WO2009106534A1

WO2009106534A1 - Novel heterocyclic carboxamides as m1 agonists

Info

Publication number: WO2009106534A1
Application number: PCT/EP2009/052205
Authority: WO
Inventors: Benny Bang-Andersen; Anette Graven Sams; Krestian Larsen
Original assignee: H. Lundbeck A/S
Priority date: 2008-02-26
Filing date: 2009-02-25
Publication date: 2009-09-03

Abstract

The present invention relates to novel M1 agonistic compounds of formula (I) and their use in the treatment of cognitive impairment associated i.a. with schizophrenia and in the treatment of other diseases mediated by the muscarinic M1 receptor.

Description

Novel heterocyclic carboxamides as Ml agonists

Field of the Invention The present invention provides compounds that are Ml agonists or partial agonists and as such are useful to treat cognitive impairment associated inter alia with schizophrenia and other diseases and disorders mediated by the muscarinic Ml receptor. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating said disorders and diseases using the compounds of the invention.

Background of the Invention

Muscarinic acetyl choline receptors are members of the G protein coupled receptor super family which mediate the action of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five muscarinic receptor subtypes (M1-M5) have been cloned. The muscarinic Ml receptor is predominantly expressed in the cerebral cortex and hippocampus, although it is also expressed in the periphery e.g. in exocrine glands.

Muscarinic receptors in the central nervous system, especially Ml, play a critical role in mediating higher cognitive processing.

It has been suggested that muscarinic agonists may improve the symptoms of schizophrenia by acting directly at postsynaptic muscarinic receptors in cortical areas (Friedman et al, Biol Psychiatry 1999, 45:1-16). Recently, polymorphism of the Ml muscarinic receptor gene was shown to be associated with a poor cognitive function in subjects with schizophrenia (Liao et al, Neuropsychobiology 2003, 48, 72-76). Data from postmortem studies show a decrease in Ml receptor protein and mRNA levels in prefrontal cortices in human subjects with schizophrenia, which is confirmed by an in vivo brain imaging study in unmedicated subjects with schizophrenia. (Raedler et al, Molecular Psychiatry 2007, 12, 232-246). Altogether this suggests that there is a decrease in Ml receptors in the frontal cortex of schizophrenia, which could result in an under-activation of cholinergic pathways, and that activating the Ml receptor would be a mechanism by which cognitive deficits could be reversed in schizophrenia. Alzheimer's disease, which is associated with cognitive impairment, is accompanied by loss of cholinergic neurons in the basal forebrain. Furthermore, in animal models, blockade or lesion of central cholinergic pathways results in profound cognitive deficits.

Cholinergic replacement therapy has largely been based on the use of acetylcholine esterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to side effects resulting from stimulation of peripheral muscarinic receptors including disturbed gastrointestinal motility and nausea.

In addition to schizophrenia and Alzheimer's Disease, cognitive impairment can be experienced in several patients groups, e.g. depressive or psychotic patients and patients with attention deficit hyperactivity disorder (ADHD), psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania, Parkinson's disease, mild cognitive impairment (MCI), dementia, anxiety, age associated memory impairment, or post-traumatic stress disorder and patients taking benzodiazepines or tricyclic antidepressants and in a range of neurodegenerative diseases in addition to Parkinson's Disease and Alzheimer's Disease.

Furthermore, there is a close link between cognitive impairment and unfavorable post- hospitalization rehabilitation outcomes, especially in elderly patients (SoIh et al, BMC Geriatr. 2006; 6: 12; Hershkovitz et al., Arch. Phys. Medicine and Rehab. 88 (7) 2007, 916- 921, such as postacute stroke rehabilitation (Massucci et al., Am. J. Phys. Medicine & Rehab. 85 (12), 2006 963-970).

Ml receptor agonists or partial agonists could potentially improve cognitive function in patients suffering from these disorders.

Ml receptor agonists may also be suitable for use in combination with typical and atypical antipsychotics and other drugs for the treatment of disorders or diseases in the central nervous system such as mood stabilisers, antidepressants, anxiolytics, drugs for extrapyrimidal side effects and cognitive enhancers, to provide improved treatment of psychotic disorders. The muscarinic family of receptors is furthermore the target for a number of pharmacological agents used for various other diseases, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.

So far the development of muscarinic Ml receptor agonists for the treatment of cognitive dysfunctions or impairment has resulted in a variety of drug candidates, but many have been discontinued from development because of undesirable side effects such as sweating, vomiting and nausea. Therefore, there is a real need to develop better therapies to improve the cognitive impairment associated with these disorders and diseases.

Di- and tri-substituted piperidine and piperazine derivatives are disclosed as compounds with activity on muscarinergic receptors in WO 99/50247, WO 2001/05763 and US Patent 6,528,529. WO 2003/057672, WO 2006/068904, US 11,019,556 and US 10,329,455 disclose tetrahydroquinoline derivatives with activity on Ml and M4 receptors. WO 2004/1089942 and WO 2003/028650 disclose benzimidazolidinone derivatives, which increase acetylcholine signaling or effect in the brain, and which are highly selective muscarinic Ml and/or M4 receptor agonists. Neither of these references discloses the heterocyclic carboxamides of the present invention.

Thus, the compounds of the invention, which are muscarinic Ml receptor agonists, are believed to be useful in the treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states. Summary of the Invention

The present invention relates to novel heterocyclic carboxamides, which the inventors have found to be highly active Ml agonists, and as such likely to be effective in the treatment of cognitive impairment and other diseases mediated by the muscarinic Ml receptor.

