RU2021121017A - MACROCYCLIC COMPOUNDS AND THEIR USE IN THE TREATMENT OF DISEASE - Google Patents

Claims (440)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I) where each of A ₁ , A ₂ and A ₃ is independently selected from optionally substituted arylene and optionally substituted heteroarylene; L₁ is a sulfonamide, amide, carbonyl or urea; L₂ is an optionally substituted alkylene, an optionally substituted alkoxylene, an optionally substituted polyalkylene oxide, an optionally substituted alkylene oxide, an optionally substituted aminoalkylene, or an optionally substituted C_3-8cycloalkylene; and X_A is an optionally substituted divalent amino, an optionally substituted divalent amide, an optionally substituted heterocycloalkylene, or -O-. 2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, where A ₁ is arylene or heteroarylene, where arylene and heteroarylene representing A ₁ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₂ is arylene or heteroarylene, where arylene and heteroarylene representing A ₂ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₃ is arylene or heteroarylene, where arylene and heteroarylene representing A ₃ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; L₁ represents -NR^AS(O)_0-2-*, -S(O)_0-2NR^A-*, -NR^AC(=O)-*, -C(=O)NR^A-*, -C(=O)- or -NR^AC(=O)NR^A-, where * denotes the point of attachment to A₂; L₂ is an alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene, or C_3-8cycloalkylene, where alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene and C_3-8cycloalkylene being L2 are unsubstituted or substituted with 1-3 groups independently selected from C₁-C₆alkyl, -OH, -(CH₂)_mC(=O)OR^A, C₁-C₆alkoxy, C₁-C₆alkyl substituted with 1-6 hydroxyl groups, deuterium substituted with deuterium C₁-C₆alkyl and spiro attached C₃-C₈cycloalkyl; X_A is an optionally substituted divalent amino, an optionally substituted divalent amide, an optionally substituted heterocycloalkylene, or -O-; R ^A is H or C ₁ -C ₆ alkyl, and m is 1, 2, 3, 4, 5, or 6. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, where A ₁ is arylene or heteroarylene, where arylene and heteroarylene representing A ₁ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₂ is arylene or heteroarylene, where arylene and heteroarylene representing A ₂ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₃ is arylene or heteroarylene, where arylene and heteroarylene representing A ₃ are unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; L₁ represents -NR^AS(O)_0-2-* or -S(O)_0-2NR^A-* where * denotes the point of attachment to A₂; L₂ is an alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene, or C_3-8cycloalkylene, where alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene and C_3-8cycloalkylene being L2 are unsubstituted or substituted with 1-3 groups independently selected from C₁-C₆alkyl, -OH, deuterium, -(CH₂)_mC(=O)OR^A, C₁-C₆alkoxy, C₁-C₆alkyl substituted with 1-6 hydroxyl groups, substituted with deuterium C₁-C₆alkyl and spiro attached C₃-C₈cycloalkyl; X_A is an optionally substituted divalent amino, an optionally substituted divalent amide, an optionally substituted heterocycloalkylene, or -O-; R ^A is H or C ₁ -C ₆ alkyl, and m is 1, 2, 3, 4, 5, or 6. 4. The compound of formula (I) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, where A ₁ is phenylene or pyridylene, wherein the phenylene or pyridylene representing A ₁ is unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₂ is phenylene or pyridylene, wherein the phenylene or pyridylene representing A ₂ is unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₃ is phenylene or pyridylene, wherein the phenylene or pyridylene representing A ₃ is unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; L₁ represents -NR^AS(O)_0-2-* or -S(O)_0-2NR^A-* where * denotes the point of attachment to A₂; L₂ is an alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene, or C_3-8cycloalkylene, where alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene and C_3-8cycloalkylene representing L₂, unsubstituted or substituted with 1-3 groups independently selected from C₁-C₆alkyl, -OH, deuterium, -(CH₂)_mC(=O)OR^A, C₁-C₆alkoxy, C₁-C₆alkyl substituted with 1-6 hydroxyl groups, substituted with deuterium C₁-C₆alkyl and spiro attached C₃-C₈cycloalkyl; X_A is an optionally substituted divalent amino, an optionally substituted divalent amide, an optionally substituted heterocycloalkylene, or -O-; R ^A is H or C ₁ -C ₆ alkyl, and m is 1, 2, 3, 4, 5, or 6. 5. The compound of formula (I) according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, where A ₁ is pyridylene, where the pyridylene representing A ₁ is substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl, deuterium-substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; A ₂ is pyridylene, where pyridylene, representing A ₂ , is unsubstituted; A ₃ is phenylene or pyridylene, wherein the phenylene or pyridylene representing A ₃ is unsubstituted or substituted with 1-2 groups independently selected from H, halogen, halogen-substituted C _1-6 alkyl, C _1-6 alkyl substituted with deuterium C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; L₁ represents -NR^AS(O)_0-2-* or -S(O)_0-2NR^A-* where * denotes the point of attachment to A₂; L₂ is an alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene, or C_3-8cycloalkylene, where alkylene, alkoxylene, alkylene oxide, polyalkylene oxide, aminoalkylene and C_3-8cycloalkylene representing L₂, unsubstituted or substituted with 1-3 groups independently selected from C₁-C₆alkyl, -OH, deuterium, -(CH₂)_mC(=O)OR^A, C₁-C₆alkoxy, C₁-C₆alkyl substituted with 1-6 hydroxyl groups, substituted with deuterium C₁-C₆alkyl and spiro attached C₃-C₈cycloalkyl; X_A is an optionally substituted divalent amino, an optionally substituted divalent amide, an optionally substituted heterocycloalkylene, or -O-; R ^A is H or C ₁ -C ₆ alkyl, and m is 1, 2, 3, 4, 5, or 6. 6. The connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, characterized by the structure of formula (I-a),

