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US 2010/0063301 A1Published application
Synthesis of thrombopoietin activity modulating compounds
AssigneeLigand Pharmaceuticals Incorporated
InventorDean Phillips
Life of this patent
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Abstract
Disclosed herein are various methods for synthesizing compounds that modulate thrombopoietin activity. Also disclosed are intermediates useful for the preparation of these compounds.
Claims36
A compound having the structure:
- wherein:
- R4 is selected from hydrogen, F, Cl, Br, C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
- R5 is selected from hydrogen, OR10, SR10, NHR11, and CO2H;
- R7 is selected from hydrogen, an optionally substituted C1-C8 aliphatic, an optionally substituted C1-C8 haloaliphatic, an optionally substituted C1-C8 heteroaliphatic, an optionally substituted C1-C8 heterohaloaliphatic, an optionally substituted ring, and (CH2)mR14;
- R10 is selected from hydrogen, a protecting group, an optionally substituted C1-C4 aliphatic, an optionally substituted C1-C4 haloaliphatic, an optionally substituted C1-C4 heteroaliphatic, and an optionally substituted ring;
- R11 is selected from hydrogen, SO2R15, C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
- R14 is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
- R15 is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring;
- Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroaliphatic, an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C3-C5 heterocycle, and an optionally substituted alicyclic;
- W is selected from a halogen, B(OH)2, B(ORA)2, Sn(RB)3 where each RA is selected from an optionally substituted C1-C6 aliphatic;
- or the two ORA groups together form an optionally substituted ring;
- and RB is selected from an optionally substituted C1-C6 aliphatic, or an optionally substituted phenyl, or an optionally substituted heteroaryl;
- and
- m is 0, 1, or 2.
11 more elements
A method of obtaining a compound having the structure:
- comprising reacting a compound having the structure:
- with a nitrite and a compound having the structure:
- wherein:
- R4 is selected from hydrogen, F, Cl, Br, C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
- R5 is selected from hydrogen, OR10, SR10, NHR11, and CO2H;
- R7 is selected from hydrogen, an optionally substituted C1-C3 aliphatic, an optionally substituted C1-C8 haloaliphatic, an optionally substituted C1-C8 heteroaliphatic, an optionally substituted C1-C8 heterohaloaliphatic, an optionally substituted ring, and (CH2)mR14;
- R10 is selected from hydrogen, a protecting group, an optionally substituted C1-C4 aliphatic, an optionally substituted C1-C4 haloaliphatic, an optionally substituted C1-C4 heteroaliphatic, and an optionally substituted ring;
- R11 is selected from hydrogen, SO2R15, C1-C4 aliphatic, C1-C4 haloaliphatic, heteroaliphatic, and a ring;
- R14 is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
- R15 is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring;
- Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroaliphatic, an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C3-C5 heterocycle, and an optionally substituted alicyclic;
- W is selected from a halogen, B(OH)2, B(ORA)2, Sn(RB)3 where each RA is selected from an optionally substituted C1-C6 aliphatic;
- or the two ORA groups together form an optionally substituted ring;
- and RB is selected from an optionally substituted C1-C6 aliphatic, or an optionally substituted phenyl, or an optionally substituted heteroaryl;
- and
- m is 0, 1, or 2.
13 more elements
A method of obtaining a compound having the structure:
- comprising reacting a compound having the structure:
- with a compound having the structure:
- wherein:
- R1 is selected from CO2R10, CONR10R11, SO3R10, and a carboxylic acid bioisostere;
- R4 is selected from hydrogen, F, Cl, Br, C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
- R5 is selected from hydrogen, OR10, SR10, NHR11, and CO2H;
- R6 is selected from hydrogen, OR12, NR12R13, F, Cl, Br, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and a ring;
- R7 is selected from hydrogen, an optionally substituted C1-C8 aliphatic, an optionally substituted C1-C8 haloaliphatic, an optionally substituted C1-C8 heteroaliphatic, an optionally substituted C1-C8 heterohaloaliphatic, an optionally substituted ring, and (CH2)mR14;
- R10 is selected from hydrogen, a protecting group, an optionally substituted C1-C4 aliphatic, an optionally substituted C1-C4 haloaliphatic, an optionally substituted C1-C4 heteroaliphatic, and an optionally substituted ring;
- R11 is selected from hydrogen, SO2R15, C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
- R12 and R13 are each independently selected from hydrogen, an optionally substituted C1-C4 aliphatic, an optionally substituted C1-C4 haloaliphatic, an optionally substituted C1-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mR14;
- or one of R12 and R13 is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12 and R13 is null;
- or R12 and R13 are linked to form an optionally substituted C3-C8 ring;
- R14 is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
- R15 is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring;
- Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 heteroaliphatic, an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C3-C5 heterocycle, and an optionally substituted alicyclic;
- W is selected from a halogen, B(OH)2, B(ORA)2, Sn(RB)3 where each RA is selected from an optionally substituted C1-C6 aliphatic;
- or the two ORA groups together form an optionally substituted ring;
- and RB is selected from an optionally substituted C1-C6 aliphatic, or an optionally substituted phenyl, or an optionally substituted heteroaryl;
- and
- m is 0, 1, or 2.
18 more elements
Dependencies are inferred from the claim text.