MUSCARINIC RECEPTOR 4 ANTAGONISTS AND METHODS OF USE
The present invention relates to compounds of Formula (Ia), pharmaceutically acceptable salts of compounds of Formula (Ia), and pharmaceutical compositions thereof that modulate the activity of the muscarinic acetylcholine receptor M4. Compounds, pharmaceutical salts of compounds, and pharmaceutical compositions of the present invention are directed to methods useful in the treatment or prophylaxis of a neurological disease, disorder, or symptom, and conditions related thereto.
1 . A compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
Z is C 1 -C 4 alkylene or absent;
R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbamoyl, C 1 -C 6 alkylsulfanyl, C 2 -C 6 dialkylamino, C 2 -C 6 dialkyl carbamoyl, C 1 -C 6 sulfinyl, C 3 -C 10 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, amino, carbamoyl, cyano, halogen, and nitro;
R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 5 -C 8 bicycloalkanyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl; each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 sulfonyl, carbamoyl, cyano, and halogen; and
a) R 3 and R 4 are each independently selected from H and C 1 -C 4 alkyl; or
b) R 3 and R 4 taken together form a bridging group selected from: CH 2 , CH 2 —CH 2 , and CH 2 —O—CH 2 ; and
c) R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .
3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is absent.
4 . The compound according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein Z is C 1 -C 4 alkylene.
5 . The compound according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein Z is CH 2 .
6 . The compound according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein Z is absent.
7 . The compound according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, halogen, and nitro.
8 . The compound according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: acetyl, bromo, chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, methoxycarbonyl, methyl, methylsulfanyl, nitro, trifluoromethoxy, and trifluoromethyl.
9 . The compound according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinoxalinyl, and thiadiazolyl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, halogen, and nitro.
10 . The compound according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinoxalinyl, and thiadiazolyl, each optionally substituted with one or more groups selected from: acetyl, bromo, chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, methoxycarbonyl, methyl, methylsulfanyl, nitro, trifluoromethoxy, and trifluoromethyl.
11 . The compound according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: 1,3,4-thiadiazol-2-yl, phenyl, pyrazin-2-yl, pyridazin-3-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, and quinoxalin-2-yl, each optionally substituted with one or more groups selected from: acetyl, bromo, chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, methoxycarbonyl, methyl, methylsulfanyl, nitro, trifluoromethoxy, and trifluoromethyl.
12 . The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: 2-cyano-4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)pyridin-2-yl, 3,4,5-trifluorophenyl, 3,6-dimethylpyrazin-2-yl, 3-cyano-4-(trifluoromethoxy)phenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-fluorophenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 4-cyano-2,5-difluorophenyl, 4-cyano-2-fluorophenyl, 4-cyano-6-(trifluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-(methoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethoxy)pyrazin-2-yl, 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-acetylpyrazin-2-yl, 5-bromo-4-(methylsulfanyl)pyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-chloropyrimidin-2-yl, 5-cyano-3-methylpyrazin-2-yl, 5-cyanopyrazin-2-yl, 5-cyanopyridin-2-yl, 5-cyanopyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5-nitropyridin-2-yl, 6-(trifluoromethyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-cyanopyrazin-2-yl, 6-fluoroquinoxalin-2-yl, 6-methoxy-3-nitropyridin-2-yl, 6-methoxypyrazin-2-yl, 6-methoxyquinoxalin-2-yl, and quinoxalin-2-yl.
13 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, carbamoyl, cyano, and halogen.
14 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl, each optionally substituted with one or more groups selected from: carbamoyl, cyano, fluoro, methoxy, and methyl.
15 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 1H-indolyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]heptenyl, butyl, cyclohexyl, cyclopropyl, oxanyl, and phenyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, carbamoyl, cyano, and halogen.
16 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 1H-indol-5-yl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]hept-5-en-2-yl, butyl, cyclohexyl, cyclopropyl, oxan-4-yl, and phenyl, each optionally substituted with one or more groups selected from: carbamoyl, cyano, fluoro, methoxy, and methyl.
