Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis

1. A method for the treatment of cystic fibrosis, comprising administering to a subject an effective amount of a compound according to Formula I

wherein

R 1 is

C 3-7 mono or spirocyclic cycloalkyl, optionally substituted with one or more independently selected R 2 groups,

4-7 membered mono or spirocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, and S, substituted with one or more independently selected R 2 groups,

C 6-10 monocyclic or bicyclic aryl optionally substituted with one or more independently selected R 3 groups,

5-10 membered monocyclic or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R 3 groups, or

C 1-6 alkyl optionally substituted with one or more independently selected R 4 groups,

each R 2 is selected from

halo,

OH,

—CN,

—OC(═O)C 1-4 alkyl,

—C(═O)—C 1-4 alkoxy,

oxo,

C 1-4 alkyl (optionally substituted with one or more independently selected R 5a ), and

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5a ),

each R 3 is selected from

halo,

—OH,

—CN,

C 1-4 alkyl (optionally substituted with one or more independently selected R 5b ),

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5b ),

C 2-4 alkenyl (optionally substituted with one or more independently selected R 5b ),

C 3-7 cycloalkyl,

4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S,

4-7 membered monocyclic heterocycloalkenyl comprising one or more heteroatoms independently selected from N, O, and S,

5-10 membered monocyclic or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and

—NHSO 2 —C 1-4 alkyl;

each R 4 is selected from

halo,

OH,

C 3-7 monocyclic cycloalkyl,

—CN, and

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5c ),

each R 5a , R 5b , and R 5a is independently selected from

halo,

OH,

—OP(═O) 2 OH,

—CN,

—NR 6a R 6b , and

C 1-4 alkoxy; and

each R 5a , or R 5b is independently selected from H, and C 1-4 alkyl;

or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.

2. A method according to claim 1 , wherein R 1 is mono or spirocyclic C 3-7 cycloalkyl substituted with one or more independently selected R 2 groups.

3. A method according to claim 1 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected R 2 groups.

4. A method according to claim 1 , wherein R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 —OH, —C(OH)(CH 3 ) 2 , —CF 3 , —CH 2 —CHF 2 , —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 N(CH 3 ) 2 .

5. A method according to claim 1 , wherein R 1 is phenyl, substituted with one or more independently selected R 3 groups.

6. A method according to claim 1 , wherein R 1 is furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidyl, or pyrazinyl.

7. A method according to claim 1 , wherein R 1 is furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidyl, or pyrazinyl, each of which is substituted with one or more independently selected R 3 groups.

8. A method according to claim 1 , wherein R 3 is F, Cl, OH, or CN.

9. A method according to claim 1 , wherein R 3 is —CH 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , or —OCH(CH 3 ) 2 , each of which is optionally substituted with one or more independently selected R 5b .

10. A method according to claim 9 , wherein R 5b is F, Cl, OH, —OP(═O) 2 OH, CN, or —OCH 3 .

11. A method according to claim 1 , wherein R 1 is —CH 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —C(CH 3 ) 2 —CH 3 , or —C(CH 3 )H—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R 4 groups.

12. A method according to claim 11 , wherein R 4 is F, Cl, OH, or CN.

13. A method according to claim 1 , wherein the compound is selected from:

2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide,

2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(4-fluoro-2-(trifluoromethyl)benzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(2,4-difluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide,

methyl 1-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-ylcarbamoyl)-cyclopropanecarboxylate,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide,

5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-1,2,4-triazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-2-fluoronicotinamide,

2-(4-fluoro-2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-6-fluoropicolinamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide,

2-(2-(1H-1,2,4-triazol-5-yl)benzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(2-(1H-imidazol-2-yl)benzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-(2-(methylsulfonamido)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-oxopyrrolidine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-2-oxopyrrolidine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide,

4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-ethyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxamide,

2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(2-hydroxy-3-methylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(1-(hydroxymethyl)cyclobutanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide,

4-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-ylcarbamoyl)tetrahydro-2H-pyran-4-yl acetate,

