Claims for Patent: 10,758,534

Summary for Patent: 10,758,534

Title:	Modulators of cystic fibrosis transmembrane conductance regulator
Abstract:	The present invention features a compound of formula I: ##STR00001## or a pharmaceutically acceptable salt thereof, where R.sub.1, R.sub.2, R.sub.3, W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.
Inventor(s):	Miller; Mark Thomas (San Diego, CA), Anderson; Corey (San Diego, CA), Arumugam; Vijayalaksmi (San Marcos, CA), Bear; Brian Richard (Carlsbad, CA), Binch; Hayley Marie (Encinitas, CA), Clemens; Jeremy J. (San Diego, CA), Cleveland; Thomas (San Diego, CA), Conroy; Erica (Columbus, OH), Coon; Timothy Richard (Carlsbad, CA), Frieman; Bryan A. (La Jolla, CA), Grootenhuis; Peter Diederik Jan (San Diego, CA), Gross; Raymond Stanley (Poway, CA), Hadida-Ruah; Sara Sabina (La Jolla, CA), Khatuya; Haripada (San Diego, CA), Joshi; Pramod Virupax (San Diego, CA), Krenitsky; Paul John (San Diego, CA), Lin; Chun-Chieh (San Diego, CA), Marelius; Gulin Erdogan (San Diego, CA), Melillo; Vito (Escondido, CA), McCartney; Jason (Cardiff by the Sea, CA), Nicholls; Georgia McGaughey (Winchester, MA), Pierre; Fabrice Jean Denis (La Jolla, CA), Silina; Alina (San Diego, CA), Termin; Andreas P. (Encinitas, CA), Uy; Johnny (San Diego, CA), Zhou; Jinglan (San Diego, CA)
Assignee:	Vertex Pharmaceuticals Incorporated (Boston, MA)
Application Number:	16/258,024
Patent Claims:	1. A compound of formula Ib-iii: ##STR03779## or a pharmaceutically acceptable salt thereof, wherein: Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring; and wherein, independently for each occurrence: R.sub.1 is halo; CN; F.sub.5S; SiR.sub.3; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; R.sub.2 is halo; OH; NRR; azide; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.2 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.3 is halo; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.3 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.4 is H; azide; CF.sub.3; CHF.sub.2; OR; CCH; CO.sub.2R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO.sub.2R; R is independently H; OH; CO.sub.2H; CO.sub.2C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; n is 0, 1, 2 or 3; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, or 5. 2. The compound or salt of claim 1, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline. 3. The compound or salt of claim 1, wherein ring B is selected from ##STR03780## 4. The compound or salt of claim 1, wherein ring C is selected from indole, piperidine, azepane, azetadine, indoline, isoindoline, or pyrrolidine. 5. The compound or salt of claim 1, wherein ring C is selected from ##STR03781## ##STR03782## 6. The compound or salt of claim 1, wherein R.sub.1 is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR, wherein all rings are optionally substituted with one or more groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH.sub.2OH, CH.sub.2OCH.sub.3, CN, CO.sub.2H, amino, amido, C3-C10 heteroaryl, and C3-C10 heterocycloalkyl. 7. The compound or salt of claim 1, wherein R.sub.1 is selected from CH.sub.3, Cl, F, CN, OCH.sub.3, CF.sub.3, CH.sub.2CH.sub.3, tBu, CH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2OCH.sub.2CH.sub.3, ##STR03783## ##STR03784## ##STR03785## ##STR03786## ##STR03787## ##STR03788## ##STR03789## ##STR03790## ##STR03791## 8. The compound or salt of claim 1, wherein R.sub.2 is selected from halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ring wherein up to 4 ring atoms are independently 0, S, N, or NR; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR. 9. The compound or salt of claim 1, wherein R.sub.2 is selected from Cl, F, OH, CN, N.sub.3, NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3, N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, =O, CH.sub.3SO.sub.2, CH.sub.3SO.sub.2NH, CF.sub.3CONH, CH.sub.3CONH, CH.sub.3CON(CH.sub.3), tBuOCONH, (CH.sub.3).sub.2CHOCONH, CH(CH.sub.3).sub.2, CHF.sub.2, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH(CH.sub.3).sub.2, OCF.sub.3, OCHF.sub.2, OC(CH.sub.3).sub.3, OCH.sub.2CH.sub.2tBu, NHCH(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3), OCH(CH.sub.3).sub.2, NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CH.sub.3, C(O)CH.