1. A compound of Formula I:
wherein:
Ar is a 5-membered heteroaryl moiety;
R0 is selected from H or CH3;
R1 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, C3-C8 cycloalkyl, \u2014(CH2)n\u2014C3-C8 cycloalkyl, \u2014(CH2)n\u2014O\u2014C3-C8 cycloalkyl, C5-C8 cycloalkenyl, \u2014(CH2), \u2014C6-C8 cycloalkenyl, \u2014(CH2)n\u2014O\u2014C6-C8 cycloalkenyl, \u2014(CH2)n-aryl, \u2014(CH2)n\u2014O-aryl, \u2014(CH2)n-heteroaryl, \u2014(CH2)n\u2014O-heteroaryl, a 4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N, a \u2014(CH2)n-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N), or a \u2014(CH2)n\u2014O-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N); with:
a) the R1C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl groups and the rings of the cycloalkyl, cycloalkenyl, aryl and heteroaryl rings of the Ria C3-C8 cycloalkyl, \u2014(CH2)n\u2014C3-C8 cycloalkyl, \u2014(CH2)n\u2014O\u2014C3-C8 cycloalkyl, C5-C8 cycloalkenyl, \u2014(CH2)n\u2014C6-C8 cycloalkenyl, \u2014(CH2)n\u2014O\u2014C5-C8 cycloalkenyl, \u2014(CH2)n-aryl, \u2014(CH2)n\u2014O-aryl, \u2014(CH2)n-heteroaryl, \u2014(CH2)n\u2014O-heteroaryl, 4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N, \u2014(CH2)n-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N), and \u2014(CH2)n\u2014O-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) groups being further optionally substituted by from 1 to 4 groups selected from halo, CN, \u2014CH2\u2014CN, \u2014CH3, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014CH3, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3; and
b) the \u2014(CH2)n\u2014 linking groups of the R1\u2014(CH2)n\u2014C3-C8 cycloalkyl, \u2014(CH2)n\u2014O\u2014C3-C8 cycloalkyl, C5-C8 cycloalkenyl, \u2014(CH2)n\u2014C6-C8 cycloalkenyl, \u2014(CH2)n\u2014O\u2014C6-C8 cycloalkenyl, \u2014(CH2)n-aryl, \u2014(CH2)n\u2014O-aryl, \u2014(CH2)n-heteroaryl, \u2014(CH2)n\u2014O-heteroaryl, \u2014(CH2)n-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N), and \u2014(CH2)n\u2014O-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) groups being further optionally substituted by from 1 to 2 groups selected from halo, CN, \u2014CH2\u2014CN, \u2014CH3, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014CH3, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3;
or R1 and R3 together can form a 5- or 6-membered fused ring containing one or two oxygen ring members;
R2a is H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C8 cycloalkyl, \u2014(CH2)n\u2014C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, \u2014(CH2)n\u2014C6-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, 4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N, \u2014(CH2)n-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N), \u2014(CH2)n\u2014O-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) or CN; with:
a) the R2a C3-C8 cycloalkyl, \u2014(CH2)n\u2014C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, \u2014(CH2)n\u2014C6-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, 4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N, \u2014(CH2)n-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) and \u2014(CH2)n\u2014O-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) groups being further optionally substituted by from 1 to 4 groups selected from halo, CN, \u2014CH2\u2014CN, \u2014CH3, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014CH3, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3; and
b) the \u2014(CF12)n\u2014 linking groups of the R2a\u2014(CH2)n\u2014C3-C8 cycloalkyl, \u2014(CH2)\u2014C5-C8 cycloalkenyl, and \u2014(CH2)-(4- to 8-membered heterocycle containing from 1 to 3 ring heteroatoms selected from O, S and N) groups being further optionally substituted by from 1 to 4 groups selected from halo, CN, \u2014CH2\u2014CN, \u2014CH3, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014CH3, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3;
with R2a also optionally being a phenyl or pyridyl group optionally substituted by from 1 to 3 substituents selected from H, CN, \u2014CH2\u2014CN, halogen, C1-C3 alkyl, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014C1-C3 alkyl, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3; and
R2b and R2c are independently selected from H, halogen, CN, \u2014CH2\u2014CN, C1-C3 alkyl, \u2014CH2F, \u2014CHF2, CF3, \u2014O\u2014C1-C3 alkyl, \u2014O\u2014CH2F, \u2014O\u2014CHF2, or \u2014O\u2014CF3;
n in each instance is an integer independently selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound of Formula II:
wherein X is CH2 or O,
m is zero or one,
R4a and R4b are independently selected from H or F;
and Ar, R0, R2a, R2b and R2c are as defined for Formula I in claim 1,
or a pharmaceutically acceptable salt thereof.