N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(methoxymethyl)-1H-pyrazole-3-carboxamide,

Cis-2-[[2-fluorocyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, Enantiomer 1,

Cis-2-[[2-fluorocyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, Enantiomer 2,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxamide,

2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(3,3-difluorocyclobutanecarbonyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2,2-difluorocyclopropanecarbonyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-(methoxymethyl)-1H-pyrazole-3-carboxamide,

2-[[2-hydroxy-3-methyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, Enantiomer 1,

2-[[2-hydroxy-3-methyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, Enantiomer 2,

2-(2-hydroxybutanoylamino)-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

5-Ethoxy-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide,

5-(2-Methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide,

2-[(3-hydroxy-3-methyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-[[3,3,3-trifluoro-2-(hydroxymethyl)propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide,

2-(3-hydroxybutanoylamino)-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[1-(1-hydroxyethyl)cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-cyclopropyl-2-hydroxy-acetyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

5-(1-Hydroxy-ethyl)-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide,

2-(3-Carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-ylcarbamoyl)-cyclopropanecarboxylic acid ethyl ester,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-[(E)-3-methoxyprop-1-enyl]-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-(1-hydroxy-1-methyl-ethyl)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide,

2-[(2-hydroxyacetyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(3-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(3-cyclopropyl-3-hydroxy-propanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-[(4,4,4-trifluoro-3-hydroxy-butanoyl)amino]-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(3-hydroxy-2-methyl-propanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-propyl-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-cyano-1H-pyrazole-3-carboxamide,

2-[[2-(hydroxymethyl)-3-methyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,2-dihydroxyethyl)-1H-pyrazole-3-carboxamide,

2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[1-[1-hydroxyethyl]cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[1-[1-hydroxyethyl]cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-(hydroxymethyl)-1-methyl-pyrazole-3-carboxamide,

2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(hydroxymethyl)cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[(1S,2S)-2-(hydroxymethyl)cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(cyclopropylmethyl)-3-hydroxy-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(hydroxymethyl)-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[2-(hydroxymethyl)butanoylamino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[(1R,3R)-3-(hydroxymethyl)-2,2-dimethyl-cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxamide,

2-[[2-(hydroxymethyl)-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(hydroxymethyl)-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[1-(hydroxymethyl)-2,2-dimethyl-cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

[5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate,

[3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2,3-dihydro-1,4-dioxin-5-yl)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide,

2-[[2-(cyclopropylmethyl)-3-hydroxy-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 1,

2-[[2-(cyclopropylmethyl)-3-hydroxy-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 2,

2-[[(2S)-3-cyclopropyl-2-hydroxy-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[(1R)-1-(hydroxymethyl)-2,2-dimethyl-cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-methoxyethoxy)-1H-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-isopropoxyethoxy)-1H-pyrazole-3-carboxamide,

[3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]-4-methyl-pyrazol-1-yl]methyl dihydrogen phosphate,

[5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]-4-methyl-pyrazol-1-yl]methyl dihydrogen phosphate,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-oxo-1,3-dihydroimidazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(methoxymethyl)-1H-pyrazole-3-carboxamide,

2-[(2-hydroxy-4,4-dimethyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-oxo-pyrrolidine-2-carboxamide,

(2R)—N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-oxo-pyrrolidine-2-carboxamide,

2-[[2-hydroxy-4,4-dimethyl-pentanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 1,

2-[[2-hydroxy-4,4-dimethyl-pentanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 2,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-[1,4-dioxan-2-yl]-1H-pyrazole-3-carboxamide, enantiomer 1,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-[1,4-dioxan-2-yl]-1H-pyrazole-3-carboxamide, enantiomer 2,

2-[[2-(difluoromethoxy)benzoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1-(difluoromethyl)pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-(difluoromethyl)pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1-(difluoromethyl)pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-3-(difluoromethyl)-1-methyl-pyrazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-(difluoromethyl)-1-methyl-pyrazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1-methyl-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-methyl-pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide,

