Cystic fibrosis transmembrane conductance regulator modulators

Abstract

The present disclosure provides cystic fibrosis transmembrane conductance regulator (CFTR) modulators having a core structure (I), pharmaceutical compositions comprising at least one such modulator, methods of treating CFTR-mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies using the modulators, and processes and intermediates for making such modulators. Further aspects of the disclosure provide intermediates and methods for making the compounds and compositions disclosed herein. TIFF2023545080001693.tif3969

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, Ring A is ■C ６ -C １０ aryl, and ■ selected from 5- to 10-membered heteroaryl; Ring B is ■C ６ -C １０ aryl; V is selected from O and NH; W １ is selected from N and CH; W ２ is N, Z is NR ＺＮ , and C(R ＺＣ ) ２ is selected from, with the proviso that L ２ is absent, Z is C(R ＺＣ ) ２ provided that: L １ are each independently C(R Ｌ１ ) ２ is selected from L ２ are each independently C(R Ｌ２ ) ２ is selected from R ３ are each independently, ■Halogen, and ■C １ -C ６ Alkyl is selected from R ４ is hydrogen and C １ -C ６ alkyl, R ５ are each independently, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R Ｎ ) ２ 、 ■ -SO-Me, -CH=C(R ＬＣ ) ２ wherein both R ＬＣ Together, C ３ -C １０ forming a cycloalkyl, —CH═C(R ＬＣ ) ２ , ■C １ -C ６ alkyl, Hydroxyl, ○C １ -C ６ Alkoxy and C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ○C ３ -C １０ cycloalkyl, ○C １ -C ６ Alkyl and C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from alkoxy ０－１ -(C ６ -C １０ aryl), 3- to 10-membered heterocyclyl, and ○N (R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ■C １ -C ６ Alkoxy, ○Halogen, ○C ６ -C １０ aryl, and ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkoxy, ■C １ -C ６ fluoroalkyl, ■C ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, and ■ 3- to 10-membered heterocyclyl, R ＹＮ but, ■ Hydrogen, ■C １ -C ９ alkyl, Hydroxyl, ○Oxo, ○Cyano, Halogens and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkoxy １ -C ６ Alkoxy, ○N(R Ｎ ) ２ 、 ○SO ２ Me、 ○C ３ -C １０ cycloalkyl, ◆ Hydroxyl, ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy, C ６ -C １０ Aryl, and N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆C １ -C ６ fluoroalkyl, ◆C １ -C ６ Alkoxy, ◆COOH, ◆N(R Ｎ ) ２ 、 ◆C ６ -C １０ aryl, and ◆Oxo and C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl; ３ -C １０ cycloalkyl, ○C ６ -C １０ aryl, ◆Halogen, ◆ Hydroxyl, ◆Cyano, ◆SiMe ３ 、 ◆SO ２ Me、 ◆SF ５ 、 ◆N(R Ｎ ) ２ 、 ◆P(O)Me ２ 、 ◆C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ０－１ -(C ３ -C １０ cycloalkyl), ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy, 5- to 10-membered heteroaryl, SO ２ Me, and N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆ Hydroxyl, oxo, N(R Ｎ ) ２ , and C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, ◆C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl; ◆-(O) ０－１ -(C ６ -C １０ aryl), and ◆ Hydroxyl, oxo, N(R Ｎ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Fluoroalkyl, and C ３ -C １０ -(O) optionally substituted with cycloalkyl ０－１ -(5-10-heteroaryl), C ６ -C １０ aryl, 3- to 10-membered heterocyclyl, ◆ Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆Oxo and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkoxy １ -C ６ Alkyl, ◆C １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, C optionally substituted with 1 to 3 groups independently selected from halogen ６ -C １０ aryl, and ◆ 3- to 10-membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from 5- to 10-membered heteroaryl; 5-10 membered heteroaryl, ◆ Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH) ２ 、 ◆N(R Ｎ ) ２ 、 ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy (1 to 3 -SiMe ３ optionally substituted with ), 3- to 10-membered heterocyclyl, and N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆Hydroxyl, oxo, halogen, C １ -C ６ Alkoxy, N(R Ｎ ) ２ , 3- to 10-membered heterocyclyl (C １ -C ６ alkyl), and C ３ -C １０ C optionally substituted with 1 to 3 groups independently selected from cycloalkyl １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, ◆Halogen, C １ -C ６ Alkyl, and C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from alkoxy ０－１ -(C ３ -C １０ cycloalkyl), ◆-(O) ０－１ -(C ６ -C １０ aryl), ◆ Hydroxyl, oxo, halogen, cyano, N(R Ｎ ) ２ , C １ -C ６ Alkyl (hydroxyl, oxo, N(R Ｎ ) ２ , and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Fluoroalkyl, C ３ -C １０ cycloalkyl, 5- to 10-membered heteroaryl (C １ -C ６ alkyl), and 3- to 10-membered heterocyclyl (C １ -C ６ -(O) optionally substituted with 1 to 4 groups independently selected from fluoroalkyl; ０－１ -(3- to 10-membered heterocyclyl), and ◆C １ -C ６ Alkyl and C ３ -C １０ 5-10 membered heteroaryl optionally substituted with 1-3 groups independently selected from cycloalkyl; １ -C ９ Alkyl, and ■C １ -C ６ fluoroalkyl; R ＺＮ but, Hydrogen, and ■C １ -C ９ Alkyl is selected from Two R's ＺＣ together to form an oxo group, R Ｌ１ are each independently, ■ Hydrogen, ■N (R Ｎ ) ２ However, two N(R Ｎ ) ２ are not attached to the same carbon atom, Ｎ ) ２ , ■C １ -C ９ alkyl, ○Halogen, Hydroxyl, ○Oxo, ○N(R Ｎ ) ２ 、 ○C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ○Halogen, C １ -C ６ Alkyl, and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, ○-O-(C ３ -C １０ cycloalkyl), ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl, and ○C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo); １ -C ９ Alkyl, ■C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, ○Halogen, ○Cyano, ○SiMe ３ 、 ○POMe ２ 、 ○C １ -C ７ alkyl, ◆ Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe ３ 、 ◆N (R Ｎ ) ２ , and ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ７ Alkyl, ○C １ -C ６ Alkoxy, ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, and ◆C １ -C ６ alkoxy, C １ -C ６ Alkoxy, ○C １ -C ６ fluoroalkyl, ○C １ -C ６ Alkyl and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, ○C ６ -C １０ aryl, ○C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl, and 5- to 10-membered heteroaryl, optionally substituted with 1 to 4 groups independently selected from ６ -C １０ aryl, ■ 3- to 10-membered heterocyclyl, ○C １ -C ６ alkyl, ◆Oxo, and ◆C １ -C ６ alkoxy, C １ -C ６ alkyl; 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from ■ 5- to 10-membered heteroaryl, ○C １ -C ６ alkyl, ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ６ alkyl, and ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl; or Two R on the same carbon atom Ｌ１ together to form an oxo group, R Ｌ２ are each independently selected from hydrogen; or Two R on the same carbon atom Ｌ２ together to form an oxo group, R Ｎ are each independently, ■ Hydrogen, ■C １ -C ８ alkyl, ○Oxo, ○Halogen, Hydroxyl, ○NH ２ 、 NHMe, ○NMe ２ 、 ○NHCOMe, ○N (R Ｎ３ ) ２ wherein R Ｎ３ are each independently C １ -C ６ Alkyl (oxo and C １ -C ６ N(R optionally substituted with 1 to 3 groups independently selected from alkoxy) Ｎ３ ) ２ , ○C ６ -C １０ Aryl, oxo, NMe ２ and C optionally substituted with 1 to 3 groups independently selected from NHMe １ -C ６ Alkoxy, ○C １ -C ６ Alkyl (C １ -C ６ alkoxy) and C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from alkoxy ０－１ -(C ３ -C １０ cycloalkyl), Halogens and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl, ○Oxo and C １ -C ６ 3- to 14-membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from alkyl, and ○Oxo and C １ -C ６ 5-14 membered heteroaryl optionally substituted with 1 to 4 groups independently selected from alkyl; C １ -C ８ Alkyl, ■C ３ -C １０ cycloalkyl, Hydroxyl, ○Halogen, ○NH ２ 、 NHMe, ○C １ -C ６ Alkoxy, and Hydroxyl and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkoxy １ -C ６ alkyl, optionally substituted with 1 to 3 groups independently selected from ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, ■C １ -C ６ a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 groups independently selected from alkyl, and ■ 3- to 10-membered heterocyclyl, or Two R on the same nitrogen atom Ｎ together with the nitrogen to which they are attached, a 3- to 10-membered heterocyclyl; ■ Hydroxyl, ■Halogen, ■Oxo, ■ Cyano, ■ Oxo, hydroxyl, C １ -C ６ Alkoxy, and N(R Ｎ２ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ alkyl, wherein R Ｎ２ are each independently hydrogen and C １ -C ６ alkyl, C １ -C ６ Alkyl, ■C １ -C ６ Alkoxy, and ■C １ -C ６ fluoroalkyl; or One R ４ and one R Ｌ１ Together, C ６ -C ８ alkylene-forming compounds, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of any of the foregoing.

