Aminopyrimidine inhibitors of histamine receptors for the treatment of disease

A method of inhibition of H1R and/or H4R comprising contacting H1R and/or H4R with a compound of structural Formula II:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Y is selected from the group consisting of a bond, NR1[C(R20)(R21)]n, NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, S—[C(R26)(R27)]n—W—[C(R28)(R29)]m, O[C(R30)(R31)]n, [C(R32)(R33)]n—W—[C(R34)(R35)]m, and [C(R36)(R37)]n;
• n and m are each independently an integer from 0 to 3;
• W is selected from the group consisting of O, S, S(O)2, NR38, NR39S(O2), C(O), C(S), C(O)O, C(O)NR40, NR41C(O), and NR42C(O)O;
• Z is selected from the group consisting of aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R1, R2, R14, and R20 to R42 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 may be joined together to form a partially saturated cycloalkyl;
• R1 and R20, or R1 and R22, or R22 and R38, or R1 and R38, may be joined together to form a heterocycloalkyl;
• and with the provisos that;
• if Y is NR1[C(R20)(R21)]n, R1 is hydrogen, and n is 0, then Z is not aryl or heteroaryl;
• and
• if Y is NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, n is 2, m is 0, W is NR38, R22, and R23 are hydrogen, and R1 and R38 are joined together to form a piperazine ring, then Z is not phenyl or methyl.

A method of treatment of the pain or inflammation resulting from cataract surgery, comprising delivering to a patient in need of such treatment with a therapeutically effective amount of a compound of structural Formula II:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Y is selected from the group consisting of a bond, NR1[C(R20)(R21)]n, NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, S—[C(R26)(R27)]n—W—[C(R28)(R29)]m, O[C(R30)(R31)]n, [C(R32)(R33)]n—W—[C(R34)(R35)]m, and [C(R36)(R37)]n;
• n and m are each independently an integer from 0 to 3;
• W is selected from the group consisting of O, S, S(O)2, NR38, NR39S(O2), C(O), C(S), C(O)O, C(O)NR40, NR41C(O), and NR42C(O)O;
• Z is selected from the group consisting of aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R1, R2, R14, and R20 to R42 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 may be joined together to form a partially saturated cycloalkyl;
• and
• R1 and R20, or R1 and R22, or R22 and R38, or R1 and R38, may be joined together to form a heterocycloalkyl.

A method of treatment of an H4R-mediated disease comprising the administration of:

• a. a therapeutically effective amount of a compound of structural Formula II:
• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Y is selected from the group consisting of a bond, NR1[C(R20)(R21)]n, NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, S—[C(R26)(R27)]n—W—[C(R28)(R29)]m, 0[C(R30)(R31)]n, [C(R32)(R33)]n—W—[C(R34)(R35)]m, and [C(R36)(R37)]n;
• n and m are each independently an integer from 0 to 3;
• W is selected from the group consisting of O, S, S(O)2, NR38, NR39S(O2), C(O), C(S), C(O)O, C(O)NR40, NR41C(O), and NR42C(O)O;
• Z is selected from the group consisting of aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R1, R2, R14, and R20 to R42 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 may be joined together to form a partially saturated cycloalkyl;
• R1 and R20, or R1 and R22, or R22 and R38, or R1 and R38, may be joined together to form a heterocycloalkyl;
• and with the provisos that;
• if Y is NR1[C(R20)(R21)]n, R1 is hydrogen, and n is 0, then Z is not aryl or heteroaryl;
• and
• if Y is NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, n is 2, m is 0, W is NR38, R22, and R23 are hydrogen, and R1 and R38 are joined together to form a piperazine ring, then Z is not phenyl or methyl;
• and
• b. another therapeutic agent.

A method for achieving an effect in a patient, wherein the effect is selected from the group consisting of reduction in the number of mast cells, inhibition of eosiniphil migration optionally to the nasal mucosa, the eye, or the wound site, reduction in inflammatory markers, reduction in inflammatory cytokines, reduction in scratching, decreased watering or redness of the eyes, and reduction in ocular pain, comprising the administration, to a patient, of a therapeutically effective amount of a compound of structural formula II:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Y is selected from the group consisting of a bond, NR1[C(R20)(R21)]n, NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, S—[C(R26)(R27)]n—W—[C(R28)(R29)]m, O[C(R30)(R31)]n, [C(R32)(R33)]n—W—[C(R34)(R35)]m, and [C(R36)(R37)]n;
• n and m are each independently an integer from 0 to 3;
• W is selected from the group consisting of O, S, S(O)2, NR38, NR39S(O2), C(O), C(S), C(O)O, C(O)NR40, NR41C(O), and NR42C(O)O;
• Z is selected from the group consisting of aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R1, R2, R14, and R20 to R42 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 may be joined together to form a partially saturated cycloalkyl;
• R1 and R20, or R1 and R22, or R22 and R38, or R1 and R38, may be joined together to form a heterocycloalkyl;
• and with the provisos that;
• if Y is NR1[C(R20)(R21)]n, R1 is hydrogen, and n is 0, then Z is not aryl or heteroaryl;
• and
• if Y is NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, n is 2, m is 0, W is NR38, R22, and R23 are hydrogen, and R1 and R38 are joined together to form a piperazine ring, then Z is not phenyl or methyl.

