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:
each of X, Y, Z is independently CR 8 or N, wherein R 8 is hydrogen, C 1 -C 4 alkyl, halogen, C 1 -C 4 alkoxy, or cyano;
each of R 1 and R 2 is independently hydrogen, halogen, amino, R 10 NH—S(═O) 2 —,R 9 —S(═O) 2 —, R 9 —S(═O)—, R 9 —S—, R 9 —S(═O)(=NR 10 )—, R 9 —O—,
(n=1, 2, or 3), cyano or C 1 -C 4 alkyl, wherein R 9 is selected from C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, and 3-7 membered heterocyclyl, wherein R 9 or
is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —OH, —NHR 10 , halogen, or cyano, and wherein R 10 is hydrogen, C 1 -C 4 alkyl, or C 3 -C 7 cycloalkyl; or R 1 , R 2 and the carbon atoms they are attached to form a 3-7 membered ring with one or more heteroatoms selected from N, O, and S;
X 1 is O or NH;
X 2 is hydrogen or C 1 -C 4 alkyl;
R 3 and R 4 are each independently selected from hydrogen and C 1 -C 4 alkyl, and R 3 and R 4 are bonded to different ethylene groups of the piperazine ring;
each of R 5 and R 6 is independently hydrogen or C 1 -C 4 alkyl, or R 5 , R and the carbon atom they are attached to form a C 3 -C 7 cycloalkyl or a 3-7 membered heterocyclyl, each optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —OH, —NHR 10 , halogen, and cyano;
R 7 is hydrogen, halogen, or C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with halogen, amino, —OH, C 1 -C 4 alkoxy, or cyano; and
m is 0, 1, or 2.
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from
3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from
4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from
5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from
6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from
7 . The compound according to any one of claims 1-6 , wherein R 1 is R 10 N—S(═O) 2 —.
8 . The compound according to any one of claims 1-6 , wherein R 1 is R 9 —S(═O) 2 —.
9 . The compound according to any one of claims 1-6 , wherein R 1 is R 9 —S(═O) 2 —.
10 . The compound according to any one of claims 1-6 , wherein R 1 is R 9 —O—.
11 . The compound according to any one of claims 1-6 , wherein R 1 is
(n=1, 2, or 3)
12 . The compound according to any one of claims 1-11 , wherein R 2 is hydrogen.
13 . The compound according to any one of claims 1-11 , wherein R 2 is halogen.
14 . The compound according to any one of claims 1-11 , wherein R 2 is C 1 -C 4 alkyl.
15 . The compound according to any one of claims 1-14 , wherein X 1 is NH.
16 . The compound according to any one of claims 1-14 , wherein X 1 is O.
17 . The compound according to any one of claims 1-16 , wherein X 2 is hydrogen.
18 . The compound according to any one of claims 1-16 , wherein X 2 is C 1 -C 4 alkyl.
19 . The compound of any one of claims 1-14 , wherein X 1 is O and X 2 is hydrogen.
20 . The compound according to any one of claims 1-19 , wherein each of R 5 and R 6 is hydrogen.
21 . The compound according to any one of claims 1-19 , wherein each of R 5 and R 6 is C 1 -C 4 alkyl.
22 . The compound according to any one of claims 1-19 , wherein R is hydrogen and R 6 is C 1 -C 4 alkyl.
23 . The compound according to any one of claims 1-22 , wherein m is 0.
24 . The compound according to any one of claims 1-22 , wherein m is 1.
25 . The compound according to any one of claims 1-22 , wherein m is 2.
26 . The compound according to any one of claims 1-25 , wherein R 10 is hydrogen.
27 . The compound according to any one of claims 1-25 , wherein R 10 is C 1 -C 4 alkyl.
28 . The compound according to any one of claims 1-27 , wherein R 9 is C 1 -C 4 alkyl.
29 . The compound according to any one of claims 1-27 , wherein R 9 is C 3 -C 7 cycloalkyl.
30 . The compound according to any one of claims 1-27 , wherein R 9 is 3-7 membered heterocyclyl.
31 . The compound according to any one of claims 28-30 , wherein said C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 3-7 membered heterocyclyl is optionally substituted with halogen, cyano, or —OH.
32 . 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 31 , or a pharmaceutically acceptable salt thereof.
33 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
34 . A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
35 . 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 31 , or a pharmaceutically acceptable salt thereof.
36 . 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 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 32 , or a pharmaceutical composition according to claim 33 .
37 . 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 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 32 , or a pharmaceutical composition according to claim 33 .
38 . The method according to claim 36 or 37 , 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.
39 . Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 31 , in the manufacture of a medicament for treating or preventing a neurological disease, disorder, or symptom in an individual.
40 . Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 31 , in the manufacture of a medicament for treating or preventing a muscarinic receptor 4 (M 4 ) mediated disease, disorder, or symptom in an individual.
41 . The use according to claim 39 or 40 , 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.
42 . A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 32 , or a pharmaceutical composition according to claim 33 , for use in a method of treatment or prophylaxis of a human or animal body by therapy.
43 . A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 32 , or a pharmaceutical composition according to claim 33 , for use in a method for treating or preventing a neurological disease, disorder, or symptom in an individual.
44 . A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 32 , or a pharmaceutical composition according to claim 33 , for use in a method for treating or preventing a muscarinic receptor 4 (M 4 ) mediated disease, disorder, or symptom in an individual.
45 . The compound, pharmaceutically acceptable salt thereof, pharmaceutical product, or pharmaceutical composition for use according to claim 39 or 40 , 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.
46 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims 36 to 45 , wherein the disease, disorder, or symptom is parkinsonism.
47 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims 36 to 45 , wherein the disease, disorder, or symptom is tremor.
48 . The method, use, or compound, pharmaceutical product, or pharmaceutical composition for use according to any one of claims 36-45 , wherein the disease, disorder, or symptom is dystonia.