Pyrazine compounds as inhibitors of FLT3
Inventors
Sperandio, David • Wang, Xiaodong • Kirschberg, Thorsten A. • Palmer, James T. • Butler, Thomas • Ungashe, Solomon B. • Squires, Neil Howard • Lin, Nan-Horng • Upasani, Ravindra B. • Adam, Amna Trinity-Turjuman • Su, Yongli • Phan, Thu
Assignees
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Publication Number
US-11945785-B2
Publication Date
2024-04-02
Expiration Date
Abstract
Disclosed herein are heterocyclic compounds, for example, according to the following formula and analogs thereof: that inhibit the activity of FLT3. Also described are specific covalent inhibitors of FLT3. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the FLT3 inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of proliferative diseases or conditions, including hematological malignancies and other diseases or conditions dependent on FLT3 activity.
Core Innovation
The invention relates to compounds according to Formula (P6-I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compounds include each A1, A2, A3, and A4 independently as —C(R7), and each L1 and L3 independently as substituted or unsubstituted C1-C4 alkylene. The disclosure also describes a pyrazine-2-carboxamide scaffold with variable substituents represented by R1, R2b, R4, R5, R6a, R6b, R6c, and R7.
R4 is —C(O)—C(R6a)≡C(R6b)(R6c), and R6a and R6b are independently H, halo, CN, or C1-6 alkyl, or are joined together to form a bond, while R6c is H, halo, CN, or C1-6 alkyl. R5 is H, cycloalkyl, heterocycloalkyl, CN, halo, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino, and R7 is independently H, halo, CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
The disclosure describes FLT3 inhibitor compounds and covalent FLT3 inhibitor compounds within the Formula (P6-I) framework, including substituted pyrazine-2-carboxamide derivatives and related intermediates. It also identifies representative compound structures and stereoisomer, salt, solvate, and isotopic variants within the defined compound class.
Claims Coverage
The consolidated claim coverage centers on one independent claim defining a Formula (P6-I) compound class, including stereoisomers and pharmaceutically acceptable salts. The inventive features are the Formula (P6-I) scaffold itself and the defined substitution patterns for A1-A4, L1/L3, R1, R2b, R4, R5, R6a/R6b/R6c, and R7, with one claim set also describing covalent FLT3 inhibitor functionality.
Formula (P6-I) compound scaffold
A compound according to Formula (P6-I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
A1-A4 as —C(R7)
Each of A1, A2, A3, and A4 is independently —C(R7).
L1 and L3 as substituted or unsubstituted C1-C4 alkylene
Each of L1 and L3 is independently substituted or unsubstituted C1-C4 alkylene, with substituents on each C1-C4 alkylene independently selected from halo, CN, C1-4 alkyl, hydroxy, and C1-4 alkoxy.
R1 substituent options
R1 is H, halo, CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
R2b selection
R2b is independently H or C1-C4 alkyl.
Carbonyl-containing R4 motif
R4 is —C(O)—C(R6a)≡C(R6b)(R6c), with R6a and R6b independently H, halo, CN, or C1-6 alkyl, or joined together to form a bond, and R6c independently H, halo, CN, or C1-6 alkyl.
R5 and R7 substituent options
R5 is H, cycloalkyl, heterocycloalkyl, CN, halo, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino; R7 is independently H, halo, CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Covalent FLT3 inhibitor functionality
The disclosure describes covalent FLT3 inhibitor compounds within the Formula (P6-I) framework, including covalent attachment to FLT3.
The claim coverage is anchored on the Formula (P6-I) compound class with defined structural variability at A1-A4, L1/L3, and the R-group positions. The provided material also identifies covalent FLT3 inhibitor functionality as part of the disclosed scope.
Stated Advantages
Exhibiting sub-nanomolar potency (IC50 <1 nM or <0.1 nM).
High FLT3 active-site occupancy in vivo in rats.
Improved cellular activity and improved off-target profile relative to C-1 and C-3.
Documented Applications
FLT3 inhibition context for embodiments shown by chemical structures, including salt, solvate, and stereoisomer forms.
In vivo FLT3 active-site occupancy in rats at low mg/kg dose.
Therapeutic use for proliferative diseases and hematologic malignancies dependent on FLT3 activity, including acute myeloid leukemia, MDS, ALL, and leukemia and AML.
Pharmaceutical compositions comprising the compounds.
FLT3 cell-based proliferation inhibition assay in AML/MV4-11/CML K562 cell lines reporting IC50 values.
Treating hematological malignancies.
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