Methods of treating pulmonary diseases and disorders

A method of treating chronic obstructive pulmonary disease, bronchitis, or asthma in a patient in need thereof, or in a patient at risk of developing chronic obstructive pulmonary disease, comprising a) administering an effective amount of a compound represented by Formula III or IV and b) optionally administering an effective amount of one or more of an additional active agent, wherein Formula II and IV are:

• and pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, wherein:
• X1 is N or CR33;
• X3 is selected from the group consisting of NRhh, O, and S;
• pp is 1, 2, or 3;
• R11 is independently selected for each occurrence from the group consisting of hydrogen, halogen, and C1-4 alkyl (optionally substituted by one, two or three halogens);
• R31 is selected from the group consisting of hydrogen, halogen, and C1-4 alkyl;
• R33 is selected from the group consisting of H, halogen, C1-4 alkyl, and —NR′R″ wherein R′ and R″ are each independently selected for each occurrence from H and C1-4 alkyl or taken together with the nitrogen to which they are attached form a heterocyclic ring;
• L1 is selected from the group consisting of C1-6 alkylene, C3-6 cycloalkylene, C3-6 cycloalkylene-C1-4 alkylene, C1-3 alkylene-NRhh—S(O)w—, —C1-3 alkylene-S(O)w—NRhh—, C3-6 cycloalkylene-C0-2 alkylene-S(O)w—NRhh, and C3-6 cycloalkylene-C0-2 alkylene NRhh—S(O)w—, wherein L1 may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C1-3 alkyl (optionally substituted by one, two or three substituents each selected independently from Rff);
• R44 is selected from the group consisting of H, halogen, hydroxyl, C1-3 alkoxy, phenyl, —O-phenyl, —NR′-phenyl, heterocycle, and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S;
• wherein phenyl, —O-phenyl, —NR′-phenyl, heterocycle and heteroaryl may be optionally substituted by one or two substituents each selected independently from Rgg;
• Rff is selected for each occurrence from group consisting of halogen, hydroxyl, C1-4 alkyl, C1-4 alkyoxy, C2-4 alkenyl, C3-6 cycloalkyl, —NR′R″, —NR′—S(O)w—C1-3 alkyl, S(O)w—NR′R″, and —S(O)w—C1-3 alkyl, where w is 0, 1, or 2, wherein C1-4 alkyl, C1-4 alkyoxy, C2-4 alkenyl and C3-6 cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, —NR′R″, —NR′—S(O)w—C1-3 alkyl, S(O)w—NR′R″, and —S(O)w—C1-3 alkyl;
• Rgg is selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, —NR′R″, —NR′—S(O)w—C1-3 alkyl, —S(O)w—NR′R″, and —S(O)w—C1-3 alkyl, where w is 0, 1, or 2;
• heterocycle, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkenyl, wherein C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkenyl are optionally substituted by one, two, or three substituents each independently selected from Rjj;
• and heterocycle is optionally substituted by one, two, or three substituents each independently selected from Rll;
• Rjj is selected for each occurrence from the group consisting of halogen, hydroxyl, C1-6 alkoxy (optionally substituted by one, two, or three substituents each independently selected from Rkk);
• C3-6 cycloalkyl, C3-6 cycloalkoxy, heterocycle, C(O)OH, —C(O)OC1-6 alkyl, —NR′R″, —NR′—S(O)w—C1-3 alkyl, —S(O)w—NR′R″, and —S(O)w—C1-3 alkyl, where w is 0, 1, or 2;
• Rkk is selected for each occurrence from the group consisting of halogen, hydroxyl, C1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from halogen, hydroxyl, C3-6 cycloalkyl, and heterocycle (optionally substituted by C1-6 alkyl)), C3-6 cycloalkyl (optionally substituted by one, two, or three substituents each independently selected from halogen, hydroxyl, and C1-6 alkyl), phenyl, heterocycle (optionally substituted by one, two or three substituents independently selected from halogen, hydroxyl, and C1-6 alkyl), and heteroaryl;
• Rll is selected for each occurrence from the group consisting of halogen, hydroxyl, C1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from halogen, hydroxyl, and C3-6 cycloalkyl) and heterocycle (optionally substituted by one, two or three substituents independently selected from halogen, hydroxyl, and C1-6 alkyl);
• R′ and R″ are each independently selected for each occurrence from H, C1-4 alkyl, phenyl and heterocycle;
• w is 0, 1 or 2;
• and
• Rhh is selected for each occurrence from the group consisting of H, C1-6 alkyl and C3-6 cycloalkyl.