IP Library › Granted Patent US 8,278,452
Granted Patent B2
US 8,278,452 · App. 12/918,801 · Granted Oct 2, 2012

Heterocyclic compounds and compositions as c-kit and PDGFR kinase inhibitors

Assignee: IRM LLC
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Quick Facts
Patent No.
US 8,278,452
App. No.
12/918,801
Granted
Oct 2, 2012
Kind
B2
Abstract

The invention provides a novel class of compounds of Formula I: (I) pharmaceutical compositions comprising such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of c-kit, PDGFRα and PDGFRβ kinases.

Claims (32)

1. A compound of Formula I:

in which

R 1 is selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein said C 1-6 alkyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, ═N(OH), C 1-4 alkoxy and benzoxy; wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —X 1 NR 3a R 3b , —X 1 C(O)R 3a , —X 1 C(O)OR 3a , —X 1 OR 3a , C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein X 1 is selected from a bond and C 1-4 alkylene; wherein R 3a and R 3b are independently selected from hydrogen and C 1-6 alkyl;

R 2 is selected from methyl and ethyl;

A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2-oxazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl; wherein the oxadiazolyl, triazolyl, isoxazolyl and thiadiazolyl of A can be optionally substituted with C 1-2 alkyl;

or the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , of Formula Ia:

in which

R 1 is selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein said C 1-6 alkyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, ═N(OH), C 1-4 alkoxy and benzoxy; wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, −X 1 NR 3a R 3b , —X 1 C(O)R 3a , —X 1 C(O)OR 3a , —X 1 OR 3a , C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein X 1 is selected from a bond and C 1-4 alkylene; wherein R 3a and R 3b are independently selected from hydrogen and C 1-6 alkyl;

R 2 is selected from methyl and ethyl;

Y 1 is selected from O, and S; and

Y 2 is selected from N and CR 4 ; wherein R 4 is selected from hydrogen and C 1-2 alkyl.

3. The compound of claim 2 in which R 1 is selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein said C 1-6 alkyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from hydroxy, halo, C 1-6 alkoxy, benzoxy and ═N(OH); wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —X 1 NR 3a R 3b , —OR 3a , —C(O)R 3a and C 3-10 heteroaryl; wherein X 1 is selected from a bond and C 1-4 alkylene; wherein R 3a and R 3b are independently selected from hydrogen and C 1-6 alkyl; and R 2 is selected from methyl and ethyl.

4. The compound of claim 3 in which R 1 is selected from ethyl, t-butyl, t-butyl-methyl, isobutyl, propyl, isopropyl, neopentyl, sec-butyl, pentan-3-yl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 1-hydroxy-propan-2-yl, 1-hydroxy-2-methylpropyl, 1,1-difluoroethyl, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, ethoxy-methyl, 1-methoxyethyl, 1-phenoxyethyl, 1-(hydroxyimino)ethyl, pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl and cyclohexyl; wherein said pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 3 radicals independently selected from chloro, fluoro, bromo, hydroxy, hydroxy-methyl, pyridinyl, cyano, methyl, methoxy, amino-methyl, methyl-carbonyl, trifluoromethyl, difluoroethyl and trifluoromethoxy.

5. The compound of claim 4 selected from: 1,7-dimethyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one; 1,7-dimethyl-3-(2-methyl-5-(5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one; 3-(5-{[5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,5-dimethylfuran-3-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-ethyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]amino}-phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-1,2,4-oxadiazol-3-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclobutyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclopentyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclohexyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1-methyl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1-methyl-1H-imidazol-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1-methylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(5-chloropyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[(2S)-butan-2-yl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-{2-methyl-5-[(5-propyl-1,2,4-oxadiazol-3-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(butan-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(oxan-4-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 4-(3-{[3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl]amino}-1,2,4-oxadiazol-5-yl)benzonitrile; 2-(3-{[3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl]amino}-1,2,4-oxadiazol-5-yl)benzonitrile; 3-(5-{[5-(3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(3-{[3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl]amino}-1,2,4-oxadiazol-5-yl)benzonitrile; 1,7-dimethyl-3-[2-methyl-5-({5-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(6-hydroxypyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[2-(pyridin-3-yl)-1,3-thiazol-4-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,5-dimethyl-1,3-oxazol-4-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(5-chloro-1H-indol-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(6-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-chloro-6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(6-chloropyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(5-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-hydroxypropyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(1-hydroxycyclopropyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(oxan-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,6-difluorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 4-(3-{[3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl]amino}-1,2,4-oxadiazol-5-yl)-3-fluorobenzonitrile; 3-(5-{[5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(3-methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(oxetan-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(1-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(2-methylpropyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[1-(hydroxymethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(pyrazin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(5-methylpyrazin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-hydroxycyclopentyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[(2S)-oxolan-2-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[(1S)-1-methoxyethyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[(2S)-oxolan-2-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(oxolan-3-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(3-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-methoxy-4-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-chloro-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-hydroxy-3-methylcyclobutyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(oxan-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-1,2,4-oxadiazol-3-yl)amino]phenyl}-6-oxido-2-oxo-1,2-dihydro-1,6-naphthyridin-6-ium; 3-(5-{[5-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[6-(1,1-difluoroethyl)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[4-(1,1-difluoroethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[4-(aminomethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[(1R)-1-hydroxy-2-methylpropyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-[5-({5-[(1S)-1-hydroxy-2-methylpropyl]-1,2,4-oxadiazol-3-yl}amino)-2-methylphenyl]-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2-acetylphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(1-phenoxyethyl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[(2R)-2-methyloxolan-2-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,3-dihydro-1-benzofuran-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[(2R)-oxan-2-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-[2-methyl-5-({5-[(2S)-oxan-2-yl]-1,2,4-oxadiazol-3-yl}amino)phenyl]-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-hydroxy-3-methylcyclobutyl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(5-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(5-methoxypyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 7-ethyl-1-methyl-3-(2-methyl-5-{[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 7-ethyl-1-methyl-3-(2-methyl-5-{[5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; and 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-1,2,4-thiadiazol-3-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one.

