# US 11,897,883 B1 · Pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid compounds as CK2 inhibitors

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- Number: US 11,897,883 B1
- Document ID: US11897883B1
- Status: Granted
- Kind: B1
- Application number: 18/459,717
- Filed: 2023-09-01
- Granted: 2024-02-13
- Earliest claimed: 2023-09-01
- Assignees: King Faisal University
- Applicants: King Faisal University
- Inventors: Michelyne Haroun; Christophe Tratrat
- Web page: https://patentgrep.com/patent/US11897883B1

## CPC

- C07D 471/14: Ortho-condensed systems
- 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 pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid 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 pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid 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, —CH2Ar, —COAr, —SO2Ar, —CH2CH2NHR3, —CH2CH2NR3R4, —CH2CH2CH2NHR3, —CH2CH2CH2NR3R4, —COCH2CH2NHR3, —COCH2CH2NR3R4, —COCH2CH2CH2NHR3, —COCH2CH2CH2NR3R4, —SO2CH2CH2NHR3, —SO2CH2CH2NR3R4, —SO2CH2CH2CH2NHR3, —SO2CH2CH2CH2NR3R4, —NHAr, —NHCH2Ar, —NHCOAr, —NHSO2Ar, —NHCH2CH2NHR3, —NHCH2CH2NR3R4, —NHCH2CH2CH2NHR3, —NHCH2CH2CH2NR3R4, —NHCOCH2CH2NHR3, —NHCOCH2CH2NR3R4, —NHCOCH2CH2CH2NHR3, —NHCOCH2CH2CH2NR3R4, —NHSO2CH2CH2NHR3, —NHSO2CH2CH2NR3R4, —NHSO2CH2CH2CH2NHR3, and —NHSO2CH2CH2CH2NR3R4;
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, —OH, —OR1, —NH2, —NHR1, —NR1R2, —CONH2, —CONHR1, —CONR1R2, —SO2NH2, —SO2NHR1, —SO2NR1R2, —NHCOR1, —NHCO2R1, —NHCONHR1, —NHSO2NHR1, —NHSO2R1, —COR1, —CO2R1, —CH2NHR1, —CH2NR1R2, —OCH2CO2R1, —OCH2CONHR1, —OCH2CONHR1R2, —OCH2COR1, —OCH2CONHR1, —OCH2CONR1R2, 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;
R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 straight chain 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
R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6 straight chain 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 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 compound of claim 1, wherein R is an optionally substituted —NHAr group, an optionally substituted —NHCH2Ar group, or an optionally substituted —NHCH2CH2CH2NR3R4 group.

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 2)

The compound of claim 2, wherein R is a —NHCH2CH2CH2NR3R4 group, wherein R3 and R4 are independently a straight chain C1-C6 alkyl group, or wherein R3 and R4 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 R3 and R4 are both methyl or wherein R3 and R4 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)amino group.

### Claim 9 (depends on 2)

The compound of claim 2, wherein R is a (pyridin-3-ylmethyl)amino) group.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
4-((3-chlorophenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (1),
4-(m-tolylamino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (2),
4-((3-methoxyphenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (3),
4-((3-(dimethylamino)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (4),
4-((4-chlorophenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (5),
4-(p-tolylamino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (6),
4-((4-methoxyphenyl)amino)-1H-pyrrolo[3,2-c][1,7]naphthyridine-2-carboxylic acid (7),
4-((4-(dimethylamino)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (8),
4-((3-(dimethylcarbamoyl)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (9),
4-((3-(N,N-dimethylsulfamoyl)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (10),
4-((3-isopropylphenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (11),
4-((2-methylpyridin-4-yl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (12),
4-((3-chlorobenzyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (13),
4-((pyridin-3-ylmethyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (14),
4-((3-(dimethylamino)propyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (15), and
4-((3-(4-methylpiperazin-1-yl)propyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (16),
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

A method of inhibiting CK2 enzyme activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.

### Claim 13 (depends on 1)

A method of treating a cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1; wherein the cancer is one or more selected from the group consisting of leukemia, melanoma, colon cancer, prostate cancer, lung cancer, pancreatic cancer, and breast cancer.

### Claim 14

A compound having the formula I:
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof, wherein:
R is —NHAr and Ar is phenyl substituted with one or more substituents independently selected from the group consisting of —NR1R2, a straight or branched C1-C6 alkyl, —OR1, —CONR1R2, —SO2NR1R2, and halogen, wherein R1 and R2 are independently a straight chain C1-C6 alkyl group; a —NHCH2CH2CH2NR3R4 group; a —NHCH2phenyl group substituted with a chlorine; a (2-methylpyridin-4-yl)amino group; and a (pyridin-3-ylmethyl)amino) group; and
R3 and R4 are independently a straight chain C1-C6 alkyl group or wherein R3 and R4 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 15 (depends on 14)

A pharmaceutically acceptable composition comprising a therapeutically effective amount of the compound of claim 14 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 14)

A method of treating a cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 14; wherein the cancer is one or more selected from the group consisting of leukemia, melanoma, colon cancer, prostate cancer, lung cancer, pancreatic cancer, and breast cancer.

### Claim 17

A compound selected from the group consisting of:
4-((3-chlorophenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (1),
4-(m-tolylamino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (2),
4-((3-methoxyphenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (3),
4-((3-(dimethylamino)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (4),
4-((4-chlorophenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (5),
4-(p-tolylamino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (6),
4-((4-methoxyphenyl)amino)-1H-pyrrolo[3,2-c][1,7]naphthyridine-2-carboxylic acid (7),
4-((4-(dimethylamino)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (8),
4-((3-(dimethylcarbamoyl)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (9),
4-((3-(N,N-dimethylsulfamoyl)phenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (10),
4-((3-isopropylphenyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (11),
4-((2-methylpyridin-4-yl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (12),
4-((3-chlorobenzyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (13),
4-((pyridin-3-ylmethyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (14),
4-((3-(dimethylamino)propyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (15), and
4-((3-(4-methylpiperazin-1-yl)propyl)amino)-1H-pyrrolo[3,2-c][1,6]naphthyridine-2-carboxylic acid (16),
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof.

### Claim 18 (depends on 17)

A pharmaceutically acceptable composition comprising a therapeutically effective amount of the compound of claim 17 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 17)

A method of treating a cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 17; wherein the cancer is one or more selected from the group consisting of leukemia, melanoma, colon cancer, prostate cancer, lung cancer, pancreatic cancer, and breast cancer.