17 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 1H-indol-5-yl, 2,2-dimethylcyclopropyl, 2,2-dimethylpropyl, 2,6-difluorophenyl, 2-cyanophenyl, 2-fluorophenyl, 3,3-dimethylbutyl, 3,4-difluorophenyl, 3-carbamoylphenyl, 3-cyano-4-fluorophenyl, 3-fluorophenyl, 4,4,4-trifluorobutyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-methoxyphenyl, bicyclo[2.2.1]hept-5-en-2-yl, cyclohexyl, cyclopropyl, oxan-4-yl, and phenyl.
18 . The compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein Z and R 2 together form a group selected from: (1H-indol-5-yl)methyl, (2,2-dimethylcyclopropyl)methyl, (2,6-difluorophenyl)methyl, (2-cyanophenyl)methyl, (2-fluorophenyl)methyl, (3,4-difluorophenyl)methyl, (3-carbamoylphenyl)methyl, (3-cyano-4-fluorophenyl)methyl, (3-fluorophenyl)methyl, (4-carbamoylphenyl)methyl, (4-cyanophenyl)methyl, (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (bicyclo[2.2.1]hept-5-en-2-yl)methyl, (cyclohexyl)methyl, (cyclopropyl)methyl, (oxan-4-yl)methyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, 4,4,4-trifluorobutyl, and benzyl.
19 . The compound according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each C 1 -C 4 alkyl.
20 . The compound according to any one of claims 1 to 19 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each methyl.
21 . The compound according to any one of claims 1 to 20 , wherein the compound is of Formula (IIg):
or a pharmaceutically acceptable salt thereof.
22 . The compound according to any one of claims 1 to 20 , wherein the compound is of Formula (IIi):
or a pharmaceutically acceptable salt thereof.
23 . The compound according to any one of claims 1 to 20 , wherein the compound is of Formula (IIk):
or a pharmaceutically acceptable salt thereof.
24 . The compound according to claim 23 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIk) for the C(3) carbon is (R) and the C(5) carbon is (R).
25 . The compound according to claim 23 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIk) for the C(3) carbon is (S) and the C(5) carbon is (S).
26 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIIa):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, and halogen;
R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, carbamoyl, cyano, and halogen; and
R 3 and R 4 are each independently selected from H and C 1 -C 4 alkyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
27 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIIa):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thiadiazolyl, each optionally substituted with one or more groups selected from: chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, trifluoromethoxy, and trifluoromethyl;
R 2 is selected from: 1H-indolyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]heptenyl, butyl, cyclohexyl, cyclopropyl, oxanyl, and phenyl; each optionally substituted with one or more groups selected from: carbamoyl, cyano, fluoro, methoxy, and methyl; and
R 3 and R 4 are each independently selected from H and methyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
28 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIIa):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
R 1 is selected from: 3,4,5-trifluorophenyl, 3-cyano-4-(trifluoromethoxy)phenyl, 3-cyano-4-fluorophenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 4-cyano-2-fluorophenyl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-chloropyrimidin-2-yl, 5-cyanopyrazin-2-yl, 5-cyanopyridin-2-yl, 5-cyanopyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 6-(trifluoromethyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, and 6-cyanopyrazin-2-yl;
Z—R 2 taken together is selected from: (1H-indol-5-yl)methyl, (2,2-dimethylcyclopropyl)methyl, (2,6-difluorophenyl)methyl, (2-cyanophenyl)methyl, (2-fluorophenyl)methyl, (3,4-difluorophenyl)methyl, (3-carbamoylphenyl)methyl, (3-cyano-4-fluorophenyl)methyl, (3-fluorophenyl)methyl, (4-carbamoylphenyl)methyl, (4-cyanophenyl)methyl, (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (bicyclo[2.2.1]hept-5-en-2-yl)methyl, (cyclohexyl)methyl, (cyclopropyl)methyl, (oxan-4-yl)methyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, 4,4,4-trifluorobutyl, and benzyl; and
R 3 and R 4 are each independently selected from H and methyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
29 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIIc):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, halogen, nitro, C 1 -C 6 alkoxycarbonyl, and C 1 -C 6 alkylsulfanyl;
R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 8 bicycloalkenyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl and halogen; and