(Ia) where each of X _1a , X _1b , X _1c and X _1d is independently selected from CR ¹ or N, where only 1 or 2 of X _1a , X _1b , X _1c and X _1d can be N and the rest are CR ¹ ; each of X _2a , X _2b , X _2c and X _2d is independently selected from CR ¹ or N, where only 1 or 2 of X _2a , X _2b , X _2c and X _2d can be N and the rest are CR ¹ ; each of X _3a , X _3b , X _3c and X _3d is independently selected from CR ² or N, where only 1 or 2 of X _3a , X _3b , X _3c and X _3d can be N and the rest are CR ² ; X ₄ represents

or -O-, where * denotes the point of attachment to L ₂ ; L₂ is -(CR^fourR^five)_n-, -O(CR ⁴ R ⁵ ) _n -**, -NR ⁷ (CR ⁴ R ⁵ ) _n -**, -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p -**, -(CR ⁴ R ⁵ ) _n (CR ⁶ R ¹⁸ )-**, -(CR ⁴ R ⁵ ) _n (CR ⁸ R ⁹ ) _p (CR ⁴ R ⁵ ) _m -, -(CR ⁴ R ⁵ ) _p NR ⁷ (CR ⁶ R ¹⁰ ) _n -**, -(CR ⁴ R ⁵ ) _n O) _t (CR ⁶ R ¹⁰ ) _p -**, or -OC ₃ -C ₈ cycloalkylene-**, where ** denotes the point of attachment to X ₄ ; each R ¹ is independently selected from H, halogen, halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium-substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy, and halogen-substituted C _{1- 6} alkoxy; each R ² is independently selected from H, halogen, nitrile, hydroxyl, halogen-substituted C _1-6 alkyl, C _1-6 alkyl, deuterium-substituted C ₁ -C ₆ alkyl, hydroxy-substituted C ₁ -C ₆ alkyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy; R ³ is H, -C _1-6 alkyl, -(CR ¹¹ R ¹² ) _y R ¹⁶ , -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O)OR ¹³ , -((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y C(=O)R ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ , -(CR ¹¹ R ¹² ) _y R ²⁰ , -((CR ¹¹ R ¹² ) _y O) _q (CR ¹⁴ R ¹⁵ ) _z C(=O)OR ¹³ , -((CR ¹¹ R ¹² ) _y O) _q (CR ¹⁴ R ¹⁵ ) _z OR ¹³ ,