The objective of the present invention is to provide novel compounds, which are agonists at the Ml receptor.

The present invention is further directed to the use of a compound, alone or in combination with other antipsychotic agents or other drugs, for the treatment of disorders or diseases in the central nervous system, for treating or preventing psychosis, such as a schizophrenic disorder or psychosis in Alzheimer's disease or bipolar disorder, for treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states. The present invention further provides a pharmaceutical composition for treating or preventing said disorders and diseases.

Furthermore, the present invention is directed to a method for the treatment, control, amelioration or reduction of risk of a disease or disorder where abnormal oscillatory activity occurs in the brain, including depression, migraine, Parkinson's disease, psychosis and schizophrenia, as well as a disease or disorder where there is abnormal coupling of activity, particularly through the thalamus and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma or pain, including acute pain, chronic pain and neuropathic pain states.

Further objectives of the invention will become apparent upon reading the present specification. Accordingly, in one aspect the present invention relates to compounds of formula I:

, wherein

G is a mono- or bicyclic heterocyclic group selected from:

Rl is Ci_6 alkyl, C3_5 cycloalkyl, Ci_6 alkyl-C3_7 cycloalkyl wherein each Ci_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with Ci_6 alkyl-Cβ-io aryl, C_6-I₀ aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-Cβ-io aryl, C_6-10 aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, may be optionally substituted with a halogen, OH, Ci_₆ thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or

Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy,

-L- is CH₂CH₂ or CH₂CH₂CH₂ or absent,

* denotes the attachment point of the group G,

R2 is independently selected from halogen and Ci_6 alkoxy,

n is an integer selected from 0, 1 and 2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;

A is a biradical selected from: O, CH₂, S, OCH₂, CH₂CH₂, SCH₂, SOCH₂, N-Ci_-6 alkyl and NRl 3CH₂,

R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF3, Ci_6 alkyl and Ci_6 alkoxy,

Rl 3 is H or Ci _₆ alkyl,

and enantiomers, diastereomers, tautomers and pharmaceutically acceptable addition salts thereof, and polymorphic forms thereof.

The invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament.

In a further aspect, the invention relates to compounds of formula I for the treatment of disorders associated with muscarinic receptors, such as cognitive impairment.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and one or more pharmaceutically acceptable carriers, diluents and excipients.

In another aspect, the invention provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, alone or in combination with one or more neuroleptic agents, for the treatment of schizophrenia.

The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of a disorder associated with muscarinic receptors, such as cognitive impairment. The invention further provides a method of treating a disorder selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia, and chemotherapy- induced cognitive impairment), ADHD, mood disorders (including depression, mania and bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain such as neuropathic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (including Crohn's disease), the method comprising administering to a mammal an effective amount of a compound of formula I.

The present invention thus provides the use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition thereof, for the treatment of a disorder associated with muscarinic receptors, such as cognitive impairment.

In separate embodiments of the invention, the compound is selected among the specific compounds disclosed in the Experimental Section.

Detailed Description of the Invention

Definition of Substitutents As used in the context of the present invention, the term "Ci_6 alkyl" refers to a straight- chained or branched saturated hydrocarbon radical having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2- propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l -butyl and n-hexyl.

The expression "Ci_6 alkoxy" refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2- propoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.

The term "C₃-₅ cycloalkyl" typically refers to cyclopropyl, cyclobutyl and cyclopentyl. The term "C3-7 cycloalkyl" typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "Ci_6 alkyl-C3-7 cycloalkyl" refers to a C3-7 cycloalkyl group as defined above, bearing a Ci_6 alkyl group substitutent as defined above.

The term "C_6-10 aryl" refers to a mono- or polycyclic aromatic group, which contains from 6 to 10 ring carbon atoms, and partially saturated variants thereof. Typical examples, which should not be considered limiting, include phenyl, indenyl, indanyl, naphthyl and tetrahydronaphthy 1.

The term "Ci_6 alkyl-C₆-₁₀ aryl" refers to a C₆-₁₀ aryl group as defined above, bearing a Ci_6 alkyl group substituent as defined above.

The term "heteroaryl group" refers to a mono- or polycyclic aromatic group which contains up to 14 ring atoms, of which 1 to 5 are selected from N, O or S, and the remaining atoms are carbon, and wherein the ring atoms selected from N, O or S may be placed in one or more rings, and partially saturated variants thereof. Typical examples, which should not be considered limiting, comprise pyridyl, thienyl, furyl, indolyl, pyranyl, benzofuranyl, benzothienyl, quinoline, isoquinoline, naphthyridyl, dihydroquinolinyl, chromenyl, thiochromenyl, benzoquinolinyl and acridinyl.

The term "Ci_6 alkyl-heteroaryl" refers to a heteroaryl group as defined above, bearing a Ci_6 alkyl group substituent as defined above. G is a mono- or bicyclic heterocyclic group selected from:

, wherein Rl, -L-, * and R2 are as defined above.

In one embodiment wherein the linking group "-L-" as defined herein is CH₂CH₂, G is a bicyclic heterocyclic group selected from:

In another embodiment, wherein the linking group "-L-" as defined herein is CH₂CH₂CH₂, G is a bicyclic heterocyclic group selected from:

In yet another embodiment, wherein the linking group "-L-" as defined herein is absent, G is a monocyclic heterocyclic group:

The asterisk * in the above embodiments denotes the attachment point of the group G The compounds of the present invention may have one or more asymmetric centre, and it is intended that any optical isomers (i.e. enantiomers or diastereomers), in the form of separated, pure or partially purified optical isomers and any mixtures thereof, including racemic mixtures, are included within the scope of the invention.

Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization. The optically active acids suitable for this purpose may include, but are not limited to d- or 1-tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation and separation, e.g. chromatographic separation, of diastereomeric derivatives from chiral derivatizing reagents, such as a chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms, and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.

Some of the compounds of the present invention, including their pharmaceutically acceptable acid addition salts, may exist in different polymorphic forms and it is intended that any polymorphic forms that the compounds are able to form are included within the scope of the present invention.

Definition of terms

The phrase "cognitive impairment" as used herein refers to difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). These can include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or difficulty in integrating thoughts, feelings and behaviour and extinction of irrelevant thoughts as well as attention and vigilance, verbal learning and memory, visual learning and memory, speed of processing and social cognition.

The term "treatment" as used herein in connection with a disease or disorder such as cognitive impairment, also includes prevention as the case may be.

The term "therapeutically effective amount" as used herein denotes an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, that will elicit the biological or medical response of a mammal that is being sought by a researcher or clinician. The therapeutically effective amount will depend on the condition to be treated, the route and duration of administration, the physical attributes of the mammal, including body weight and on whether anyother medications are being administered concurrently, and may be determined according to methods well known to those skilled in the art in light of the present disclosure.

The mammal treated in the present methods is preferably a human, male or female, in whom activation of muscarinic Ml receptor activity is desired. In the present invention, it is preferred that the subject mammal is a human. Although the present invention is applicable to both old and young people, in certain aspects such as in treating cognitive impairment, it would typically find greater application in elderly people.

Accordingly, the present invention includes within its scope the use of a compound of formula I, alone or in combination with other agents, for the treatment of diseases mediated by the muscarinic Ml receptor, such as cognitive impairment and neuropathic pain in a mammal.

The preferred mammal for purposes of this invention is human.

The term "leaving group" as used herein refers to a group that is displaced in a substitution or elimination reaction. Typical leaving groups include, but are not limited to, the chloride ion (Cl^"), bromide ion (Br^") and methanesulfonate ion (CH3SO3 ).

As used herein, the orientation of the biradical A, which is a selected from O, OCH₂, S, N-Ci_-6 alkyl, N(RD)CH₂, CH₂CH₂, CH₂, SCH₂, and SOCH₂, wherein Rl 3 is selected from hydrogen and Ci_6 alkyl, such as methyl, is as shown below:

C_L6 alkyl R13

^H2 H.

,0. ,o-c> N. ,N — C.

O

H₂ H₂ ^H2 ^H2 H. ,C-(X .S-C -S-C

\

More specifically, the orientation of the non-symmetrical embodiments of A (OCH₂, N(RD)CH₂, SCH₂, SOCH₂) is shown below:

As used herein, the term "substantially pure enantiomer" refers to a substance that has preferably between about 95% and 100% of one form (either R or S) and between about 5% and 0% of the other form, more preferably between about 99% and 100% of one form (either R or S) and between about 1% and 0% of the other form, and, most preferably, between about 99.9% and 100% of one form (either R or S) and about 0.1% and 0% of the other form. As used herein, the term "substantially pure diastereomer" refers to a substance that has preferably between about 95% and 100% of one diastereomeric form and between about 5% and 0% of the other form, more preferably between about 99% and 100% of one form and between about 1% and 0% of the other form, and, most preferably, between about 99.9% and 100% of one diastereomeric form and about 0.1% and 0% of the other form.

As used herein, the term rac means a racemic mixture of enantiomers.

Accordingly, in one aspect the present invention relates to compounds of formula I:

, wherein

G is a mono- or bicyclic heterocyclic group selected from:

Rl is Ci_6 alkyl, C3-5 cycloalkyl, Ci_6 alkyl-C3-7 cycloalkyl wherein each Ci_6 alkyl, C3-5 cycloalkyl and C3-7 cycloalkyl may be optionally substituted with Ci_6 alkyl-Cβ-io aryl, Cβ-io aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-Cβ-io aryl, Cβ-io aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, may be optionally substituted with a halogen, OH, Ci_₆ thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy,

L is CH₂CH₂ or CH₂CH₂CH₂ or absent,

* denotes the attachment point of the group G,

R2 is independently selected from halogen and Ci_6 alkyl,

n is an integer selected from 0, 1 and 2,

R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;

A is a biradical selected from: O, CH₂, S, OCH₂, CH₂CH₂, SCH₂, SOCH₂, N-Ci_-6 alkyl, and NRl 3CH₂,

R13 is H, Ci_-6 alkyl,

and enantiomers, diastereomers, tautomers and pharmaceutically acceptable addition salts thereof and polymorphic forms thereof.

In one embodiment of the present invention wherein the linking group "-L-" is CH₂CH₂, G is a bicyclic heterocyclic group selected from:

wherein the asterisk * denotes the attachment point of the group G and wherein Rl is selected from Ci_₆ alkyl, C₃_₅ cycloalkyl and Ci_6 alkyl-C3_7 cycloalkyl, wherein each Ci_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with Ci_6 alkyl-Cβ-io aryl, C_6-10 aryl, Ci_6 alkyl- heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-Cβ-io aryl, C_6-10 aryl, Ci_6 alkyl-heteroaryl and heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy;

or, alternatively, Rl is Ci_₆ alkyl substituted with halogen or Ci_6 alkoxy,

and wherein R2 is independently selected from halogen and Ci_6 alkyl, and

n is an integer selected from 0, 1 and 2,

R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, C i_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;

R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF₃, Ci_₆ alkyl and Ci_6 alkoxy, and wherein R13 is selected from H and Ci_6 alkyl.

