Modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-11426407-B2
Application number	US-202016836155-A
Country	US
Kind code	B2
Filing date	Mar 31, 2020
Priority date	Oct 6, 2014
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

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.

First claim

The invention claimed is:

1. A compound of formula Ib:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, or a C3-C10 mono- or bicyclic cycloalkyl ring;
Y is CRR, CO, O, S, SO, SO 2 , S(O)NH or NR;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C2-C6 alkenyl; C2-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; C2-C6 alkenyl; C2-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; C2-C6 alkenyl; C2-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; C2-C6 alkenyl; C2-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;
o is 0 or 1;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.

2. The compound, salt, or deuterated derivative of claim 1 , wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

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

4. The compound, salt, or deuterated derivative of claim 1 , wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or dihydroindene.

5. The compound, salt, or deuterated derivative of claim 1 , wherein ring C is

6. The compound, salt, or deuterated derivative of claim 1 , wherein Y is O.

7. The compound, salt, or deuterated derivative of claim 1 , wherein Y is CH 2 .

8. The compound, salt, or deuterated derivative of claim 1 , wherein Y is CH(C1-C6 aliphatic).

9. The compound, salt, or deuterated derivative of claim 1 , wherein Y is CH(CH 3 ).

10. The compound, salt, or deuterated derivative of claim 1 , wherein Y is CH(CH 2 CH 3 ).

11. The compound, salt, or deuterated derivative 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, or thiophene ring, wherein all rings may be substituted with 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, C3-C10 heterocycloalkyl, or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

12. The compound, salt, or deuterated derivative 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 ,

13. The compound, salt, or deuterated derivative 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 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

14. The compound, salt, or deuterated derivative of claim 1 , wherein R 2 is selected from 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 ,

15. The compound, salt, or deuterated derivative of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

16. The compound, salt, or deuterated derivative of claim 1 , wherein R 3 is selected from 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,

17. The compound, salt, or deuterated derivative of claim 1 , wherein o is 0.

18. The compound, salt, or deuterated derivative of claim 1 , wherein o is 1.

19. The compound, salt, or deuterated derivative of claim 1 , wherein n is 0.

20. The compound, salt, or deuterated derivative of claim 1 , wherein n is 1.

21. The compound, salt, or deuterated derivative of claim 1 , wherein n is 2.

22. The compound, salt, or deuterated derivative of claim 1 , wherein p is 0.

23. The compound, salt, or deuterated derivative of claim 1 , wherein p is 1.

24. The compound, salt, or deuterated derivative of claim 1 , wherein p is 2.

25. The compound, salt, or deuterated derivative of claim 1 , wherein ring B is pyridyl.

26. The compound, salt, or deuterated derivative of claim 1 , wherein ring B is phenyl.

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

• A61J1/035

  Blister-type containers (blisters in general B65D75/36) · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title