R 3 and R 4 are each independently selected from H and C 1 -C 4 alkyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
30 . The compound according to any one of claims 1 to 7 , wherein the compound is of Formula (IIIc):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and quinoxalinyl, each optionally substituted with one or more groups selected from: acetyl, bromo, cyano, fluoro, methoxy, methyl, nitro, trifluoromethoxy, trifluoromethyl, methoxycarbonyl, and methylsulfanyl;
R 2 is selected from: 2,2-dimethylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]hept-5-en-2-yl, cyclohexyl, cyclopropyl, and phenyl, each optionally substituted with one or more groups selected from: methyl and fluoro; and
R 3 and R 4 are each independently selected from H and methyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
31 . The compound according to any one of claims 1 to 3 , wherein the compound is of Formula (IIIc):
or a pharmaceutically acceptable salt thereof:
wherein:
Y is CH 2 or absent;
R 1 is selected from: 2-cyano-4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)pyridin-2-yl, 3,4,5-trifluorophenyl, 3,6-dimethylpyrazin-2-yl, 3-cyano-4-(trifluoromethoxy)phenyl, 3-cyano-5-fluorophenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 4-cyano-2,5-difluorophenyl, 4-cyano-2-fluorophenyl, 4-cyano-6-(trifluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, 5-(methoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethoxy)pyrazin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-acetylpyrazin-2-yl, 5-bromo-4-(methylsulfanyl)pyrimidin-2-yl, 5-cyano-3-methylpyrazin-2-yl, 5-cyanopyrazin-2-yl, 5-cyanopyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-nitropyridin-2-yl, 6-(trifluoromethyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-fluoroquinoxalin-2-yl, 6-methoxy-3-nitropyridin-2-yl, 6-methoxypyrazin-2-yl, 6-methoxyquinoxalin-2-yl, and quinoxalin-2-yl;
Z—R 2 taken together is selected from: (2,2-dimethylcyclopropyl)methyl, (2,6-difluorophenyl)methyl, (bicyclo[2.2.1]hept-5-en-2-yl)methyl, (cyclohexyl)methyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, and benzyl; and
R 3 and R 4 are each independently selected from H and methyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring.
32 . The compound according to anyone of claims 1 to 6 , wherein the compound is of Formula (IIi):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, halogen, and nitro; and
R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, carbamoyl, cyano, and halogen.
33 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIi):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and quinoxalinyl, each optionally substituted with one or more groups selected from: acetyl, bromo, chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, methoxycarbonyl, methyl, methylsulfanyl, nitro, trifluoromethoxy, and trifluoromethyl; and
R 2 is selected from: 1H-indolyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]heptenyl, butyl, cyclohexyl, cyclopropyl, oxanyl, and phenyl, each optionally substituted with one or more groups selected from: carbamoyl, cyano, fluoro, methoxy, and methyl.
34 . The compound according to claim any one of claims 1 to 6 , wherein the compound is of Formula (IIi):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
R 1 is selected from: 3-(trifluoromethyl)pyridin-2-yl, 3,4,5-trifluorophenyl, 4-(trifluoromethyl)phenyl, 4-cyano-6-(trifluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-(methoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethoxy)pyrazin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-acetylpyrazin-2-yl, 5-bromo-4-(methylsulfanyl)pyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-chloropyrimidin-2-yl, 5-cyano-3-methylpyrazin-2-yl, 5-cyanopyrazin-2-yl, 5-cyanopyridin-2-yl, 5-cyanopyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5-nitropyridin-2-yl, 6-(trifluoromethyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-cyanopyrazin-2-yl, 6-fluoroquinoxalin-2-yl, 6-methoxy-3-nitropyridin-2-yl, and quinoxalin-2-yl; and
Z—R 2 taken together is selected from: (1H-indol-5-yl)methyl, (2,2-dimethylcyclopropyl)methyl, (2,6-difluorophenyl)methyl, (2-cyanophenyl)methyl, (2-fluorophenyl)methyl, (3,4-difluorophenyl)methyl, (3-carbamoylphenyl)methyl, (3-cyano-4-fluorophenyl)methyl, (3-fluorophenyl)methyl, (4-carbamoylphenyl)methyl, (4-cyanophenyl)methyl, (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (bicyclo[2.2.1]hept-5-en-2-yl)methyl, (cyclohexyl)methyl, (cyclopropyl)methyl, (oxan-4-yl)methyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, 4,4,4-trifluorobutyl, and benzyl.
