Methods and compositions associated with the granulocyte colony-stimulating factor receptor

Patent metadata

Field	Value
Publication number	US-9492430-B2
Application number	US-201214357551-A
Country	US
Kind code	B2
Filing date	Nov 12, 2012
Priority date	Nov 14, 2011
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Some embodiments include compositions and methods of using or identifying compounds that modulate the activity of the granulocyte colony-stimulating factor receptor (GCFR). Some embodiments include use of compounds to treat certain disorders, such as hematopoietic or neurological disorders.

First claim

What is claimed is:

1. A compound of Formula (III):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from hydrogen, OR 6 , NO 2 , CN, NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , SO 2 NR 6 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted C 3 -C 6 cycloalkenyl, an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, and an optionally substituted heteroarylalkyl;
R 5 is selected from NO 2 , CN, CF 3 , OR 6 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , and SO 2 NR 6 R 8 , an optionally substituted aryl, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;
R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;
R 8 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;
Q is selected from the group consisting of NR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted non-aromatic heterocycle;
L 1 is NH;
Z is O (oxygen);
n is 1, 2 or 3; and
with the proviso that if R 2 is methyl, R 4 is phenyl, and Q is N-Ph-R 1 in Formula III, R 1 of Formula III is not selected from the group of halogen, alkyl, substituted alkyl, carboxylic acid, and carboxylic esters.

2. The compound of claim 1 having the structure of Formula (IIIa):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl;
R 5 is selected from CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;
R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 6 alkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;
R 8 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;
Q is selected from NR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl;
Z is O (oxygen); and
n is 1, or 2.

3. The compound of claim 2 , wherein:
R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl;
R 5 is selected from CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;
R 6 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;
R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 6 alkyl;
R 8 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;
Q is selected from NR 6 , an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl;
Z is O (oxygen); and
n is 1.

4. The compound of claim 3 , wherein:
R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , C(═O)NR 6 R 7 , an optionally substituted arylalkyl, and an optionally substituted heteroaryl;
R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 4 is an optionally substituted aryl;
R 5 is selected from CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;
R 6 is selected from hydrogen, and an optionally substituted C 1 -C 3 alkyl;
R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 3 alkyl;
R 8 is selected from hydrogen, and an optionally substituted C 1 -C 3 alkyl; and
Q is selected from optionally substituted C 1 -C 3 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl.

5. The compound of claim 1 , wherein the compound is a GCSF receptor agonist or a GCSF receptor partial agonist.

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

7. A method of treating a hematopoietic or neurological disorder comprising administering an effective amount of a compound of claim 1 to a subject in need thereof, wherein the disorder is selected from the group consisting of granulocytopenia, neutropenia, amyotrophic lateral sclerosis, multiple sclerosis, multiple dystrophy, and spinal co

Assignees

• Ligand Pharm Inc
• Ligand Pharm Inc

Inventors

• Zhi Lin
• Marschke Keith
• Grant Virginia H
• Roach Steven L
• Shen Yixing
• Pickens Jason C
• Pedram Bijan
• Van Oeveren C Arjan
• Valdez Lino J
• Hudson Andrew R

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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