or

; each R ⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; each R ⁵ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; each R ⁶ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; each R ⁷ is independently selected from H and C _1-6 alkyl; each of R ⁸ and R ⁹ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, C _1-6 alkyl or -OH; or R ⁸ and R ⁹ together with the carbon atom in CR ⁸ R ⁹ form C _3-8 cycloalkyl; each R ¹⁰ is independently selected from H, D and C _1-6 alkyl; each R ¹¹ is independently selected from H, D and C _1-6 alkyl; each R ¹² is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; each R ¹³ is independently selected from H and C _1-6 alkyl; each R ¹⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; each R ¹⁵ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, and C _1-6 alkyl; R ¹⁶ is a 4-6 membered heterocycloalkyl containing 1-2 ring members independently selected from N, O and S, wherein said 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1-2 R ¹⁷ groups; each R ¹⁷ is independently selected from C _1-6 alkyl and hydroxyl; R ¹⁸ is H, C _1-6 alkyl, -C(R ⁴ R ⁵ ) _m OR ¹⁹ or -(CH ₂ ) _m C(=O)OR ¹⁹ ; each R ¹⁹ is independently selected from H and C _1-6 alkyl; R ²⁰ is

or

; each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each w is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each z is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and each q is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. 7. The compound according to claim. 6 or its pharmaceutically acceptable salt, characterized by the structure of formula (I-b),

(Ib), 8. The compound according to p. 7 or its pharmaceutically acceptable salt, characterized by the structure of formula (I-c) or formula (I-d),

(Ic),

(Id) where X _1a represents CH or N; X _2a is CH or N; and X _3a is CH or N. 9. Connection according to any one of paragraphs. 6-8 or a pharmaceutically acceptable salt thereof, characterized by the structure of formula (I-e), formula (I-f), formula (I-g) or formula (I-h), where

(Ie)

(If),

(Ig),

(Ih) where X _1a represents CH or N; and X _2a is CH or N. 10. Connection according to any one of paragraphs. 6-9 or a pharmaceutically acceptable salt thereof, characterized by the structure of formula (I-i), formula (I-j), formula (I-k) or formula (I-l), where

(ii),

(Ij),

(Ik),

(il). 11. The connection according to any one of paragraphs. 6-9 or a pharmaceutically acceptable salt thereof, characterized by the structure of formula (I-m), formula (I-n), formula (I-o) or formula (I-p), where

(im)

(In),

(io)

(IP). 12. The compound according to claim 6 or 7, or a pharmaceutically acceptable salt thereof, characterized by the structure of formula (I-q),

(Iq). 13. Connection according to any one of paragraphs. 6-12 or a pharmaceutically acceptable salt thereof, where X ₄ represents

or -O-, where * denotes the point of attachment to L ₂ ; L₂ is -(CR^fourR^five)_n-, -O(CR ⁴ R ⁵ ) _n -**, -NR ⁷ (CR ⁴ R ⁵ ) _n -**, -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p -**, -(CR ⁴ R ⁵ ) _n (CR ⁶ R ¹⁸ )-**, -(CR ⁴ R ⁵ ) _n (CR ⁸ R ⁹ ) _p (CR ⁴ R ⁵ ) _m -, -(CR ⁴ R ⁵ ) _p NR ⁷ (CR ⁶ R ¹⁰ ) _n -**, or -OC _3-8 cycloalkylene-**, where ** denotes the point of attachment to X ₄ ; R ¹ is H, halogen substituted with C _1-6 alkyl, C _1-6 alkyl, or C _1-6 alkoxy; R ² is H or halogen; R ³ is H, -C _1-6 alkyl, -(CR ¹¹ R ¹² ) _y R ¹⁶ , -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O)OR ¹³ , -((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y C(=O)R ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ , -(CR ¹¹ R ¹² ) _y R ²⁰ ,

