ANTAGONISTS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
Disclosed herein are substituted hexahydro-1H-cyclopenta[c]pyrrole compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is
R 1a is G 1a or halogen;
G 1a is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C 3-12 carbocyclyl, wherein G 1a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —OR 10 , —N(R 10 ) 2 , —NR 10 C(O)R 10 , —CONR 10 R 10 , —NR 10 SO 2 R 11 , —C 1-3 alkylene-OR 10 , C 3-6 cycloalkyl, and —C 1-3 alkylene-C 3-6 cycloalkyl;
R 1b is C 1-4 alkyl, C 1-4 difluoroalkyl, —OC 1-4 alkyl, —OC 1-4 fluoroalkyl, —OC 3-6 cycloalkyl, —OCH 2 C 3-6 cycloalkyl, —SO 2 C 1-4 alkyl, —SO 2 C 3-6 cycloalkyl, phenyl, or C 3-6 cycloalkyl, wherein the phenyl and each C 3-6 cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, and —OC 1-4 haloalkyl;
R 1c is hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl;
R 10 , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or C 1-3 alkylene-C 3-4 cycloalkyl, wherein alternatively two R 10 , together with a nitrogen to which the two R 10 attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;
R 11 , at each occurrence, is independently C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
R is hydrogen, C 1-4 alkyl, C 3-4 cycloalkyl, or —C 1-3 alkylene-C 3-4 cycloalkyl;
R 3 is G 2 , -L 1 -G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , —C 2-6 alkylene-R 3a , or C 3-7 alkyl;
L 1 is C 1-5 alkylene;
L 2 is 1,1-cyclopropylene;
G 2 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C 3-12 carbocyclyl optionally fused to a 6-membered arene, wherein G 2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, oxo, C 1-4 alkyl, C 1-4 haloalkyl, —OR 13 , —N(R 13 ) 2 , —C 1-3 alkylene-OR 13 , and —C 1-3 alkylene-N(R 13 ) 2 ;
R 3a is —OR 14 or —N(R 14 ) 2 ; and
R 13 and R 14 , at each occurrence, are independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, or C 1-3 alkylene-C 3-4 cycloalkyl, wherein alternatively two R 13 or two R 14 , together with a nitrogen to which the two R 13 or two R 14 attach form a 4- to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1b is —CH 3 , —C(CH 3 ) 3 , —CHF 2 , —C(CH 3 )F 2 , —OCH 3 , —SO 2 CH 3 , 5-fluoro-2-methylphenyl, cyclopropyl, 2,2-difluorocyclopropyl, 1-trifluoromethylcyclopropyl, or cyclobutyl; and
R 1c is hydrogen, cyano, CH 3 , or CF 3 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
6 . The compound of any of claims 1 - 5 , or a pharmaceutically acceptable salt thereof, wherein R 1a is G 1a .
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 6- to 12-membered aryl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the 6- to 12-membered aryl at G 1a is a naphthyl or a phenyl.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the naphthyl is unsubstituted and the phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, —OC 1-4 alkyl and —OC 1-4 fluoroalkyl.
10 . The compound of claim 8 or 9 , or a pharmaceutically acceptable salt thereof, wherein the naphthyl is unsubstituted and the phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, and —OC 1-4 alkyl.
11 . The compound of claim 8 or 9 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
12 . The compound of any of claims 8 - 11 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
13 . The compound of claim 8 or 9 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
14 . The compound of any of claims 8 , 9 , 10 , or 13 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
15 . The compound of any of claims 8 , 9 , 11 , or 13 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
16 . The compound of any of claims 8 - 15 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
17 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 5- to 12-membered heteroaryl.
18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the 5- to 12-membered heteroaryl at G 1a is a 9-membered heteroaryl having 1-3 ring nitrogen atoms.
19 . The compound of claim 17 or 18 , or a pharmaceutically acceptable salt thereof, wherein the 5- to 12-membered heteroaryl at G 1a is an indazolyl.
20 . The compound of any of claims 17 - 19 , or a pharmaceutically acceptable salt thereof, wherein G 1a is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.
21 . The compound of any of claims 17 - 20 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
22 . The compound of any of claims 17 - 20 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
23 . The compound of any of claims 17 - 22 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
24 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein G 1a is the 4- to 12-membered heterocyclyl.
25 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein the 4-to 12-membered heterocyclyl at G 1a is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N and O.
26 . The compound of claim 24 or 25 , or a pharmaceutically acceptable salt thereof, wherein G 1a is optionally substituted with 1-2 substituents independently selected from fluoro and methyl.
27 . The compound of any of claims 24 - 26 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
28 . The compound of any of claims 24 - 26 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
29 . The compound of any of claims 24 - 28 , or a pharmaceutically acceptable salt thereof, wherein G 1a is
30 . The compound of any of claims 1 - 5 , or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen.
31 . The compound of any of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, wherein R 3 is -L 1 -G 2 .
32 . The compound of any of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the 4- to 12-membered heterocyclyl.
33 . The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein the 4- to 12-membered heterocyclyl at G 2 is a 4- to 8-membered monocyclic heterocyclyl, a 6- to 10-membered bridged bicyclic heterocyclyl, a 7- to 12-membered fused bicyclic heterocyclyl, or a 7- to 12-membered spiro heterocyclyl, wherein the heterocyclyls contain 1-2 heteroatoms independently selected from O, N, and S.
34 . The compound of claim 32 or 33 , or a pharmaceutically acceptable salt thereof, wherein the 4- to 12-membered heterocyclyl at G 2 is a tetrahydropyranyl, 7-oxabicyclo[2.2.1]heptanyl, or 1,4-dioxanyl.
