Sulfonyl amide derivatives for the treatment of abnormal cell growth
Inventors
Luzzio, Michael J. • Freeman-Cook, Kevin D. • Bhattacharya, Samit K. • Hayward, Matthew M. • Hulford, Catherine A. • Autry, Christopher L. • Zhao, Xumiao • Xiao, Jun • Nelson, Kendra L.
Assignees
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Publication Number
US-10450297-B2
Publication Date
2019-10-22
Expiration Date
Abstract
The present invention relates to a compound of the formula I wherein R1 to R6, A, B, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Core Innovation
The disclosed subject matter provides chemical structures and identifiers for a series of substituted pyrimidinyl, benzamide, and sulfonamide compounds, including free bases and salt forms such as hydrochloride, sodium salt, trifluoroacetic acid salt, trifluoroacetic acid, and formic acid salt. The series shares a common core architecture that includes a pyrimidine or trifluoromethylpyrimidine core and sulfonamide or benzamide motifs, with peripheral substituents varying across pyridinyl, pyrimidyl, pyrazinyl, anilide, and related ring systems.
The compounds further differ in side-chain and amide substituents, including alkyl, aryl, hydroxyethyl, aminoethyl, aminoacetamide, carboximidamide, glycinamide, carbamate/amide-type variants, piperidinyl, pyrrolidinyl, morpholinyl, benzyl, hydroxyalkyl, hydroxycyclobutyl, tetrahydrofuran-yl, cyclopropylmethyl, azetidinyl, cyclobutyl, hydroxypyrrolidinyl, hydroxypiperidinyl, difluoropyrrolidinyl, and acetamide or acetylaminoethyl groups. The provided content also includes broader Formula I, Ia, Ib, Ic, Id, and Formula (1) definitions with extensive substituent ranges, stereoisomers, tautomers, prodrugs, hydrates, solvates, isotopically labeled compounds, and pharmaceutically acceptable salts.
The method aspect described in the claims provides a way to make a compound of Formula (1) by reacting a compound of Formula (C3) with a compound of Formula (B5), thereby providing the compound of Formula (1). The disclosed content includes this reaction framework together with dependent refinements that specify reaction time, base identity, solvent system and ratio, and EtOAc treatment for isolation or workup.
The invention further includes therapeutic-use descriptions for abnormal cell growth, including cancer types, as well as osteoporosis and low bone mass, and it provides synthesis frameworks using schemes and intermediate compounds.
Claims Coverage
The consolidated claim coverage centers on one independent method claim: making a compound of Formula (1) by reacting a compound of Formula (C3) with a compound of Formula (B5). Across the supplied items, the inventive features consistently total 6 refinements: reaction pairing, reaction time, base identity, solvent system, solvent ratio, and EtOAc isolation/workup.
Reacting a compound of formula (c3) with a compound of formula (b5) to provide the compound of formula (1)
A method of making a compound of Formula (1) comprising reacting a compound of Formula (C3) with a compound of Formula (B5), thereby providing the compound of Formula (1).
Reaction time of 20 hours
The method is carried out by performing the reaction between the compound of Formula (C3) and the compound of Formula (B5) for 20 hours.
Using diethylamine (DIEA) as the base
The method is carried out using diethylamine (DIEA) as the base.
Using a solvent mixture of 1,2-dichloroethane (DCE) and t-BuOH
The method is carried out using a solvent mixture of 1,2-dichloroethane (DCE) and t-BuOH.
Using a 1:1 (v/v) ratio of 1,2-dichloroethane (DCE) to t-BuOH
The method is carried out using a 1:1 (v/v) ratio of 1,2-dichloroethane (DCE) to t-BuOH.
Treating with EtOAc for isolation
Isolating the compound of Formula (1) is done by treating the reaction between the compound of Formula (C3) and the compound of Formula (B5) with EtOAc.
Overall, the claim set defines preparation of Formula (1) by reacting Formula (C3) with Formula (B5), with dependent claims further specifying a 20-hour reaction time, diethylamine (DIEA) as base, a DCE/t-BuOH solvent system including a 1:1 (v/v) ratio, and EtOAc treatment for isolation.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic uses for abnormal cell growth, including cancer types.
Therapeutic uses for osteoporosis and low bone mass.
Treatment of abnormal cell growth in mammals and humans (including cancer).
Compounds prepared in the examples were evaluated for FAK kinase inhibition, with FAK IC50 values summarized alongside structures.
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