In another embodiment wherein the linking group "-L-" is CH₂CH₂CH₂, G is a bicyclic heterocyclic group selected from:

wherein the asterisk * denotes the attachment point of the group G and wherein Rl is selected from Ci_6 alkyl, C3_5 cycloalkyl and Ci_6 alkyl-C3-7 cycloalkyl, wherein each Ci_6 alkyl, C3-5 cycloalkyl and C₃_₇ cycloalkyl may be optionally substituted with Ci_6 alkyl-C_6-10 aryl, C_6-10 aryl, Ci_₆ alkyl-heteroaryl or heteroaryl, and wherein each Ci_6 alkyl-C_6-10 aryl, C_6-10 aryl, Ci_6 alkyl-heteroaryl or heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy;

or, alternatively, Rl is Ci_₆ alkyl substituted with halogen and Ci_6 alkoxy,

and wherein R2 is independently selected from halogen and Ci_6 alkyl, and

n is an integer selected from 0, 1 and 2,

A is a biradical selected from: O, CH₂, S, OCH₂, CH₂CH₂, SCH₂, SOCH₂, N-Ci_₆ alkyl and NRl 3CH₂,

R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF₃, Ci_₆ alkyl and Ci_6 alkoxy,

and wherein R13 is selected from H and Ci_6 alkyl.

In yet another embodiment wherein the linking group "-L-" is absent, G is a monocyclic heterocyclic group:

wherein the asterisk * denotes the attachment point of the group G and wherein Rl is selected from Ci_6 alkyl (preferably ethyl, 1-propyl and 2-propyl), C3-5 cycloalkyl and Ci_6 alkyl-C3-7 cycloalkyl, wherein each Ci_₆ alkyl, C₃_₅ cycloalkyl and C₃_₇ cycloalkyl may be optionally substituted with C₆-10 aryl (preferably 3-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4-

(methylenedioxy)benzyl and 4-chlorobenzyl), heteroaryl, and wherein each C_6-10 aryl, or heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci-6 alkoxy;

or, alternatively, Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy,

and wherein R2 is independently selected from halogen and Ci_6 alkyl, and

n is an integer selected from 0, 1 and 2, preferably 0

A is a biradical selected from: O, CH₂, S, OCH₂, CH₂CH₂, SCH₂, SOCH₂, N-Ci_-6 alkyl, and NRl 3CH₂, preferably OCH₂, CH₂CH₂, SCH₂;

R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF₃, Ci_-6 alkyl, Ci_6 alkoxy; R9 and RlO are preferably both hydrogen; RI l is preferably selected from hydrogen and Ci_6 alkoxy such as methoxy, or from halogen such as F; R12 is preferably selected from hydrogen and halogen such as F;

and wherein R13 is selected from H and Ci_6 alkyl, preferably methyl. In a particular embodiment, Rl is Ci_₆ alkyl, such as methyl, 2-propyl, 2-butyl, 2-methyl-2- propyl, 2-methyl-l -butyl and n-hexyl.

In another embodiment, Rl is C₃-₅ cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.

In another embodiment, Rl is Ci_₆ alkyl-C₃_₇ cycloalkyl, such as cyclohexylmethyl or cyclopentylmethyl

In another embodiment, Rl is Ci_6 alkyl-Cβ-io aryl, such as benzyl, 3-chlorobenzyl, 4-chloro- benzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl or 3,4- (methylenedioxy)benzyl.

In another embodiment, Rl is Ci_₆ alkyl-heteroaryl, such as 2-methyl-thiophene, 2-methyl- pyridine, 3-methyl-pyridine or 4-methyl-pyridine.

In another embodiment, Rl is methyl. In another embodiment, Rl is Ethyl. In another embodiment, Rl is 1 -Propyl. In another embodiment, Rl is 2-Propyl. In another embodiment, Rl is 2-Butyl. In another embodiment, Rl is 3-Pentyl. In another embodiment, Rl is cyclobutyl.

In another embodiment, Rl is cyclopropyl. In another embodiment, Rl is cyclohexylmethyl. In another embodiment, Rl is cyclopentylmethyl. In another embodiment, Rl is 2-Thienyl- methyl. In another embodiment, Rl is Benzyl. In another embodiment, Rl is 3- Methoxybenzyl.

In another embodiment, Rl is 4-Methoxybenzyl. In another embodiment, Rl is 3,4- dimethoxybenzyl. In another embodiment, Rl is 3,4-(methylendioxy)benzyl. In another embodiment, Rl is 3-chlorobenzyl. In another embodiment, Rl is 4-chlorobenzyl. In another embodiment, Rl is 3,4-dichlor-Benzyl.

In a further embodiment, -L-is absent. In another embodiment, -L-is CH₂CH₂. In another embodiment, -L-is CH₂CH₂CH₂.

In a further embodiment, of the invention, n is 0. In another embodiment, n is 1. In another embodiment, n is 2.

In a different embodiment, R3, R4, R5, R6, R7 and R8 are all hydrogen.

