# US 11,999,736 B1 · Pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridines compounds as CK2 inhibitors

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- Number: US 11,999,736 B1
- Document ID: US11999736B1
- Status: Granted
- Kind: B1
- Application number: 18/395,982
- Filed: 2023-12-26
- Granted: 2024-06-04
- Earliest claimed: 2023-12-26
- Assignees: King Faisal University
- Applicants: King Faisal University
- Inventors: Michelyne Haroun; Christophe Tratrat
- Web page: https://patentgrep.com/patent/US11999736B1

## CPC

- C07D 471/22: in which the condensed systems contains four or more hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridines, a method of synthesizing said compounds, a pharmaceutical composition comprising said compounds and a suitable carrier, and a method of using the compounds. The pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridine compounds, identified as CK2 inhibitors, are useful as anticancer and/or antitumor agents, and as agents for treating other kinase-associated conditions including inflammation, pain, and certain immunological disorders, and other types of diseases such as diabetes, viral infection, neurodegenerative diseases.

## Claims

### Claim 1

A compound having the formula I:
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof, wherein:
R is selected from the group consisting of —Ar, —NHAr, —NHCH2Ar, —NHCH2CH2Ar, —NHCOAr, —NHSO2Ar, —NHCOCH2Ar, —NHCH2CH2NHR1, —NHCH2CH2NR1R2, —NHCH2CH2CH2NHR1, —NHCH2CH2CH2NR1R2, —NHCOCH2NHR1, —NHCOCH2NR1R2, —NHCOCH2CH2NHR1, and —NHCOCH2CH2NR1R2;
Ar is an aryl ring or a 5 or 6 membered heteroaryl ring, either of the aryl ring or the heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, —CF3, —OH, —OR1, —NH2, —NHR1, —NR1R2, —CONH2, —CONHR1, —CONR1R2, —SO2NH2, —SO2NHR1, —SO2NR1R2, —NHCOR1, —NHCO2R1, —NHCONHR1, —NHSO2NHR1, —NHSO2R1, —NHCH2COR1, —NHCH2CO2R1, —NHCH2CONHR1, —OCH2COR1, —OCH2CO2R1, —OCH2CONHR1, —COR1, —CO2R1, C1-C6 straight chained alkyl, C1-C6 branched alkyl, C3-C6 cycloalkyl, halo-C1-C6 straight chain alkyl, halo-C1-C6 branched alkyl, halo-C3-C6 cycloalkyl, cyano-C1-C6 straight chain alkyl, cyano-C1-C6 branched alkyl, and cyano-C3-C6 cycloalkyl; and
R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 straight chained alkyl, C1-C6 branched alkyl, C3-C6 cycloalkyl, halo-C1-C6 straight chain alkyl, halo-C1-C6 branched alkyl, halo-C3-C6 cycloalkyl, cyano-C1-C6 straight chain alkyl, cyano-C1-C6 branched alkyl, and cyano-C3-C6 cycloalkyl, or wherein R1 and R2, taken together with a nitrogen atom to which they are attached, form a nitrogen-containing heterocycle, such nitrogen-containing heterocycle being optionally substituted with from one to three substituents independently selected from the group consisting of a straight or branched C1-C6 alkyl group, a halogen atom, a straight or branched C1-C6 alkoxy group, a straight or branched C1-C6 trihaloalkyl group, and a hydroxy group.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is an optionally substituted —NHAr group, an optionally substituted —NHCH2Ar group, an optionally substituted —NHCH2CH2Ar group, an optionally substituted —NHCH2CH2CH2NR1R2 group, or an —Ar group.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R is —NHphenyl substituted with one or more substituents independently selected from the group consisting of halogen, —CF3, —OR1, a straight or branched C1-C6 alkyl, —NR1R2, —NHCOR1, —CONR1R2, and —SO2NR1R2.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R is —NHphenyl substituted with one or more substituents independently selected from the group consisting of methyl, chlorine, —N(CH3)2, —CON(CH3)2, —SO2N(CH3)2, —CF3, —NHCOCH3, isopropyl, and methoxy.

### Claim 5 (depends on 2)

The compound of claim 2, wherein R is a —NHCH2CH2CH2NR1R2 group, wherein R1 and R2 are independently a straight chain C1-C6 alkyl group, or wherein R1 and R2 are taken together with the nitrogen atom to which they are attached to form a nitrogen-containing heterocycle, such nitrogen-containing heterocycle being optionally substituted with a straight or branched C1-C6 alkyl group.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1 and R2 are both methyl or wherein R1 and R2 are taken together to form a 4-methylpiperazin-1-yl ring.