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2, NH(CH.sub.2).sub.2OH, N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, NHCH.sub.2CH.sub.2COOH, NH(CH.sub.2).sub.2N(CH.sub.3).sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2OCH.sub.3, NHCH(CH.sub.3).sub.2, ##STR03792## ##STR03793## 10. The compound or salt of claim 1, wherein R.sub.3 is selected from halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR. 11. The compound or salt of claim 1, wherein R.sub.3 is selected from Cl, I, deuterium, F, CN, CH.sub.3, OH, OCH.sub.3, CF.sub.3, CH.sub.2CH.sub.3, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CH.sub.3, OCH.sub.2CH(CH.sub.3).sub.2, OCH(CH.sub.3).sub.2, CO.sub.2H, CO.sub.2NH.sub.2, OCH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CH(CH.sub.3).sub.2, CCH, CH.sub.2CONH.sub.2, CO.sub.2CH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, CO.sub.2tBu, tBu, =CH.sub.2, =O, ##STR03794## 12. A compound of formula Ib-iv: ##STR03795## or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring; R.sub.1 is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R.sub.2 is halo; OH; NRR; azide; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.2 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.3 is halo; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.3 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.4 is H; azide; CF.sub.3; CHF.sub.2; OR; CCH; CO.sub.2R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO.sub.2R; R is independently H; OH; CO.sub.2H; CO.sub.2C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, or 5. 13. A compound of formula Ib-v: ##STR03796## or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R.sub.1 is halo; CN; F.sub.5S; SiR.sub.3; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; R.sub.2 is halo; OH; NRR; azide; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.2 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.3 is halo; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.3 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.4 is H; azide; CF.sub.3; CHF.sub.2; OR; CCH; CO.sub.2R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO.sub.2R; R is independently H; OH; CO.sub.2H; CO.sub.2C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; n is 0, 1, 2 or 3; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, or 5. 14. A compound of formula Ib-vi: ##STR03797## or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R.sub.1 is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R.sub.2 is halo; OH; NRR; azide; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.2 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.3 is halo; CN; CO.sub.2R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R.sub.4 wherein up to four CH.sub.2 units are independently replaced with O, CO, S, SO, SO.sub.2 or NR; or two R.sub.3 groups taken together may form a=CH.sub.2 or .dbd.O group; R.sub.4 is H; azide; CF.sub.3; CHF.sub.2; OR; CCH; CO.sub.2R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO.sub.2R; R is independently H; OH; CO.sub.2H; CO.sub.2C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, or 5. 15. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ##STR03798## ##STR03799## ##STR03800## ##STR03801## ##STR03802## ##STR03803## ##STR03804## ##STR03805## ##STR03806## ##STR03807## ##STR03808## ##STR03809## ##STR03810## ##STR03811## ##STR03812## ##STR03813## ##STR03814## ##STR03815## ##STR03816## ##STR03817## ##STR03818## ##STR03819## ##STR03820## ##STR03821## ##STR03822## ##STR03823## ##STR03824## ##STR03825## ##STR03826## ##STR03827## ##STR03828## ##STR03829## ##STR03830## ##STR03831## ##STR03832## ##STR03833## ##STR03834## ##STR03835## ##STR03836## ##STR03837## ##STR03838## ##STR03839## ##STR03840## ##STR03841## ##STR03842## ##STR03843## ##STR03844## ##STR03845## ##STR03846## ##STR03847## ##STR03848## ##STR03849## ##STR03850## ##STR03851## ##STR03852## ##STR03853## ##STR03854## ##STR03855## ##STR03856## ##STR03857## ##STR03858## ##STR03859## ##STR03860## ##STR03861## ##STR03862## ##STR03863## ##STR03864## ##STR03865## ##STR03866## ##STR03867## ##STR03868## ##STR03869## ##STR03870## ##STR03871## ##STR03872## ##STR03873## ##STR03874## ##STR03875## ##STR03876## ##STR03877## ##STR03878## ##STR03879## ##STR03880## ##STR03881## ##STR03882## ##STR03883## ##STR03884## ##STR03885## ##STR03886## ##STR03887## ##STR03888## ##STR03889## ##STR03890## ##STR03891## ##STR03892## ##STR03893## ##STR03894## ##STR03895## ##STR03896## ##STR03897## ##STR03898## ##STR03899## ##STR03900## ##STR03901## ##STR03902## ##STR03903## ##STR03904## ##STR03905## ##STR03906## ##STR03907## ##STR03908## ##STR03909## ##STR03910## ##STR03911## ##STR03912## ##STR03913## ##STR03914## ##STR03915## ##STR03916## ##STR03917## ##STR03918## ##STR03919## ##STR03920## ##STR03921## ##STR03922## ##STR03923## ##STR03924## ##STR03925## ##STR03926## ##STR03927## ##STR03928## ##STR03929## ##STR03930## ##STR03931## ##STR03932## ##STR03933## ##STR03934## ##STR03935## ##STR03936## ##STR03937## ##STR03938## ##STR03939## ##STR03940## ##STR03941## ##STR03942## ##STR03943## ##STR03944## ##STR03945## ##STR03946## ##STR03947## ##STR03948## ##STR03949## ##STR03950## ##STR03951## ##STR03952## ##STR03953## ##STR03954## ##STR03955## ##STR03956## ##STR03957## ##STR03958## ##STR03959## ##STR03960## ##STR03961## ##STR03962## ##STR03963## ##STR03964## ##STR03965## ##STR03966## ##STR03967## ##STR03968## ##STR03969## ##STR03970## ##STR03971## ##STR03972## ##STR03973## ##STR03974## ##STR03975## ##STR03976## ##STR03977## ##STR03978## ##STR03979## ##STR03980## ##STR03981## ##STR03982## ##STR03983## ##STR03984## ##STR03985## ##STR03986## ##STR03987## ##STR03988## ##STR03989## ##STR03990## ##STR03991## ##STR03992## ##STR03993## ##STR03994## ##STR03995## ##STR03996## ##STR03997## ##STR03998## ##STR03999## ##STR04000## ##STR04001## ##STR04002## ##STR04003## ##STR04004## ##STR04005## ##STR04006## ##STR04007## ##STR04008## ##STR04009## ##STR04010## ##STR04011## ##STR04012## ##STR04013## ##STR04014## ##STR04015## ##STR04016## ##STR04017## ##STR04018## ##STR04019## ##STR04020## ##STR04021## ##STR04022## ##STR04023## ##STR04024## ##STR04025## ##STR04026## ##STR04027## ##STR04028## ##STR04029## ##STR04030## ##STR04031## ##STR04032## ##STR04033## ##STR04034## ##STR04035## ##STR04036## ##STR04037## ##STR04038## ##STR04039## ##STR04040## ##STR04041## ##STR04042## ##STR04043## ##STR04044## ##STR04045## ##STR04046## ##STR04047## ##STR04048## ##STR04049## ##STR04050## ##STR04051## ##STR04052## ##STR04053## ##STR04054## ##STR04055## ##STR04056## ##STR04057## ##STR04058## ##STR04059## ##STR04060## ##STR04061## ##STR04062## ##STR04063## ##STR04064## ##STR04065## ##STR04066## ##STR04067## ##STR04068## ##STR04069## ##STR04070## ##STR04071## ##STR04072## ##STR04073## ##STR04074## ##STR04075## ##STR04076## ##STR04077## ##STR04078## ##STR04079## ##STR04080## ##STR04081## ##STR04082## ##STR04083## ##STR04084## ##STR04085## ##STR04086## ##STR04087## ##STR04088## ##STR04089## ##STR04090## ##STR04091## ##STR04092## ##STR04093## ##STR04094## ##STR04095## ##STR04096## ##STR04097## ##STR04098## ##STR04099## ##STR04100## ##STR04101## ##STR04102## ##STR04103## ##STR04104## ##STR04105## ##STR04106## ##STR04107## ##STR04108## ##STR04109## ##STR04110## ##STR04111## ##STR04112## ##STR04113## ##STR04114## ##STR04115## ##STR04116## ##STR04117## ##STR04118## ##STR04119## ##STR04120## ##STR04121## ##STR04122## ##STR04123## ##STR04124## ##STR04125## ##STR04126## ##STR04127## ##STR04128## ##STR04129## ##STR04130## ##STR04131## ##STR04132## ##STR04133## ##STR04134## ##STR04135## ##STR04136## ##STR04137## ##STR04138