2. A compound of formula Ia, 【Transformation 3】 During the ceremony, Ring A is ■C ６ -C １０ aryl, and ■ selected from 5- to 10-membered heteroaryl; Ring B is ■C ６ -C １０ Aryl is selected from V is selected from O and NH; W １ is selected from N and CH; W ２ is N, Z is NR ＺＮ , and C(R ＺＣ ) ２ is selected from, with the proviso that L ２ is absent, Z is C(R ＺＣ ) ２ provided that: L １ are each independently C(R Ｌ１ ) ２ is selected from L ２ are each independently C(R Ｌ２ ) ２ is selected from R ３ are each independently, ■Halogen, and ■C １ -C ６ Alkyl is selected from R ４ is hydrogen and C １ -C ６ alkyl, R ５ are each independently, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R Ｎ ) ２ 、 ■ -SO-Me, -CH=C(R ＬＣ ) ２ wherein both R ＬＣ Together, C ３ -C １０ forming a cycloalkyl, —CH═C(R ＬＣ ) ２ , ■C １ -C ６ alkyl, Hydroxyl, ○C １ -C ６ Alkoxy and C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ○C ３ -C １０ cycloalkyl, ○C １ -C ６ Alkyl and C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from alkoxy ０－１ -(C ６ -C １０ aryl), 3- to 10-membered heterocyclyl, and ○N (R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ■C １ -C ６ Alkoxy, ○Halogen, ○C ６ -C １０ aryl, and ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkoxy, ■C １ -C ６ fluoroalkyl, ■C ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, and ■ 3- to 10-membered heterocyclyl, R ＹＮ but, ■ Hydrogen, ■C １ -C ９ alkyl, Hydroxyl, ○Oxo, ○Cyano, Halogens and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkoxy １ -C ６ Alkoxy, ○N(R Ｎ ) ２ 、 ○SO ２ Me、 ○C ３ -C １０ cycloalkyl, ◆ Hydroxyl, ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy, C ６ -C １０ Aryl, and N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆C １ -C ６ fluoroalkyl, ◆C １ -C ６ Alkoxy, ◆COOH, ◆N(R Ｎ ) ２ 、 ◆C ６ -C １０ aryl, and ◆Oxo and C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl; ３ -C １０ cycloalkyl, ○C ６ -C １０ aryl, ◆Halogen, ◆ Hydroxyl, ◆Cyano, ◆SiMe ３ 、 ◆SO ２ Me、 ◆SF ５ 、 ◆N(R Ｎ ) ２ 、 ◆P(O)Me ２ 、 ◆C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ０－１ -(C ３ -C １０ cycloalkyl), ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy, 5- to 10-membered heteroaryl, SO ２ Me, and N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆ Hydroxyl, oxo, N(R Ｎ ) ２ , and C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, ◆C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl; ◆-(O) ０－１ -(C ６ -C １０ aryl), and ◆ Hydroxyl, oxo, N(R Ｎ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Fluoroalkyl, and C ３ -C １０ -(O) optionally substituted with cycloalkyl ０－１ -(5-10-heteroaryl), C ６ -C １０ aryl, 3- to 10-membered heterocyclyl, ◆ Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆Oxo and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkoxy １ -C ６ Alkyl, ◆C １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, C optionally substituted with 1 to 3 groups independently selected from halogen ６ -C １０ aryl, and ◆ 3- to 10-membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from 5- to 10-membered heteroaryl, and 5-10 membered heteroaryl, ◆ Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH) ２ 、 ◆N(R Ｎ ) ２ 、 ◆ Hydroxyl, oxo, C １ -C ６ Alkoxy (1 to 3 -SiMe ３ Optionally substituted with N(R Ｎ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl, ◆Hydroxyl, oxo, halogen, C １ -C ６ Alkoxy, N(R Ｎ ) ２ , and C ３ -C １０ C optionally substituted with 1 to 3 groups independently selected from cycloalkyl １ -C ６ Alkoxy, ◆C １ -C ６ fluoroalkyl, ◆Halogen, C １ -C ６ Alkyl, and C １ -C ６ -(O) optionally substituted with 1 to 3 groups independently selected from alkoxy ０－１ -(C ３ -C １０ cycloalkyl), ◆-(O) ０－１ -(C ６ -C １０ aryl), ◆ Hydroxyl, oxo, halogen, cyano, N(R Ｎ ) ２ , C １ -C ６ Alkyl (hydroxyl, oxo, N(R Ｎ ) ２ , and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Fluoroalkyl, and 3- to 10-membered heterocyclyl (C １ -C ６ -(O) optionally substituted with 1 to 4 groups independently selected from fluoroalkyl; ０－１ -(3- to 10-membered heterocyclyl), and ◆C １ -C ６ Alkyl and C ３ -C １０ 5-10 membered heteroaryl optionally substituted with 1-3 groups independently selected from cycloalkyl; １ -C ９ Alkyl, and ■C １ -C ６ fluoroalkyl; R ＺＮ but, Hydrogen, and ■C １ -C ９ Alkyl is selected from Two R's ＺＣ together to form an oxo group, R Ｌ１ are each independently, ■ Hydrogen, ■N (R Ｎ ) ２ However, two N(R Ｎ ) ２ are not attached to the same carbon atom, Ｎ ) ２ , ■C １ -C ９ alkyl, ○Halogen, Hydroxyl, ○Oxo, ○N(R Ｎ ) ２ 、 ○C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, Halogens and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl, and ○C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo); １ -C ９ Alkyl, ■C ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, ○Halogen, ○Cyano, ○SiMe ３ 、 ○POMe ２ 、 ○C １ -C ７ alkyl, ◆ Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe ３ 、 ◆N (R Ｎ ) ２ , and ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ７ Alkyl, ○C １ -C ６ Alkoxy, ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, and ◆C １ -C ６ alkoxy, C １ -C ６ Alkoxy, ○C １ -C ６ fluoroalkyl, ○C １ -C ６ Alkyl and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, ○C ６ -C １０ aryl, ○C １ -C ６ 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from alkyl, and 5- to 10-membered heteroaryl, optionally substituted with 1 to 4 groups independently selected from ６ -C １０ aryl, ■ 3- to 10-membered heterocyclyl, ○C １ -C ６ alkyl, ◆Oxo, and ◆C １ -C ６ alkoxy, C １ -C ６ alkyl; 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from ■ 5- to 10-membered heteroaryl, ○C １ -C ６ alkyl, ◆C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from fluoroalkyl ３ -C １０ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ６ alkyl, and ○C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl; and 5-10 membered heteroaryl optionally substituted with 1-3 groups independently selected from or Two R on the same carbon atom Ｌ１ together to form an oxo group, R Ｌ２ are each independently selected from hydrogen; or Two R on the same carbon atom Ｌ２ together to form an oxo group, R Ｎ are each independently, ■ Hydrogen, ■C １ -C ８ alkyl, ○Oxo, ○Halogen, Hydroxyl, ○NH ２ 、 NHMe, ○NMe ２ 、 ○NHCOMe, ○C ６ -C １０ C optionally substituted with 1 to 3 groups independently selected from aryl １ -C ６ Alkoxy, ○-(O) ０－１ -(C ３ -C １０ cycloalkyl), Halogens and C １ -C ６ C optionally substituted with 1 to 3 groups independently selected from alkyl ６ -C １０ aryl, and ○Oxo and C １ -C ６ 3- to 14-membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from alkyl, and ○Oxo and C １ -C ６ 5-14 membered heteroaryl optionally substituted with 1 to 4 groups independently selected from alkyl; C １ -C ８ Alkyl, ■C ３ -C １０ cycloalkyl, Hydroxyl, ○NH ２ 、 NHMe, and C optionally substituted with 1 to 3 groups independently selected from hydroxyl １ -C ６ alkyl, optionally substituted with 1 to 3 groups independently selected from ３ -C １０ cycloalkyl, ■C ６ -C １０ aryl, and ■ 3- to 10-membered heterocyclyl, or Two R on the same nitrogen atom Ｎ together with the nitrogen to which they are attached, a 3- to 10-membered heterocyclyl; ■ Hydroxyl, ■Halogen, ■Oxo, ■ Cyano, ■ Oxo, hydroxyl, C １ -C ６ Alkoxy, and N(R Ｎ２ ) ２ C optionally substituted with 1 to 3 groups independently selected from １ -C ６ alkyl, wherein R Ｎ２ are each independently hydrogen and C １ -C ６ alkyl, C １ -C ６ Alkyl, ■C １ -C ６ Alkoxy, and ■C １ -C ６ fluoroalkyl; or One R ４ and one R Ｌ１ Together, C ６ -C ８ alkylene-forming compounds, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of any of the foregoing.

