US 9,963,444 B2Granted

N-acylethanolamine hydrolyzing acid amidase (NAAA) inhibitors and their use thereof

AssigneeNortheastern University

InventorsMichael Malamas, Alexandros Makriyannis, Kumara Vadivel Subramanian, Kyle M. Whitten, Nikolai M. Zvonok, Jay Matthew West, Michael Mccormack, Spiro Pavlopoulos

Life of this patent

Estimating the term…

Abstract

A compound is represented as Formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Compounds of Formula I are inhibitors of N-acylethanolamine hydrolyzing acid amidase (NAAA). The present technology is directed to compounds, compositions, and methods to inhibit N-acylethanolamine hydrolyzing acid amidase and to treat N-acylethanolamine hydrolyzing acid amidase mediated conditions in a subject.

Claims14

Dependent claims

A compound of Formula II, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:
Z is CN or —CH2-CN;
and
C is
or
Z is NCS;
and
C is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or
and
D is hydrogen, C1-C3 alkyl, aryl, or heteroaryl;
T is O or NR1, wherein R1 is H or C1-C3 alkyl;
Y is absent or C1-C3 alkylene;
B is a substituted or unsubstituted 5-10 membered aryl or heteroaryl;
V is absent or O;
A is a substituted or unsubstituted 5-10 membered aryl or heteroaryl;
and
n is 0, 1, 2, or 3, wherein
A, B and C, when substituted, are each independently substituted with one or more substituent groups selected from halogen, hydroxyl, alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, carbonyl, carboxylate, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, pentafluorosulfanyl, sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro, nitrile or alkyl optionally substituted one or more times with halo, hydroxy, thio, amino, alkylamino, dialkylamino, alkoxy or carboxy.

15 more elements

A compound selected from the group consisting of:

