Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

Patent metadata

Field	Value
Publication number	US-11414439-B2
Application number	US-201915733738-A
Country	US
Kind code	B2
Filing date	Apr 12, 2019
Priority date	Apr 13, 2018
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis by administering such modulators and pharmaceutical compositions, and processes for making such modulators.

First claim

The invention claimed is:

1. A compound of Formula (1):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
at least one of the carbon atoms at positions 2 and 8 of Formula (1) is replaced by a silicon atom;
at least one of the methyl groups at positions 3, 4, 5, 5′, 6, 7, and 10 of Formula (1) is replaced by a group chosen from —Si(R) 3 groups, —Si(R)2(OR) groups, and —Si(R)(OR) 2 groups;
at least one of the methylene groups at positions 1, 9, and 12 of Formula (1) is replaced by a group chosen from >Si(R) 2 groups and >Si(R)(OR) groups; and/or
the methine group at position 11 of Formula (1) is replaced by a group chosen from ≡Si(R) groups and ≡Si(OR) groups; and

wherein each R, which may be identical or different, is independently chosen from hydrogen, hydroxyl, and C 1 -C 4 alkyl groups.

2. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein at least one of the carbon atoms at positions 2 and 8 of Formula (1) is replaced by a silicon atom.

3. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein at least one of the methyl groups at positions 3, 4, 5, 5′, 6, 7, and 10 of Formula (1) is replaced by a group chosen from —Si(R) 3 groups, —Si(R) 2 (OR) groups, and —Si(R)(OR)2 groups.

4. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein at least one of the methylene groups at positions 1, 9, and 12 of Formula (1) is replaced by a group chosen from >Si(R) 2 groups and >Si(R)(OR) groups.

5. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the methine group at position 11 of Formula (1) is replaced by a group chosen from ≡Si(R) groups and ≡Si(OR) groups.

6. A compound according to claim 1 chosen from Compound (1-1):

and pharmaceutically acceptable salts and deuterated derivatives thereof.

7. A compound according to claim 1 chosen from Compound (1-2):

and pharmaceutically acceptable salts and deuterated derivatives thereof.

8. A compound according to claim 1 chosen from compounds of Formula (1-3), compounds of Formula (1-4), compounds of Formula (1-5), compounds of Formula (1-6), compounds of Formula (1-7), compounds of Formula (1-8), compounds of Formula (1-9), compounds of Formula (1-10), and compounds of Formula (1-11):

wherein each R is independently selected from H, —OH, —O(C 1 -C 4 alkyl), and C 1-4 alkyl groups, and pharmaceutically acceptable salts and deuterated derivatives thereof.

9. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein at least one hydrogen atom of at least one R group is replaced by a deuterium atom.

10. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R is independently chosen from C 1 alkyl groups and C2 alkyl groups.

11. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R is independently —CH 3 or —CD 3 .

12. A compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R is independently —CH 3 .

13. A compound according to claim 1 chosen from compounds of Formulae (1-12) and (1-13):

and pharmaceutically acceptable salts and deuterated derivatives thereof.

14. A compound of Formula (1-14):

or a pharmaceutically acceptable salt or deuterated derivative thereof, wherein R is H, —OH, —O(C 1 -C 4 alkyl), or C 1 -C 4 alkyl groups.

15. A compound according to claim 14 , wherein R is a C 1 -C 4 alkyl group.

16. A pharmaceutical composition comprising:
(a) at least one compound chosen from compounds according to claim 1 , pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing;
(b) at least one pharmaceutically acceptable carrier; and
optionally one or more of:
(c) Compound (II):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and
(d) Compound (III):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

17. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition according to claim 16 , pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

18. A compound of Formula (2):

or a pharmaceutically acceptable salt or deuterated derivative thereof, wherein:
X is selected from —Si(CH 3 ) 3 ,

Z is selected from

 and
wherein each compound of Formula (2) contains at least one Si atom.

19. The compound of claim 18 , wherein the compound is chosen from:

and pharmaceutically acceptable salts and deuterated derivatives thereof.

20. A compound of Formula (3):

or a pharmaceutically acceptable salts or deuterated derivative thereof, wherein:

X is selected from —Ge(CH 3 ) 3 ,
Z is selected from

 and

wherein each compound of Formula (3) contains at least one Ge atom.

21. The compound of claim 20 , wherein the compound is chosen from:

Assignees

• Vertex Pharma

Inventors

• Abela Alexander Russell
• Clemens Jeremy J
• Grootenhuis Peter Diederik Jan
• Hadida Ruah Sara Sabina
• Ishihara Yoshihiro
• Khatuya Haripada
• Mccartney Jason
• Miller Mark Thomas
• Pierre Fabrice Jean Denis
• Tran Joe Anh
• Zhou Jinglan

Classifications

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• C07F7/30

  Germanium compounds · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07F7/0816 Primary

  said ring comprising Si as a ring atom · CPC title

• C07F7/0814

  said ring is substituted at a C ring atom by Si · CPC title