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

Patent metadata

Field	Value
Publication number	US-9963444-B2
Application number	US-201515311817-A
Country	US
Kind code	B2
Filing date	May 13, 2015
Priority date	May 19, 2014
Publication date	May 8, 2018
Grant date	May 8, 2018

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.

First claim

What is claimed is:

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

wherein:
Z is CN or —CH 2 -CN; and

C is

or
Z is NCS; and C is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or

and
D is hydrogen, C 1 -C 3 alkyl, aryl, or heteroaryl; T is O or NR 1 , wherein R 1 is H or C 1 -C 3 alkyl; Y is absent or C 1 -C 3 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.

2. The compound of claim 1 , wherein C is

and Z is CN or —CH 2 —CN.

3. The compound of claim 1 , wherein C is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or

and Z is NCS.

4. The compound of claim 1 , wherein B is phenyl.

5. The compound of claim 1 , wherein B is substituted phenyl.

6. The compound of claim 1 , wherein n is 0.

7. 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

Assignees

• Univ Northeastern

Inventors

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

Classifications

• C07D319/18

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07D317/54

  Radicals substituted by oxygen atoms · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title