Substituted benzamides as intermediates in the synthesis of inhibitors of tyrosine kinase enzymatic activity

Inventors

Romero, F. Anthony • Kirschberg, Thorsten A. • HALCOMB, Randall • XU, Yingzi

Assignees

Terns Pharmaceuticals Inc

Abstract

Provided herein are compounds, preferably compounds inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1, compositions thereof, and methods of their preparation, and methods of inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1, and methods for treating diseases wherein modulation of BCR-ABL1 activity prevents, inhibits, or ameliorates the pathology and/or symptomology of the disease. Intermediates such as compounds of Formula (S23), which are useful in the synthesis of compounds inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1, are also provided.

Core Innovation

The disclosed subject matter provides a process for synthesizing a compound of Formula (S23) by contacting a compound of Formula (24c) with an amine of Formula (S1), H2N—R2. The product Formula (S23) is characterized by a broadly defined substituent variable R2, where R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, with optional substitution by 1, 2, or 3 substituents independently selected from halo, CN, C(O)NHC1-C6 alkyl, C(O)NHC3-C6 cycloalkyl, OH, OC1-C6 alkyl, —O—, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

The C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl portions are optionally substituted with the listed group, and the C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl portions are similarly optionally substituted with 1, 2, or 3 substituents independently selected from the same listed group. The description further states that R2 and R3 together form ring A, described as a 5-6 membered heterocycloalkyl optionally substituted with 1-3 groups.

The description content also presents substituted benzimidazole-containing intermediates and final compounds prepared through multiple transformations, including Pd-catalyzed coupling, cyclization to benzimidazoles, hydrolysis, and amidation. Additional examples describe heterocycle coupling and formation of carboxamide derivatives, with supporting characterization for multiple named compounds and intermediates.

Claims Coverage

The independent claim set centers on one process claim for synthesizing a compound of Formula (S23) by contacting a compound of Formula (24c) with an amine of Formula (S1). The inventive scope is defined by broad R2 and optional substitution patterns, with dependent refinements including restricting R2 to C1-C6 alkyl and requiring a base, specifically triethylamine.

Across the independent claim and dependent refinements, the process centers on forming Formula (S23) by contacting Formula (24c) with an H2N—R2 amine. The inventive scope is defined by broad R2 and optional substitution rules, with dependent claims narrowing R2 to C1-C6 alkyl and requiring a base, specifically triethylamine.

Stated Advantages

Documented Applications

No documented applications found