### Claim 7 (depends on 2)

The compound of claim 2, wherein R is a —NHCH2phenyl group substituted with a chlorine.

### Claim 8 (depends on 2)

The compound of claim 2, wherein R is a (2-methylpyridin-4-yl) group.

### Claim 9 (depends on 2)

The compound of claim 2, wherein R is a —NHCH2CH2Ar group, wherein the Ar group is a phenyl group substituted with a chlorine.

### Claim 10 (depends on 2)

The compound of claim 2, wherein R is a 4-methylpiperazin-1-yl ring.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
N-(3-chlorophenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (1);
N-(3-(trifluoromethyl)phenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (2);
N-(3-methoxyphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (3);
N-(m-tolyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (4);
N-(3,4-dimethylphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (5);
N-(3-isopropylphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (6);
N1,N1-dimethyl-N3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-yl)benzene-1,3-diamine (7);
N-(3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)phenyl)acetamide (8);
N,N-dimethyl-3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)benzamide (9);
N,N-dimethyl-3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)benzenesulfonamide (10);
N-(2-methylpyridin-4-yl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (11);
N-(3-chlorobenzyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (12);
N-(3-chlorophenethyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (13);
N1,N1-dimethyl-N3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-yl)propane-1,3-diamine (14);
N-(3-(4-methylpiperazin-1-yl)propyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (15);
11-(4-methylpiperazin-1-yl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridine (16); and
a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof.

### Claim 12 (depends on 1)

A pharmaceutically acceptable composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1)

A method of inhibiting casein kinase 2 (CK2) enzyme activity in a patient, comprising administering to a patient in need of inhibition of CK2 enzyme activity a therapeutically effective amount of the compound of claim 1.

### Claim 14 (depends on 1)

A method of treating a cancer in a patient, comprising administering to a patient in need of treatment for cancer a therapeutically effective amount of the compound of claim 1.

### Claim 15

A compound having the formula I:
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof, wherein:
R is:
—NHphenyl substituted with one or more substituents independently selected from the group consisting of halogen, —CF3, —OR1, a straight or branched C1-C6 alkyl, —NR1R2, —NHCOR1, —CONR1R2, and —SO2NR1R2; a —NHCH2CH2CH2NR1R2 group;
a —CH2phenyl group substituted with a chlorine;
a pyridyl group substituted with a methyl;
a —NHCH2CH2Ar group, wherein the Ar group is a phenyl group substituted with a chlorine; and
a 4-methylpiperazin-1-yl ring; and
R1 and R2 are independently a straight chain C1-C6 alkyl group or wherein R1 and R2 are taken together with the nitrogen atom to which they are attached to form a nitrogen-containing heterocycle, such nitrogen-containing heterocycle being optionally substituted with a straight or branched C1-C6 alkyl group.

### Claim 16 (depends on 15)

A pharmaceutically acceptable composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 15)

A method of treating a cancer in a patient, comprising administering to a patient in need of treatment for cancer a therapeutically effective amount of the compound of claim 15.

### Claim 18

A compound selected from the group consisting of:
N-(3-chlorophenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (1);
N-(3-(trifluoromethyl)phenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (2);
N-(3-methoxyphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (3);
N-(m-tolyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (4);
N-(3,4-dimethylphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (5);
N-(3-isopropylphenyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (6);
N1,N1-dimethyl-N3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-yl)benzene-1,3-diamine (7);
N-(3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)phenyl)acetamide (8);
N,N-dimethyl-3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)benzamide (9);
N,N-dimethyl-3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-ylamino)benzenesulfonamide (10);
N-(2-methylpyridin-4-yl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (11);
N-(3-chlorobenzyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (12);
N-(3-chlorophenethyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (13);
N1,N1-dimethyl-N3-(pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-yl)propane-1,3-diamine (14);
N-(3-(4-methylpiperazin-1-yl)propyl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridin-11-amine (15);
11-(4-methylpiperazin-1-yl)pyrazino[2′,1′:2,3]imidazo[4,5-b][1,7]naphthyridine (16); and
a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof.

### Claim 19 (depends on 18)

A pharmaceutically acceptable composition comprising the compound of claim 18 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 18)

A method of treating a cancer in a patient, comprising administering to a patient in need of treatment for cancer a therapeutically effective amount of the compound of claim 18.