3. A compound selected from:
N-(3,4-dimethylisoxazol-5-yl)-4-3-(tetrahydro-2H-pyran-2-ylmethoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-isoxazol-4-yl-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(3-isoxazol-4-ylpropoxy)benzylidenepiperidine-1-carboxamide;
4-3-(3-isoxazol-4-ylpropoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(3-isoxazol-4-ylpropoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(3-isoxazol-4-ylpropoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}piperidine-1-carboxamide;
4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-N-isoxazol-4-ylpiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
N-isoxazol-4-yl-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
4-3-(2-cyclopropylethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-3-(2-cyclopropylethoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-3-(2-cyclopropylethoxy)benzylidene-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-3-(2-cyclopropylethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
4-3-(3-methylbutoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(2-isopropoxyethoxy)benzylidenepiperidine-1-carboxamide;
4-3-(2-isopropoxyethoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-3-(2-isopropoxyethoxy)benzylidene-N-isoxazol-4-ylpiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(2-isopropoxyethoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}piperidine-1-carboxamide;
4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
N-isoxazol-4-yl-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(1-methylbutoxy)benzylidenepiperidine-1-carboxamide;
4-3-(1-methylbutoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(1-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(1-methylbutoxy)benzylidenepiperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-(5-methylisoxazol-4-yl)-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-isoxazol-4-yl-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
4-3-(cyclopentylmethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-3-(cyclopentylmethoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-3-(cyclopentylmethoxy)benzylidene-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-3-(cyclopentylmethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
4-(3-butoxybenzylidene)-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-(3-butoxybenzylidene)-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-(3-butoxybenzylidene)-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-(3-butoxybenzylidene)-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}piperidine-1-carboxamide;
4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-N-isoxazol-4-ylpiperidine-1-carboxamide;
N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}piperidine-1-carboxamide;
4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-(3,4-dimethylisoxazol-5-yl)piperidine-1-carboxamide;
4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-isoxazol-4-ylpiperidine-1-carboxamide;
4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-(4,5-dimethylisoxazol-3-yl)piperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-{3-2-(3-thienyl)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-4-3-(3-isoxazol-4-ylpropoxy)benzylidene-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(3-isoxazol-4-ylpropoxy)benzylidene-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-4-3-(3-isoxazol-4-ylpropoxy)benzylidene-3-methylpiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-4-3-(3-isoxazol-4-ylpropoxy)benzylidene-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-fluorophenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-{3-2-(3-methylphenoxy)ethoxybenzylidene}piperidine-1-carboxamide;
(4E)-4-3-(2-cyclopropylethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(2-cyclopropylethoxy)benzylidene-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-3-(2-cyclopropylethoxy)benzylidene-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(2-cyclopropylethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(4,4,4-trifluorobutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-4-3-(3-methylbutoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(3-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(cyclohex-3-en-1-ylmethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(4,4,4-trifluoro-2-methylbutoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(2-pyridin-3-ylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-4-3-(2-isopropoxyethoxy)benzylidene-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(2-isopropoxyethoxy)benzylidene-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-3-(2-isopropoxyethoxy)benzylidene-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-4-3-(2-isopropoxyethoxy)benzylidene-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(3-methoxyphenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethyl isoxazol-5-yl)-3-methyl-4-3-(1-methyl butoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-4-3-(1-methylbutoxy)benzylidene-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(1-methyl butoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethyl isoxazol-3-yl)-3-methyl-4-3-(1-methyl butoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-3-methyl-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-3-methyl-N-(5-methylisoxazol-4-yl)-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-isoxazol-4-yl-3-methyl-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-3-methyl-4-3-(1-methyl-2-phenylethoxy)benzylidenepiperidine-1-carboxamide;
(4E)-4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-(3,4-dimethylisoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-isoxazol-4-yl-3-methyl piperidine-1-carboxamide;
(4E)-4-{3-(4,4-difluorocyclohexyl)methoxybenzylidene}-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(cyclopentylmethoxy)benzylidene-N-(3,4-dimethylisoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(cyclopentylmethoxy)benzylidene-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-3-(cyclopentylmethoxy)benzylidene-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-4-3-(cyclopentylmethoxy)benzylidene-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-(3-butoxybenzyl idene)-N-(3,4-dimethyl isoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-(3-butoxybenzylidene)-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-(3-butoxybenzyl idene)-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-4-(3-butoxybenzylidene)-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
(4E)-N-(3,4-dimethylisoxazol-5-yl)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-N-(4,5-dimethylisoxazol-3-yl)-4-{3-2-(4-fluorophenyl)ethoxybenzylidene}-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-(3,4-dimethylisoxazol-5-yl)-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-3-methyl-N-(5-methylisoxazol-4-yl)piperidine-1-carboxamide;
(4E)-4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-isoxazol-4-yl-3-methylpiperidine-1-carboxamide;
(4E)-4-{3-(4,4-dimethylcyclohexyl)oxybenzylidene}-N-(4,5-dimethylisoxazol-3-yl)-3-methylpiperidine-1-carboxamide;
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and optionally a further therapeutic agent,
5-9. (canceled)
10. A method of treating a FAAH-mediated disease or condition comprising administration of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
11. A method according to claim 10 wherein the FAAH-mediated disease or condition is acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, or cardiovascular disease.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A process for making a hydrogenated product comprising:
(a) providing a clarified fermentation broth containing an ammonium salt of succinic acid;
(b) optionally adding at least one of MAS, DAS, SA, NH3 and NH4+ to the broth depending on pH of the broth;
(c) distilling the broth to form an overhead that comprises water and optionally ammonia and a liquid bottoms that comprises MAS, at least some DAS, and at least about 20 wt % water;
(d) cooling andor evaporating the bottoms, and optionally adding an antisolvent to the bottoms, to attain a temperature and composition sufficient to cause the bottoms to separate into a DAS-containing liquid portion and a MAS-containing solid portion that is substantially free of DAS;
(e) separating the solid portion from the liquid portion;
(f) recovering the solid portion;
(g) hydrogenating the solid portion in the presence of at least one hydrogenation catalyst to produce the hydrogenated product comprising at least one of THF, GBL or BDO; and
(h) recovering the hydrogenated product.
