Modulators of cystic fibrosis transmembrane conductance regulator

A compound of Formula I:

• a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
• Ring A is selected from:
• C6-C10 aryl,
• C3-C10 cycloalkyl,
• 3- to 10-membered heterocyclyl, and
• 5- to 10-membered heteroaryl;
• Ring B is selected from:
• C6-C10 aryl,
• C3-C10 cycloalkyl,
• 3- to 10-membered heterocyclyl, and
• 5- to 10-membered heteroaryl;
• V is selected from O and NH;
• W1 is selected from N and CH;
• W2 is selected from N and CH;
• provided that at least one of W1 and W2 is N;
• X is selected from NRXN and C(RXC)2;
• Y is selected from O, NRYN, and C(RYC)2;
• Z is selected from O, NRZN, and C(RZC)2, provided that when L2 is absent, either Y is C(RYC)2 or Z is C(RZC)2;
• each L1 is independently selected from C(RL1)2 and
• each L2 is independently selected from C(RL2)2;
• Ring C is selected from C6-C10 aryl optionally substituted with 1-3 groups independently selected from:
• halogen,
• C1-C6 alkyl, and
• N(RN)2;
• R1 is selected from:
• hydrogen,
• halogen,
• cyano,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, and N(RN)2,
• C-C6 alkoxy,
• C1-C6 fluoroalkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy,
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from RN, and
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl;
• each R3 is independently selected from:
• halogen,
• C1-C6 alkyl,
• C1-C6 alkoxy,
• C3-C10 cycloalkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and
• 3- to 10-membered heterocyclyl;
• R4 is selected from hydrogen and C1-C6 alkyl;
• each R5 is independently selected from:
• hydrogen,
• halogen,
• hydroxyl,
• N(RN)2,
• —SO-Me,
• —CH═C(RLC)2, wherein both RLC are taken together to form a C3-C10 cycloalkyl,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C6-C10 aryl,
• C3-C10 cycloalkyl,
• —(O)0-1-(C6-C10 aryl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy,
• 3- to 10-membered heterocyclyl, and
• N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from:
• halogen,
• C6-C10 aryl, and
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl,
• C1-C6 fluoroalkyl,
• C3-C10 cycloalkyl,
• C6-C10 aryl, and
• 3- to 10-membered heterocyclyl;
• each RXN, RYN, and RZN is independently selected from:
• hydrogen,
• C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• oxo,
• cyano,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy,
• N(RN)2,
• SO2Me,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, C6-C10 aryl, and N(RN)2,
• C1-C6 fluoroalkyl,
• C1-C6 alkoxy,
• COOH,
• N(RN)2,
• C6-C10 aryl, and
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from:
• halogen,
• hydroxyl,
• cyano,
• SiMe3,
• SO2Me,
• SF5,
• N(RN)2,
• P(O)Me2,
• —(O)0-1—(C3-C10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(RN)2, and C6-C10 aryl,
• C1-C6 fluoroalkyl,
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• —(O)0-1—(C6-C10 aryl), and
• —(O)0-1-(5- to 10-heteroaryl) optionally substituted with hydroxyl, oxo, N(RN)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and C3-C10 cycloalkyl,
• 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:
• hydroxyl,
• oxo,
• N(RN)2,
• C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy),
• C1-C6 alkoxy,
• C1-C6 fluoroalkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from halogen, and
• 5- to 10-membered heteroaryl,
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• cyano,
• oxo,
• halogen,
• B(OH)2,
• N(RN)2,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3-SiMe3), and N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, N(RN)2, and C3-C10 cycloalkyl,
• C1-C6 fluoroalkyl,
• —(O)0-1-(C3-C10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• —(O)0-1—(C6-C10 aryl),
• —(O)0-1-(3- to 10-membered heterocyclyl) optionally substituted with 1-4 groups independently selected from hydroxyl, oxo, halogen, cyano, N(RN)2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(RN)2, and C1-C6 alkoxy), C1-C6 alkoxy, C1-C6 fluoroalkyl, 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl), and
• 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl and C3-C10 cycloalkyl,
• C1-C6 fluoroalkyl,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• oxo,
• halogen,
• cyano,
• N(RN)2,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• oxo,
• N(RN)2,
• C1-C6 alkoxy, and
• C6-C10 aryl,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C6-C10 aryl, and N(RN)2,
• halogen,
• C3-C10 cycloalkyl,
• 3- to 10-member heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• cyano,
• oxo,
• halogen,
• N(RN)2,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, and N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6 alkoxy, N(RN)2, and C3-C10 cycloalkyl,
• C1-C6 fluoroalkyl,
• —(O)0-1—(C3-C10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• C6-C10 aryl, and
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• C6-C10 aryl,
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
• oxo,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
• oxo,
• hydroxyl,
