18-20 member bi-polycyclic compounds

Patent metadata

Field	Value
Publication number	US-2018362467-A1
Application number	US-201715833530-A
Country	US
Kind code	A1
Filing date	Dec 6, 2017
Priority date	Jun 4, 2014
Publication date	Dec 20, 2018
Grant date	—

Abstract

The invention relates to 18-20 member bi-polycyclic compounds, methods of making these compounds, and methods of using them in treating hyperproliferative disorders (e.g., cancer) and non-malignant tumors; promoting muscle formation; inhibiting muscle degeneration or the loss of muscle mass or muscle function; and myofibers ex vivo.

First claim

1 . A compound of Formula I: A-W—Z (I) or a pharmaceutically acceptable salt thereof, wherein A is

W is a heterocyclylene, arylene, heteroarylene, alkenylenearylene, arylenealkenylene alkenyleneheteroarylene, or heteroarylenealkenylene; and Z is —C(O)NR 1 R 2 , wherein R 1 and R 2 are each independently hydrogen (H), hydroxyl (OH), C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, or aminoaryl; a hydrogen bond donor, with the proviso that the compound is not

2 . The compound of claim 1 , wherein W is an indolinylene linked to A at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene; a quinolinene linked to A at any one of positions 2, 3, 4, 5, 6, 7, or 8; or an isoquinolinene linked to A at any one of positions 1, 3, 4, 5, 6, 7, or 8.

3 . The compound of claim 1 , wherein W is -propylene-phenylene-.

4 . (canceled)

5 . The compound of claim 2 , wherein Z is linked to the indolinylene, quinolinene, or isoquinolinene at any one of the positions that is not linked to A.

6 . The compound of claim 41 , wherein W is

7 . The compound of claim 1 , wherein W is an indolinylene linked to A at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene; Z is —C(O)NR 1 R 2 , wherein R 1 and R 2 are each independently hydrogen, hydroxyl, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, or aminoaryl; and wherein Z is linked to the indolinylene at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene not linked to A.

8 . The compound of claim 1 , wherein W is a quinolinene linked to A at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the quinolinene; Z is —C(O)NR 1 R 2 , wherein R 1 and R 2 are each independently hydrogen, hydroxyl, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, or aminoaryl; and wherein Z is linked to the quinolinene at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the quinolinene.

9 . The compound of claim 1 , W is a isoquinolinene linked to A at one of positions 1, 3, 4, 5, 6, 7 or 8 of the isoquinolinene moiety; Z is —C(O)NR 1 R 2 , wherein R 1 and R 2 are each independently hydrogen, hydroxyl, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, or aminoaryl; and wherein Z is linked to the quinoline ring at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the isoquinolinene.

10 . The compound of claim 7 , wherein Z is —C(O)NR 1 R 2 ; R 1 is H; and R 2 is OH or aminoaryl.

11 . The compound of claim 8 , wherein Z is —C(O)NR 1 R 2 ; R 1 is H; and R 2 is OH or aminoaryl.

12 . The compound of claim 9 , wherein Z is —C(O)NR 1 R 2 ; R 1 is H; and R 2 is OH or aminoaryl.

13 . (canceled)

14 . The compound of claim 1 , wherein the compound is

15 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

16 . A method of treating a subject who has cancer or a non-malignant tumor, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a composition comprising thereof.

17 . The method of claim 16 , wherein the cancer is non-small cell lung cancer, colon cancer, melanoma, breast cancer, renal cancer, ovarian cancer, prostate cancer, cancer of the central nervous system, a blood cancer, or a neuroblastoma.

18 . The method of claim 16 , wherein the non-malignant tumor is a pheochromocytoma.

19 . A method of inhibiting loss of muscle mass or muscle function, or preventing muscle degeneration in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:
A-W—Z   (I)
or a pharmaceutically acceptable salt thereof, wherein A is

W is a heterocyclylene, arylene, heteroarylene, alkenylenearylene, arylenealkenylene or alkenyleneheteroarylene, heteroarylenealkenylene; and
Z is —C(O)NR1R2, wherein R1 and R2 are each independently hydrogen (H), hydroxyl (OH), C1-6 alkyl, hydroxyC1-6 alkyl, aminoC1-6 alkyl, or aminoaryl.

20 . The method of claim 19 , wherein the loss of muscle mass is associated with any one of an inherited myopathy, muscular dystrophy, neuromyotonia, nemaline myopathy, multi/minicore myopathy, centronuclear myopathy, mitochondrial myopathy, inflammatory myopathy, metabolic myopathy, intensive care unit-acquired weakness (ICUAW), chronic obstructive pulmonary disease (COPD), heart failure, traumatic injury or malignancy.

21 . (canceled)

22 . (canceled)

23 . (canceled)

Assignees

• Haro Pharmaceutical Inc
• The Royal Institution For The Advancement Of Learning/Mcgill Univ
• Univ Montreal

Inventors

• Bettoun David
• Martinez Eduardo
• Gleason James
• Mader Sylvie
• Xing Shuo

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D215/54 Primary

  attached in position 3 · CPC title

• C07C259/10

  having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings · CPC title