35 . The compound of any of claims 32 - 34 , or a pharmaceutically acceptable salt thereof, wherein the 4- to 12-membered heterocyclyl at G 2 is a tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, or 1,4-dioxan-2-yl.
36 . The compound of any of claims 32 - 35 , or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with 1-4 substituents independently selected from the group consisting of hydroxy, C 1-4 alkyl, and —OC 1-4 alkyl.
37 . The compound of any of claims 32 - 36 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
38 . The compound of any of claims 32 - 37 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
39 . The compound of any of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the 5- to 12-membered heteroaryl.
40 . The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein the 5-to 12-membered heteroaryl at G 2 is a pyridinyl.
41 . The compound of claim 39 or 40 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
42 . The compound of any of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein G 2 is the C 3-12 carbocyclyl optionally fused to a 6-membered arene.
43 . The compound of claim 42 , or a pharmaceutically acceptable salt thereof, wherein the C 3-12 carbocyclyl optionally fused to a 6-membered arene at G 2 is a C 3-8 cycloalkyl.
44 . The compound of claim 42 or 43 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
45 . The compound of any of claims 1 - 44 , or a pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 , CD 2 , CH 2 CH 2 , C(CH 3 )(H), or C(CH 3 )(D).
46 . The compound of any of claims 1 - 45 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
47 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
(3aR,5s,6aS)-N-(6-(3-fluorophenyl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2-fluorophenyl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(4-fluorophenyl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-methoxy-6-(2-methyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,4-dimethyl-2H-indazol-5-yl)-4-methoxypyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-4-(methylsulfonyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4,6-bis(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-4-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-methyl-6-(2-methyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,4-dimethyl-2H-indazol-5-yl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)-5-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-methyl-6-(2-methyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-4-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(3-fluorophenyl)-4-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-methyl-6-(2-methyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,4-dimethyl-2H-indazol-5-yl)-4-methylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-methyl-6-phenylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclopropyl-6-(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclopropyl-6-(2,5-difluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclopropyl-6-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclobutyl-6-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclobutyl-6-(2,5-difluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclobutyl-6-(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(2,2-difluorocyclopropyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-cyclopropyl-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-methyl-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(tert-butyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-methyl-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)-N-(5-(1-(trifluoromethyl)cyclopropyl)-6-(2,4,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)-N-(5-(1-(trifluoromethyl)cyclopropyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(5-fluoro-2-methoxyphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)-5-(difluoromethyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(1,1-difluoroethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-2-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine having tetrahydro-2H-pyran-2-yl stereochemistry the same as (−)-(tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-2-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine having tetrahydro-2H-pyran-2-yl stereochemistry the same as (+)-(tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine having tetrahydro-2H-pyran-3-yl stereochemistry the same as (+)-(tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-3-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine having tetrahydro-2H-pyran-3-yl stereochemistry the same as (−)-(tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-(1-(pyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-(1-(pyridin-2-yl)ethyl-1-d)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-2-(cyclohexylmethyl)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
1-(((3aR,5s,6aS)-5-((5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexan-1-ol;
4-(((3aR,5s,6aS)-5-((5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)tetrahydro-2H-pyran-4-ol;
(3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl)-N-(5-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(5-fluoro-2-methylphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-4,5-dimethylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(3-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-4,5-dimethylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
6-(2,5-difluorophenyl)-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
6-chloro-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
3-(((3aR,5s,6aS)-2-(((2R)-7-oxabicyclo[2.2.1]heptan-2-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(2,5-difluorophenyl)-5-methylpyridazine-4-carbonitrile;
6-(2-chloro-5-fluorophenyl)-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
6-(2-fluorophenyl)-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
6-(3-fluorophenyl)-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
(3aR,5s,6aS)-N-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4,5-dimethyl-6-(naphthalen-2-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
5-methyl-6-(2-methyl-2H-indazol-5-yl)-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
6-(4-fluorophenyl)-5-methyl-3-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazine-4-carbonitrile;
(3aR,5s,6aS)-N-(6-(5-fluoro-2-methylphenyl)-5-methyl-4-(trifluoromethyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(6-(2,5-difluorophenyl)-5-methyl-4-(trifluoromethyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-methyl-6-phenyl-4-(trifluoromethyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(5-cyclopropyl-4-(trifluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
4-(((3aR,5s,6aS)-5-((4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)tetrahydro-2H-pyran-4-ol;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)-2-((4-methyltetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5S,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl)-N-(4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5R,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl)-N-(4-(difluoromethyl)-6-(2,5-difluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2-methyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2,4-dimethyl-2H-indazol-5-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(5-fluoro-2-methoxyphenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2-(trifluoromethoxy)phenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine;
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(5-fluoro-2-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine; and
(3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(2,3,5-trifluorophenyl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine;
or a pharmaceutically acceptable salt thereof.
48 . The compound of any of claims 1 - 47 , or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.
49 . A pharmaceutical composition comprising the compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
50 . A method for antagonizing mAChR M 4 in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
51 . A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M 4 , comprising administering to the mammal a therapeutically effective amount of the compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
52 . The method of claim 51 , wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.
53 . The method of claim 52 , wherein the disorder is a movement disorder.
54 . The method of claim 52 , wherein the disorder is selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
55 . A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
56 . The method of claim 55 , wherein the subject has a disorder selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
57 . A compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 , for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.
58 . The use of a compound of any of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 , for the preparation of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.