35 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIg):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more groups selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, cyano, halogen, and nitro; and
R 2 is selected from: C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 8 bicycloalkenyl, 5-10 membered heteroaryl, and heterocyclyl, each optionally substituted with one or more groups selected from: C 1 -C 4 alkyl, C 1 -C 6 alkoxy, carbamoyl, cyano, and halogen.
36 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIg):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
Z is CH 2 or absent;
R 1 is selected from: phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and quinoxalinyl, each optionally substituted with one or more groups selected from: acetyl, bromo, chloro, cyano, difluoromethoxy, difluoromethyl, fluoro, methoxy, methoxycarbonyl, methyl, methylsulfanyl, nitro, trifluoromethoxy, and trifluoromethyl; and
R 2 is selected from: 1H-indolyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, bicyclo[2.2.1]heptenyl, butyl, cyclohexyl, cyclopropyl, oxanyl, and phenyl, each optionally substituted with one or more groups selected from: carbamoyl, cyano, fluoro, methoxy, and methyl.
37 . The compound according to any one of claims 1 to 6 , wherein the compound is of Formula (IIg):
or a pharmaceutically acceptable salt thereof:
wherein:
X is O or NH;
Y is CH 2 or absent;
R 1 is selected from: 3-(trifluoromethyl)pyridin-2-yl, 3,4,5-trifluorophenyl, 4-(trifluoromethyl)phenyl, 4-cyano-6-(trifluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-(methoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethoxy)pyrazin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-acetylpyrazin-2-yl, 5-bromo-4-(methylsulfanyl)pyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-chloropyrimidin-2-yl, 5-cyano-3-methylpyrazin-2-yl, 5-cyanopyrazin-2-yl, 5-cyanopyridin-2-yl, 5-cyanopyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5-nitropyridin-2-yl, 6-(trifluoromethyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 6-cyanopyrazin-2-yl, 6-fluoroquinoxalin-2-yl, 6-methoxy-3-nitropyridin-2-yl, and quinoxalin-2-yl; and
Z—R 2 taken together is selected from: (1H-indol-5-yl)methyl, (2,2-dimethylcyclopropyl)methyl, (2,6-difluorophenyl)methyl, (2-cyanophenyl)methyl, (2-fluorophenyl)methyl, (3,4-difluorophenyl)methyl, (3-carbamoylphenyl)methyl, (3-cyano-4-fluorophenyl)methyl, (3-fluorophenyl)methyl, (4-carbamoylphenyl)methyl, (4-cyanophenyl)methyl, (4-fluorophenyl)methyl, (4-methoxyphenyl)methyl, (bicyclo[2.2.1]hept-5-en-2-yl)methyl, (cyclohexyl)methyl, (cyclopropyl)methyl, (oxan-4-yl)methyl, 2,2-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbutyl, 4,4,4-trifluorobutyl, and benzyl.
38 . The compound according to any one of claims 1 to 25 and 32 to 37 , or a pharmaceutically acceptable salt thereof, wherein X is O.
39 . The compound according to any one of claims 1 to 25 and 32 to 37 , or a pharmaceutically acceptable salt thereof, wherein X is NH.
40 . The compound according to any one of claims 1 to 37 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, pyridinyl, pyrazinyl, and pyrimidinyl.
41 . The compound according to any one of claims 1 to 37 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, pyridinyl, pyrazinyl, and pyrimidinyl.
42 . The compound according to any one of claims 1 to 41 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl.
43 . The compound according to any one of claims 32 to 34 and 38 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIi) for the C(2) carbon is (R) and the C(6) carbon is (R).
44 . The compound according to any one of claims 32 to 34 and 38 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIi) for the C(2) carbon is (S) and the C(6) carbon is (S).
45 . The compound according to any one of claims 32 to 34 and 38 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIi) for the C(2) carbon is (R) and the C(6) carbon is (S).
46 . The compound according to any one of claims 35 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIg) for the C(2) carbon is (R) and the C(5) carbon is (S).
