Modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-10758534-B2
Application number	US-201916258024-A
Country	US
Kind code	B2
Filing date	Jan 25, 2019
Priority date	Oct 6, 2014
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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 claims is:

1. A compound of formula Ib-iii:

or a pharmaceutically acceptable salt thereof, wherein:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring;

and wherein, independently for each occurrence:
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 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;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; 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)-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; CO 2 R; 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)-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; 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 SO 2 R;
R is independently H; OH; CO 2 H; CO 2 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.

2. The compound or salt of claim 1 , wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

3. The compound or salt of claim 1 , wherein ring B is selected from

4. The compound or salt of claim 1 , wherein ring C is selected from indole, piperidine, azepane, azetadine, indoline, isoindoline, or pyrrolidine.

5. The compound or salt of claim 1 , wherein ring C is selected from

6. The compound or salt of claim 1 , wherein R 1 is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR, wherein all rings are optionally substituted with one or more groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C3-C10 heteroaryl, and C3-C10 heterocycloalkyl.

7. The compound or salt 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 , OCH 2 CH 2 OCH 2 CH 3 ,

8. The compound or salt of claim 1 , wherein R 2 is selected from halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ring wherein up to 4 ring atoms are independently 0, S, N, or NR; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

9. The compound or salt of claim 1 , wherein R 2 is selected from Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , =O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, 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 ,

10. The compound or salt of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR.

11. The compound or salt of claim 1 , wherein R 3 is selected from Cl, I, deuterium, F, CN, CH 3 , OH, OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , OCH(CH 3 ) 2 , CO 2 H, CO 2 NH 2 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CH 2 CONH 2 , CO 2 CH 3 , —CH 2 N(CH 3 ) 2 , CO 2 tBu, tBu, =CH 2 , =O,

12. A compound of formula Ib-iv:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring;
R 1 is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; 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)-R 4 wherein up to four CH 2 units are independently re

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

• 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

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title