Heterocyclic inhibitors of ERK1 and ERK2 and their use in the treatment of cancer

Patent metadata

Field	Value
Publication number	US-11925629-B2
Application number	US-202117368559-A
Country	US
Kind code	B2
Filing date	Jul 6, 2021
Priority date	Jun 15, 2015
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

The present application provides novel heterocyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful for inhibiting ERK1/2. By administering to a patient in need a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, Z, J, M, and R1 to R8 are defined herein, these compounds are effective in treating conditions associated with dysregulation of the RAS/RAF/MEK/ERK pathway. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer.

First claim

What is claimed is:

1. A method of inhibiting ERK1/2, the method comprising contacting ERK1/2 with a compound that is N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The method of claim 1 , wherein the contacting step is in vitro.

3. The method of claim 1 , wherein the contacting step is in vivo.

4. The method of claim 1 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

6. The method of claim 4 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

mandelic acid salt.

7. The method of claim 4 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

hydrochloric acid salt.

8. The method of claim 4 , wherein the compound is S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

benzenesulfonic acid salt.

9. A method of treating colorectal cancer, colon cancer, pancreatic cancer, thyroid cancer, lung cancer, or melanoma, in a subject, the method comprising administrating a compound that is N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The method of claim 9 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

12. The method of claim 9 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

mandelic acid salt.

13. The compound of claim 9 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

hydrochloric acid salt.

14. The method of claim 9 , wherein the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

benzenesulfonic acid salt.

Assignees

• Asana Biosciences Llc

Inventors

• Venkatesan Aranapakam M
• Thompson Scott K
• Smith Roger A
• Reddy Sanjeeva P
• Kethiri Raghava Reddy
• Dewang Purushottam M
• Hallur Gurulingappa
• Mulakala Chandrika

Classifications

• A61K31/443 Primary

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title