or

; each R ⁴ is H; each R ⁵ is H; each R ⁶ is H; each R ⁷ is independently selected from H and C _1-6 alkyl; each R ⁸ and R ⁹ is independently selected from H, C _1-6 alkyl or -OH; or R ⁸ and R ⁹ together with the carbon atom in CR ⁸ R ⁹ form C _3-8 cycloalkyl; each R ¹⁰ is H; each R ¹¹ is H; each R ¹² is H; each R ¹³ is independently selected from H and C _1-6 alkyl; each R ¹⁴ is H; each R ¹⁵ is H; R ¹⁶ is a 4-6 membered heterocycloalkyl containing 1-2 ring members independently selected from N or O, wherein said 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1-2 R ¹⁷ groups; each R ¹⁷ is independently selected from C _1-6 alkyl and hydroxyl; R ¹⁸ is -C(R ⁴ R ⁵ ) _m OR ¹⁹ or -(CH ₂ ) _m C(=O)OR ¹⁹ ; each R ¹⁹ is H; R ²⁰ is

or

; each m is independently selected from 1, 2 and 3; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8 and 9; each p is independently selected from 1, 2, and 3; each w is independently selected from 1 and 2; each y is independently selected from 1, 2, 3, 4 and 5; each z is independently selected from 1, 2 and 3; and each q is independently chosen from 1 and 2. 14. Connection according to any one of paragraphs. 6-13 or a pharmaceutically acceptable salt thereof, wherein X ₄ represents

or -O-, where * denotes the point of attachment to L ₂ ; L₂ is -(CR^fourR^five)_n-, -O(CR ⁴ R ⁵ ) _n -**, or -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p -**, where ** denotes the point of attachment to X ₄ ; R ¹ is halo or halo-substituted C _1-6 alkyl; R ² is H or halogen (F; R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , each R ⁴ is H; each R ⁵ is H; each R ⁶ is H; each R ⁸ and R ⁹ is independently selected from H or C _1-6 alkyl; or R ⁸ and R ⁹ together with the carbon atom in CR ⁸ R ⁹ form C _3-8 cycloalkyl; each R ¹⁰ is H; each R ¹¹ is H; each R ¹² is H; each R ¹³ is independently selected from H and C _1-6 alkyl; each R ¹⁴ is H; each R ¹⁵ is H; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8 and 9; each p is independently selected from 1, 2, and 3; each y is independently selected from 1, 2, 3, 4 and 5; each z is independently selected from 1, 2 and 3; and each q is independently chosen from 1 and 2. 15. Connection according to any one of paragraphs. 6-14 or a pharmaceutically acceptable salt thereof, where X ₄ represents

or -O-, where * denotes the point of attachment to L ₂ ; L₂ is -(CR^fourR^five)_n-, -O(CR ⁴ R ⁵ ) _n -** or -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p -**, where ** denotes the point of attachment to X ₄ ; R ¹ is Cl, F or CF ₃ ; R ² is H or F; R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O )OR ¹³ or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , each R ⁴ is H; each R ⁵ is H; each R ⁶ is H; each R ⁸ and R ⁹ is independently selected from H or methyl; or R ⁸ and R ⁹ together with the carbon atom in CR ⁸ R ⁹ form cyclopropyl; each R ¹⁰ is H; each R ¹¹ is H; each R ¹² is H; each R ¹³ is independently selected from H, methyl and ethyl; each R ¹⁴ is H; each R ¹⁵ is H; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8 and 9; each p is independently selected from 1, 2, and 3; each y is independently selected from 1, 2, 3, 4 and 5; z is 1; and q equals 1. 16. Connection according to any one of paragraphs. 6-15 or a pharmaceutically acceptable salt thereof, where X ₄ represents

