US 12,324,802 B2
Modulators of cystic fibrosis transmembrane conductance regulator
Jeremy J. Clemens, San Diego, CA (US); William Schulz Bechara, Laval (CA); Brett C. Bookser, San Diego, CA (US); Thomas Cleveland, San Marcos, CA (US); Timothy R. Coon, Carlsbad, CA (US); Michel Gallant, Pierrefonds (CA); Peter Grootenhuis, Del Mar, CA (US); Sara Sabina Hadida Ruah, La Jolla, CA (US); Julie Laterreur, San Diego, CA (US); Mark Thomas Miller, Rancho Santa Fe, CA (US); Prasuna Paraselli, San Diego, CA (US); Yeeman K. Ramtohul, Pierrefonds (CA); Thumkunta Jagadeeswar Reddy, Pierrefonds (CA); Claudio Sturino, Ile Bizard (CA); Lino Valdez, San Diego, CA (US); Jinglan Zhou, San Diego, CA (US); and Minson Baek, San Diego, CA (US)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Nov. 17, 2021, as Appl. No. 17/528,729.
Claims priority of provisional application 63/115,552, filed on Nov. 18, 2020.
Prior Publication US 2023/0099745 A1, Mar. 30, 2023
Int. Cl. A61K 31/436 (2006.01); A61K 31/404 (2006.01); A61K 31/439 (2006.01); A61K 31/443 (2006.01); A61K 31/4439 (2006.01); A61K 31/4995 (2006.01); A61K 31/529 (2006.01); A61P 3/00 (2006.01); A61P 43/00 (2006.01); C07D 498/18 (2006.01); C07D 498/22 (2006.01); C07D 515/04 (2006.01)
CPC A61K 31/439 (2013.01) [A61K 31/404 (2013.01); A61K 31/443 (2013.01); A61K 31/4439 (2013.01); A61K 31/4995 (2013.01); A61K 31/529 (2013.01); C07D 498/18 (2013.01); C07D 498/22 (2013.01)] 53 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
and a deuterated derivative thereof, or a pharmaceutically acceptable salt of the foregoing, wherein:
X is selected from —N(RX1)— and

OG Complex Work Unit Chemistry
Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and oxo;
RX1 is selected from H, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, —ORX2, and —N(RX2)2), and C3-C8 cycloalkyl;
each RX2 is independently selected from H and C1-C6 alkyl;
each Y is independently selected from —C(RY)2—,—O—,—CO—,—NRYN—, and

OG Complex Work Unit Chemistry
wherein each RYN is independently selected from H, C1-C4 alkyl, and CO2RYN1, wherein each RYN1 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl;
each RY is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, —ORY1, —CO2RY1,—CORY1,—CON(RY1)2, and —N(RY1)2;
or two RY on the same atom are taken together to form a ring selected from C3-C8 cycloalkyl and 3- to 7-membered heterocyclyl; or two RY, one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;
each RY1 is independently selected from hydrogen and C1-C6 alkyl, or two RY1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;
Ring B is selected from:
C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy),
C3-C8 cycloalkyl,
5- to 10-membered heteroaryl, and
3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl);
each Q is independently selected from:
C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
halogen,
oxo,
C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF3), and
C3-C8 cycloalkyl,
C3-C8 cycloalkyl optionally substituted with 1-3 groups independently selected from:
halogen,
CN,
C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH2, and —NHCOMe),
C1-C6 alkoxy,
C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), and
C3-C8 cycloalkyl,
C6-C10 aryl optionally substituted with 1-3 groups independently selected from:
halogen,
CN,
C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy),
C1-C6 alkoxy optionally substituted with 1-4 groups independently selected from:
halogen,
C3-C8 cycloalkyl (optionally substituted with CF3),
C3-C8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and
C6-C10 aryl,
5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
halogen,
C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen),
C3-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and
3- to 10-membered heterocyclyl,
3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C3-C8 cycloalkyl), and
oxo;
each R1 is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from hydroxy, C6-C10 aryl, and 5- to 6-membered heteroaryl), —OR2, —N(R2)2, —CO2R2, —CO—N(R2)2, —CN, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, —B(OR2)2, —SO2R2, —SR2, —SOR2, —PO(OR2)2, and —PO(R2)2;
each R2 is independently selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy);
Z is selected from

OG Complex Work Unit Chemistry
wherein Ring C is selected from C6-C10 aryl and 5- to 10-membered heteroaryl;
RZ1 is selected from hydrogen, —CN, C1-C6 alkyl (optionally substituted with 1-3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C10 aryl, and 5- to 6-membered heteroaryl;
RZ2 is selected from hydrogen, halogen, hydroxy, NH2, NH(CO) (C1-C6 alkyl), and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl),
or RZ1 and RZ2 taken together form a group selected from oxo and ═N—OH;
each RZ3 is independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C10 aryl; or two RZ3 are taken together to form a 3- to 6-membered heterocyclyl;
n is selected from 4, 5, 6, 7, and 8; and
m is selected from 0, 1, 2, and 3.