3. A compound of formula Ib, 【Transformation 5】 In the formula, ring A, ring B, W １ , W ２ , Z, L １ , L ２ , R ３ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

4. A compound of formula IIa, 【Transformation 6】 In the formula, rings B, W １ , W ２ , Z, L １ , L ２ , R ３ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

5. A compound of formula IIb, 【Transformation 7】 In the formula, rings A, W １ , W ２ , Z, L １ , L ２ , R ３ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

6. A compound of formula III, 【Transformation 8】 During the ceremony, W １ , W ２ , Z, L １ , L ２ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

7. A compound of formula IV, 【Chemistry 9】 In the formula, Z, L １ , L ２ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

8. A compound of formula V, 【Chemistry 10】 In the formula, Z, L １ , L ２ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

9. A compound of formula VI, 【Chemistry 11】 In the ceremony, L １ , R ４ , R ５ , and R ＹＮ is defined by claim 2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 【Request Item 10】 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】 【Chemistry 12-12】 [Chemistry 12-13] 【Chemistry 12-14】 【Chemistry 12-15】 【Chemistry 12-16】 【Chemistry 12-17】 【Chemistry 12-18】 【Chemistry 12-19】 【Chemistry 12-20】 【Chemistry 12-21】 【Chemistry 12-22】 [Chemistry 12-23] [Chemistry 12-24] [Chemistry 12-25] [Chemistry 12-26] [Chemistry 12-27] [Chemistry 12-28] [Chemistry 12-29] 【Chemistry 12-30】 【Chemistry 12-31】 【Chemistry 12-32】 【Chemistry 12-33】 [Chemistry 12-34] 【Chemistry 12-35】 【Chemistry 12-36】 【Chemistry 12-37】 【Chemistry 12-38】 【Chemistry 12-39】 【Chemistry 12-40】 【Chemistry 12-41】 【Chemistry 12-42】 [Chemistry 12-43] [Chemistry 12-44] 【Chemistry 12-45】 [Chemistry 12-46] [Chemistry 12-47] [Chemistry 12-48] [Chemistry 12-49] 【Chemistry 12-50】 【Chemistry 12-51】 【Chemistry 12-52】 【Chemistry 12-53】 [Chemistry 12-54] 【Chemistry 12-55】 [Chemistry 12-56] 【Chemistry 12-57】 [Chemistry 12-58] [Chemistry 12-59] 【Chemistry 12-60】 【Chemistry 12-61】 【Chemistry 12-62】 [Chemistry 12-63] [Chemistry 12-64] 【Chemistry 12-65】 【Chemistry 12-66】 【Chemistry 12-67】 【Chemistry 12-68】 【Chemistry 12-69】 【Chemistry 12-70】 【Chemistry 12-71】 【Chemistry 12-72】 【Chemistry 12-73】 [Chemistry 12-74] 【Chemistry 12-75】 【Chemistry 12-76】 【Chemistry 12-77】 【Chemistry 12-78】 【Chemistry 12-79】 【Chemistry 12-80】 【Chemistry 12-81】 【Chemistry 12-82】 [Chemistry 12-83] [Chemistry 12-84] 【Chemistry 12-85】 【Chemistry 12-86】 【Chemistry 12-87】 【Chemistry 12-88】 【Chemistry 12-89】 【Chemistry 12-90】 【Chemistry 12-91】 【Chemistry 12-92】 【Chemistry 12-93】 【Chemistry 12-94】 【Chemistry 12-95】 【Chemistry 12-96】 【Chemistry 12-97】 【Chemistry 12-98】 【Chemistry 12-99】 【Chemistry 12-100】 【Chemistry 12-101】 【Chemistry 12-102】 【Chemistry 12-103】 【Chemistry 12-104】 【Chemistry 12-105】 【Chemistry 12-106】 【Chemistry 12-107】 【Chemistry 12-108】 【Chemistry 12-109】 【Chemistry 12-110】 【Chemistry 12-111】 【Chemistry 12-112】 【Chemistry 12-113】 【Chemistry 12-114】 【Chemistry 12-115】 【Chemistry 12-116】 【Chemistry 12-117】 【Chemistry 12-118】 【Chemistry 12-119】 【Chemistry 12-120】 【Chemistry 12-121】 【Chemistry 12-122】 【Chemistry 12-123】 【Chemistry 12-124】 【Chemistry 12-125】 【Chemistry 12-126】 【Chemistry 12-127】 【Chemistry 12-128】 【Chemistry 12-129】 【Chemistry 12-130】 【Chemistry 12-131】 【Chemistry 12-132】 【Chemistry 12-133】 [Chemistry 12-134] 【Chemistry 12-135】 【Chemistry 12-136】 【Chemistry 12-137】 【Chemistry 12-138】 【Chemistry 12-139】 【Chemistry 12-140】 【Chemistry 12-141】 【Chemistry 12-142】 [Chemistry 12-143] [Chemistry 12-144] 【Chemistry 12-145】 [Chemistry 12-146] 【Chemistry 12-147】 [Chemistry 12-148] [Chemistry 12-149] 【Chemistry 12-150】 【Chemistry 12-151】 【Chemistry 12-152】 , a tautomer thereof, a deuterated derivative of said compound and said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

11. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11, further comprising one or more additional therapeutic agents.

13. 13. The pharmaceutical composition of claim 12, wherein the one or more additional therapeutic agents are selected from tezacaftor, ivacaftor, deutivacaftor, lumacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and pharmaceutically acceptable salts thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the composition comprises tezacaftor and ivacaftor.

15. 14. The pharmaceutical composition of claim 13, wherein the composition comprises tezacaftor and deutoivacaftor.

16. 14. The pharmaceutical composition of claim 13, wherein the composition comprises tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol.

17. 11. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 10 in the manufacture of a medicament for the treatment of cystic fibrosis in a patient in need thereof.

18. 18. The use of claim 17, wherein the treatment further comprises administering to the patient one or more additional therapeutic agents prior to, simultaneously with, or following the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 10.

19. 19. The use of claim 18, wherein the one or more additional therapeutic agents is a compound selected from tezacaftor, ivacaftor, deutoivacaftor, lumacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and pharmaceutically acceptable salts thereof.

20. 20. The use of claim 19, wherein the one or more additional therapeutic agents are tezacaftor and ivacaftor.

21. 20. The use of claim 19, wherein the one or more additional therapeutic agents are tezacaftor and deutoivacaftor.

22. 20. The use of claim 19, wherein the one or more additional therapeutic agents are tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol.

23. 12. The pharmaceutical composition of claim 11 for use in the treatment of cystic fibrosis in a patient in need thereof.

24. 24. The pharmaceutical composition for use according to claim 23, wherein said treatment further comprises administering to said patient one or more additional therapeutic agents prior to, simultaneously with, or after the pharmaceutical composition of claim 11.

25. 25. The pharmaceutical composition for use according to claim 24, wherein the one or more additional therapeutic agents is a compound selected from tezacaftor, ivacaftor, deutoivacaftor, lumacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and pharmaceutically acceptable salts thereof.

26. 26. The pharmaceutical composition for use according to claim 25, wherein the one or more additional therapeutic agents are tezacaftor and ivacaftor.

27. 26. The pharmaceutical composition for use according to claim 25, wherein the one or more additional therapeutic agents are tezacaftor and deutoivacaftor.

28. 26. The pharmaceutical composition for use according to claim 25, wherein the one or more additional therapeutic agents are tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol.

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