Modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-9782408-B2
Application number	US-201514876525-A
Country	US
Kind code	B2
Filing date	Oct 6, 2015
Priority date	Oct 6, 2014
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention features a compound of formula I:

or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , 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.

First claim

The invention claimed is:

1. 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;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 , or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a ═CH 2 or ═O group;
R 3 is halo; CN; OH; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 alkoxy or fluoroalkoxy; or C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 groups taken together may form a ═CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 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.

2. The compound of claim 1 , wherein R 1 is halo, CN, C 1 -C 6 aliphatic, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, azetidine, or thiophene ring, wherein all rings may be substituted with halo, C 1 -C 6 aliphatic, C 1 -C 6 alkoxy, C 1 -C 6 fluoroaliphatic, C 1 -C 6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, or a (C 1 -C 8 aliphatic)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

3. The compound of claim 1 , wherein R 1 is selected from CH 3 , Cl, F, CN, OCH 3 , CF 3 , CH 2 , CH 3 , tBu, CH(CH 3 ) 2

4. The compound of claim 1 , wherein R 2 is halo, OH, CN, azide, amino, C 1 -C 6 aliphatic or fluoroaliphatic, C 1 -C 6 alkoxy or fluoroalkoxy, C 3 -C 10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C 1 -C 8 aliphatic)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

5. The compound of claim 1 , wherein R 2 is Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CH 2 OH, CH 2 CH 3 , CH(CH 3 ) 2 , CHF 2 OCH 3 , OCF 3 , OCHF 2 , OCH(CH 3 ) 2 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

6. The compound of claim 1 , wherein R 3 is halo, CN, C 1 -C 6 aliphatic or fluoroaliphatic, C 1 -C 6 alkoxy, or C 3 -C 10 mono- or bicyclic heteroaryl or heterocycloalkyl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

7. The compound of claim 1 , wherein R 3 is Cl, F, CN, CH 3 , OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CO 2 CH 3 , tBu, ═CH 2 , ═O,

8. The compound of claim 1 , wherein n is 1.

9. The compound of claim 1 , wherein n is 2.

10. The compound of claim 1 , wherein p is 0.

11. The compound of claim 1 , wherein p is 1.

12. The compound of claim 1 , wherein p is 2.

13. 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;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl;C 1 -C 6 alkoxy or fluoroalkoxy;C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a ═CH 2 or ═O group;
R 3 is halo; CN; OH; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 alkoxy or fluoroalkoxy; or C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR:
or two R 3 groups taken together may form a ═CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 1 -C 6 alkenyl;

Assignees

• Vertex Pharma

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title