6. The compound of claim 1 , of Formula Ib:

in which

R 1 is selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein said C 1-6 alkyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-4 alkoxy and benzoxy; wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —X 1 NR 3a R 3b , —X 1 C(O)R 3a , —X 1 C(O)OR 3a , —X 1 OR 3a , C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein X 1 is selected from a bond and C 1-4 alkylene; wherein R 3a and R 3b are independently selected from hydrogen and C 1-6 alkyl;

R 2 is selected from methyl and ethyl;

Y 3 is selected from O, S and NR 4 ; wherein R 4 is selected from hydrogen and C 1-2 alkyl.

7. The compound of claim 6 in which R 1 is selected from ethyl, t-butyl, t-butyl-methyl, isobutyl, propyl, isopropyl, neopentyl, sec-butyl, pentan-3-yl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 1-hydroxy-propan-2-yl, 1-hydroxy-2-methylpropyl, 1,1-difluoroethyl, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, ethoxy-methyl, 1-methoxyethyl, 1-phenoxyethyl, 1-(hydroxyimino)ethyl, pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl and cyclohexyl; wherein said pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 3 radicals independently selected from chloro, fluoro, bromo, hydroxy, hydroxy-methyl, pyridinyl, cyano, methyl, methoxy, amino-methyl, methyl-carbonyl, trifluoromethyl, difluoroethyl and trifluoromethoxy.

8. The compound of claim 7 selected from: 1,7-dimethyl-3-(2-methyl-5-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-1,3,4-oxadiazol-2-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(2-methylpropyl)-1,3,4-oxadiazol-2-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclohexyl-1,3,4-oxadiazol-2-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclopentyl-4H-1,2,4-triazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[5-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(2,2-dimethylpropyl)-4H-1,2,4-triazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-4H-1,2,4-triazol-3-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one; 3-(5-{[5-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl]amino}-2-methylphenyl)-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; 3-{5-[(5-cyclobutyl-4H-1,2,4-triazol-3-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one; and 1,7-dimethyl-3-{2-methyl-5-[(5-phenyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one.

9. The compound of claim 1 , of Formula Ic:

in which

R 1 is selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein said C 1-6 alkyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-4 alkoxy and benzoxy; wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —X 1 NR 3a R 3b , —X 1 C(O)R 3a , —X 1 C(O)OR 3a , —X 1 OR 3a , C 3-12 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 3-10 heteroaryl; wherein X 1 is selected from a bond and C 1-4 alkylene; wherein R 3a and R 3b are independently selected from hydrogen and C 1-6 alkyl;

R 2 is selected from methyl and ethyl;

Y 4 is selected from CR 4 and N 4 ; wherein R 4 is selected from hydrogen and C 1-2 alkyl.

10. The compound of claim 9 in which R 1 is selected from ethyl, t-butyl, t-butyl-methyl, isobutyl, propyl, isopropyl, neopentyl, sec-butyl, pentan-3-yl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 1-hydroxy-propan-2-yl, 1-hydroxy-2-methylpropyl, 1,1-difluoroethyl, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, ethoxy-methyl, 1-methoxyethyl, 1-phenoxyethyl, 1-(hydroxyimino)ethyl, pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl and cyclohexyl; wherein said pyridinyl, piperazinyl, furanyl, phenyl, thiazolyl, 2,3-dihydrobenzofuran-2-yl, 3-oxocyclobutyl, oxetan-3-yl, oxetan-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydrofuranyl, 1H-indol-2-yl, cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 3 radicals independently selected from chloro, fluoro, bromo, hydroxy, hydroxy-methyl, pyridinyl, cyano, methyl, methoxy, amino-methyl, methyl-carbonyl, trifluoromethyl, difluoroethyl and trifluoromethoxy.

11. The compound of claim 10 selected from: 1,7-dimethyl-3-{2-methyl-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)amino]phenyl}-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; 1,7-dimethyl-3-(2-methyl-5-{[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one; and 1,7-dimethyl-3-(2-methyl-5-{[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]amino}phenyl)-1,2-dihydro-1,6-naphthyridin-2-one.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 - 11 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 , wherein the pharmaceutically acceptable excipient is suitable for parenteral administration.

14. The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable excipient is suitable for oral administration.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 18, 2011
From: LI, XIAOLIN; LIU, XIAODONG; LOREN, JON C.; MOLTENI, VALENTINA; NABAKKA, JULIET; YEH, VINCE; CHIANELLI, DONATELLA
To: IRM LLC, A DELAWARE LIMITED LIABILITY CORPORATION
Reel/Frame 025833/0304 →
Continuity (2)
Provisional Application 61030912 · Feb 22, 2008
Related Publication 20110183997A1 · Jul 28, 2011