Benzoxazole kinase inhibitors and methods of use
Inventors
Ren, Pingda • Liu, Yi • Wilson, Troy Edward • Li, Liansheng • Chan, Katrina
Assignees
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Publication Number
US-8476431-B2
Publication Date
2013-07-02
Expiration Date
Abstract
The present invention provides chemical entities, compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. For example, the invention provides compounds of Formula:Also provided in the present invention are methods of making such compounds or compositions, and methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications such as treatment of cancer.
Core Innovation
The invention relates to a process for synthesizing a compound of Formula C by allowing a compound of Formula A to react with a compound of Formula B under conditions effective for synthesizing a compound of Formula C. The process is defined by structural constraints on the reactants and product, including T1 being halo, X1 being N, X2 being N, and X3 being C, together with defined substituent and linker constraints for R1, L, G, W2, k, and R2.
A central structural requirement is that M of Formula B is a M1 moiety, and the M moiety of Formula B and the M1 moiety of Formula C are identical having a specified structure. The definitions further require that R1 of Formula A and R1 of Formula C are the same, and that R31 and R32 of Formula A and Formula C are the same, with additional ring-forming rules for G groups and related substituent relationships.
The claimed scope also includes extensive enumerated options for W2 and R2, including oxygen, amine, sulfoxide/sulfone, carbonyl, and related moieties, as well as hydrogen, halogen, hydroxyl, and multiple functional group classes. The process framework is anchored by the same M1 moiety structure between Formula B and Formula C and by tightly defined substitution patterns across the formula classes.
Claims Coverage
One independent claim is present, directed to a process for synthesizing Formula C by reacting Formula A with Formula B under effective conditions. The claim includes multiple inventive structural constraints, including T1/X1/X2/X3, the identical M-moiety condition between Formula B and Formula C, and extensive substituent definitions for R1, L, G, W2, k, and R2.
Process for synthesizing formula c from formula a and formula b
A process for synthesizing a compound of Formula C by allowing a compound of Formula A to react with a compound of Formula B under conditions effective for synthesizing a compound of Formula C.
Identical m-moiety structure between formula b and formula c
M of Formula B is a M1 moiety, and the M moiety of Formula B and the M1 moiety of Formula C are identical having the structure defined in the claim.
Shared substituent constraints between formula a and formula c
R1 of Formula A and R1 of Formula C are the same, and R31 of Formula A and R31 of Formula C are the same, and R32 of Formula A and R32 of Formula C are the same.
Defined t1, x1-x3, l, g, w2, k, and r2 scope
T1 is halo, X1 is N, X2 is N, and X3 is C; L is selected from the enumerated bond and linker options; each G is independently H or RG1 and may join to form a 5- or 6-membered cyclic moiety; W2 is selected from the listed linkage types; k is 1; and R2 is selected from the listed substituent options.
Inventive coverage centers on the single process claim for forming Formula C from Formula A and Formula B, with the key requirement that the M moiety of Formula B and the M1 moiety of Formula C are identical and with strict, enumerated structural constraints linking the formula classes.
Stated Advantages
Compounds are evaluated with biological activity reported as IC50/EC50 values against mTOR and PI3K isoforms (PI3Kα/β/γ/δ) and PC3.
Documented Applications
Compounds are evaluated with Table 1 biological activity reported as IC50/EC50 values against mTOR and PI3K isoforms (PI3Kα/β/γ/δ) and PC3.
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