Compounds and methods of use
View Patent ↗Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation, and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
1. A compound of formula II′
wherein the C ring is a 5 to 6-membered saturated carbocyclic moiety;
wherein R′ is in the 1-position relative to the fused phenyl ring and is
wherein R′ is phenyl or pyridinyl optionally substituted with one to five groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , (C 1 -C 6 )alkylamino, halo(C 1 -C 6 )alkyl, oxo, (C 1 -C 6 )alkoxy, haloalkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, di(C 1 -C 6 )alkylamino, —C(O)R 8 , —COOR 8 , —C(O)NR 8 R 8′ , and —NR 8 C(O)R 8′ , and
(C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is optionally substituted with one to three groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , (C 1 -C 6 )alkylamino, halo(C 1 -C 6 )alkyl, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, di(C 1 -C 6 )alkylamino, —C(O)R 8 , —COOR 8 , —C(O)NR 8 R 8′ , and —NR 8 C(O)R 8′ ;
wherein R 2 is phenyl, benzothienyl or naphthyl optionally substituted with one to five groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , (C 1 -C 6 )alkylamino, oxo, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, di(C 1 -C 6 )alkylamino, —C(O)R 8 , —COOR 8 , —C(O)NR 8 R 8′ , —NR 8 C(O)R 8′ , and
(C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with one to three groups independently selected from halo, —NH 2 , —OH, —CN, —CF 3 , (C 1 -C 6 )alkylamino, halo(C 1 -C 6 )alkyl, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, di(C 1 -C 6 )alkylamino, —C(O)R 8 , —COOR 8 , —C(O)NR 8 R 8′ , and —NR 8 C(O)R 8′ ;
wherein R a is H;
wherein R 4 and R 5 are hydrogen;
wherein R 3 represents a basic moiety; and
wherein R 8 and R 8′ independently are selected from H, and
lower alkyl, aryl and heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or dialkylamino, and trifluoromethyl;
provided at least one of R 3 , R 4 and R 5 is a basic moiety; and pharmaceutically acceptable derivatives thereof.
2. The compound of claim 1 wherein R 3 is selected from —NH 2 , aminomethyl, aminoethyl, aminopropyl, isopropylaminomethyl, t-butylaminomethyl, iso-butylaminomethyl, 1-methylpropylaminomethyl, 2-methylbutylaminomethyl, 2,2′-dimethylpropylamnomethyl, 2,2′,3-trimethylpropylaminomethyl, allyl-aminomethyl, isopropylaminopropyl, 1-(isobutylamino)ethyl, 1-(isopropylamino)-1-methylethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, N,N-di(allyl)-aminomethyl, cyclopropylaminomethyl, 1-(cyclopropylamino)ethyl, cyclobutylaminomethyl, 2-(cyclobutylamino)ethyl, 1-(cyclobutylamino)ethyl, cyclopentylaminomethyl, 1-cyclopentylaminoethyl, cyclopropylmethylaminomethyl, hydroxyethylamino-allyl, isopropylamino-allyl, t-butylamino-allyl, cyclopropylmethylamino-allyl, piperidin-1-yl-allyl, pyrrolidin-1-yl-allyl, azetidin-1-yl-allyl, 3-hydroxypyrrolidin- 1-yl-allyl, aminocarbonylethylaminomethyl, methoxyethylaminomethyl, 1-(methoxyethylamino)ethyl, 1-piperidinylmethyl, 2-(piperidin-1-yl)ethyl, 3,4-dihydropiperidin-1-ylmethyl, 4-fluoropiperidinylmethyl, 4,4′-difluoropiperidinylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 3-aminocarbonylpiperidin-1-ylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 3,3-dimethylpiperidin-1-ylmethyl, piperidin-1-yl-2-methylethyl, 3-hydroxypiperidin-1-yl, 4-morpholinylmethyl, 4-morpholinylethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 1-(methylpyrrolidin-1-yl)ethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, 1 -azetidinylmethyl, 7-aza-bicyclo[2.2. 1]heptyl, piperazin- 1-ylmethyl, 4-methylpiperazin- 1-ylmethyl, and 1-pyrrolidinylethylaminomethyl; and pharmaceutically acceptable derivatives thereof.
