# US 11,999,735 B1 · 5-substituted aminopyrimido [6′,1′:2,3] imidazo [4,5-c] [2,6] naphthyridine compounds as CK2 inhibitors

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- Number: US 11,999,735 B1
- Document ID: US11999735B1
- Status: Granted
- Kind: B1
- Application number: 18/395,299
- Filed: 2023-12-22
- Granted: 2024-06-04
- Earliest claimed: 2023-08-21
- Assignees: King Faisal University
- Applicants: King Faisal University
- Inventors: Michelyne Haroun; Christophe Tratrat
- Web page: https://patentgrep.com/patent/US11999735B1

## CPC

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

## Abstract

Novel 5-substituted aminopyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridine compounds, a method of synthesizing said compounds, a pharmaceutical composition comprising said compounds and a suitable carrier, and a method of using the compounds. The 5-substituted aminopyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]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 method of inhibiting CK2 enzyme activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R is selected from the group consisting of —Ar, —CH2Ar, —CH2CH2Ar, —COAr, —SO2Ar, —CH2CH2NHR3, —CH2CH2NR3R4, —CH2CH2CH2NHR3, —CH2CH2CH2NR3R4, —COCH2CH2NHR3, —COCH2CH2NR3R4, —COCH2CH2CH2NHR3, —COCH2CH2CH2NR3R4, —SO2CH2CH2NHR3, —SO2CH2CH2NR3R4, —SO2CH2CH2CH2NHR3, and —SO2CH2CH2CH2NR3R4;
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, hydroxy, —OR1, —NH2, —NHR1, —NR1R2, —CONH2, —CONHR1, —CONR1R2, —SO2NH2, —SO2NHR1, —SO2NR1R2, —NHCOR1, —NHCO2R1, —NHCONHR1, —NHSO2NHR1, —NHSO2R1, —COR1, —CO2R1, a C1-C6 straight chain alkyl, a C1-C6 branched alkyl, a C3-C6 cycloalkyl, a halo-C1-C6 straight chain alkyl, a halo-C1-C6 branched alkyl, a halo-C3-C6 cycloalkyl, a cyano-C1-C6 straight chain alkyl, a cyano-C1-C6 branched chain alkyl, and a cyano-C3-C6 cycloalkyl;
R1 and R2 are each independently selected from the group consisting of hydrogen, a C1-C6 straight chain alkyl, a C1-C6 branched alkyl, a C3-C6 cycloalkyl, a halo-C1-C6 straight chain alkyl, a halo-C1-C6 branched alkyl, a halo-C3-C6 cycloalkyl, a cyano-C1-C6 straight chain alkyl, a cyano-C1-C6 branched alkyl, and a cyano-C3-C6 cycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen, a C1-C6 straight chain alkyl, a C1-C6 branched alkyl, a C3-C6 cycloalkyl, a halo-C1-C6 straight chain alkyl, a halo-C1-C6 branched alkyl, a halo-C3-C6 cycloalkyl, a cyano-C1-C6 straight chain alkyl, a cyano-C1-C6 branched alkyl, and a cyano-C3-C6 cycloalkyl, or wherein R3 and R4, 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 method of claim 1, wherein R is an optionally substituted —Ar group, an optionally substituted —CH2Ar group, or an optionally substituted —CH2CH2CH2NR3R4 group.

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 3)

The method of claim 3, wherein R is phenyl substituted with one or more substituents independently selected from the group consisting of methyl, —CON(CH3)2, chlorine, —N(CH3)2, hydroxy, and methoxy.

### Claim 5 (depends on 2)

The method of claim 2, wherein R is a —CH2CH2CH2NR3R4, wherein R3 and R4 are independently a straight chain C1-C6 alkyl group.

### Claim 6 (depends on 5)

The method of claim 5, wherein R3 and R4 are both methyl.

### Claim 7 (depends on 2)

The method of claim 2, wherein R is a —CH2 phenyl group substituted with a chlorine.

### Claim 8 (depends on 2)

The method of claim 2, wherein R is a 2-methylpyridin-4-yl group.

### Claim 9 (depends on 2)

The method of claim 2, wherein R is a pyridin-3-ylmethyl group.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
N-(3-chlorophenyl)pyrimido[6′,1′: 2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (1),
N-(m-tolyl)pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (2),
N,N-dimethyl-3-(pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-ylamino)benzamide (3),
N1,N1-dimethyl-N3-(pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-yl)benzene-1,3-diamine (4),
N-(3-methoxyphenyl)pyrimido[6′,1′: 2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (5),
3-(pyrimido[6′,1′: 2,3]imidazo[4,5-c][2,6]naphthyridin-5-ylamino)phenol (6),
N-(3,5-dimethylphenyl)pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (7),
N-(3,5-dichlorophenyl)pyrimido[6′,1′: 2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (8),
N-(2-methylpyridin-4-yl)pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (9),
N-(3-chlorobenzyl)pyrimido[6′,1′: 2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (10),
N-(pyridin-3-ylmethyl)pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-amine (11),
N1,N1-dimethyl-N3-(pyrimido[6′,1′:2,3]imidazo[4,5-c][2,6]naphthyridin-5-yl)propane-1,3-diamine (12),
and a pharmaceutically acceptable salt or stereoisomer thereof.