Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators

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-methylisoquinoline-6-carboxamide;

or pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle, diluent or carrier.

7. A pharmaceutical combination comprising a therapeutically effective amount:

a first compound; a second compound; and a pharmaceutically acceptable carrier, vehicle, or diluent; wherein

the first compound is a compound of claim 5 or a pharmaceutically acceptable salt thereof;

the second compound is 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.

8. The combination of claim 7 wherein the second compound is a janus kinase inhibitor.

9. The combination of claim 8 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.

10. A method of treating a disease selected from systemic lupus erythematosus (SLE), lupus nephritis, rheumatoid arthritis, psoriasis, or atopic dermatitis, in a human comprising administering to the human having said disease a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.