2. The process of claim 1, further comprising purifying the second solid portion before step g.
3. The process of claim 2, further comprising dissolving the second solid portion in a solvent to form a solution.
4. The process of claim 1, wherein step g is conducted such that THF is recovered in a vapor phase.
5. The process of claim 1, wherein step g is conducted such that BDO is recovered in a liquid phase.
6. The process of claim 1, wherein the hydrogenation catalyst comprises at least one metal from Group VIII of the Periodic Table of the Elements.
7. The process of claim 6, wherein the at least one metal consists essentially of:
(i) about 0.5 to about 10% by weight ruthenium, and
(ii) about 2.0 to about 20% by weight rhenium,
based on total weight of the catalyst.
8. The process of claim 7, further comprising about 0.1 to about 5.0% by weight of tin.
9. The process of claim 4, wherein the catalyst is supported on at least one selected from the group consisting of carbon, silica, alumina, silica-alumina, silica-titania, titania, titania-alumina, barium sulfate, calcium carbonate and strontium carbonate.
10. The process of claim 1, wherein the ammonium salt of succinic acid is selected from the group consisting of DAS and MAS.
11. A process for making a hydrogenated product comprising:
(a) providing a clarified fermentation broth containing an ammonium salt of succinic acid;
(b) distilling the broth to form a first overhead that comprises water and ammonia, and a first liquid bottoms that comprises MAS, at least some DAS, and at least about 20 wt % water;
(c) cooling andor evaporating the first bottoms, and optionally adding an antisolvent to the bottoms, to attain a temperature and composition sufficient to cause the first bottoms to separate into a DAS-containing liquid portion and a MAS-containing first solid portion that is substantially free of DAS;
(d) separating the first solid portion from the first liquid portion;
(e) recovering the first solid portion;
(f) dissolving the first solid portion in water to produce an aqueous MAS solution;
(g) distilling the aqueous MAS solution at a temperature and pressure sufficient to form a second overhead that comprises water and ammonia, and a second bottoms that comprises a major portion of SA, a minor portion of MAS, and water;
(h) cooling the second bottoms to cause the second bottoms to separate into a second liquid portion and a second solid portion that consists essentially of SA and is substantially free of MAS;
(i) separating the second solid portion from the second liquid portion;
(j) recovering the second solid portion;
(k) hydrogenating the second solid portion in the presence of at least one hydrogenation catalyst to produce the hydrogenated product comprising at least one of THF, GBL or BDO; and
(l) recovering the hydrogenated product.
12. The process of claim 11, further comprising purifying the second solid portion before step k.
13. The process of claim 12, further comprising dissolving the second solid portion in a solvent to form a solution.
14. The process of claim 11, wherein step k is conducted such that THF is recovered in a vapor phase.
15. The process of claim 11, wherein step k is conducted such that BDO is recovered in a liquid phase.
16. The process of claim 11, wherein the hydrogenation catalyst comprises at least one metal from Group VIII of the Periodic Table of the Elements.
17. The process of claim 16, wherein the at least one metal consists essentially of:
(i) about 0.5 to about 10% by weight ruthenium, and
(ii) about 2.0 to about 20% by weight rhenium,
based on total weight of the catalyst.
18. The process of claim 17, further comprising about 0.1 to about 5.0% by weight of tin.
19. The process of claim 11, wherein the catalyst is supported on at least one selected from the group consisting of carbon, silica, alumina, silica-alumina, silica-titania, titania, titania-alumina, barium sulfate, calcium carbonate and strontium carbonate.
20. The process of claim 11, wherein the ammonium salt of succinic acid is selected from the group consisting of DAS and MAS.