US 11,866,450 B2
Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators
Jeremy J. Clemens, San Diego, CA (US); Alexander Russell Abela, Escondido, CA (US); Corey Don Anderson, San Diego, CA (US); Brett B. Busch, San Diego, CA (US); Weichao George Chen, San Diego, CA (US); Thomas Cleveland, San Marcos, CA (US); Timothy Richard Coon, Carlsbad, CA (US); Bryan Frieman, La Jolla, CA (US); Senait G. Ghirmai, San Diego, CA (US); Peter Grootenhuis, Del Mar, CA (US); Anton V. Gulevich, San Diego, CA (US); Sara Sabina Hadida Ruah, La Jolla, CA (US); Clara Kuang-Ju Hsia, San Diego, CA (US); Ping Kang, San Diego, CA (US); Haripada Khatuya, San Diego, CA (US); Jason McCartney, Cardiff by the Sea, CA (US); Mark Thomas Miller, San Diego, CA (US); Prasuna Paraselli, San Diego, CA (US); Fabrice Pierre, La Jolla, CA (US); Sara E. Swift, San Diego, CA (US); Andreas Termin, Encinitas, CA (US); Johnny Uy, San Diego, CA (US); Carl V. Vogel, Carlsbad, 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 May 18, 2021, as Appl. No. 17/323,267.
Application 17/323,267 is a division of application No. 16/276,350, filed on Feb. 14, 2019, granted, now 11,066,417.
Claims priority of provisional application 62/631,453, filed on Feb. 15, 2018.
Prior Publication US 2022/0106331 A1, Apr. 7, 2022
Int. Cl. C07D 513/22 (2006.01); A61K 31/439 (2006.01); A61P 11/00 (2006.01); A61K 31/47 (2006.01); A61K 31/404 (2006.01); C07D 515/22 (2006.01)
CPC C07D 513/22 (2013.01) [A61K 31/404 (2013.01); A61K 31/439 (2013.01); A61K 31/47 (2013.01); A61P 11/00 (2018.01); C07D 515/22 (2013.01)] 41 Claims
 
1. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of Formula I:

OG Complex Work Unit Chemistry
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
Ring B is a pyridinyl ring;
Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
X is O, NH, or an N(C1-C4 alkyl);
each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
m is 0, 1, 2, 3, or 4;
each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
n is 0, 1, or 2;
each R3 is methyl;
each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein:
k is 0, 1, 2, 3, 4, 5, or 6;
each Y is independently chosen from C(R5)(R6) groups, —O—, and —NRa— groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein:
each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo;
 each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and
each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and
R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens;
q is 1, 2, 3 or 4; and
Z is a divalent linker of formula (L)r, wherein:
r is 1, 2, 3, 4, 5, or 6;
each L is independently chosen from C(R8)(R9) groups, —O—, and —NRb— groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein:
each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and
each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.