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US 2019/0055202 A1Published application
Pyrimidines and variants thereof, and uses therefor
AssigneeAfferent Pharmaceuticals, Inc.
InventorsRonald Charles Hawley, Prabha Ibrahim, Anthony P. Ford, Joel R. Gever
Life of this patent
Estimating the term…
Abstract
The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof for example, for the potential treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.
Claims20
A compound of Formula 1:
- or a pharmaceutically acceptable salt thereof, wherein:
- W is selected from CH2, O, S and NH;
- X1 is N or CR2;
- X2 is CR3;
- X3 is CR4;
- X4 is CR5;
- X5 is N or CR6, provided, however, when X1 is C—R2, W is not O or —CH2—;
- Y is selected from hydrogen or —NRdRe, wherein one of Rd and Re is hydrogen, and the other is:
- hydrogen;
- C1-12-alkyl;
- C3-12-cycloalkyl;
- C4-12-cycloalkylalkyl;
- C1-12-haloalkyl;
- C1-12-haloalkoxy;
- C1-12-hydroxyalkyl;
- C2-12-alkoxyalkyl;
- acetyl;
- C1-12-alkylsulfonyl;
- C2-12-alkylsulfonylalkyl;
- C2-12-aminocarbonyloxyalkyl;
- C1-12-hydroxycarbonylalkyl;
- C2-12-hydroxylalkyloxycarbonylalkyl;
- C5-12-aryl;
- C6-12-arylalkyl;
- C5-12-arylsulfonyl;
- C5-12-heteroaryl;
- C6-12-heteroarylalkyl;
- C5-12-heteroarylsulfonyl;
- C3-12-heterocyclyl;
- and C4-12-heterocyclylalkyl;
- D is an optional oxygen;
- R1 is selected from C1-12-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- C3-12-cycloalkyl;
- C3-12-cycloalkenyl;
- halo;
- C1-12-haloalkyl;
- and C1-12-hydroxyalkyl;
- R2, R3, R4 and R5 are each independently selected from hydrogen;
- C1-12-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- amino;
- halo;
- amido;
- C1-12-haloalkyl;
- C1-12-alkoxy;
- hydroxy;
- C1-12-haloalkoxy;
- nitro;
- C1-12-hydroxyalkyl;
- C2-12-alkoxyalkyl;
- C1-12-hydroxyalkoxy;
- C3-12-alkynylalkoxy;
- C1-12-alkylsulfonyl;
- C5-12-arylsulfonyl;
- cyano;
- C6-12-aryl;
- C5-12-heteroaryl;
- C3-12-heterocyclyl;
- C4-12-heterocyclylalkoxy;
- C6-12-aryloxy;
- C5-12-heteroaryloxy;
- C7-12-arylalkyloxy;
- C6-12-heteroaralkyloxy;
- optionally substituted phenoxy;
- —(CH2)m—(Z)n—(CO)—Rf and —(CH2)m—(Z)n—SO2—(NRg)n′—Rf, where m, n and n′ are each independently 0 or 1;
- Z is O or NRg;
- Rf is selected from hydrogen, C1-12-alkyl, hydroxy, C1-12-alkoxy, amino, C1-12-hydroxyalkyl and C2-12-alkoxyalkyl;
- each Rg is independently hydrogen or C1-12-alkyl;
- or alternatively, R3 and R4 together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms independently selected from O, S and N;
- or alternatively, R2 and R3 may together form an alkylene dioxy;
- or R2 and R3 together with the atoms to which they are attached form a five or six-membered ring that optionally includes one or two heteroatoms independently selected from O, S and N;
- R6 is selected from hydrogen;
- and C1-12-alkyl;
- and
- R7 is selected from hydrogen;
- C1-12-alkyl;
- C3-12-cycloalkyl;
- C4-12-cycloalkylalkyl;
- C1-12-haloalkyl;
- C1-12-haloalkoxy;
- C1-12-hydroxyalkyl;
- C2-12-alkoxyalkyl;
- acetyl;
- C1-12-alkylsulfonyl;
- C2-12-alkylsulfonylalkyl;
- C2-12-aminocarbonyloxyalkyl;
- C2-12-hydroxycarbonylalkyl;
- C3-12-hydroxyalkyloxycarbonylalkyl;
- C6-12-aryl;
- C7-12-arylalkyl;
- C6-12-arylsulfonyl;
- C5-12-heteroaryl;
- C6-12-heteroarylalkyl;
- C5-12-heteroarylsulfonyl;
- C3-12-heterocyclyl;
- and C1-12-heterocyclylalkyl.
