PDE4B inhibitors and uses therefor

A compound having the chemical structure

• wherein:
• X is selected from the group consisting of S, O, and NR15;
• R12 is selected from the group consisting of hydrogen, —OR16, —SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• R13 is selected from the group consisting of —OR16, —SR16, and optionally substituted amine;
• R14 is selected from the group consisting of —OR16, —SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(Z)R19, —C(Z)NR20R21, —S(O2)NR20R21, and —S(O2)R22;
• R15 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(Z)R19, —C(Z)NR20R21, —S(O2)NR20R21, and —S(O2)R22;
• R16 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and —C(Z)R19;
• Z is selected from the group consisting of O and S;
• R19 is selected from the group consisting of hydroxy, alkoxy, thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• R20 and R21 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl, or
• R20 and R21 may combine to form a 5-7 membered carbocyclic or heterocyclic ring;
• and
• R22 is selected from the group consisting of hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• and
• salts, prodrugs, and isomers thereof.

A compound having structure

• wherein
• R12a is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, acyl, and sulfonyl;
• and
• R19a is selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, optionally substituted aryl,, amino, amido, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxyl, optionally substituted heterocycle, optionally substituted hetaryl, nitro, cyano, thiol, sulfonamido, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, attached at any available point to produce a stable compound.

A compound having the chemical structure

• wherein
• R23 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• or
• R23 can combine with R26, (R25)m or both R26 and (R25)m,to form a 5-7 membered optionally substituted carbocyclic ring system or an optionally substituted heterocyclic ring system;
• R24 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• provided, however, that
• if R24 is substituted aryl, then said aryl substitution is not substituted isopropyl;
• if R24 is optionally substituted lower alkenyl, then any double bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds;
• and
• if R24 is optionally substituted lower alkynyl, then any triple bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds;
• R25, if present, is optionally substituted lower alkylene;
• R26 is an optionally substituted carbocyclic or an optionally substituted heterocyclic structure having 3-14 ring atoms,
• wherein when R26 is aryl, then the substitution of R26, if present, is not substituted isopropyl.;
• m is 0-3;
• and
• salts, prodrugs, and isomers thereof.

A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising

• administering to said patient an effective amount of a PDE4B modulator having a chemical structure of
• wherein:
• X is selected from the group consisting of O, S, and Nk7;
• R1, R2, R4, R5, R7, R9 and R10 are independently selected from the group consisting of hydrogen, acyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl,
• provided, however, that R1 and R2, or R4 and R5, or R9 and R10, or R2 and R3 can combine to form an optionally substituted heterocycle;
• R3 is selected from the group consisting of cyano, nitro, —C(Z)R8, —S(O2)NR9R10, —S(O2)R11, and optionally substituted lower alkyl;
• Y and Z are independently selected from the group consisting of O and S;
• R6 and R8 are selected from the group consisting of, hydroxy, alkoxy, thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and optionally substituted heterocycle;
• and
• R11 is independently selected from the group consisting of hydroxy, alkoxy, thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl.

A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising

• administering to said patient an effective amount of a PDE4B modulator having a chemical structure of
• wherein:
• X is selected from the group consisting of S, O, and NR15;
• R12 is selected from the group consisting of hydrogen, —OR16, —SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• R13 is selected from the group consisting of —OR16, —SR16, and optionally substituted amine;
• R14 is selected from the group consisting of-OR16, —SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(Z)R19, —C(Z)NR20R21, —S(O2)NR20R21, and —S(O2)R22;
• R15 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(Z)R19, —C(Z)NR20R21, —S(O2)NR20R21, and —S(O2)R22;
• R16 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and —C(Z)R19;
• Z is selected from the group consisting of O and S;
• R19 is selected from the group consisting of hydroxy, alkoxy, thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• R20 and R21 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl, or
• R20 and R20 may combine to form a 5-7 membered carbocyclic or heterocyclic ring;
• and
• R22 is selected from the group consisting of hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl.

A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising

• administering to said patient an effective amount of a PDE4B modulator having a chemical structure of
• wherein
• R23 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• or
• R23 can combine with R26, (R25)m or both R26 and (R25)m,to form a 5-7 membered optionally substituted carbocyclic ring system or an optionally substituted heterocyclic ring system;
• R24 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• provided, however, that
• if R24 is substituted aryl, then said aryl substitution is not substituted isopropyl;
• if R24 is optionally substituted lower alkenyl, then any double bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds;
• and
• if R24 is optionally substituted lower alkynyl, then any triple bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds;
• R25, if present, is optionally substituted lower alkylene;
• R26 is an optionally substituted carbocyclic or an optionally substituted heterocyclic structure having 3-14 ring atoms,
• wherein when R26 is aryl, then the substitution of R26, if present, is not substituted isopropyl.;
• m is 0-3.