In a further embodiment, A is O. In another embodiment, A is S. In another embodiment, A is OCH₂. In another embodiment, A is CH₂CH₂. In another embodiment, A is N-C _1-6 alkyl such as N(CH₃). In another embodiment, A is N(R13)CH₂ such as N(CH₃)-CH₂. In another embodiment, A is NH-CH_2. In another embodiment, A is SCH₂. In another embodiment, A is SOCH₂.

In another embodiment, R9 is H. In another embodiment, R9 is F.

In another embodiment, RlO is CH₃O. In another embodiment, RlO is CH₃. In another embodiment, RlO is Cl. In another embodiment, RlO is F. In another embodiment, RlO is hydrogen.

In another embodiment, Rl 1 is CH₃O. In another embodiment, Rl 1 is Cl. In another embodiment, Rl 1 is H. In another embodiment, Rl 1 is F.

In another embodiment, R12 is H. In another embodiment, R12 is F.

In a further embodiment, R9, RlO, Rl 1 and Rl 2 are all hydrogen.

In a particular embodiment, of the invention at least one of R9, RlO, Rl 1 and R12 is not hydrogen.

In another embodiment, at least one of R9, RlO, Rl 1 and R12 is halogen. In another embodiment, at least one of R9, RlO, Rl 1 and R12 is Ci_6 alkoxy, such as methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.

It should be understood that the various aspects, embodiments, implementations or features of the invention mentioned herein can be used and may be claimed separately, or in any combination, which can be illustrated by the following non-limiting examples:

In a specific embodiment, Rl is selected from Ci_6 alkyl, such as ethyl, 1-propyl, 2-propyl or from Ci_6 alkyl-Cδ-io aryl, such as 3,4-dimethoxybenzyl, 3,4-(methylenedioxy)benzyl or 4- chlorobenzyl; -L-is absent; n is 0; R3, R4, R5, R6, R7 and R8 are all hydrogen; A is selected from OCH₂, CH₂CH₂ and SCH₂; RlO is selected from hydrogen andCi_6 alkyl, such as methyl, or from Ci_6 alkoxy, such as methoxy, or from halogen, such as F or Cl; R9 and RlO are both hydrogen; RI l is selected from hydrogen and Ci_6 alkoxy, such as methoxy, or from halogen, such as F; R12 is selected from hydrogen and halogen, such as F.

In another embodiment, Rl is selected from Ci_₆ alkyl such as methyl, ethyl, 1-propyl or 2- propyl, or from C3_5 cycloalkyl such as cyclopropyl, or from Ci_6 alky 1-C₆-I o aryl, such as 3,4- dichlorobenzyl, benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4- (methylenedioxy)benzyl or 4-chlorobenzyl, or from Ci_₆ alkyl-heteroaryl, such as thiophene- 2-methyl; -L-is absent; n is 0; R3, R4, R5, R6, R7 and R8 are all hydrogen; A is selected from OCH₂, CH₂CH₂ and SCH₂,O; R9 is hydrogen; RlO is selected from hydrogen and Ci_-6 alkyl, such as methyl, or from Ci_6 alkoxy, such as methoxy, or from halogen, such as F or Cl; Rl 1 is selected from hydrogen and Ci_6 alkoxy such as methoxy or from halogen, such as F; R12 is selected from hydrogen and halogen, such as F.

In yet another aspect of the invention, Rl 1 and RlO are both F, so that the compound according formula I, as described above, can be represented by formula Ib,

wherein

G is a mono- or bicyclic heterocyclic group selected from:

wherein the groups R1-R9 and R12 and Rl 3 are as previously described for formula I.

In an embodiment, of the invention R1-R9 and R12 and 13 may be defined as,

Rl is Ci alkyl, C_4-6 alkyl, C3_5 cycloalkyl, Ci_6 alkyl-C3_7 cycloalkyl wherein each Ci alkyl, C4_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with Cβ-io aryl or heteroaryl, and wherein each Cβ-io aryl or heteroaryl, may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or

RHs Ci alkyl or C_4-6 alkyl are substituted with halogen or Ci_6 alkoxy,

L is CH₂CH₂ or CH₂CH₂CH₂ or absent,

the asterisk * denotes the attachment point of the group G,

R2 is independently selected from halogen and Ci_6 alkyl, n is an integer selected from O, 1 and 2,

R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;

R9 and R12 are independently selected from H, halogen, CN, CF3, Ci_6 alkyl and

Ci_6 alkoxy, and

R13 is H or Ci_-6 alkyl,

Further embodiments for formula Ib are evident from the above-given embodiments of formula I, and will be evident from the claims.

In an embodiment of the present invention, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 1 μM or less as evaluated by the Muscarinic FLIPR³⁸⁴ assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 500 nM or less as evaluated by the Muscarinic FLIPR³⁸⁴ assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 100 nM or less as evaluated by the Muscarinic FLIPR³⁸⁴ assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 50 nM or less as evaluated by the Muscarinic FLIPR³⁸⁴ assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 10 nM or less as evaluated by the Muscarinic FLIPR³⁸⁴ assay. In a separate embodiment, of the invention, the compound of formula I and/or Ib is a substantially pure enantiomer. In another embodiment, the compound of formula I and/or Ib is a substantially pure diastereomer.

