Compounds useful for the treatment of degenerative and inflammatory diseases

Patent metadata

Field	Value
Publication number	US-9415037-B2
Application number	US-201414507396-A
Country	US
Kind code	B2
Filing date	Oct 6, 2014
Priority date	Jul 25, 2008
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

[1,2,4]triazolo[1,5-a]pyridine compounds are disclosed that have a formula represented by the following:

The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.

First claim

What is claimed is:

1. A method for the treatment of ulcerative colitis, said method comprising administering a therapeutically effective amount of a compound according to Formula III:

wherein the group

is selected from:

n2 is n1, and n1 is 0, 1, 2, 3 or 4;
R 3b is
—OPh, and O-(4-F-Ph), or
CO—R 3c ; and R 3c is:

or
R 3b is

Cy3 is selected from:

each R 5a is independently C 1 -C 4 alkyl, halo, CF 3 or Phenyl;
R 5b is H, aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocycloalkyl;
R 5c is H, or C 1 -C 4 alkyl;
m5 is 0, 1, or 2;
n5 is 0, 1, or 2,
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said compound is prepared and administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of said compound or a pharmaceutically acceptable salt thereof.

3. A method for the treatment of ulcerative colitis, said method comprising administering a therapeutically effective amount of a compound according to formulae Va, Vb, Vc, or Vd:

4. A method for the treatment of ulcerative colitis, said method comprising administering a therapeutically effective amount of a compound according to formulae VIc, or VId:

5. A method for the treatment of ulcerative colitis, said method comprising administering a therapeutically effective amount of a compound according to formulae VIIa, VIIb, VIIc, VIId, VIIe or VIIf:

6. A method for the treatment of ulcerative colitis, said method comprising administering a therapeutically effective amount of a compound selected from
N-(5-(4-(4-methylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(3-(morpholinomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(biphenyl-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-benzoylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-cyclopropylbenzamide,
N-(5-(4-(benzyloxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(N-cyclopropylsulfamoyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(3-(benzyloxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(benzyloxy)-3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(2-(benzyloxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(piperidine-1-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(morpholinomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(pyrrolidine-1-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(thiophen-2-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)benzamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)-4-(trifluoromethyl)benzamide,
N-(5-(4-(2-phenylacetamido)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(morpholine-4-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(pyridin-4-yl)benzamide,
N-cyclohexyl-4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzamide,
N-(5-(4-(4-tert-butylpiperidine-1-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(1,4-diazepane-1-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(3-fluorobenzyl)benzamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-methyl-N-phenylbenzamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(4-methoxybenzyl)-N-methylbenzamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(1-methylpiperidin-4-yl)benzamide,
N-(5-(4-(4-fluorophenylsulfonamido)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)-2-fluorobenzamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)pyrazine-2-carboxamide,
N-(5-(4-(pyridin-3-ylmethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(pyridin-2-ylmethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(3-(trifluoromethoxy)benzyloxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(cyclobutylmethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(cyclopentyloxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(cyclohexylmethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(pyridin-3-ylmethyl)benzamide,
4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-phenylbenzamide,
N-(5-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)benzamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)cyclohexanecarboxamide,
N-(5-(4-phenoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-((1-methyl-1H-pyrazol-3-yl)methylmethyl-1H-pyrazol-3-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-((1,3-dimethyl-1H-pyrazol-5-yl)methyldimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-(2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyldimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(5-(4-((5-methylisoxazol-3-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)-3-methoxybenzamide,
N-(5-(4-(2-fluorophenylsulfonamido)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide,
N-(4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)picolinamide,
N-benzyl-4-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzamide,
N-(5-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarbox

Assignees

• Menet Christel Jeanne Marie
• Van Rompaey Luc Juliaan Corina
• Fletcher Stephen Robert
• Blanc Javier
• Jouannigot Nolwenn
• Hodges Alastair James
• Smits Koen Kurt
• Galapagos Nv

Inventors

• Menet Christel Jeanne Marie
• Van Rompaey Luc Juliaan Corina
• Fletcher Stephen Robert
• Blanc Javier
• Jouannigot Nolwenn
• Hodges Alastair James
• Smits Koen Kurt

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P41/00

  Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title