, where * denotes the point of attachment to L ₂ ; L₂ is -(CR^fourR^five)_n-; R ¹ is CF ₃ ; R ² is H; R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ; each R ⁴ is H; each R ⁵ is H; each R ¹¹ is H; each R ¹² is H; each R ¹³ is H; n is 1, 2, 3, 4, 5, 6, 7, 8 or 9; and y is 2, 3, or 4. 17. The compound according to claim 6, selected from 6-(2-morpholinoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 2-(4,4-dioxido-2 ³ -(trifluoromethyl)-1 ¹ -oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -6-yl)acetic acid; 2 ³ -(trifluoromethyl)-4-thia-3,6,1 ¹ -triaza-1(3,2),2,5(2,6)-tripyridinecycloundecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinecyclododecaphan-4,4-dioxide; 4-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1, 2)-benzenecycloundecaphan-6-yl)butyric acid; 3-(2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6 -yl)ethoxy)propanoic acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-6-yl) butyric acid; 2 ³ -(trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclopentadecaphan-6-yl) butyric acid; 6-(2-(3-hydroxypropoxy)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 4,4-dioxides; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) butyric acid; 4-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafane -6-yl)butyric acid; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotetradecafan-6-yl) propanoic acid; 6-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) caproic acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotetradecafan-6-yl) butyric acid; 3-(4,4-dioxido ^- 2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-6-yl) propanoic acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 6-yl)butyric acid; ^butyric acid ; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) butanal; 2-(2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6 -yl)ethoxy)acetic acid; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclopentadecaphan-6-yl) propanoic acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6-yl) butyric acid; 5-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) pentanoic acid; 5-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafan-6-yl) pentanoic acid; ^butyric acid ; 5-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-6-yl) pentanoic acid; 3-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1, 2)-benzenecycloundecaphan-6-yl)propanoic acid; 6-(2 ³ -chloro-4,4-dioxido-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl)caproic acid ; ^butyric acid ; 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide ; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6-yl) propanoic acid; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide ; 6-(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-ethyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 3-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafane -6-yl) propanoic acid; 4-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -6-yl)butyric acid; 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide ; 3-(2 ³ -(difluoromethyl)-4,4-dioxido-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-6-yl) propanoic acid; 6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide ; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan- 6-yl)butyric acid; 3-(2 ³ -chloro-4,4-dioxido-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl)propanoic acid ; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-6-yl) butyric acid; 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2 )-benzenecycloundecaphan-4,4-dioxide; ^butyric acid ; 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2 )-benzenecycloundecaphan-4,4-dioxide; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) propanoic acid; 2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-6,12-dioxa-4-thia-3-aza-1(3.2),2,5(2.6)-tripyridinecyclododecaphan-4,4-dioxide; 2 ³ -chloro-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinecyclododecaphan-4,4-dioxide; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 3-(4,4-dioxydo-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl)propanoic acid; 1-((4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl )methyl)cyclopropane-1-carboxylic acid; 1-((4,4-dioxido-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafane -6-yl)methyl)cyclopropan-1-carboxylic acid; 3-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -6-yl)-2,2-dimethylpropanoic acid; 3-(1 ⁵ -fluoro-4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -6-yl) propanoic acid; 6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide ; 6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4 ,4-dioxide; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan- 6-yl) propanoic acid; 2 ³ -chloro-14-methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinecyclododecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinecyclododecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinecyclotridecaphan-4,4-dioxide; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6-yl) -2,2-dimethylpropanoic acid; 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 4,4-dioxides; 6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -4,4-dioxide; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) -2,2-dimethylpropanoic acid; 