Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators

Patent metadata

Field	Value
Publication number	US-10316018-B2
Application number	US-201816206166-A
Country	US
Kind code	B2
Filing date	Nov 30, 2018
Priority date	Aug 27, 2015
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula Ia,

as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

First claim

We claim:

1. A method of treating rheumatoid arthritis in a human comprising administering to the human having rheumatoid arthritis a therapeutically effective amount of a compound selected from the group consisting of
8-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-2-methoxyquinoline-3-carboxamide;
4-(1,3-oxazol-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(4-methyl-1H-imidazol-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(1-methyl-1H-pyrazol-3-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(1-methyl-1H-pyrazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(4-methyl-1,3-oxazol-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(4,5-dimethyl-1,3-oxazol-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-[4-(hydroxymethyl)-1H-imidazol-2-yl]-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-(5-methyl-1,3-oxazol-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-4-[(phenylsulfonyl)amino]-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)-4-[(pyridin-3-ylsulfonyl)amino]isoquinoline-6-carboxamide;
1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-4-[(1H-imidazol-4-ylsulfonyl)amino]-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-4-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}-1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
4-amino-1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;
1-{[(4R,7S)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-{[(4S)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-{[(4R,7R)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;
1-(((4S,7R)-7-fluoro-6-oxo-5-azaspiro[2.4]heptan-4-yl)methoxy)-7-isopropoxyisoquinoline-6-carboxamide;
1-{[(4S,7R)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;
1-{[(4R,7S)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;
1-{[(4R,7R)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;
1-{[(4S,7S)-7-fluoro-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;
(3S,6R)-5-oxo-2,3,4,5,6,7,9,10-octahydro-12,14-(ethanediylidene)-3,6-methanopyrido[2,3-I][1,4,11,8]trioxazacyclopentadecine-19-carboxamide;
7-methoxy-1-[(3-oxo-2-azabicyclo[3.1.0]hex-1-yl)methoxy]isoquinoline-6-carboxamide;
7-methoxy-1-{[(1S,5S)-3-oxo-2-azabicyclo[3.1.0]hex-1-yl]methoxy}isoquinoline-6-carboxamide;
7-methoxy-1-{[(1R,5R)-3-oxo-2-azabicyclo[3.1.0]hex-1-yl]methoxy}isoquinoline-6-carboxamide; and
5-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-3-methoxy-1,6-naphthyridine-2-carboxamide;
or pharmaceutically acceptable salt thereof.

2. The method of claim 1 further comprising the administration of a second compound selected from the group consisting of a corticosteroid, hydroxychloroquine, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, janus kinase inhibitor, statin, calcipotriene, angiotensin-converting enzyme inhibitor and angiotensin receptor blocker.

3. The method of claim 2 wherein the second compound is a janus kinase inhibitor.

4. The method of claim 3 wherein the janus kinase inhibitor is selected from ruxolitinib, baricitinib, tofacitinib, Decernotinib, Cerdulatinib, JTE-052, Peficitinib, GLPG-0634, INCB-47986, INCB-039110, PF-04965842, XL-019, ABT-494, R-348, GSK-2586184, AC-410, BMS-911543 and PF-06263276.

Assignees

• Pfizer

Inventors

• Lee Katherine Lin
• Allais Christophe Philippe
• Dehnhardt Christoph Martin
• Gavrin Lori Krim
• Han Seungil
• Hepworth David
• Lee Arthur
• Lovering Frank Eldridge
• Mathias John Paul
• Owen Dafydd Rhys
• Papaioannou Nikolaos
• Saiah Eddine
• Strohbach Joseph Walter
• Trzupek John David
• Wright Stephen Wayne
• Zapf Christoph Wolfgang

Classifications

• A61P37/08

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/00

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

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title