In separate embodiments of the invention, the compounds of formula I and/or Ib are selected among the following specific compounds, either as the free base, a tautomer thereof or as a pharmaceutically acceptable acid addition salt thereof:

N- { 1 -[3-(2-Oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -2-phenyl- acetamide

N- { 1 -[3-(2-Oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -acetamide

3-Methyl-N- { 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - butyramide

Cyclobutanecarboxylic acid {l-[3-(2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]- piperidin-4-yl} -amide

2-(4-Chloro-phenyl)-N- { 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4- yl} -acetamide

2-Cyclopentyl-N- { 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - acetamide

2-Ethyl-N- { 1 -[3-(3-oxo-2,3-dihydro-benzo[ 1 ,4]oxazin-4-yl)-propyl]-piperidin-4-yl} - butyramide

2-(4-Methoxy-phenyl)-N-{l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -acetamide

2-(3-Chloro-phenyl)-N-{l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -acetamide

2-(3-Methoxy-phenyl)-N-{l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -acetamide

2-Cyclohexyl-N- { 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl] -piperidin-4-yl} - acetamide

2-(3,4-Dichloro-phenyl)-N-{l-[3-(2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin- 4-yl} -acetamide

N-{l-[3-(3-Oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- isobutyramide

N- { 1 -[3-(6-Methoxy-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl] -piperidin-4-yl} - isobutyramide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl} -acetamide

N-{l-[3-(6-Chloro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-2- (3,4-dimethoxy-phenyl)-acetamide

N- { 1 -[3-(6-Methyl-3-oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl} - propionamide

Cyclopropanecarboxylic acid (l-[3-(6-methyl-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl} -amide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(6-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl}-acetamide 2-Benzo[l,3]dioxol-5-yl-N-{l-[3-(6-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl}-acetamide

N- { 1 -[3-(7-Chloro-3-oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl} - isobutyramide

N- { 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl} - propionamide

2-(3-Methoxy-phenyl)-N- { 1 -[3-(3-oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]- piperidin-4-yl} -acetamide

N- { 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl} - isobutyramide

N- { 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl} -2-phenyl- acetamide

2-(3-Methoxy-phenyl)-N- { 1 -[3-(2-oxo-benzooxazol-3-yl)-propyl]-piperidin-4-yl} - acetamide

N- { 1 -[3-(8-Fluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - propionamide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-fluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl} -acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - propionamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - isobutyramide N-{l-[3-(6,7-Difluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- isobutyramide

N-{l-[3-(7-Fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- propionamide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl}-acetamide

N-{l-[3-(7-Fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-2- thiophen-2-yl-acetamide

2-Benzo[l,3]dioxol-5-yl-N-{l-[3-(7-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl} -acetamide

N-{l-[3-(7-Fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- butyramide

N- { 1 -[3-(5-Fluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - propionamide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(5-fluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl}-acetamide

N- { 1 -[3-(5-Fluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - butyramide

N- { 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl} -acetamide

Cyclopropanecarboxylic acid {l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -amide N- { 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl} -2-phenyl- acetamide

N-{8-[3-(3-Oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-8-aza-bicyclo[3.2.1]oct-3- yl} -2-phenyl-acetamide

N-{2-[3-(3-Oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-2-aza-bicyclo[2.2.2]oct-5- yl} -2-phenyl-acetamide

N-{3-[3-(3-Oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-3-aza-bicyclo[3.2.1]oct-8- yl} -2-phenyl-acetamide

rac-N-{2-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4- yl} -2-phenyl-acetamide

rac-N-{3-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4- yl} -2-phenyl-acetamide

N- { 1 -[3-(2-Oxo-3,4-dihydro-2H-quinoxalin- 1 -yl)-propyl]-piperidin-4-yl} -2-phenyl- acetamide

N- { 1 -[3-(4-Methyl-2-oxo-3,4-dihydro-2H-quinoxalin- 1 -yl)-propyl]-piperidin-4-yl} -2- phenyl-acetamide

N- { 1 -[3-(1 ,3-Dioxo-2,3-dihydro- IH- 1 λ⁴-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl} ■ 2-phenyl-acetamide

2-Phenyl-N-{l-[3-(l,l,3-trioxo-2,3-dihydro-lH-lλ⁶-benzo[l,4]thiazin-4-yl)-propyl]- piperidin-4-yl}-acetamide

N- { 1 -[3-(2-Oxo-benzothiazol-3-yl)-propyl]-piperidin-4-yl} -2-phenyl-acetamide N- { 1 -[3-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol- 1 -yl)-propyl]-piperidin-4-yl} -2- phenyl-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -2-(3- methoxy-phenyl)-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -2- (3,4-dimethoxy-phenyl)-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -2- phenyl-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -3- methyl-butyramide

Cyclopropanecarboxylic acid {l-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl} -amide

2-Benzo[ 1 ,3]dioxol-5-yl-N- { 1 -[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)- propyl]-piperidin-4-yl}-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} -2- thiophen-2-yl-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl} - butyramide (rac)-N-{(lS,3S,5R)-8-[3-(l,3-Dioxo-2,3-dihydro-lH-llambda*4^!i:-benzo[l,4]thiazin-4- yl)-propyl]-8-aza-bicyclo[3.2.1 ]oct-3-yl} -isobutyramide

N-{(lS,3S,5R)-8-[3-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-l-yl)-propyl]-8-aza- bicyclo[3.2.1 ]oct-3-yl} -propionamide

N-{(lS,3S,5R)-8-[3-(2-Oxo-benzooxazol-3-yl)-propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}- isobutyramide

N- { 1 -[3-(2-Oxo-benzothiazol-3-yl)-propyl]-piperidin-4-yl} -isobutyramide

N-{(lS,3S,5R)-8-[3-(7-Methoxy-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-8-aza- bicyclo[3.2.1 ]oct-3-yl} -propionamide

N- { 1 -[3-(2-Oxo-3,4-dihydro-2H-quinoxalin- 1 -yl)-propyl]-piperidin-4-yl} -propionamide, and

(rac)-N-{(3S,4S)-3-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl}-2-phenyl-acetamide

Each of these compounds is considered a specific embodiment, and may be made the subject of an individual claim.

