Cyclopropanecarboxamide modulators of cystic fibrosis transmembrane conductance regulator

1. A compound of Formula I:

or a salt thereof, wherein:

R 1 -R 3 and R 6 -R 23 are, independently, hydrogen or deuterium;

R 4 -R 5 are, independently, —CH 3 , —CH 2 D, —CD 2 H, or —CD 3 ;

at least one of R 1 -R 23 is deuterium or contains deuterium; and

at least one of R 1 -R 23 independently has deuterium enrichment of no less than about 10%.

2. The compound, or a salt thereof, of claim 1 , wherein R 1 , R 6 , R 9 , and R 16 are hydrogen.

3. The compound, or a salt thereof, of claim 2 , wherein R 2 and R 3 are deuterium.

4. The compound, or a salt thereof, of claim 2 , wherein R 4 and R 5 are —CD 3 .

5. The compound, or a salt thereof, of claim 2 , wherein R 7 and R 8 are deuterium.

6. The compound, or a salt thereof, of claim 2 , wherein R 7 , R 8 , and R 10 are deuterium.

7. The compound, or a salt thereof, of claim 2 , wherein R 2 , R 3 , R 7 , R 8 , and R 10 are deuterium.

8. The compound, or a salt thereof, of claim 2 , wherein R 17 -R 20 are deuterium.

9. The compound, or a salt thereof, of claim 2 , wherein R 2 , R 3 , and R 17 -R 20 are deuterium.

10. The compound, or a salt thereof, of claim 2 , wherein R 7 , R 8 , and R 17 -R 20 are deuterium.

11. The compound, or a salt thereof, of claim 2 , wherein R 7 , R 8 , R 10 , and R 17 -R 20 are deuterium.

12. The compound, or a salt thereof, of claim 2 , wherein R 2 , R 3 , R 7 , R 8 , and R 17 -R 20 are deuterium.

13. The compound, or a salt thereof, of claim 2 , wherein R 2 , R 3 , R 7 , R 8 , R 10 , and R 17 -R 20 are deuterium.

14. The compound, or a salt thereof, of claim 2 , wherein R 21 -R 23 and R 13 -R 15 are hydrogen.

15. The compound, or a salt thereof, of claim 1 wherein at least one of R 1 -R 23 independently has deuterium enrichment selected from of no less than about 50%, of no less than about 90%, or of no less than about 98%.

16. The compound, or a salt thereof, as recited in claim 1 , wherein the compound is:

or a salt thereof.

17. A pharmaceutical composition comprising the compound, or a salt thereof, of claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating a cystic fibrosis transmembrane conductance regulator-mediated disorder, comprising administering a therapeutically effective amount of the compound, or a salt thereof, of claim 1 to a patient in need thereof.

19. The method of claim 18 , wherein the disorder is cystic fibrosis, sarcoglycanopathies, Brody's disease, cathecolaminergic polymorphic ventricular tachycardia, limb girdle muscular dystrophy, asthma, smoke induced chronic obstructive pulmonary disorder, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens, mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis, liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatombral pallidoluysian, and myotonic dystrophy, as well as spongifiorm encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Gerstrnarm-Straussler-Scheinker syndrome, chronic obstructive pulmonary disorder, dry-eye disease, or Sjogren's disease, osteoporosis, osteopenia, bone healing and bone growth, Gorham's Syndrome, chloride channelopathies such as myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus, PCD without situs inversus, and ciliary aplasia.

20. The method of claim 19 , further comprising administering an additional therapeutic agent.