Modulators of cystic fibrosis transmembrane conductance regulator

1. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, smoke induced COPD, pancreatitis, pancreatic insufficiency, hereditary emphysema, COPD, and dry-eye disease, said method comprising the step of administering to said patient an effective amount of a compound of Formula I

or pharmaceutically acceptable salts thereof, wherein:

ring A is selected from:

wherein:

R 1 is —CH 3 , —CF 3 or —CN;

R 2 is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH;

R 3 is hydrogen, —CH 3 , —OCH 3 , or —CN;

R a is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM);

provided that both R 2 and R 3 are not simultaneously hydrogen; and

one of X and Y is nitrogen and the other is carbon.

2. The method according to claim 1 , wherein said disease is cystic fibrosis, COPD, smoke induced COPD, hereditary emphysema, or dry-eye disease.

3. The method of claim 2 , wherein the disease is cystic fibrosis, hereditary emphysema, or dry-eye disease.

4. The method of claim 3 , wherein the disease is cystic fibrosis.

5. The method of claim 4 , wherein the patient is homozygous for ΔF508 mutation.

6. The method of claim 4 , wherein the patient is homozygous for G551D mutation.

7. The method of claim 4 , wherein the patient is homozygous for R117H mutation.

8. The method of claim 4 , wherein the patient is heterozygous for ΔF508 mutation.

9. The method of claim 4 , wherein the patient is heterozygous for G551D mutation.

10. The method of claim 4 , wherein the patient is heterozygous for R117H mutation.