US 2018/0222894 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

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).

Claims16

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-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methyl-1,1′-biphenyl;
4-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
4-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,4′-difluoro-4-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-4′-methoxy-1,1′-biphenyl;
4′-(((1R,3R)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4′-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-3-methoxy-1,1′-biphenyl;
4-ethoxy-3,3′-difluoro-4′-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
3,3′-difluoro-4-isopropoxy-4′-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-1,1′-biphenyl;
6-(3-fluoro-4-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine;
5-(3-fluoro-4-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)phenyl)benzo[d][1,3]dioxole;
3-fluoro-4-(((1 S,3 S)-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′-(((1 S,3 S)-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-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-4-phenoxybenzene;
4.2-(((1 S,3 S)-3-isothiocyanatocyclobutoxy)methyl)-5-phenoxy-1,1′-biphenyl;
3-fluoro-4′-((1R,3R)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl;
3-fluoro-4′-((1 S,3 S)-3-isothiocyanatocyclobutoxy)-4-methoxy-1,1′-biphenyl;
(1R,3R)-n-([1,1′-biphenyl]-4-ylmethyl)-3-isothiocyanato-n-methylcyclobutan-1-amine;
(1 S,3 S)-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-(((1 S,3 S)-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;
(1 S,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-carbo nitrile;
3-((4-(1-methyl-h-pyrazol-4-yl)phenyl)(phenyl)methoxy)azetidine-1-carbonitrile;
3-((4-(1-methyl-h-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;
(1 S,3 S)-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: 15/942,345Filed 30 Mar 2018
Priority: 19 May 2014
Published: 9 Aug 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
Application15/311,817Division · filed 16 Nov 2016
Application15/942,345Division
US 10,640,494 B2Related patent
US 2017/0114050 A1Published application
US 9,963,444 B2Related patent
US 2018/0222894 A1This patent

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

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Abstract

Facts

Application

15/942,345Filed 30 Mar 2018

Priority

19 May 2014

Published

9 Aug 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

Application15/311,817Division · filed 16 Nov 2016

Application15/942,345Division

US 10,640,494 B2Related patent

US 2017/0114050 A1Published application

US 9,963,444 B2Related patent

US 2018/0222894 A1This patent

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