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafane -4,4-dioxide; 6,13-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinecyclotridecaphan-4,4-dioxide; 2 ³ -chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinecyclododecaphan-4,4-dioxide; 6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-7- yl) propanoic acid; 6,10-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinecyclodecaphan-4,4-dioxide; (4 ¹ s,4 ⁵ s)-1 ³ -(trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2.6),2(3,2)-tripyridine-4 (1,5)-cyclooctanacyclooctaphan-7,7-dioxide; 6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4 ,4-dioxide; 1 ⁵ -fluoro-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinecyclodecaphan-4,4-dioxide; 7-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4 -dioxide; ethyl 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6- yl)-2,2-dimethylpropanoate; 2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide; 2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafan-6-yl) acetic acid; 2 ³ -(trifluoromethyl)-6-((2S,3S)-2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1, 2)-benzenecycloundecaphan-4,4-dioxide; 2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide; 6-(2-(piperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)- benzenecycloundecaphan-4,4-dioxide; 6-(2-(4-methylpiperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2 )-benzenecycloundecaphan-4,4-dioxide; (2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl )ethyl)glycine; 6-(2-(3-hydroxyazetidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2 )-benzenecycloundecaphan-4,4-dioxide; ^23- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide; 6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2.5(2.6) -dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6- diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide; 6-methyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide; 2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4,4-dioxide; ethyl 2-(4,4-dioxido-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)- benzenecycloundecaphan-6-yl)acetate; 6-(2,3-dihydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4 -dioxide; 6-(2-(pyrrolidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)- benzenecycloundecaphan-4,4-dioxide; methyl-(2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6 -yl)ethyl)glycinate; 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine -1(1,2)-benzenecycloundecaphan-4,4-dioxide; 2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide ; 2 ³ -(trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-4,4-dioxide; 2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclononaphan-4,4-dioxide; 8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-(2-aminoethyl)-2 ³ -(difluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 2-(3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6 -yl)propyl)isoindoline-1,3-dione; 2-(3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6 -yl)propyl)hexahydro-1H-isoindole-1,3(2H)-dione; methyl-2-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6- yl)acetate, 6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-4 ,4-dioxide; 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-4,4-dioxide ; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclopentadecaphan-4,4-dioxide ; 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotetradecaphan-4,4-dioxide ; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotetradecaphan-4,4-dioxide ; 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclopentadecaphan-4,4-dioxide ; 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan- 4,4-dioxides; 6-(6-hydroxyhexyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide ; 6-(2-(2-hydroxyethoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 4,4-dioxides; 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide ; 2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan- 4,4-dioxides; 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 4,4-dioxides; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-4 ,4-dioxide; 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide ; 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-4,4-dioxide; 6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide; 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan -4,4-dioxide; 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1, 2)-benzenecyclododecaphan-4,4-dioxide; 1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1 ,2)-benzenecycloundecaphan-4,4-dioxide; 3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-6-yl) propanoic acid; 5-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-6-yl) pentanoic acid; 6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-4,4-dioxide and (R)-3-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan- 7-yl) propanoic acid. 18. The compound according to claim 6, selected from 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclodecaphan-6-yl) butyric acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecycloundecaphan-6-yl) butyric acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecaphan-6-yl) butyric acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotridecaphan-6-yl) butyric acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclotetradecafan-6-yl) butyric acid; 4-(4,4-dioxido-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclopentadecaphan-6-yl) butyric acid and 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridine-1(1,2)-benzenecyclododecafane -4,4-dioxide. 