2-[[3-(difluoromethyl)benzoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(difluoromethyl)benzoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(3,3-difluoro-1-methyl-cyclobutanecarbonyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-methyl-oxazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1-(2,2-difluoroethyl)pyrazole-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)thiazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)oxazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-thiazole-2-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2,4-dimethyl-oxazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)isoxazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)thiazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-oxazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)oxazole-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1-methyl-5-(trifluoromethyl)pyrazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)pyrazine-2-carboxamide,

6-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-oxo-1H-pyridine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-3,5-dimethyl-isoxazole-4-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-pyrazine-2-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrrole-2-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-6-methyl-pyridine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-8-methyl-4-oxo-pyrido[1,2-a]pyrimidine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-isoxazole-4-carboxamide,

5,5,7,7-tetramethyl-2-[(3-methyloxetane-3-carbonyl)amino]-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-methyl-4-oxo-3H-quinazoline-5-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4,7-dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-methyl-4-oxo-3H-quinazoline-7-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide,

5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(4-hydroxytetrahydropyran-4-carbonyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-hydroxy-3-methoxy-2-methyl-propanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-hydroxy-3-methoxy-propanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide,

5,5,7,7-tetramethyl-2-(tetrahydropyran-4-carbonylamino)-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-ethoxyacetyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-methoxyacetyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-(2-methoxyethoxy)acetyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-(tetrahydrofuran-2-carbonylamino)-4H-thieno[2,3-c]pyran-3-carboxamide,

5,5,7,7-tetramethyl-2-(tetrahydrofuran-3-carbonylamino)-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[(2-methoxy-2-methyl-propanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide,

2-[[2-hydroxy-3-methoxy-2-methyl-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 1,

2-[[(2S)-2-hydroxy-3-methoxy-2-methyl-propanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide, enantiomer 2,

5,5,7,7-tetramethyl-2-[(3,3,3-trifluoro-2-hydroxy-propanoyl)amino]-4H-thieno[2,3-c]pyran-3-carboxamide,

6-Oxo-1,6-dihydro-pyridazine-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide, and

2-(1,4-dioxane-2-carboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide.

14. A method for the treatment of cystic fibrosis, comprising administering to a subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to Formula I

wherein

R 1 is

C 3-7 mono or spirocyclic cycloalkyl, optionally substituted with one or more independently selected R 2 groups,

4-7 membered mono or spirocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, and S, substituted with one or more independently selected R 2 groups,

C 6-10 monocyclic or bicyclic aryl optionally substituted with one or more independently selected R 3 groups,

5-10 membered monocyclic or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R 3 groups, or

C 1-6 alkyl optionally substituted with one or more independently selected R 4 groups,

each R 2 is selected from

halo,

OH,

—CN,

—OC(═O)C 1-4 alkyl,

—C(═O)—C 1-4 alkoxy,

oxo,

C 1-4 alkyl (optionally substituted with one or more independently selected R 5a ), and

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5a ),

each R 3 is selected from

halo,

—OH,

—CN,

C 1-4 alkyl (optionally substituted with one or more independently selected R 5b ),

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5b ),

C 2-4 alkenyl (optionally substituted with one or more independently selected R 5b ),

C 3-7 cycloalkyl,

4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S,

4-7 membered monocyclic heterocycloalkenyl comprising one or more heteroatoms independently selected from N, O, and S,

5-10 membered monocyclic or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and

—NHSO 2 —C 1-4 alkyl;

each R 4 is selected from

halo,

OH,

C 3-7 monocyclic cycloalkyl,

—CN, and

C 1-4 alkoxy (optionally substituted with one or more independently selected R 5c ),

each R 5a , R 5b , and R 5c is independently selected from

halo,

OH,

—OP(═O) 2 OH,

—CN,

—NR 6a R 6b , and

C 1-4 alkoxy; and

each R 5a , or R 5b is independently selected from H, and C 1-4 alkyl;

or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.