Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators

Patent metadata

Field	Value
Publication number	US-10174000-B2
Application number	US-201615754650-A
Country	US
Kind code	B2
Filing date	Aug 16, 2016
Priority date	Aug 27, 2015
Publication date	Jan 8, 2019
Grant date	Jan 8, 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 compound of Formula IIc, IIe, IIf, IIg, IIh, IIi, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIs, IIt, IIu, IIv, or IIx:

wherein
R 1 is C 1 -C 6 alkyl or —(C 1 -C 6 alkyl) n (C 1 -C 6 cycloalkyl), wherein the alkyl or cycloalkyl is optionally substituted with deuterium, halogen, CN, OH, or C 1 -C 6 alkoxy;
R 2 is hydrogen;
R 3 is hydrogen, deuterium, halogen, nitrile, —(CH 2 ) t NR 8a R 8b , —(CH 2 ) t (6- to 10-membered aryl) or a —(CH 2 ) t (5- to 10-membered heteroaryl), having one to three heteroatoms selected from N, O or S, wherein said aryl or heteroaryl is optionally substituted by one to three C 1 -C 6 alkyl, deuterium, halogen, CN, OH, hydroxyC 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 4a and R 4b are each independently hydrogen, fluorine, OH, C 1 -C 3 alkoxy, or CH 2 OR 7 , wherein R 7 taken together with R 1 is a C 1 -C 4 alkylene, optionally substituted with halogen or alkyl;
R 5a and R 5b are independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 -alkoxy, wherein said alkyl or alkoxy is optionally substituted with one to three deuterium, halogen, OH or CN; or R 5a and R 5b taken together with the atom to which they are bonded forms a C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three deuterium, halogen, OH, CN or C 1 -C 3 alkyl;
R 6 is hydrogen or C 1 -C 3 alkyl; or R 5b and R 6 taken together with the atoms to which they are bonded form a C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three deuterium, halogen, OH, CN or C 1 -C 3 alkyl;
R 8a and R 8b are each independently hydrogen, —S(O) 2 R 9 or —C(O)R 9 ;
R 9 is C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, having one to three heteroatoms, wherein said alkyl, cycloalkyl, aryl or heteroaryl are optionally substituted by one to three C 1 -C 6 alkyl, halogen, CN, OH, C 1 -C 6 alkoxy or C 1 -C 6 hydroxy;
n is 0 or 1;
t is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein
R 1 is C 1 -C 6 alkyl;
R 2 is hydrogen;
R 3 is hydrogen, deuterium, —(CH 2 ) t NR 8a R 8b , —(CH 2 ) t (6- to 10-membered aryl) or a —(CH 2 ) t (5- to 10-membered heteroaryl), having one to three heteroatoms selected from N, O or S, wherein said aryl or heteroaryl is optionally substituted by one to three C 1 -C 6 alkyl, deuterium, halogen, CN, OH, hydroxyC 1 -C 6 alkyl or C 1 -C 6 alkoxy;
R 6 is hydrogen;
R 8a and R 8b are each independently hydrogen, —S(O) 2 R 9 or —C(O)R 9 ;
R 9 is C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, having one to three heteroatoms, wherein said alkyl, cycloalkyl, aryl or heteroaryl are optionally substituted by one to three C 1 -C 6 alkyl, halogen, CN, OH, C 1 -C 6 alkoxy or C 1 -C 6 hydroxy; and
t is 0 or 1;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein the aryl and heteroaryl of R 3 is selected from phenyl, pyrazolyl, imidazolyl and oxazolyl, optionally substituted by one or two C 1 -C 6 alkyl or C 1 -C 6 hydroxyalkyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 wherein
R 3 is hydrogen, deuterium or —(CH 2 ) t NR 8a R 8b ;
R 8a and R 8b are each independently hydrogen or —S(O) 2 R 9 ;
R 9 is C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, having one to three heteroatoms, wherein said alkyl, cycloalkyl, aryl or heteroaryl are optionally substituted by one to three C 1 -C 6 alkyl, halogen, CN, OH, C 1 -C 6 alkoxy or C 1 -C 6 hydroxy; and
t is 0 or 1;
or a pharmaceutically acceptable salt thereof.

5. A compound selected from:
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;
4-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyisoquinoline-7-carboxamide;
4-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyisoquinoline-7-carboxamide;
5-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;
(3S,6R)-5-oxo-2,3,4,5,6,7,9,10-octahydro-12,14-(ethanediylidene)-3,6-methanopyrido[2,3-l][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;
5-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-3-methoxy-1,6-naphthyridine-2-carboxamide; and
1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxy-N-methyli

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

• A61P37/02

  Immunomodulators · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title