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-8476282-B2
Publication Date
2013-07-02
Expiration Date
Abstract
The present invention provides chemical entities or 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 using 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 isolated compounds of Formula II-A-1 and pharmaceutically acceptable salts thereof, with X1 being N and X2 being N, k being 1, and E2 being H. W2 is selected from a listed set of oxygen-, nitrogen-, and sulfur-containing substitution patterns, and the structural definition further constrains R1, R2, R3, R7, and R8 through broad substituent classes and ring-forming relationships.
The scaffold definition also includes L as a bond or one of several linking groups, including C(O), —C(=O)O—, —C(=O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—. R31, R32, and R33 are independently H or unsubstituted C1-10 alkyl, and R34 and R35 taken together with the nitrogen atom form a 3-10 membered saturated or unsaturated ring that is independently unsubstituted or substituted and contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom.
The patent also provides an isolated compound of a separate Formula in which R1 is selected from C1-10 alkyl, C3-8 cycloalkyl, or C1-10 alkylheterocyclyl, with pharmaceutically acceptable salts. The disclosure further includes pharmaceutically acceptable compositions comprising the compound or salt with a pharmaceutically acceptable carrier, and in certain embodiments a solid dosage form such as powder, capsule, or tablet.
Claims Coverage
Two independent claims are present. One is directed to an isolated compound of Formula II-A-1 or a pharmaceutically acceptable salt thereof with extensive structural-variable constraints, and the other is directed to an isolated compound of a separate Formula with R1 limited to three classes. The claim set further includes dependent refinements for mTOR inhibition potency and pharmaceutical composition limitations.
Formula II-A-1 isolated compound with fixed heteroatom core
An isolated compound of Formula II-A-1 or a pharmaceutically acceptable salt thereof wherein X1 is N, X2 is N, k is 1, and E2 is H, with W2 selected from the listed oxygen/nitrogen/sulfur-containing substitution patterns and R1, L, R2, R3, R7, and R8 defined by the stated allowed classes.
Ring-constrained nitrogen substituent formation using R34 and R35
R34 and R35 are taken together with the nitrogen atom to form a 3-10 membered saturated or unsaturated ring that is independently unsubstituted or substituted and contains 0, 1, or 2 additional heteroatoms in addition to the nitrogen atom.
Isolated compound with R1 limited to alkyl, cycloalkyl, or alkylheterocyclyl
An isolated compound of a separate Formula or a pharmaceutically acceptable salt thereof wherein R1 is selected from C1-10 alkyl, C3-8 cycloalkyl, or C1-10 alkylheterocyclyl.
mTOR inhibition potency threshold by the compound or salt
A compound or a pharmaceutically acceptable salt that inhibits mTOR with an IC50 value of 10 nM or lower, and in related refinements 5 nM or lower.
The claim coverage centers on a structurally defined Formula II-A-1 scaffold with fixed X1/X2, k, and E2 values plus enumerated W2, L, R1, R2, and R3 options and a defined ring-forming role for R34/R35. A second independent claim restricts R1 to alkyl, cycloalkyl, or alkylheterocyclyl, and dependent claims further narrow substituents and impose quantitative mTOR potency thresholds.
Stated Advantages
Selective inhibition of mTORC1 and/or mTORC2 over PI3K isoforms including PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ.
Improved potency versus rapamycin, including IC50 values down to pM.
ATP-site competition at mTORC1 and mTORC2.
Inhibition of enhanced Akt phosphorylation at S473 and T308.
Apoptosis and cell-cycle arrest, together with cell proliferation inhibition.
Functional selectivity with preferential inhibition of mTOR versus upstream PI3K.
Reduction of tumor growth in xenograft models.
Potential superiority over rapamycin in rapamycin-resistant settings.
Inhibits mTOR with an IC50 value of 10 nM or lower.
Inhibits mTOR with an IC50 value of 5 nM or lower.
Provides pharmaceutical compositions comprising the compound or pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
Documented Applications
Treating cancer and hyperproliferative disorders.
Treating inflammatory, immune, metabolic, cardiac, nervous, and respiratory diseases.
Combination therapy with a second therapeutic agent, including anti-cancer agents, rapamycin, and gleevec or derivatives.
Use in mTOR and/or PI3K assay contexts for determining biological activity against listed kinases.
Xenograft model settings described as showing reduced tumor growth.
Pharmaceutical composition use, including compositions comprising the compound or pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
Solid dosage form use as a powder, capsule, or tablet.
mTOR inhibition use, as stated by the IC50 thresholds against mTOR.
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