47 . The compound according to any one of claims 35 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIg) for the C(2) carbon is (R) and the C(5) carbon is (R).
48 . The compound according to any one of claims 35 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIg) for the C(2) carbon is (S) and the C(5) carbon is (R).
49 . The compound according to any one of claims 35 to 42 , or a pharmaceutically acceptable salt thereof, wherein the stereochemistry in Formula (IIg) for the C(2) carbon is (S) and the C(5) carbon is (S).
50 . A compound, which is selected from the compounds in TABLE A, or a pharmaceutically acceptable salt thereof.
51 . A compound, which is (2R,6S)—N-{2-benzyl-2-azaspiro[3.3]heptan-6-yl}-2,6-dimethyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.
52 . A compound, which is 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,5S)-2,5-dimethyl-4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
53 . A compound, which is 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-2,6-dimethyl-4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
54 . A compound, which is 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-2,6-dimethyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
55 . A pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof.
56 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
57 . A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
58 . A method for antagonizing a muscarinic receptor 4 (M 4 ) of a cell, comprising contacting the cell with the compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof.
59 . A method for treating or preventing a neurological disease, disorder, or symptom in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 55 , or a pharmaceutical composition according to claim 56 .
60 . A method for treating or preventing a muscarinic receptor 4 (M 4 ) mediated disease, disorder, or symptom in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 55 , or a pharmaceutical composition according to claim 56 .
61 . The method according to claim 59 or 60 , wherein the disease, disorder, or symptom is selected from: Tourette's syndrome (TS), Alzheimer's Disease (AD), schizophrenia, Lewy Body Dementia (LBD), cognitive deficits associated with schizophrenia, Parkinson's Disease, parkinsonism, tremor, dyskinesias, excessive daytime sleepiness, dystonia, chorea, levodopa induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), Multiple System Atrophy (MSA), Huntington's disease (HD), and chorea associate with Huntington's disease.
62 . Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 54 , in the manufacture of a medicament for treating or preventing a neurological disease, disorder, or symptom in an individual.
63 . Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 54 , in the manufacture of a medicament for treating or preventing a muscarinic receptor 4 (M 4 ) mediated disease, disorder, or symptom in an individual.
64 . The use according to claim 62 or 63 , wherein the disease, disorder, or symptom is selected from: Tourette's syndrome (TS), Alzheimer's Disease (AD), schizophrenia, Lewy Body Dementia (LBD), cognitive deficits associated with schizophrenia, Parkinson's Disease, parkinsonism, tremor, dyskinesias, excessive daytime sleepiness, dystonia, chorea, levodopa induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), Multiple System Atrophy (MSA), Huntington's disease (HD), and chorea associate with Huntington's disease.
65 . A compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 55 , or a pharmaceutical composition according to claim 56 , for use in a method of treatment or prophylaxis of a human or animal body by therapy.
66 . A compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 55 , or a pharmaceutical composition according to claim 56 , for use in a method for treating or preventing a neurological disease, disorder, or symptom in an individual.
67 . A compound according to any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 55 , or a pharmaceutical composition according to claim 56 , for use in a method for treating or preventing a muscarinic receptor 4 (M 4 ) mediated disease, disorder, or symptom in an individual.
68 . The compound, pharmaceutically acceptable salt thereof, pharmaceutical product, or pharmaceutical composition for use according to claim 66 or 67 , wherein the disease, disorder, or symptom is selected from: Tourette's syndrome (TS), Alzheimer's Disease (AD), schizophrenia, Lewy Body Dementia (LBD), cognitive deficits associated with schizophrenia, Parkinson's Disease, parkinsonism, tremor, dyskinesias, excessive daytime sleepiness, dystonia, chorea, levodopa induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), Multiple System Atrophy (MSA), Huntington's disease (HD), and chorea associate with Huntington's disease.
69 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims 59 to 64 and 66 to 68 , wherein the disease, disorder, or symptom is parkinsonism.
70 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims any one of claims 59 to 64 and 66 to 68 , wherein the disease, disorder, or symptom is tremor.
71 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims any one of claims 59 to 64 and 66 to 68 , wherein the disease, disorder, or symptom is dystonia.