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US 2011/0257137 A1Published application
Heterocyclic inhibitors of histamine receptors for the treatment of disease
AssigneeKalypsys, Inc.
InventorsAllen Borchardt, Robert Davis, Clay Beauregard, Daniel Becker, Daniel Gamache, Stewart A. Noble, Mark Hellberg, Peter Klimko, Zhihai Qiu, Joseph Payne, John Yanni
Life of this patent
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Abstract
The present invention relates to compounds and methods which may be useful as inhibitors of H1R and/or H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
Claims89
A compound of structural Formula (I):
- or a salt thereof, wherein:
- the ring comprising X1-X5 is aromatic;
- X1 and X5 are independently selected from the group consisting of C, CH and N;
- X2 is selected from the group consisting of [C(R6)(R7)]n, NR8, O and S;
- X3 is selected from the group consisting of [C(R9)(R10)]m, NR11, O, and S;
- X4 is selected from the group consisting of [C(R12)(R13)], NR14, O and S;
- n and m are each an integer from 1 to 2;
- Y1 is selected from the group consisting of a bond, lower alkyl, lower alkoxy, OR15, NR16R17, and lower aminoalkyl;
- R1 is selected from the group consisting of:
- null, when Y1 is selected from the group consisting of OR15, and NR16R17;
- and
- aryl, heterocycloalkyl, cycloalkyl, and heteroaryl, any of which may be optionally substituted, when Y1 is a bond;
- R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
- R6, R7, R9, R10, R12, and R13 are independently selected from the group consisting of null, hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
- R8, R11, and R14 are independently selected from the group consisting of null, hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, perhaloalkyl, aminoalkyl, C-amido, carboxyl, acyl, hydroxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
- R15 and R16 are independently selected from the group consisting of aminoalkyl, alkylaminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
- and
- R17 is independently selected from the group consisting of hydrogen, aminoalkyl, alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted.
15 more elements
A compound chosen from any one of Examples 251-415 and 417-519, or a salt thereof.
A compound of structural Formula (Va):
- or a salt thereof, wherein:
- X1 is chosen from C, CH and N;
- X2 is chosen from [C(R6)(R7)]n, NR8, and O;
- X3 is chosen from [C(R9)(R10)]m and NR11, and O;
- the ring comprising X1-X3 is aromatic;
- R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
- R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
- R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
- R6, R7, R9, and R10, are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted;
- and
- R8, R11, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
- and with the proviso that:
- when X1 is C, X2 is NR8, R8 is null, X3 [C(R9)(R10)]m, m is 1, R9 is null, R1 is methylpiperazine, R4 is perfluoromethyl, and R5 is fluoro,
- then R10 is hydrogen.
11 more elements
A compound having a structural formula chosen from:
- or a salt thereof, wherein:
- R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
- R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
- R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
- R6, R8, R10, and R14 are independently chosen from null and hydrogen;
- and
- R9 and R11 are independently chosen from null, hydrogen and lower alkyl.
4 more elements
A compound of structural formula (VI)
- or a salt thereof, wherein:
- X3 and X5 are each independently chosen from C(R9) and N(R10);
- R1 is 4- to 7-membered monocyclic heterocycloalkyl optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro;
- R2, R3, R4 and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
- and
- R9 and R10 are each independently chosen from null, hydrogen and lower alkyl;
- wherein
- if R5 is hydrogen, then X3 must be N;
- and
- wherein the compound is not
- 8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]quinoline;
- 8-chloro-2-methyl-4-(piperazin-1-yl)-2H-pyrazolo[3,4-c]quinoline;
- 8-chloro-4-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]quinoline;
- 8-chloro-4-(piperazin-1-yl)-2H-pyrazolo[3,4-c]quinoline;
- 4-(8-chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)-1,1-dimethylpiperazin-1-ium;
- 2-methyl-4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline;
- 2-methyl-4-piperazinyl-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline HCl salt;
- or
- 4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline
16 more elements
A compound of structural Formula (XI):
- or a salt thereof, wherein:
- X1 and X5 are independently chosen from C, CH and N;
- X2 is chosen from [C(R6)(R7)]n, NR8, and O;
- X3 is chosen from [C(R9)(R10)]m and NR11, and O;
- X4 is chosen from [C(R12)(R13)] and NR14;
- R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
- R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
- R6, R7, R9, R10, R12, and R13 are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted;
- R8, R11, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
- and
- R24 is chosen from hydrogen, lower amino, and lower alkyl;
- with the proviso that
- when X1 is N, X2 is [C(R6)(R7)]n, X3 is NR11, X4 is NR14, X5 is C, R2 is hydrogen, R3 is hydrogen, R5 is hydrogen, R6-R10 and R12-R14 are chosen from null and hydrogen, and R24 is NH2,
- then R5 is not chlorine.
11 more elements
A compound of structural Formula (XIII):
- or a salt thereof, wherein:
- the ring comprising X4 is aromatic;
- X4 is chosen from CH and N;
- R1 is chosen from piperazin-1-yl and 4-methylpiperazin-1-yl;
- R3 is chosen from hydrogen, cyano, monocyclic heteroaryl, C(O)NHZ, CO2Z, CF3, NHC(O)Y, NHSO2Z, and SO2NHZ;
- R4 is different than R3 and is chosen from cyano, monocyclic heteroaryl, C(O)NHZ, CO2Z, CF3, NHC(O)Y, NHSO2Z, and SO2NHZ;
- Z is chosen from hydrogen, lower alkyl, phenyl, and benzyl;
- and
- Y is chosen from lower alkyl, phenyl, benzyl, and lower alkoxy.
6 more elements
A pharmaceutical composition comprising at least one compound chosen from those recited in Examples 251-415 and 417-519 or a salt thereof, together with a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.