US 12,168,009 B2
Modulators of cystic fibrosis transmembrane conductance regulator
Mark Thomas Miller, San Diego, CA (US); Corey Anderson, San Diego, CA (US); Vijayalaksmi Arumugam, San Marcos, CA (US); Brian Richard Bear, Carlsbad, CA (US); Hayley Marie Binch, Encinitas, CA (US); Jeremy J. Clemens, San Diego, CA (US); Thomas Cleveland, San Diego, CA (US); Erica Conroy, Columbus, OH (US); Timothy Richard Coon, Carlsbad, CA (US); Bryan A. Frieman, La Jolla, CA (US); Peter Diederik Jan Grootenhuis, San Diego, CA (US); Raymond Stanley Gross, Poway, CA (US); Sara Sabina Hadida-Ruah, La Jolla, CA (US); Haripada Khatuya, San Diego, CA (US); Pramod Virupax Joshi, San Diego, CA (US); Paul John Krenitsky, San Diego, CA (US); Chun-Chieh Lin, San Diego, CA (US); Gulin Erdogan Marelius, San Diego, CA (US); Vito Melillo, Escondido, CA (US); Jason McCartney, Cardiff by the Sea, CA (US); Georgia McGaughey Nicholls, Winchester, MA (US); Fabrice Jean Denis Pierre, La Jolla, CA (US); Alina Silina, San Diego, CA (US); Andreas P. Termin, Encinitas, CA (US); Johnny Uy, San Diego, CA (US); and Jinglan Zhou, San Diego, CA (US)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Jul. 14, 2022, as Appl. No. 17/865,220.
Application 16/836,155 is a division of application No. 16/258,024, filed on Jan. 25, 2019, granted, now 10,758,534, issued on Sep. 1, 2020.
Application 15/675,000 is a division of application No. 14/876,525, filed on Oct. 6, 2015, granted, now 9,782,408, issued on Oct. 10, 2017.
Application 17/865,220 is a continuation of application No. 16/836,155, filed on Mar. 31, 2020, granted, now 11,426,407.
Application 16/258,024 is a continuation of application No. 15/675,000, filed on Aug. 11, 2017, granted, now 10,258,624, issued on Apr. 16, 2019.
Claims priority of provisional application 62/153,120, filed on Apr. 27, 2015.
Claims priority of provisional application 62/114,767, filed on Feb. 11, 2015.
Claims priority of provisional application 62/060,182, filed on Oct. 6, 2014.
Prior Publication US 2023/0233560 A1, Jul. 27, 2023
Int. Cl. A61K 31/506 (2006.01); A61J 1/03 (2023.01); A61K 31/404 (2006.01); A61K 31/415 (2006.01); A61K 31/44 (2006.01); A61K 31/4418 (2006.01); A61K 31/4439 (2006.01); A61K 31/444 (2006.01); A61K 31/4525 (2006.01); A61K 31/4545 (2006.01); A61K 31/4709 (2006.01); A61K 31/496 (2006.01); A61K 31/497 (2006.01); C07D 209/18 (2006.01); C07D 209/42 (2006.01); C07D 209/49 (2006.01); C07D 213/64 (2006.01); C07D 213/73 (2006.01); C07D 213/82 (2006.01); C07D 213/84 (2006.01); C07D 231/12 (2006.01); C07D 231/14 (2006.01); C07D 231/20 (2006.01); C07D 235/24 (2006.01); C07D 239/34 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/10 (2006.01); C07D 403/12 (2006.01); C07D 405/14 (2006.01); C07D 407/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01)
CPC A61K 31/506 (2013.01) [A61J 1/035 (2013.01); A61K 31/404 (2013.01); A61K 31/415 (2013.01); A61K 31/44 (2013.01); A61K 31/4418 (2013.01); A61K 31/4439 (2013.01); A61K 31/444 (2013.01); A61K 31/4525 (2013.01); A61K 31/4545 (2013.01); A61K 31/4709 (2013.01); A61K 31/496 (2013.01); A61K 31/497 (2013.01); C07D 209/18 (2013.01); C07D 209/42 (2013.01); C07D 209/49 (2013.01); C07D 213/64 (2013.01); C07D 213/73 (2013.01); C07D 213/82 (2013.01); C07D 213/84 (2013.01); C07D 231/12 (2013.01); C07D 231/14 (2013.01); C07D 231/20 (2013.01); C07D 235/24 (2013.01); C07D 239/34 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/10 (2013.01); C07D 403/12 (2013.01); C07D 405/14 (2013.01); C07D 407/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01)] 46 Claims
 
1. A compound of formula Ia:

OG Complex Work Unit Chemistry
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, 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 C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, or a C3-C10 cycloalkyl ring;
X is O or NR;
Y is CRR, CO, O, S, SO, SO2, S(O)NH or NR;
R1 is halo; CN; F5S; SiR3; OH; NRR; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; (C1-C9 alkylene)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 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;
R2 is halo; OH; NRR; azide; CN; CO2R; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R2 may form a ═CH2 or ═O group;
R3 is halo; CN; CO2R; C1-C6 alkyl; C1-C6 fluoroalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; C1-C6 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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R3 may form a ═CH2 or ═O group;
R4 is H; azide; CF3; CHF2; OR; CCH; CO2R; 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 SO2R;
R is independently H; OH; CO2H; CO2; C1-C6 alkyl; C1-C6 alkyl; C2-C6 alkenyl; C2-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;
o is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.