4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-4′-methyl-1,1′-biphenyl;
4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methyl-1,1′-biphenyl;
4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,4′-difluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methoxy-1,1′-biphenyl;
4′-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4-ethoxy-3,3′-difluoro-4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-isopropoxy-4′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
6-(3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine;
5-(3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)benzo[d][1,3]dioxole;
3-fluoro-4-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-3′,4′-dimethoxy-1,1′-biphenyl;
3-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-2-methoxypyridine;
5-(3-fluoro-4-methoxyphenyl)-2-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)pyridine;
3,4′-difluoro-3′-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-4-methoxy-1,1′-biphenyl;
4-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-3,5-dimethylisoxazole;
4-(3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-1-methyl-1H-pyrazole;
3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-3′-(trifluoromethyl)-1,1′-biphenyl;
3′-(benzyloxy)-3-fluoro-4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
2-bromo-1-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-4-phenoxybenzene;
2-(((1S,3S)-3-isothiocyanatocyclobutoxy)methyl)-5-phenoxy-1,1′-biphenyl;
3-fluoro-4′-((1R,3R)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl;
3-fluoro-4′-((1S,3S)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl;
(1R,3R)—N-([1,1′-biphenyl]-4-ylmethyl)-3-isothiocyanato-N-methylcyclobutan-1-amine,
(1S,3S)—N-([1,1′-biphenyl]-4-ylmethyl)-3-isothiocyanato-N-methylcyclobutan-1-amine,
(1R,3R)—N-(4-(benzo[d][1,3]dioxol-5-yl)benzyl)-3-isothiocyanato-N-methylcyclobutan-1-amine;
(1R,3R)—N-(4-(benzo[d][1,3]dioxol-5-yl)benzyl)-N-ethyl-3-isothiocyanatocyclobutan-1-amine;
4′-(((3-isothiocyanatocyclohexyl)oxy)methyl)-3-(trifluoromethyl)-1,1′-biphenyl;
3-fluoro-4′-((((1R,4R)-4-isothiocyanatocyclohexyl)oxy)methyl)-4-methoxy-1,1′-biphenyl;
(1R,2S)-1-isothiocyanato-2-((3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-2,3-dihydro-1H-indene;
(1S,2R)-2-((3′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)-1-isothiocyanato-2,3-dihydro-1H-indene;
3-((4′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-([1,1′-biphenyl]-4-ylmethoxy)azetidine-1-carbonitrile;
3-((2′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-([1,1′-biphenyl]-3-ylmethoxy)azetidine-1-carbonitrile;
3-((3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((2′,5′-dimethoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((2′,3′-dimethoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((4-(pyridin-3-yl)benzyl)oxy)azetidine-1-carbonitrile;
3-((4-(6-methoxypyridin-3-yl)benzyl)oxy)azetidine-1-carbonitrile;
3-((4-(2-methoxypyridin-3-yl)benzyl)oxy)azetidine-1-carbonitrile;
3-((2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((4′-methyl-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((4′-fluoro-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((3-fluoro-3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((3′-methoxy-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((4-phenoxybenzyl)oxy)azetidine-1-carbonitrile;
3-((2′,6′-dimethoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyl)oxy)azetidine-1-carbonitrile;
3-((3′-(benzyloxy)-[1,1′-biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile;
3-(([1,1′-biphenyl]-4-ylmethoxy)methyl)azetidine-1-carbonitrile;
3-((5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((2′-methoxy-5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((3′-methoxy-5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((4′-methoxy-5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((2-(2-methoxypyridin-3-yl)-4-phenoxybenzyl)oxy)azetidine-1-carbonitrile;
3-((4′-cyano-5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((2′-cyano-5-phenoxy-[1,1′-biphenyl]-2-yl)methoxy)azetidine-1-carbonitrile;
3-((3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)-3-methylazetidine-1-carbonitrile;
3-((3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)-3-phenylazetidine-1-carbonitrile;
3-((4-(benzo[d][1,3]dioxol-5-yl)benzyl)oxy)-3-phenylazetidine-1-carbonitrile;
3-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyl)oxy)-3-phenylazetidine-1-carbonitrile;
3-(([1,1′-biphenyl]-4-ylmethyl)(methyl)amino)azetidine-1-carbonitrile;
(S)-3-([1,1′-biphenyl]-4-ylmethoxy)pyrrolidine-1-carbonitrile;
(R)-3-([1,1′-biphenyl]-4-ylmethoxy)pyrrolidine-1-carbonitrile;
(1R,3R)-3-([1,1′-biphenyl]-4-ylmethoxy)cyclobutane-1-carbonitrile;
(1S,3S)-3-([1,1′-biphenyl]-4-ylmethoxy)cyclobutane-1-carbonitrile;
2-(3-((3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)azetidin-1-yl)acetonitrile;
5-((2-bromo-4-phenoxybenzyl)oxy)picolinonitrile;
5-([1,1′-biphenyl]-4-ylmethoxy)picolinonitrile;
5-([1,1′-biphenyl]-4-ylmethoxy)-3-fluoropicolinonitrile;
and
3-([1,1′-biphenyl]-4-ylmethoxy)-5-fluoropicolinonitrile;
or
a tautomer thereof;
a stereoisomer thereof;
or
a pharmaceutically acceptable salt thereof.

79 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/311,817Filed 13 May 2015 · us provisional application
Priority: 19 May 2014
Published: US 2017/0114050 A127 Apr 2017
Granted: 8 May 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07C 255/46
Having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings: to carbon atoms of non-condensed rings
C07C 331/20
Having isothiocyanate groups bound to acyclic carbon atoms: of a saturated carbon skeleton
C07C 331/24
Of an unsaturated carbon skeleton: the carbon skeleton containing six-membered aromatic rings

Family

Application62/000,331Us provisional application · filed 19 May 2014
US 2017/0114050 A1Pre-grant publication · published 27 Apr 2017
US 9,963,444 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

15/311,817Filed 13 May 2015 · us provisional application

Priority

19 May 2014

Published

US 2017/0114050 A127 Apr 2017

Granted

8 May 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07C 255/46
Having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings: to carbon atoms of non-condensed rings
C07C 331/20
Having isothiocyanate groups bound to acyclic carbon atoms: of a saturated carbon skeleton
C07C 331/24
Of an unsaturated carbon skeleton: the carbon skeleton containing six-membered aromatic rings