# US 12,180,208 B1 · Pyrazolo[1,5-c]pyrido[3,4-e]pyrimidines as CK2 inhibitors

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- Number: US 12,180,208 B1
- Document ID: US12180208B1
- Status: Granted
- Kind: B1
- Application number: 18/418,168
- Filed: 2024-01-19
- Granted: 2024-12-31
- Earliest claimed: 2024-01-19
- Assignees: King Faisal University
- Applicants: King Faisal University
- Inventors: Michelyne Haroun; Christophe Tratrat
- Web page: https://patentgrep.com/patent/US12180208B1

## CPC

- C07D 471/14: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine 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 pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine 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, —CH2CH2Ar, —COAr, —SO2Ar, —CH2CH2NHR3, —CH2CH2NR3R4, —CH2CH2CH2NHR3, —CH2CH2CH2NR3R4, —COCH2CH2NHR3, —COCH2CH2NR3R4, —COCH2CH2CH2NHR3, —COCH2CH2CH2NR3R4, —SO2CH2CH2NHR3, —SO2CH2CH2NR3R4, —SO2CH2CH2CH2NHR3, —SO2CH2CH2CH2NR3R4, C1-C6 alkyl, C1-C6 branched alkyl, C3-C6 cycloalkyl, halo-C1-C6 alkyl, halo-C1-C6 branched alkyl, halo-C3-C6 cycloalkyl, cyano-C1-C6 alkyl, cyano-C1-C6 branched alkyl, and cyano-C3-C6 cycloalkyl;
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, 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 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
R3 and R4 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 branched alkyl, C3-C6 cycloalkyl, halo-C1-C6 alkyl, halo-C1-C6 branched alkyl, halo-C3-C6 cycloalkyl, cyano-C1-C6 alkyl, cyano-C1-C6 branched alkyl, and a cyano-C3-C6 cycloalkyl, or wherein R3 and R4, 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-C6alkyl 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 —Ar group, an optionally substituted —CH2Ar group, or an optionally substituted —CH2CH2CH2NR3R4 group.

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 2)

The compound of claim 2, wherein R is a —CH2CH2CH2NR3R4 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 —CH2 phenyl 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 —CH2 pyridine group.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
6-((3-chlorophenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (1);
6-(m-tolylamino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (2);
6-((3-methoxyphenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (3);
6-((3-(dimethylamino)phenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (4);
6-((4-chlorophenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (5);
6-(p-tolylamino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (6);
6-((4-methoxyphenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (7);
6-((4-(dimethylamino)phenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (8);
6-((3-(dimethylcarbamoyl)phenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (9);
6-((3-(N,N-dimethylsulfamoyl)phenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (10);
6-((3-isopropylphenyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (11);
6-((2-methylpyridin-4-yl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (12);
6-((3-chlorobenzyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (13);
6-((pyridin-3-ylmethyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (14);
6-((3-(dimethylamino)propyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9 carboxylic acid (15);
6-((3-(4-methylpiperazin-1-yl)propyl)amino)pyrazolo[1,5-c]pyrido[3,4-e]pyrimidine-9-carboxylic acid (16); and
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.

### Claim 14 (depends on 13)

The method of claim 13, 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 15

A compound having the formula I:
or a pharmaceutically acceptable salt, ester, stereoisomer, or solvate thereof, wherein:
R is phenyl substituted with one or more substituents independently selected from the group consisting of methyl, chlorine, —N(CH3)2, —CON(CH3)2, —SO2N(CH3)2, isopropyl, and methoxy; a —CH2CH2CH2NR3R4 group; a pyridyl group substituted with a methyl; a —CH2 pyridine group; or a —CH2 phenyl group substituted with a chlorine; 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 16 (depends on 15)

A pharmaceutically acceptable composition comprising a therapeutically effective amount of 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 thereof a therapeutically effective amount of the compound of claim 15.

### Claim 18

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

### Claim 19 (depends on 18)

A pharmaceutically acceptable composition comprising a therapeutically effective amount of 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 thereof a therapeutically effective amount of the compound of claim 18.