Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activities
AssigneeDeciphera Pharmaceuticals, LLC
InventorsDANIEL L. FLYNN, MICHAEL D. KAUFMAN
Life of this patent
Estimating the term…
Abstract
The disclosed compounds are useful in the treatment of mammalian cancers and especially human cancers. Compounds, pharmaceutical compositions, and methods of Formula I are disclosed: or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer, or tautomer thereof.
Claims27
A compound of Formula I,
- or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer, or tautomer thereof,
- wherein
- X is halogen;
- Z1 and Z2 are independently and individually CR2 or N;
- Z3 is CH or N;
- with the proviso that ring B is not a tetrazine;
- each R1 is independently and individually halogen, H, C1-C6 alkyl, branched C3-C7 alkyl, C3-C7 cycloalkyl, or —CN;
- each R2 is individually and independently H, halogen, C1-C6 alkyl, or cyano;
- R3 is —C(O)R4, —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl, wherein
- aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl;
- and
- with the proviso that when R3 is —C(O)—C4-C6-heterocyclyl, the heterocyclyl does not have a N bonding hand to —C(O);
- R4 is C1-C7 alkyl, C3-C8 cycloalkyl, —(CH2)p—CN, —(CH2)p—OR6, —(CH2)p—NR6(R7), —(CH2)p—SO2—C1-C6-alkyl, —(CH2)p—C6-C10-aryl, —(CH2)p—C5-C6-heteroaryl, or —(CH2)p—C4-C6-heterocyclyl, wherein
- each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
- and
- aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl;
- each R6 and R7 is individually and independently H, C1-C6 alkyl, or C3-C8 branched alkyl;
- each cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with —(R25)m;
- each R25 is individually and independently C1-C6 alkyl, branched C3-C8 alkyl, halogen, —(CH2)m—CN, —(CH2)m—OR6, —(CH2)m—NR6(R7), —(CH2)m—SO2—C1-C6-alkyl, —(CH2)m—C(O)NR6(R7), —(CH2)m—C(O)—C4-C6-heterocyclyl, or —(CH2)m—C4-C6-heterocyclyl, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
- each m is individually and independently 0, 1, 2, or 3;
- and
- p is 1, 2, or 3.
A compound selected from the group consisting of N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-5-chloro-2-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide, N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate, N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and pharmaceutically acceptable salts, solvates, hydrates and tautomers thereof.
A compound selected from N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
Dependencies are inferred from the claim text.