US 2017/0114050 A1Published application

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

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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.

Claims24

Dependent claims

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

wherein:
M is N, C, or CR, wherein R is H or alkyl;
Z is NCS, —(CH2)nNCS, CN, —(CH2)nCN, or —CR1R2CN, wherein n is 1, 2, 3, 4, or 5, R1 and R2 are each independently H or C1-C4 alkyl, or R1 and R2 together with the carbon to which they are joined form a C3-C8 cycloalkyl;
with the proviso that where Z is —NCS, M is C or CR;
W is (CH2)n, and n is 0, 1, 2, or 3;
D is a cycloalkyl, aryl, heterocyclyl, heteroaryl, or D is an a C1-C3 alkylenyl linking Y and M;
Y is (CH2)n, O(CH2)n, NR3(CH2)n, (CH2)nO, (CH2)nNR3, where n is 0, 1, or 2, and R3 is H or C1-C4 alkyl;
X is CR4R5 or (CH2)n, where n is 0, 1, or 2, and R4 and R5 are each independently H, C1-C4 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or together with the C to which they are attached form a saturated or unsaturated ring;
with the proviso that one of R4 and R5 is H or that R4 and R5 together with the C to which they are attached form a saturated or unsaturated ring;
V is absent, O, NR5, SO2, SO, CO, CONR6, CR7R8, or (CH2)n, wherein R6 is H or C1-C4 alkyl;
and R7 and R8 are each independently H, C1-C4 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or together with the C to which they are attached form a saturated or unsaturated ring;
B is (CH2)n′ where n is 2, 3, or 4, cycloalkyl, heterocyclyl, aryl, heteroaryl;
and
A is absent, cycloalkyl, aryl, heterocyclyl, heteroaryl.

11 more elements

A compound selected from the group consisting of:

n-(2-isothiocyanatoethyl)palmitamide;
n-(2-isothiocyanatoethyl)-7-(naphthalene-2-yl)heptanamide;
1-isothiocyanato-2-(4-benzylpiperazino)ethane;
4-(4-(isothiocyanatomethyl)phenyl)morpholine;
4-benzyl-1-(2-isothiocyanatoethyl)piperidine;
4-(morpholinomethyl)benzylisothiocyanate;
benzyl-4-(isothiocyanatomethyl)tetrahydro-1(2h)-pyridinecarboxylate;
2-(4-(isothiocyanatomethyl)phenoxy)-6-methylpyrazine;
1-(isothiocyanatomethyl)-4-(phenoxymethyl)benzene;
2-(10-isothiocyanatodecyl)pyridine;
4-(10-isothiocyanatodecyl)pyridine;
2-(10-isothiocyanatodecyl)pyrimidine;
((2-(2-(2-isothiocyanatoethoxy)ethoxy)ethoxy)methyl)benzene;
3-((3-isothiocyanatopropoxy)methyl)-1,1′-biphenyl;
4-((3-isothiocyanatopropoxy)methyl)-1,1′-biphenyl;
1-((3-isothiocyanatopropoxy)methyl)-4-phenoxybenzene;
4-benzyl-1-(5-isothiocyanatopentyl)piperidine;
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-bromo-2-fluoro-1-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)benzene;
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;
4.2-(((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-(((1S,3S)-3-(isothiocyanatomethyl)cyclobutoxy)methyl)-1,1′-biphenyl;
4′-(((3-isothiocyanatocyclohexyl)oxy)methyl)-3-(trifluoromethyl)-1,1′-biphenyl;
3-fluoro-4′-((((1R,4r)-4-isothiocyanatocyclohexyl)oxy)methyl)-4-methoxy-1,1′-biphenyl;
1-bromo-4-((((1R,3R)-3-isothiocyanatocyclopentyl)oxy)methyl)benzene;
(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-((1-(3′-methoxy-[1,1′-biphenyl]-4-yl)cyclopropyl)methoxy)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-((4-(bis(4-fluorophenyl)methoxy)-2-bromobenzyl)oxy)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-((4-bromophenyl)(phenyl)methoxy)azetidine-1-carbonitrile;
3-((3′-methoxy-[1,1′-biphenyl]-4-yl)(phenyl)methoxy)azetidine-1-carbonitrile;
3-((4-(3,5-dimethylisoxazol-4-yl)phenyl)(phenyl)methoxy)azetidine-1-carbonitrile;
3-((4(1-methyl-1h-pyrazol-4-yl)phenyl)(phenyl)methoxy)azetidine-1-carbonitrile;
3-((4-(1-methyl-1h-pyrazol-4-yl)phenyl)(phenyl)methoxy)azetidine-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;
3-([1,1′-biphenyl]-4-ylmethoxy)-5-fluoropicolinonitrile;
5-phenylpentyl6-cyanopicolinate;
5-((6-phenylhexyl)oxy)pyrimidine-2-carbonitrile;
5-((5-phenylpentyl)oxy)pyrimidine-2-carbonitrile;
5-(2-(2-(benzyloxy)ethoxy)ethoxy)pyrimidine-2-carbonitrile;
a tautomer thereof;
a stereoisomer thereof;
and
a pharmaceutically acceptable salt thereof.

108 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/311,817Filed 13 May 2015
Priority: 19 May 2014
Published: 27 Apr 2017
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