Pharmaceutically Acceptable Salts The present invention also comprises salts of the compounds of formula I and/or Ib, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8- halotheophyllines, for example 8 -bromo theophylline and the like.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Pharmaceutical compositions

The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and/or Ib and a pharmaceutically acceptable carrier or diluent. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.

The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington:

The Science and Practice of Pharmacy, 19^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the mammal to be treated, the nature of the condition to be treated and the active ingredient. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages of a compound of formula I and/or formula Ib range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the mammal treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg of a compound of formula I and/or formula Ib.

For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration. The present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and/or formula Ib and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the present invention, the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.

The compounds of this invention are generally utilized as the free base or as a pharmaceutically acceptable salt thereof. Such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I and/or formula Ib with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula I and/or Ib in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I and/or Ib may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula I and/or Ib and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil- in- water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like.

Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Treatment of Disorders

As mentioned above, the compounds of formula I and/or Ib are agonists at the Ml receptor and as such are useful for treating or reducing the severity of a Ml muscarinic receptor mediated diseases such as cognitive impairment and neuropathic pain.

The phrase "treating or reducing the severity of a Ml muscarinic receptor mediated disease" refers both to treatments for diseases that are directly caused by muscarinic activities and alleviation of symptoms of diseases not directly caused by muscarinic activities. Examples of diseases whose symptoms may be affected by muscarinic activity include, but are not limited to, CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes such as neuropathic pain, Huntington's Chorea, Friederich's ataxia, Gilles de Ia Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intraocular pressure in Glaucoma and treatment of dry eyes and dry mouth (xerostomia) including Sjogren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances and wound healing.

The present invention thus provides a method of treating a mammal suffering from cognitive impairment, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or formula Ib.

This invention also provides a method of treating a mammal suffering from cognitive impairment associated with a psychiatric disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib. Examples of psychiatric disorders include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

The present invention provides a method of treating a mammal suffering from cognitive impairment associated with a cognition disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib. Examples of cognition disorders include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and age-related cognitive decline.

The compounds of formula I and/or Ib or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.

It has thus been found that the compounds of formula I and/or Ib, or pharmaceutically acceptable salts thereof, may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or atypical antipsychotic agent) to provide improved treatment of schizophrenia. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to other known treatments.

The present invention thus provides a method of treating a mammal suffering from schizophrenia, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib, either alone or as combination therapy with at least one neuroleptic agent.

The term "neuroleptic agent" as used herein refers to drugs, which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenyl- butylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.

Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

Other examples of combinations of the compounds of formula I and/or Ib include combinations with anti-Alzheimer's Disease agents, for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSRl 80711 and MEM63908; gamma-secretase inhibitors, such as LY450139 and TAK 070; tau phosphorylation inhibitors; blockers of Aβ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962, SL- 65.0155, SRA-333 and xaliproden; 5-HT1 a antagonists, such as lecozotan; p25/CDK5 inhibitors; NKl /NK3 receptor antagonists; COX-2 inhibitors; HMG- CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACCOOl, CAD 106, AZD3102, Hl 2Al IVl; anti- inflammatory compounds such as (R)-flurbiprofen, nitroflurbiprofen, rosiglitazone, ND- 1251, VP-025, HT-0712 and EHT-202; CB-I receptor antagonists or CB-I receptor inverse agonists, such as AVE 1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMD A) receptor antagonists, such as memantine, neramexane and EVTlOl ; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT- 089; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP 16795; AMPA agonists or AMPA modulators, such as CX-717, LY 451395, LY404187 and S- 18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABAA inverse agonists; GSK3β inhibitors, including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective Ml agonists; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.

Examples of combinations of the compounds of formula I and/or Ib include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-I antagonists, such as AMG517, 705498, 782443, PAC20030, Vl 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240612 and NVPSAA 164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such as AZD4282; potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED 160; GABA-A receptor IO modulators (e.g., GABA- A receptor agonists); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase B15 ("MAO-B") inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as AZD9272; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as AZD4282; NKI antagonists; with antidepressants, including SSRIs and SNRIs such as escitalopram, citalopram, fluoxetine, duloxetine paroxetine, and venlafaxine; tricyclic antidepressant drugs, norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the invention may also be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafmil, APD- 125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, circadin, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafmil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, pro tripty line, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, Zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of formula I and/or formula Ib may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

The compounds of the invention may also be administered in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.

The combination therapies of the invention are preferably administered adjunctively. By adjunctive administration is meant the concurrent or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as addon therapeutic administration.

In a further aspect, the invention provides a method of treatment of schizophrenia by adjunctive therapeutic administration of a compound of formula I and/or Ib, or a pharmaceutically acceptable salt thereof, to a mammal receiving therapeutic administration of at least one neuroleptic agent.

In preferred embodiments, the present invention provides methods of treating disorders selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment, cognitive impairment associated with schizophrenia, and chemotherapy-induced cognitive impairment), ADHD, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (including Crohn's disease), comprising: administering to a mammal an effective amount of a compound of the present invention. That is, the present invention provides for the use of a compound of the present invention or pharmaceutical composition thereof for the treatment disorders associated with muscarinic receptors.