A compound, for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of H1R and/or H4R, of structural formula II:

• or a salt thereof, wherein:
• Xi is selected from the group consisting of [C(R2)] and N;
• Y is selected from the group consisting of a bond, NR1[C(R20)(R21)]n, NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, S—[C(R26)(R27)]n—W—[C(R28)(R29)]m, O[C(R30)(R31)]n, [C(R32)(R33)]n—W—[C(R34)(R35)]m, and [C(R36)(R37)]n;
• n and m are each independently an integer from 0 to 3;
• W is selected from the group consisting of O, S, S(O)2, NR38, NR39S(O2), C(O), C(S), C(O)O, C(O)NR40, NR41C(O), and NR42C(O)O;
• Z is selected from the group consisting of aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R1, R2, R14, and R20 to R42 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 may be joined together to form a partially saturated cycloalkyl;
• R1 and R20, or R1 and R22, or R22 and R38, or R1 and R38, may be joined together to form a heterocycloalkyl;
• and with the provisos that;
• if Y is NR1[C(R20)(R21)]n, R1 is hydrogen, and n is 0, then Z is not aryl or heteroaryl;
• and
• if Y is NR1[C(R22)(R23)]n—W—[C(R24)(R25)]m, n is 2, m is 0, W is NR38, R22, and R23 are hydrogen, and R1 and R38 are joined together to form a piperazine ring, then Z is not phenyl or methyl.

A compound having a structural formula selected from the group consisting of structural Formula III and structural formula IV:

• or a salt thereof, wherein:
• A1 and A2 are each independently selected from the group consisting of a bond, —CH2—, —CH2CH2—, and —CH2CH2CH2—;
• X1 is selected from the group consisting of [C(R2)] and N;
• R2 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R14 is is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R43 and R46 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, C2-C6 alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R44 and R45 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, C2-C6 alkoxy, halogen, haloalkyl, amino, aminoalkyl, acyl, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• and
• with the proviso that;
• if the compound has structural formula III, A1 is —CH2—, R11 is hydrogen or methyl, and R14 is hydrogen, methyl, or isopropyl, then at least one of R43 to R46 is not hydrogen.

A compound of structural Formula II:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Y is NR1[C(R20)(R21)]n;
• n is an integer from 2 to 3;
• Z is
• R1, R20, and R21 are each independently selected from the group consisting of hydrogen and lower alkyl;
• R11 and R14 are independently selected from the group consisting of hydrogen and C1-C3 alkyl;
• R2, R47 to R51 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• any two adjacent R47, R48, R49, R50, or R51 may be joined together to form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl;
• with the provisos that;
• if X1 is [C(R2)], R1, R2, R20, and R21 are hydrogen, R11 is ethyl and R14 is hydrogen, then at least one of R47 to R51 is not hydrogen;
• if X1 is N, then at least one of R20 and R21 is lower alkyl;
• and
• if X1 is N, R11, R14, and R47 to R51 are hydrogen, then Y is not —CH2C(CH3)2—.

A compound of structural Formula V:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Z is a 5- to 7-membered saturated cycloalkyl, which is substituted with at least one substituent selected from the group consisting of lower alkyl, lower alkanoyl, lower heteroalkyl, lower haloalkyl, lower perhaloalkyl, lower perhaloalkoxy, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl, oxo, lower acyloxy, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, thiol, lower alkylthio, lower haloalkylthio, and lower perhaloalkylthio;
• R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, and alkylsulfonamido, any of which may be optionally substituted;
• R11 and R14 are independently selected from the group consisting of hydrogen and C1-C3 alkyl;
• with the provisos that;
• if R11 is methyl and R14 is hydrogen, then Z is not 2,3-dimethylcyclohexyl;
• if R11 and R14 are both hydrogen, if R11 and R14 are both methyl, or if R11 is ethyl and R14 is hydrogen, then Z is not 4-hydroxycyclohexyl;
• if R11 and R14 are both hydrogen or if R11 and R14 are both methyl, then Z is not 2-methylcyclohexyl;
• if R11 and R14 are both hydrogen or if R11 and R14 are both methyl, then Z is not 3-methylcyclohexyl;
• and
• if R11 and R14 are both hydrogen or if R11 and R14 are both methyl, then Z is not 4-methylcyclohexyl.

A compound of structural Formula VI:

• or a salt thereof, wherein:
• X1 is selected from the group consisting of [C(R2)] and N;
• Z is selected from the group consisting of hydrogen, aryl, alkyl, heterocycloalkyl, alkoxylcarbonyl, acyl, and cycloalkyl, any of which may be optionally substituted;
• R2, R14, and R34 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, mercaptyl, alkylsulfonyl, sulfonamide, and alkylsulfonamido, any of which may be optionally substituted;
• and
• R11 and R14 may be joined together to form a partially saturated cycloalkyl.