Pyrrolopyrimidine compounds as inhibitors of CDK4/6

Patent metadata

Field	Value
Publication number	US-9309252-B2
Application number	US-201414568410-A
Country	US
Kind code	B2
Filing date	Dec 12, 2014
Priority date	Feb 19, 2010
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The invention is directed to novel pyrrolopyrimidine compounds of formula (1) wherein R 1 , R 2y , R 4 , R 8 -R 11 , A and L are defined herein and to salts, including pharmaceutically acceptable salts thereof. The compounds of the present invention are CDK4/6 inhibitors and could be useful in the treatment of diseases and disorders mediated by CDK4/6, such as cancer, including mantle cell lymphoma, liposarcoma, non small cell lung cancer, melanoma, squamous cell esophageal cancer and breast cancer. The invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CDK4/6 activity and to the treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

First claim

What is claimed is:

1. A method for the treatment of a carcinoma with genetic aberrations that activate CDK 4/6 kinase activity in a patient in need of treatment thereof comprising administration of an effective amount of a compound selected from the group consisting of:
7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;
7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;
7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;
7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; and
7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein the compound is 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 wherein the compound is 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 wherein the compound is 7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 wherein the carcinoma is mantle cell lymphoma, multiple myeloma, breast cancer, squamous cell esophageal cancer, liposarcoma, melanoma, non small cell lung cancer or pancreatic cancer.

8. The method according to claim 1 wherein the compound is 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

9. The method according to claim 7 wherein the compound is 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

10. The method according to claim 7 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

11. The method according to claim 7 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

12. The method according to claim 7 wherein the compound is 7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 wherein the carcinoma is breast cancer or melanoma.

14. The method according to claim 13 wherein the compound is 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

15. The method according to claim 13 wherein the compound is 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

16. The method according to claim 13 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

17. The method according to claim 13 wherein the compound is 7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

18. The method according to claim 13 wherein the compound is 7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide; or a pharmaceutically acceptable salt thereof.

Assignees

• Brain Christopher Thomas
• Cho Young Shin
• Giraldes John William
• Lagu Bharat
• Levell Julian Roy
• Luzzio Michael Joseph
• Perez Lawrence Blas
• Wang Yaping
• Yang Fan
• Novartis Ag

Inventors

• Brain Christopher Thomas
• Cho Young Shin
• Giraldes John William
• Lagu Bharat
• Levell Julian Roy
• Luzzio Michael Joseph
• Perez Lawrence Blas
• Wang Yaping
• Yang Fan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title