Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-2016115133-A1
Application number	US-201514837201-A
Country	US
Kind code	A1
Filing date	Aug 27, 2015
Priority date	Jun 17, 2004
Publication date	Apr 28, 2016
Grant date	—

Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

First claim

1 . A compound having a structure of Formula I

or a pharmaceutically acceptable salt thereof, wherein
W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;
n is one, two, or three;
R 1 is optionally substituted amino or optionally substituted heterocycloalkyl;
R 2 is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,
R 3 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3 is absent when W is —N═;
R 4 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4 is absent when Y is —N═; and
R 5 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5 is absent when X is —N═;
R 13 is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13 is absent when Z is —N═; and;
R 6 and R 7 are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6 and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring.

2 .- 50 . (canceled)

51 . A method of treating heart disease in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 1 .

52 .- 54 . (canceled)

55 . A method for modulating the cardiac sarcomere in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 1 .

56 . A method for potentiating cardiac myosin in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 1 .

57 .- 60 . (canceled)

61 . A method of preparing a compound of Formula I

comprising the steps of
converting a compound of Formula 400

to a compound of Formula 401;

hydrolyzing the compound of Formula 401 to a compound of Formula 402

wherein R is chosen from O and NH;
contacting a compound of Formula 402 with a compound of formula R 1 —H wherein R 1 is optionally substituted amino or optionally substituted heterocycloalkyl to form a compound of Formula 403; and

contacting a compound of Formula 403 with a compound of the formula R 2 —NCO to yield a compound of Formula I:
wherein
n is one, two or three;
W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;
R 2 is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,
R 3 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3 is absent when W is —N═;
R 4 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4 is absent when Y is —N═; and
R 5 is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5 is absent when X is —N═;
R 13 is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13 is absent when Z is —N═; and;
R 6 and R 7 are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6 and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring.

Assignees

• Cytokinetics Inc

Inventors

• Morgan Bradley Paul
• Muci Alex
• Lu Pu-Ping
• Kraynack Erica Anne
• Tochimoto Todd
• Morgans Jr David J

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D271/113

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title