US 9,782,408 B2Granted

Modulators of cystic fibrosis transmembrane conductance regulator

AssigneeVertex Pharmaceuticals Incorporated

InventorsMark Thomas Miller, Corey Anderson, Vijayalaksmi Arumugam, Brian Richard Bear, Hayley Marie Binch, Jeremy J. Clemens, Thomas Cleveland, Erica Conroy, Timothy Richard Coon, Bryan A. Frieman, Peter Diederik Jan Grootenhuis, Raymond Stanley Gross, Sara Sabina Hadida Ruah, Haripada Khatuya, Pramod Virupax Joshi, Paul John Krenitsky, Chun-Chieh Lin, Gulin Erdogan Marelius, Vito Melillo, Jason McCartney, Georgia McGaughey Nicholls, Fabrice Jean Denis Pierre, Alina Silina, Andreas P. Termin, Johnny Uy, Jinglan Zhou

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Abstract

The present invention features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R1, R2, R3, 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.

Claims84

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring A is pyridine;
Ring B is phenyl;
Ring C is pyrrolidine;
W is O;
X is O;
Y is a bond;
Z is NH;
R1 is halo;
CN;
F5S;
SiR3;
OH;
NRR;
C1-C6 alkyl or fluoroalkyl;
C1-C6 alkoxy or fluoroalkoxy;
C1-C6 alkenyl;
C1-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 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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R2 groups taken together may form a ═CH2 or ═O group;
R3 is halo;
CN;
OH;
CO2R;
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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R3 groups taken together 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;
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;
is a single bond or a double bond;
provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A.

75 more elements

A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring A is pyridine;
Ring B is phenyl;
Ring C is pyrrolidine;
W is O;
X is O;
Y is a bond;
Z is NH;
R1 is halo;
CN;
F5S;
SiR3;
OH;
NRR;
C1-C6 alkyl or fluoroalkyl;
C1-C6 alkoxy or fluoroalkoxy;
C1-C6 alkenyl;
C1-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 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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R2 groups taken together may form a ═CH2 or ═O group;
R3 is halo;
CN;
OH;
CO2R;
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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR:
or two R3 groups taken together 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;
CO2C1-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;
is a single bond or a double bond;
provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A;
and
a pharmaceutically acceptable carrier.

74 more elements

A kit comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring A is pyridine;
Ring B is phenyl;
Ring C is pyrrolidine;
W is O;
X is O;
Y is a bond;
Z is NH;
R1 is halo;
CN;
F5S;
SiR3;
OH;
NRR;
C1-C6 alkyl or fluoroalkyl;
C1-C6 alkoxy or fluoroalkoxy;
C1-C6 alkenyl;
C1-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 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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO SO2 or NR;
or two R2 groups taken together may form a ═CH2 or ═O group;
R3 is halo;
CN;
OH;
CO2R;
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)-R4 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
or two R3 groups taken together 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;
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;
is a single bond or a double bond;
provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A.

75 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/876,525Filed 6 Oct 2015 · us provisional application
Priority: 6 Oct 2014
Published: US 2016/0095858 A17 Apr 2016
Granted: 10 Oct 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification42 codes

A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61J 1/035
For pills or tablets: blister-type containers
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles

Family

Application62/060,182Us provisional application · filed 6 Oct 2014
Application62/114,767Us provisional application · filed 11 Feb 2015
Application62/153,120Us provisional application · filed 27 Apr 2015
US 2016/0095858 A1Pre-grant publication · published 7 Apr 2016
US 2017/0196862 A2Pre-grant publication · published 13 Jul 2017
US 9,782,408 B2This patent

From the US filing history. Foreign family members aren’t listed.