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

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-([1,1′-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.

8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. A method for inhibiting N-acylethanolamine hydrolyzing acid amidase, the method comprising contacting the N-acylethanolamine hydrolyzing acid amidase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

10. A method for treating a N-acylethanolamine hydrolyzing acid amidase mediated condition in a subject, the method comprising administering to the subject a composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A method of treating an inflammatory gastrointestinal motility disorder, irritable bowel syndrome, or an inflammatory bowel disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method for treating ulcerative colitis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A method for treating Crohn's disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method for modulating the activity of N-acylethanolamine hydrolyzing acid amidase, the method comprising contacting a receptor thereof with an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.