US 11,891,394 B1Granted

Pyrrolo[2,3-c][1,6]naphthyridine-8-carboxylic acid compounds as CK2 inhibitors

AssigneeKing Faisal University

InventorsChristophe Tratrat, Michelyne Haroun

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Abstract

Novel pyrrolo[2,3-c][1,6]naphthyridine-8-carboxylic acid compounds, a method of synthesizing these compounds, a pharmaceutical composition comprising these compounds and a suitable carrier, and a method of using the compounds. The pyrrolo[2,3-c][1,6]naphthyridine-8-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.

Claims19

Dependent claims

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, —NHCOAr, —NHSO2Ar, —NHCH2CH2NHR3, —NHCH2CH2NR3R4, —NHCH2CH2CH2NHR3, —NHCH2CH2CH2NR3R4, —NHCOCH2CH2NHR3, —NHCOCH2CH2NR3R4, —NHCOCH2CH2CH2NHR3, —NHCOCH2CH2CH2NR3R4, —NHSO2CH2CH2NHR3, —NHSO2CH2CH2NR3R4, —NHSO2CH2CH2CH2NHR3, —NHSO2CH2CH2CH2NR3R4, —CH2Ar, —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, —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.

3 more elements

A compound selected from the group consisting of:

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

13 more elements

Dependencies are inferred from the claim text.

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Abstract

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, —NHCOAr, —NHSO2Ar, —NHCH2CH2NHR3, —NHCH2CH2NR3R4, —NHCH2CH2CH2NHR3, —NHCH2CH2CH2NR3R4, —NHCOCH2CH2NHR3, —NHCOCH2CH2NR3R4, —NHCOCH2CH2CH2NHR3, —NHCOCH2CH2CH2NR3R4, —NHSO2CH2CH2NHR3, —NHSO2CH2CH2NR3R4, —NHSO2CH2CH2CH2NHR3, —NHSO2CH2CH2CH2NR3R4, —CH2Ar, —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, —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.

3 more elements