with (C1-C2) alkyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein each Re and each Rf are independently selected from the group consisting of —H and methyl; or Re is —H and Rf is cyclopropyl, cyclobutyl or oxetanyl each optionally substituted with methyl.

### Claim 14 (depends on 7)

The method of claim 7, wherein ach R3 is independently selected from the group consisting of chloro, fluoro, —CN, —C(O)NH(cyclopropyl), —C(O)NH2, —C(O)NH(CH3), —C(O)N(CH3)2,
—C(O)NH(cyclobutyl),
—C(═NH)NHCH3, and methyl.

### Claim 15 (depends on 5)

The method of claim 5, wherein R2 is —H or (C1-C5)alkyl.

### Claim 16 (depends on 15)

The method of claim 15, wherein R2 is —H or methyl.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound is of the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is F or methyl; and
R3 is —CN, —C(═NH)NHCH3,
or methyl.

### Claim 18 (depends on 17)

The method of claim 17, wherein:
R1 is F; and
R3 is —CN.

### Claim 19 (depends on 1)

The method of claim 1, wherein the compound is 6-[(3S)-4-[3-(6-fluoro-4-oxo-3H-quinazolin-2-yl)propanoyl]-3-methyl-piperazin-1-yl]pyridine-3-carbonitrile.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is 6-[(3S)-4-[3-(5-fluoro-4-oxo-3H-quinazolin-2-yl)propanoyl]-3-methyl-piperazin-1-yl]pyridine-3-carbonitrile.