Inhibitors of RAD52 Recombination Protein and Methods Using Same

• US 20180134727A1
• Filed: 06/03/2016
• Published: 05/17/2018
• Est. Priority Date: 06/04/2015
• Status: Active Grant

• Current Assignee: Drexel University
• Original Assignee: Drexel University
• Inventors: MAZIN, Alexander V.
• Granted Patent: US 10,442,817 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 307/82 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention includes novel RAD52 inhibitors for preventing or treating cancers in a subject in need thereof. The present invention further includes a method of preventing or treating cancers in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the subject is further administered at least one additional therapeutic agent.

Claims

1. A compound of formula (I):

3. The compound of claim 1, wherein one of the following applies:

(a) R¹ is

9. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, wherein the at least one compound is selected from the group consisting of:

1-(3-(diethylamino)propyl)-3-(3-(dimethylamino)propyl)-1-((6-oxo-5,6-dihydro-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)thiourea;

1-(3,4-dimethoxyphenyl)-N-(3-morpholinopropyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

7-chloro-3-methyl-N-(4-(N-methyl-N-(1-methylpiperidin-4-yl)sulfamoyl)phenyl) benzofuran-2-carboxamide;

N-(5-chloro-2-(4-methylbenzoyl) benzofuran-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;

N-(3-morpholinopropyl)-1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

1-(2-((2-aminoethyl)(methyl)amino)-4-methylquinolin-6-yl)-3-(3-(4-ethylpiperazin-1-yl)propyl)thiourea;

1-(3-(butyl(ethyl)amino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

1-(3-(dipropylamino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

3-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)propan-1-ol;

1-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)-3-(3-(4-methylpiperazin-1-yl)propyl)thiourea;

1-(2-(diethylamino)ethyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

2-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)ethan-1-ol;

3-(4-chlorophenyl)-1-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(2-(butyl(ethyl)amino)ethyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(3-(azepan-1-yl)propyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-(4-chlorophenyl)-1-methyl-N-(3-(pyrrolidin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-((2-((2-methoxyphenyl)amino) quinazolin-4-yl)amino)propan-1-ol;

a salt, solvate, tautomer, enantiomer, diastereoisomer, or N-oxide thereof, and any combinations thereof.

11. The composition of claim 9, further comprising at least one additional therapeutic agent that treats or prevents cancer.

2. A compound of formula (IX):

4-8. -8. (canceled)

12. A method of preventing or treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one selected from the group consisting of:

a compound of formula (I);

13. The method of claim 12, wherein the method further comprises administering to the subject at least one additional therapeutic agent that treats or prevents cancer.

16. The method of claim 12, wherein the compound is selected from the group consisting of:

1-(3-(diethylamino)propyl)-3-(3-(dimethylamino)propyl)-1-((6-oxo-5,6-dihydro-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)thiourea;

1-(3,4-dimethoxyphenyl)-N-(3-morpholinopropyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

7-chloro-3-methyl-N-(4-(N-methyl-N-(1-methylpiperidin-4-yl)sulfamoyl)phenyl) benzofuran-2-carboxamide;

N-(5-chloro-2-(4-methylbenzoyl) benzofuran-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;

N-(3-morpholinopropyl)-1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

1-(2-((2-aminoethyl)(methyl)amino)-4-methylquinolin-6-yl)-3-(3-(4-ethylpiperazin-1-yl)propyl)thiourea;

1-(3-(butyl(ethyl)amino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

1-(3-(dipropylamino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

3-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)propan-1-ol;

1-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)-3-(3-(4-methylpiperazin-1-yl)propyl)thiourea;

1-(2-(diethylamino)ethyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

2-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)ethan-1-ol;

3-(4-chlorophenyl)-1-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(2-(butyl(ethyl)amino)ethyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(3-(azepan-1-yl)propyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-(4-chlorophenyl)-1-methyl-N-(3-(pyrrolidin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-((2-((2-methoxyphenyl)amino)quinazolin-4-yl)amino)propan-1-ol;

a salt, solvate, tautomer, enantiomer, diastereoisomer, or N-oxide thereof, and any combinations thereof.

18. The method of claim 12, wherein the cancer is selected from the group consisting of squamous cell cancer, lung cancer vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

19. The method of claim 12, wherein the cancer is ovarian cancer or breast cancer.

20. The method of claim 12, wherein the human has mutations in at least one selected from the group consisting of BRCA1 and BRCA2.

14. (canceled)

15. (canceled)

17. (canceled)

21. (canceled)

22. A method of preventing or treating a RAD52 related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one selected from the group consisting of:

a compound of formula (I);

23. The method of claim 22, wherein the RAD52 related disease or disorder comprises cancer.

24. The method of claim 23, the method further comprising administering to the subject at least one additional therapeutic agent that treats or prevents cancer.

27. The method of claim 22, wherein the compound is selected from the group consisting of:

1-(3-(diethylamino)propyl)-3-(3-(dimethylamino)propyl)-1-((6-oxo-5,6-dihydro-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)thiourea;

1-(3,4-dimethoxyphenyl)-N-(3-morpholinopropyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

7-chloro-3-methyl-N-(4-(N-methyl-N-(1-methylpiperidin-4-yl)sulfamoyl)phenyl) benzofuran-2-carboxamide;

N-(5-chloro-2-(4-methylbenzoyl) benzofuran-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;

N-(3-morpholinopropyl)-1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

1-(2-((2-aminoethyl)(methyl)amino)-4-methylquinolin-6-yl)-3-(3-(4-ethylpiperazin-1-yl)propyl)thiourea;

1-(3-(butyl(ethyl)amino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

1-(3-(dipropylamino)propyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

3-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)propan-1-ol;

1-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)-3-(3-(4-methylpiperazin-1-yl)propyl)thiourea;

1-(2-(diethylamino)ethyl)-3-(4-methyl-2-(4-methylpiperazin-1-yl)quinolin-6-yl)thiourea;

2-((2-((2,5-dimethoxyphenyl)amino) quinazolin-4-yl)amino)ethan-1-ol;

3-(4-chlorophenyl)-1-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(2-(butyl(ethyl)amino)ethyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

N-(3-(azepan-1-yl)propyl)-3-(4-chlorophenyl)-1-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-(4-chlorophenyl)-1-methyl-N-(3-(pyrrolidin-1-yl)propyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3-((2-((2-methoxyphenyl)amino)quinazolin-4-yl)amino)propan-1-ol;

a salt, solvate, tautomer, enantiomer, diastereoisomer, or N-oxide thereof, and any combinations thereof.

29. The method of claim 23, wherein the cancer is selected from the group consisting of squamous cell cancer, lung cancer vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

30. The method of claim 23, wherein the cancer is ovarian cancer or breast cancer.

31. The method of claim 23, wherein the human has mutations in at least one selected from the group consisting of BRCA1 and BRCA2.

25. (canceled)

26. (canceled)

28. (canceled)