96 more elements
4-12. (canceled)
A compound of Formula 3, or a pharmaceutically acceptable salt thereof:
- wherein:
- R3 and R4 each independently is:
- hydrogen;
- C1-12-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- amino;
- halo;
- amido;
- C1-12-haloalkyl;
- C1-12-alkoxy;
- hydroxy;
- C1-12-haloalkoxy;
- nitro;
- C1-12-hydroxyalkyl;
- C2-12-alkoxyalkyl;
- C1-12-hydroxyalkoxy;
- C3-12-alkynylalkoxy;
- C1-12-alkylsulfonyl;
- C6-12-arylsulfonyl;
- cyano;
- C6-12-aryl;
- C5-12-heteroaryl;
- C3-12-heterocyclyl;
- C4-12-heterocyclylalkoxy;
- C6-12-aryloxy;
- C5-12-heteroaryloxy;
- C7-12-arylalkyloxy;
- C1-12-heteroaralkyloxy;
- optionally substituted phenoxy;
- —(CH2)m—(Z)n—(CO)—Rf or —(CH2)m—(Z)n—SO2—(NRg)n′—Rf, where m, n and n′ are each independently 0 or 1;
- Z is O or NRg;
- Rf is hydrogen, C1-12-alkyl, hydroxy, C1-12-alkoxy, amino, C1-12-hydroxyalkyl or C2-12-alkoxyalkyl, and each Rg is independently hydrogen or C1-12-alkyl;
- or alternatively, R3 and R4 together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms independently selected from O, S and N;
- R7 is selected from:
- hydrogen;
- C1-12-alkyl;
- C3-12-cycloalkyl;
- C4-12-cycloalkylalkyl;
- C1-12-haloalkyl;
- C1-12-haloalkoxy;
- C1-12-hydroxyalky;
- C2-12-alkoxyalkyl;
- acetyl;
- C1-12-alkylsulfonyl;
- C2-12-alkylsulfonylalkyl;
- C2-12-aminocarbonyloxyalkyl;
- C2-12-hydroxycarbonylalkyl;
- C2-12-hydroxyalkyloxycarbonylalkyl;
- C6-12-aryl;
- C7-12-arylalkyl;
- C6-12-arylsulfonyl;
- C5-12-heteroaryl;
- C1-12-heteroarylalkyl;
- C5-12-heteroarylsulfonyl;
- C3-12-heterocyclyl;
- and C4-12-heterocyclylalkyl;
- and
- Rd is selected from:
- hydrogen;
- C1-12-alkyl;
- C3-12-cycloalkyl;
- C4-12-cycloalkylalkyl;
- C1-12-haloalkyl;
- C1-12-haloalkoxy;
- C1-12-hydroxyalky;
- C2-12-alkoxyalkyl;
- acetyl;
- C1-12-alkylsulfonyl;
- C2-12-alkylsulfonylalkyl;
- C2-12-aminocarbonyloxyalkyl;
- C2-12-hydroxycarbonylalkyl;
- C2-12-hydroxyalkyloxycarbonylalkyl;
- C6-12-aryl;
- C7-12-arylalkyl;
- C6-12-arylsulfonyl;
- C5-12-heteroaryl;
- C1-12-heteroarylalkyl;
- C5-12-heteroarylsulfonyl;
- C3-12-heterocyclyl;
- and C4-12-heterocyclylalkyl.
78 more elements
25-30. (canceled)
Dependencies are inferred from the claim text.