## ##STR04139## ##STR04140## ##STR04141## ##STR04142## ##STR04143## ##STR04144## ##STR04145## ##STR04146## ##STR04147## ##STR04148## ##STR04149## ##STR04150## ##STR04151## ##STR04152## ##STR04153## ##STR04154## ##STR04155## ##STR04156## ##STR04157## ##STR04158## ##STR04159## ##STR04160## ##STR04161## ##STR04162## ##STR04163## ##STR04164## ##STR04165## ##STR04166## ##STR04167## ##STR04168## ##STR04169## ##STR04170## ##STR04171## ##STR04172## ##STR04173## ##STR04174## ##STR04175## ##STR04176## ##STR04177## ##STR04178## ##STR04179## ##STR04180## ##STR04181## ##STR04182## ##STR04183## ##STR04184## ##STR04185## ##STR04186## ##STR04187## ##STR04188## ##STR04189## ##STR04190## ##STR04191## ##STR04192## ##STR04193## ##STR04194## ##STR04195## ##STR04196## ##STR04197## ##STR04198## ##STR04199## ##STR04200## ##STR04201## ##STR04202## ##STR04203## ##STR04204## ##STR04205## ##STR04206## ##STR04207## ##STR04208## ##STR04209## ##STR04210## ##STR04211## ##STR04212## ##STR04213## ##STR04214## ##STR04215## ##STR04216## ##STR04217## ##STR04218## ##STR04219## ##STR04220## ##STR04221## ##STR04222## ##STR04223## ##STR04224## ##STR04225## ##STR04226## ##STR04227## ##STR04228## ##STR04229## ##STR04230## ##STR04231## ##STR04232## ##STR04233## 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ##STR04234## 17. A pharmaceutical composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier. 18. The pharmaceutical composition of claim 17, further comprising one or more additional therapeutic agent(s). 19. The pharmaceutical composition of claim 18, wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator. 20. The pharmaceutical composition of claim 18, wherein at least one additional therapeutic agent is ##STR04235## or pharmaceutically acceptable salt thereof. 21. The pharmaceutical composition of claim 18, wherein at least one additional therapeutic agent is ##STR04236## or pharmaceutically acceptable salt thereof. 22. The pharmaceutical composition of claim 18, wherein the additional therapeutic agents are ##STR04237## or pharmaceutically acceptable salts thereof. 23. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound or salt of claim 1. 24. The method of claim 23, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound or salt. 25. The method of claim 24, wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator. 26. The method of claim 24, wherein at least one additional therapeutic agent is ##STR04238## or a pharmaceutically acceptable salt thereof. 27. The method of claim 24, wherein at least one additional therapeutic agent is ##STR04239## or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition comprising the compound or salt of claim 15 and a pharmaceutically acceptable carrier. 29. The pharmaceutical composition of claim 28, further comprising one or more additional therapeutic agent(s). 30. The pharmaceutical composition of claim 29, wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator. 31. The pharmaceutical composition of claim 29, wherein at least one additional therapeutic agent is ##STR04240## or pharmaceutically acceptable salt thereof. 32. The pharmaceutical composition of claim 29, wherein at least one additional therapeutic agent is ##STR04241## or pharmaceutically acceptable salt thereof. 33. The pharmaceutical composition of claim 29, wherein the additional therapeutic agents are ##STR04242## or pharmaceutically acceptable salts thereof. 34. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound or salt of claim 15. 35. The method of claim 34, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound or salt. 36. The method of claim 35, wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator. 37. The method of claim 35, wherein at least one additional therapeutic agent is ##STR04243## or a pharmaceutically acceptable salt thereof. 38. The method of claim 35, wherein at least one additional therapeutic agent is ##STR04244## or a pharmaceutically acceptable salt thereof.