Amino-substituted heteroaryls for treating cancers with EGFR mutations
Inventors
Andrews, Kristin Lynne • Gerard, Baudouin • Horan, Joshua Courtney • MENTE, SCOT RICHARD • Pelish, Henry Efrem • Shair, Matthew D. • Sun, Yuting • Tangpeerachaikul, Anupong
Assignees
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Publication Number
US-12037346-B2
Publication Date
2024-07-16
Expiration Date
Abstract
Disclosed are amino-substituted heteroaromatic compounds such as a compound of Formula (I): pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof. Also disclosed are methods of treating or preventing cancer using the amino-substituted heteroaromatic compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof.
Core Innovation
The invention concerns compounds of Formula (I-i), or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, with extensive structural definitions for substituents and ring variables including R1, R2, J, X1, U, V, W, Y1, Y2, ring B, and related indices. The framework allows R1 to be selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, or 3- to 6-membered heterocyclyl, each optionally substituted by independently selected Ra substituents. Ra includes halo, CN, C(O)OC1-5 alkyl, N(Rn1)2, OC1-5 alkyl, OC1-5 alkylene-OC1-5 alkyl, and 3- to 6-membered heterocyclyl, with further optional substitution by an enumerated group.
The Formula (I-i) definitions further constrain the scaffold through connectivity and heteroatom requirements. In one arrangement, J is —NRb— with Rb being H or C1-5 alkyl and X1 is CH; in another arrangement, J is a bond and X1 is N. Additional variables U, V, W, Y1, and Y2 are defined as CRc or N, CRd or N, and CH, CR4, or N, together with provisos that at least one of U and V is N and at least one of Y1 and Y2 is CH or CR4.
Ring B is defined as 6- to 10-membered aryl or 5- to 10-membered heteroaryl, and the claim includes indices such as m, s, t, n, and p, together with substituent variables including R5 and bridge-forming R2 conditions. The definition includes geminal and non-geminal R2 relationships, where two geminal R2 taken together form O or two non-geminal R2 taken together form a C1-4 alkylene bridge. The provided content also describes representative compounds, substituted heteroaromatic embodiments, pharmaceutical compositions comprising the compounds and pharmaceutically acceptable excipients, and analytical characterization by 1H NMR and LCMS.
Claims Coverage
The consolidated claim coverage centers on independent claim 1, directed to a compound of Formula (I-i) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, together with at least one pharmaceutical composition claim including an excipient. The inventive features below merge the principal structural restrictions and dependent refinements present across the provided claim sets.
Formula (I-i) compound with defined substituent architecture
A compound of Formula (I-i) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1 is C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, or 3- to 6-membered heterocyclyl, each optionally substituted with one or more independently selected Ra substituents, and where multiple additional variables J, X1, U, V, W, Y1, Y2, ring B, and indices n, s, t, p, and m are defined with enumerated substitution and structural constraints.
Ra substituent set with broad optional substitution
Ra is independently halo, CN, NO2, aralkyl, alkyl, alkoxy, amino-containing groups, C(O)OC1-5 alkyl, N(Rn1)2, OC1-5 alkyl, OC1-5 alkylene-OC1-5 alkyl, or 3- to 6-membered heterocyclyl, wherein the substituent classes are optionally and independently substituted as provided in the claim and Rn1 is independently H or C1-5 alkyl.
Conditional definitions for J and X1
J is —NRb— with Rb being H or C1-5 alkyl, or J is a bond with X1 being N; in the alternative arrangement, J is —NRb— with X1 being CH.
R2 geminal or non-geminal bridge formation options
Each R2 is independently C1-5 alkyl, with dependent refinement to CH3 or CH2F, or two geminal R2 taken together form O, or two non-geminal R2 taken together form a C1-4 alkylene bridge such as —CH2— or —CH2CH2—.
U, V, W and Y1/Y2 structural constraints
U is CRc or N; V is CRd or N; W is CRc or N; Y1 is CH, CR4, or N; and Y2 is CH, CR4, or N, with the provisos that at least one of U and V is N and at least one of Y1 and Y2 is CH or CR4. In a dependent refinement, U is N and Y1 and Y2 are CR4.
Ring B size limitation and R5 substituent set
Ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, and each R5 is independently halo, C1-5 alkyl, or OC1-5 alkyl, wherein the C1-5 alkyl or OC1-5 alkyl is optionally substituted with one or more substituents selected from the enumerated group.
R36 and R37 heterocycle formation
R36 and R37 are each independently H or hydrocarbyl, and when taken together with the nitrogen atom to which they are attached, they can form a 4- to 8-membered heterocyclyl.
Pharmaceutical composition including excipient
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of Formula (I-i), including its pharmaceutically acceptable salts, stereoisomers, or tautomers.
Across the provided independent claim, the scope is defined around a Formula (I-i) compound with extensive optional substitution and multiple structural constraints governed by variables including J/X1, U/V/W, Y1/Y2, ring B, and indices n, s, t, p, and m. The provided dependent refinements narrow R2, fix U to N, set Y1 and Y2 to CR4, restrict R4 to F, Cl, CH3, CHF2, or OCH3, and include a pharmaceutical composition category.
Stated Advantages
Selectivity/sparing versus wild-type EGFR/HER2 is asserted using fold-difference ranges.
CNS penetration is mentioned for CNS metastases.
Prevents or treats proliferative diseases, including HER2-associated cancers.
Improves drug delivery through effects on the tumor-stroma microenvironment and tumor-immune microenvironment components.
Documented Applications
Treating or preventing cancer, including HER2-associated cancer and EGFR mutations such as exon 20 insertion coverage.
Preventing or treating proliferative diseases, including HER2-associated cancers such as non-small cell lung cancer (NSCLC) and squamous head and neck cancer.
Addressing CNS metastases.
Normalizing the tumor microenvironment by targeting tumor stromal and immune cells.
Combination therapy with immunomodulators and chemo/radiation regimens, including CAR-T, checkpoint inhibitors, MEK/MET/EGFR/PI3K/PDGF inhibitors, DNA damaging agents, and ER stress inducers.
Pharmaceutical compositions comprising the compound of Formula (I-i) and a pharmaceutically acceptable excipient.
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