19. Pharmaceutical composition containing a compound according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 20. Pharmaceutical composition according to claim 19, additionally containing one or more additional pharmaceutical agents. 21. The pharmaceutical composition of claim 20, wherein the additional pharmaceutical agent(s) is(are) selected from a mucolytic agent, nebulised hypertonic saline, a bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator, and an anti-inflammatory agent. 22. The pharmaceutical composition of claim 20 wherein the additional pharmaceutical agent is a CFTR corrector. 23. The pharmaceutical composition of claim 20, wherein the additional pharmaceutical agent is a CFTR potentiator. 24. The pharmaceutical composition of claim 20 wherein the additional pharmaceutical agents are a CFTR corrector and a CFTR potentiator. 25. A method of treating a CFTR-mediated disease in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 or a pharmaceutical composition according to any one of paragraphs. 19-24. 26. The method of claim 25, wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, COPD, and chronic bronchitis. 27. The method of claim 25 or 26 wherein the CFTR mediated disease is cystic fibrosis, COPD, or emphysema. 28. The method of claim 25 or 26, wherein the CFTR-mediated disease is cystic fibrosis. 29. The method according to any one of paragraphs. 25-28, further comprising administering to the subject one or more additional pharmaceuticals before, concurrently with, or after administration of a compound according to any one of paragraphs. 1-18 or a pharmaceutical composition according to any one of paragraphs. 19-24. 30. The method of claim 29, wherein the additional pharmaceutical agent(s) is(are) selected from a mucolytic agent, nebulized hypertonic saline, a bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator, and an anti-inflammatory agent. 31. The method of claim 29 wherein the additional pharmaceutical agent is a CFTR corrector. 32. The method of claim 29 wherein the additional pharmaceutical agent is a CFTR potentiator. 33. The method of claim 29 wherein the additional pharmaceutical agents are a CFTR corrector and a CFTR potentiator. 34. The use of a compound according to any one of paragraphs. 1-18 in the manufacture of a medicament for the treatment of a disease mediated by CFTR. 35. Use according to claim 34, where the medicinal product additionally contains one or more additional pharmaceutical agents. 36. Use according to claim 35, wherein the additional pharmaceutical agent(s) is(are) selected from mucolytic agent, nebulized hypertonic saline solution, bronchodilator, antibiotic, anti-infective agent, CFTR modulator and anti-inflammatory agent. 37. Use according to claim 35, wherein the additional pharmaceutical agent is a CFTR corrector. 38. The use of claim 35 wherein the additional pharmaceutical agent is a CFTR potentiator. 39. The use of claim 35 wherein the additional pharmaceutical agents are a CFTR corrector and a CFTR potentiator. 40. A method of treating pancreatitis in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 or a pharmaceutical composition according to any one of paragraphs. 19-24. 41. The method according to p. 40, further comprising the introduction to the subject of one or more additional pharmaceutical agents before the introduction, in parallel with the introduction or after the introduction of the compounds according to any one of paragraphs. 1-18 or a pharmaceutical composition according to any one of paragraphs. 19-24. 42. The method of claim 41, wherein the additional pharmaceutical agent(s) is(are) selected from a mucolytic agent, nebulised hypertonic saline, a bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator, and an anti-inflammatory agent. 43. The method of claim 41 wherein the additional pharmaceutical agent is a CFTR corrector. 44. The method of claim 41 wherein the additional pharmaceutical agent is a CFTR potentiator. 45. The method of claim 41 wherein the additional pharmaceutical agents are a CFTR corrector and a CFTR potentiator. 46. Connection according to any one of paragraphs. 1-18 or its pharmaceutically acceptable salt or pharmaceutical composition according to any one of paragraphs. 19-24 for use in the treatment of CFTR mediated disease. 47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46, wherein the CFTR-mediated disease is selected from cystic fibrosis, asthma, COPD, and chronic bronchitis. 48. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46, wherein the CFTR-mediated disease is cystic fibrosis, COPD, or emphysema. 49. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46, wherein the CFTR-mediated disease is cystic fibrosis. 50. Connection according to any one of paragraphs. 1-18 or its pharmaceutically acceptable salt or pharmaceutical composition according to any one of paragraphs. 19-24 for use in the treatment of pancreatitis.