3. The compound of claim 1 wherein R 2 is 2-naphthyl.
4. The compound of claim 1 wherein R 2 is 3,4-dichiorophenyl.
5. The compound of claim 1 wherein R 2 is 3-trifluoromethyiphenyl.
6. The compound of claim 1 and/or pharmaceutically acceptable derivatives thereof selected from
3-(Naphthalen-2-yl-sulfonylamino)-3-phenyl-N-(5-piperidin-1-ylmethyl-indan-1-yl)-propionamide;
3-(Naphthalen-2-yl-sulfonylamino)-3-phenyl-N-(6-piperidin- 1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide;
(3S)-N-((1R)-6-(((1,1-dimethylethyl)amino)-methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(4-fluorophenyl)-3-(((3-(trifluoromethyl)phenyl)-sulfonyl)amino)propanamide;
(3R)-3-phenyl-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl) amino)propanamide;
(3R)-N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenyl-3-(((3-(trifluoromethyl)phenyl)-sulfonyl)amino)propanamide;
(3R)-N-((1R)-5-((4,4-difluoro-1-piperidinyl)methyl)-2,3-dihydro-1H-inden-1-yl)-3-phenyl-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3R)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(4-fluorophenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)-amino)propanamide;
(3R)-3-(4-fluorophenyl)-N-((1R)-6-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)-amino)propanamide;
(3R)-N-((1R)-6-((4,4-difluoro- 1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenyl-3-(((3-(trifluoromethyl)phenyl)-sulfonyl)amino)propanamide;
(3R)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-3-phenyl-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)propanamide;
(3R)-3-(((5-chloro-3-methyl- 1-benzothien-2-yl)sulfonyl)amino)-N-(6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenylpropanamide;
(3R)-3-(((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)amino)-3-phenyl-N-(6-( 1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)propanamide;
(3R)-N-((1R)-6-(3,6-dihydro-1(2H)-pyridinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenyl-3-(((3-(trifluoromethyl)phenyl)sulfonyl) amino)propanamide;
(3R)-3-(((5-chloro-1-benzothien-2-yl)sulfonyl)amino)-3-(6-(methyloxy)-3-pyridinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)propanamide;
(3R)-3-(6-(methyloxy)-3-pyridinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3S)-3-(4-fluorophenyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenylpropanamide;
(3R)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-3-phenylpropanamide;
(3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenylpropanamide;
3-(3,4-Dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-N-[6-(isobutylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-propionamide;
3-(3,4-Dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-N-[6-(isopropylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-propionamide;
3-(3,4-Dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-N-{6-[(2-methoxy-ethylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide;
N-(6-Cyclobutylaminomethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-Fluoro-phenyl)-N-[6-(isobutylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-Fluoro-phenyl)-N-[6-(isopropylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-Fluoro-phenyl)-N-{6-[(2-methoxy-ethylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3-nitro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3-cyano-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-tert-Butyl-benzenesulfonylamino)-N-(6-cyclobutylaminomethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(4-fluoro-phenyl)-propionamide;
3-(4-tert-Butyl-benzenesulfonylamino)-3-(4-fluoro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide;
3-(4-tert-Butyl-benzenesulfonylamino)-3-(4-fluoro-phenyl)-N-[6-(isobutylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(4-tert-butyl-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide;
3-(3-Fluoro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
N-(6-Cyclopentylaminomethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3,4-dichloro-benzenesulfonylamino)-3-(3-fluoro-phenyl)-propionamide;
3-(4-Fluoro-phenyl)-N-[6-(4-fluoro-piperidin- 1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(3-Chloro-phenyl)-3-(3,4-dichloro-benzenesulfonylamino)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide;
3-(3,4-Dichloro-benzenesulfonylamino)-3-(3-fluoro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(3-fluoro-phenyl)-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(3-fluoro-phenyl)-propionamide;
N-{6-[(Cyclopropylmethyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(4-nitro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-Chloro-phenyl)-N-(6-piperidin- 1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3-trifluoromethyl-benzenesulfonylarnino)-propionamide;
3-(3,5-Dichloro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3-trifluoromethyl-benzenesulfonylarnino)-propionamide;
3-(2-Fluoro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
3-(4-Fluoro-phenyl)-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide;
(3R)-3-((2-Naphthalenylsulfonyl)amino)-3-phenyl-N-((1S)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)propanamide;
(3R)-3-((2-Naphthalenylsulfonyl)amino)-3-phenyl-N-((1S)-5-(1-piperidinylmethyl)-2,3-dihydro-1H-inden-1-yl)propanamide;
(3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-3-phenyl-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)propanamide;
(3R)-N-((1R)-6-( 1-(((3S)-3-hydroxy-1-pyrrolidinyl)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenyl-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3R)-3-phenyl-N-((1R)-6-(1-(1-pyrrolidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3R)-3-phenyl-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)propanamide;
(3R)-3-((hydroxy(oxido)(3-(trifluoromethyl)phenyl)-lambda˜-4˜-sulfanyl)amino)-N-((1R)-6-((1R)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phenylpropanamide; and
(3R)-N-((1R)-6-((1R)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-((2-naphthalenylsulfonyl)amino)-3-phenylpropanamide.