Substituted quinazolines for inhibiting kinase activity
Inventors
Qian, Xiangping • Zhu, Yong-Liang
Assignees
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Publication Number
US-11865120-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.
Core Innovation
The document describes a process for preparing a compound having the structure of Formula Ib. The process includes contacting a compound having the structure of Formula A with a compound having the structure of Formula B in the presence of a base and a palladium catalyst under reaction conditions that provide a compound having the structure of Formula C, then contacting Formula C with acryloyl chloride to provide the compound having the structure of Formula Ib.
In the structural definitions, X1 is N or C—R2, each of R1, R2, R4, and R5 is independently H or halo, R3 is optionally substituted heterocycloalkyl, and each of R6, R12, R13, and R14 is independently H. R′ are each independently OH or both R′ taken together with the oxygen atoms to which they are attached form a 5-membered optionally substituted boronic ester.
The provided description and examples relate these Formula Ib compounds to substituted quinazolin-8-yl acrylamide derivatives and related quinazoline acrylamide analogs. The examples include substituted piperazine and morpholine side groups, fluorinated aniline-derived precursors, and characterization data such as LRMS and 1H NMR for multiple products.
Claims Coverage
One independent claim is explicitly provided. It covers a two-stage preparation of Formula Ib through a palladium-catalyzed formation of Formula C from Formula A and Formula B, followed by reaction of Formula C with acryloyl chloride; dependent claims refine the base, palladium catalyst, acid component, temperature, and the listed Formula Ib products.
Palladium-catalyzed formation of Formula C followed by acrylamide conversion with acryloyl chloride
Contacting a compound having the structure of Formula A with a compound having the structure of Formula B in the presence of a base and a palladium catalyst under reaction conditions that provide a compound having the structure of Formula C, and contacting the compound having the structure of Formula C with acryloyl chloride to provide the compound having the structure of Formula Ib.
Defined structural variables for Formula Ib
X1 is N or C—R2; each of R1, R2, R4, and R5 is independently H or halo; R3 is optionally substituted heterocycloalkyl; each of R6, R12, R13, and R14 is independently H; and R′ are each independently OH or both R′ taken together with the oxygen atoms to which they are attached to form a 5-membered optionally substituted boronic ester.
Carbonate base selection for the palladium-catalyzed step
The process uses a base selected from Na2CO3, K2CO3, or Cs2CO3.
Pd(dppf)Cl2 palladium catalyst
The process uses a palladium catalyst comprising [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2).
Trifluoroacetic acid as an acid component
The process uses trifluoroacetic acid as the acid component.
Temperature range constraint
The process is carried out at a temperature ranging from about 25°C to about 240°C.
Enumerated acrylamide-linked quinazoline derivatives as Formula Ib products
The compound having the structure of Formula Ib is selected from a listed group of specific acrylamide-linked quinazoline derivatives bearing different substituted piperazine and morpholine side groups.
The claim coverage centers on preparing Formula Ib by forming Formula C from Formula A and Formula B under base and palladium catalyst conditions, then converting Formula C with acryloyl chloride. Dependent claims narrow the process through carbonate base options, Pd(dppf)Cl2, trifluoroacetic acid, a temperature range, and an enumerated set of Formula Ib acrylamide-linked quinazoline derivatives.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Kinase inhibition and binding assays are described for compounds binding to and selectively inhibiting kinases such as EGFR, including mutants L858R, T790M, and del E746-A750, as well as EGFR L858R/T790M, HER2/HER4, ALK, BTK, FGFRs, KDR, Src, Met, and Pim kinases.
Bioscreening/proliferation model use is described with cell lines A549, A431, HCC827, and H1975.
An axenograft mouse model is described.
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