Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists

Patent metadata

Field	Value
Publication number	US-9593106-B2
Application number	US-201414766520-A
Country	US
Kind code	B2
Filing date	Feb 7, 2014
Priority date	Feb 7, 2013
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present invention provides muscarinic M 4 receptor agonists of formula (I) and pharmaceutically acceptable salts thereof, wherein m, n, p, q, R, R 2 and R 3 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases such as schizophrenia, Alzheimer's disease and various cognitive disorders as well as in the treatment or alleviation of pain.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
m, p and q each independently represent 0 or 1;
n represents an integer 2;
R 1 is selected from hydrogen, fluorine, cyano, hydroxyl, amino, and a C 1 -C 9 non-aromatic hydrocarbon group which is optionally substituted with from one to six fluorine atoms and wherein one, two or three carbon atoms of the hydrocarbon group may optionally be replaced by one, two or three heteroatoms independently selected from nitrogen, oxygen and sulphur;
R 2 is hydrogen or a C 1 -C 6 non-aromatic hydrocarbon group which is optionally substituted with from one to six fluorine atoms and wherein one, two or three carbon atoms of the hydrocarbon group may optionally be replaced by one, two or three heteroatoms independently selected from nitrogen, oxygen and sulphur;
R 3 represents a 5-or 6-membered monocyclic aromatic heterocyclic group containing 1, 2, 3or 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, which heterocyclic group may be optionally substituted by at least one substituent selected from halogen, cyano, oxo, —NR 4 R 5 , —C(O)NR 6 R 7 , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —R 8 , —OCH 2 R 8 , C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl and C 1 -C 6 alkyl, the alkyl substituent itself being optionally substituted by at least one substituent selected from cyano, —C(O)NR 9 R 10 , C 1 -C 6 alkoxy and —NHC(O)R 11 , or
R 3 represents a group of formula (II)

in which X represents a bond, C(O), C(O)O, C(O)NR 13 or SO 2 , and R 12 represents a C 1 -C 6 alkyl group or a 3-to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system, each of which may be optionally substituted by at least one substituent selected from halogen, hydroxyl, cyano, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulphinyl, C 1 -C 6 alkylsulphonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxycarbonyl, —N(R 14 ) 2 , —CON(R 15 ) 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy and C 3 -C 6 cycloalkylmethyl;
R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkylmethyl;
R 8 represents a 5-or 6-membered monocyclic aromatic group optionally containing 1, 2, 3 or 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the aromatic group being optionally substituted by at least one substituent selected from halogen and C 1 -C 6 alkyl;
R 9 , R 10 and R 11 each independently represent a hydrogen atom, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and
each R 13 , R 14 and R 15 independently represents a hydrogen atom or C 1 -C 6 alkyl group.

2. A compound according to claim 1 , wherein, in R 3 , the 5-or 6-membered monocyclic aromatic heterocyclic group contains from 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur.

3. A compound according to claim 1 , wherein, in R 3 , the 5-or 6-membered monocyclic aromatic heterocyclic group contains 1 or 2 nitrogen ring atoms and optionally one further ring heteroatom selected from oxygen and sulphur.

4. A compound according to claim 3 , wherein the 5-or 6-membered monocyclic aromatic heterocyclic group is selected from pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl and pyrazinyl.

5. A compound according to claim 1 , wherein, in R 3 , the 5-or 6-membered monocyclic aromatic heterocyclic group is optionally substituted by one, two, three or four substituents independently selected from fluorine, chlorine, cyano, oxo, —NR 4 R 5 , —C(O)NR 6 R 7 , C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, —R 8 , —OCH 2 R 8 , C 1 -C 2 alkoxy, C 3 -C 6 cycloalkyl and C 1 -C 4 alkyl, the alkyl substituent itself being optionally substituted by one, two or three substituents independently selected from cyano, —C(O)NR 9 R 10 , C 1 -C 2 alkoxy and —NHC(O)R 11 .

6. A compound according to claim 1 , wherein R 1 is selected from hydrogen and methoxy.

7. A compound according to claim 1 , wherein R 2 is ethyl.

8. A compound according to claim 1 , wherein p and q are each 1.

9. A compound according to claim 1 , wherein m is 0.

10. A compound of formula (I) as defined in claim 1 selected from the group consisting of:
Ethyl 4-(4-{1-[(cyclohexylcarbamoyl)methyl]-1H-imidazol-2-yl}piperidin-1-yl)azepane-1-carboxylate,
Ethyl 4-[4-(1H-pyrrol-1-yl)piperidin-1 yl]azepane-1-carboxylate,
Ethyl 4-[4-(1H-pyrazol-1-yl)piperidin-1 yl]azepane-1-carboxylate,
Ethyl 4-{4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-[4-(1H-pyrazol-3-yl)piperidin-1 yl]azepane-1-carboxylate,
Ethyl 4-{4-[5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-{4-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(1-ethyl-1H-imidazol-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(1-prop yl-1H-imidazol-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(5-methyl-1H-pyrazol-1-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-(4-(5-isopropyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)azepane-1-carboxylate,
Ethyl 4-[4-(3-methyl-1H-pyrazol-1-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-{4-[3-(thiophen-2-yl)-1H-pyrazol-5-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-{4-[4-(4-fluorophenyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-(4-{1-[(cyclopropylcarbamoyl)methyl]-1H-imidazol-2-yl}piperidin-1-yl)azepane-1-carboxylate,
Ethyl 4-[4-(5-cyclopropyl-1H-pyrazol-1-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-{4-[5-(dimethylcarbamoyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-(4-{5-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)azepane-1-carboxylate,
Ethyl 4-{4-[5-(methoxymethyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-(4-{5-[(cyclopropylmethyl)carbamoyl]-1H-pyrazol-1-yl}piperidin-1-yl)azepane-1-carboxylate,
Ethyl 4-{4-[5-(dimethyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-[4-(1,3-thiazol-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(5-cyano-1H-pyrazol-1-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-{4-[5-(acetamidomethyl)-1H-pyrazol-1-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-[4-(pyridin-4-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(6-methoxypyridin-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(2-methoxypyridin-3-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(3-methoxypyridin-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(3-methoxypyrazin-2-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(2-methylpyridin-3-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(2-ethoxy-5-methylpyridin-3-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-{4-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]piperidin-1-yl}azepane-1-carboxylate,
Ethyl 4-[4-(3-methoxypyridin-4-yl)piperidin-1-yl]azepane-1-carboxylate,
Ethyl 4-[4-(5-methoxypyridin-3-yl)piperidin-1-yl]azepane-1

Assignees

• Heptares Therapeutics Ltd

Inventors

• Livermore David
• White Kathryn
• Congreve Miles
• Brown Giles
• O'Brien Michael

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title