• N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C6-C10 aryl, and
• —(O)0-1—(C3-C10 cycloalkyl),
• C1-C6 fluoroalkyl,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen, and
• 3- to 10-membered heterocyclyl,
• 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 oxo, C1-C6 alkoxy, and N(RN)2, and
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy, and C6-C10 aryl), and
• RF;
• each RXC, RYC, and RZC is independently selected from:
• hydrogen,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl),
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and
• RF;
• or two RXC are taken together to form a group selected from oxo and C3-C10 cycloalkyl;
• or two RYC are taken together to form an oxo group;
• or two RZC are taken together to form an oxo group;
• each RL1 is independently selected from:
• hydrogen,
• N(RN)2, provided that two N(RN)2 are not bonded to the same carbon,
• C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:
• halogen,
• hydroxyl,
• oxo,
• N(RN)2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C10 aryl,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C1-C6 fluoroalkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and
• 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 hydroxyl and oxo),
• C3-C10 cycloalkyl,
• C6-C10 aryl optionally substituted with 1-4 groups independently selected from:
• halogen,
• cyano,
• SiMe3,
• POMe2,
• C1-C7 alkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• oxo,
• cyano,
• SiMe3,
• N(RN)2, and
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from:
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and
• C1-C6 alkoxy,
• C1-C6 fluoroalkyl,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl,
• C6-C10 aryl,
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and
• 5- to 10-membered heteroaryl,
• 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
• C1-C6 alkoxy,
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and
• RF;
• or two RL1 on the same carbon atom are taken together to form an oxo group;
• each RL2 is independently selected from hydrogen and RF;
• or two RL2 on the same carbon atom are taken together to form an oxo group;
• each RN is independently selected from:
• hydrogen,
• C1-C8alkyl optionally substituted with 1-3 groups independently selected from:
• oxo,
• halogen,
• hydroxyl,
• NH2,
• NHMe,
• NMe2,
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C10 aryl,
• —(O)0-1—(C3-C10 cycloalkyl),
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkyl,
• 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6 alkyl, and
• 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from oxo and C1-C6 alkyl,
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from:
• hydroxyl,
• NH2,
• NHMe, and
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl,
• C6-C10 aryl, and
• 3- to 10-membered heterocyclyl;
• or two RN on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from:
• hydroxyl,
• oxo,
• cyano,
• C1-C6 alkyl optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, C1-C6 alkoxy, and N(RN2)2, wherein each RN2 is independently selected from hydrogen and C1-C6 alkyl,
• C1-C6 alkoxy, and
• C1-C6 fluoroalkyl;
• or one R4 and one RL1 are taken together to form a C6-C8 alkylene;
• when RF is present, two RF taken together with the atoms to which they are bonded form a group selected from:
• C3-C10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from:
• halogen,
• C1-C6 alkyl,
• N(RN)2, and
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from hydroxyl,
• 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
• oxo,
• N(RN)2,
• C1-C9 alkyl optionally substituted with 1-4 groups independently selected from:
• oxo,
• halogen,
• hydroxyl,
• N(RN)2,
• —SO2—(C1-C6 alkyl),
• C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, C6-C10 aryl,
• C6-C10 aryl optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy), C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C6-C10 aryl), —(O)0-1—(C1-C6 fluoroalkyl), and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy),
• —(O)0-1—(C3-C10 cycloalkyl) optionally substituted with 1-4 groups independently selected from hydroxyl, halogen, N(RN)2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy), C1-C6 fluoroalkyl, and C6-C10 aryl,
• 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogens)), C1-C6 alkoxy, C3-C10 cycloalkyl, and RN,
• —O-(5- to 12-membered heteroaryl) optionally substituted with 1-3 groups independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen) and C1-C6 alkyl, and
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(RN)2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from cyano), C1-C6 alkoxy, —(O)0-1—(C1-C6 fluoroalkyl), —O—(C6-C10 aryl), and C3-C10 cycloalkyl,
• C3-C12 cycloalkyl optionally substituted with 1-4 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl,
• C6-C10 aryl,
• 3- to 10-membered heterocyclyl, and
• 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl, and
• 5- to 12-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl.