Modulators of cystic fibrosis transmembrane conductance regulator

1. A method of treating or lessening the severity of a disease in a patient, wherein the disease is cystic fibrosis, COPD, smoked induced COPD, hereditary emphysema, pancreatitis, pancreatic insufficiency or 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

R 1 is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ;

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

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

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

2. The method of claim 1 , wherein the disease is cystic fibrosis, hereditary emphysema, or dry-eye disease.

3. A method of modulating CFTR activity in a patient comprising the step of contacting said CFTR with a compound of Formula (I):

or pharmaceutically acceptable salts thereof, wherein

ring A is selected from

R 1 is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ;

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

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

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

4. The method of claim 1 , wherein the disease is cystic fibrosis, COPD, smoke induced COPD, hereditary emphysema, or dry-eye disease.

5. The method according to claim 4 , wherein said disease is cystic fibrosis.

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

7. The method of claim 5 , wherein the patient is homozygous for G551D mutation.

8. The method of claim 5 , wherein the patient is homozygous for R117H mutation.

9. The method of claim 5 , wherein the patient is heterozygous for ΔF508 mutation.

10. The method of claim 5 , wherein the patient is heterozygous for G551D mutation.

11. The method of claim 5 , wherein the patient is heterozygous for R117H mutation.