Of the disorders to be treated according to the present invention a number are particularly preferred. Particularly preferred disorders include the treatment of cognitive disorders (particularly mild cognitive impairment and cognitive impairment associated with schizophrenia), Alzheimer's disease, and psychosis, including schizophrenia.

The present invention will be better understood from the Experimental Section that follows. However, one skilled in the art will readily appreciate that the specific methods and results discussed therein are merely illustrative of the invention as described more fully in the claims that follow thereafter.

Experimental Section

General Methods

LC-MS, general: Solvent system: A is water/TFA (100:0.05) and B is water/acetonitrile/TFA (5:95:0.035) (TFA is trifluoroacetic acid). Retention times (RT) are expressed in minutes. MS instruments are from PESciex (API), equipped with APPI-source and operated in positive ion mode.

Method A: API 150EX and Shimadzu LC8/SLC-10A LC system. Column: 30 x 4.6 mm Waters Symmetry Cl 8 with 3.5 μm particles operated at 60 °C. Linear Gradient elution with 10% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min. Method B: API 150EX and Shimadzu LCIOAD/SLC-IOA LC system. Column: 30 x 4.6 mm Waters Atlantis dC18 with 3 μm particles operated at 40 °C. Linear Gradient elution with 2% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min.

Method C: API 300 and Shimadzu LC10ADvp/SLC-10Avp LC system. Column: 30 x 4.6 mm Waters Symmetry Cl 8 with 3.5 μm particles operated at 60 °C. Linear Gradient elution with 10% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min.

¹H NMR spectra may be recorded at 500.13 MHz on a Bruker Avance AV500 instrument or at 250.13 MHz on a Bruker Avance DPX250 instrument. TMS was used as internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplicity of NMR signals: s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptet, dd is double doublet, dt is double triplet, dq is double quartet, tt is triplet of triplets, m is multiplet, br s is broad singlet and br is broad signal.

Preparation of the compounds of the invention

The compounds of the invention may be prepared by the following general methods:

a) Reaction of a compound of formula II

II

wherein A and R3 - Rl 2 are as previously described, and where E is a leaving group such as chloride, bromide or methylsulphonate.

with a compound of formula IHa, IHb, or IHc

IHa IHb IHc

wherein n, Rl, R2 and -L-are as described above.

The reaction of compounds with formula II with compounds with formula IHa, IHb, or IHc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula II and compounds with formula IHa, IHb, or IHc in a suitable solvent such as DMF, in the presence of a suitable base such as diisopropyl-ethyl amine, at a suitable temperature such as 0-60°C. The base may be immobilized on a solid support such as polystyrene beads.

b) Reaction of a compound with formula IV

IV wherein A and R5-R12 are as described above, with a compound with formula IHa, IHb or IHc as described above. The reaction of compounds with formula IV with compounds with formula IHa, IHb or IHc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula IV and compounds with formula IHa, IHb or IHc in a suitable solvent such as 1 ,2-dichloroethane or THF in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride at a suitable temperature such as 20-40°C, in the presence or absence of a suitable acid such as acetic acid.

c) Reaction of a compound with formula Va, Vb or

Vc

wherein A, n, -L-and R2 - Rl 2 are as described above, with a carboxylic acid chloride RlCOCl or a carboxylic acid RlCOOH, wherein Rl is as defined above.

The reaction of compounds with formula Va, Vb, or Vc with a carboxylic acid chloride RlCOCl may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula Va, Vb, or Vc and compounds RlCOCl in a suitable solvent such as acetonitrile or 1,2-di-chloroethane at a suitable temperature such as O- 60 °C, in the presence of a suitable base such as diisopropyl-ethyl amine. The base may be immobilized on a solid support such as polystyrene beads.

The reaction of compounds of formula Va, Vb, or Vc with carboxylic acids is performed by methods known to the skilled chemist, such as reaction in the presence of a carbodiimide coupling reagent such as diisopropyl carbodiimide in the presence of a suitable base such as triethylamine, and in the presence or absence of an additive such as 1-hydroxy-benzotriazole, in a suitable solvent such as 1 ,2-dichloroethane at a suitable temperature such as 0-60 °C;

Compounds of formula II may be commercially available or may be prepared according to standard procedures known to chemists skilled in the art as outlined below:

a) Reaction of a compound with formula VI

wherein A and R9 - Rl 2 are as described above, with a compound R7 R5 R3

E'-

R8 R6 R4

wherein R3 - R8 are as described above, and E' and E are leaving groups such as chloride or bromide, and where E' and E may be the same or different, under basic conditions.

The reaction of compounds with formula VI with a compound

may be performed by standard procedures known to chemists skilled in the art. This includes reacting compounds with formula VI with a suitable base such as sodium hydride in a suitable solvent such as DMF at a suitable temperature such as 0-60 °C, followed by addition of a compound:

R7 R5 R3

E'-

R8 R6 R4

b) Reaction of a compound with formula VI with a compound

wherein R3 - R8 are as described above, and E' is a leaving group such as chloride or bromide, and PG is a suitable protecting group, such as the trimethylsilyl group ((CE^Si-) under basic conditions. For a general reference on protecting groups in synthesis, see Greene and Wutts: Protecting groups in organic synthesis. 3^rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0-471-16019-9.

The reaction of compounds with formula VI with a compound R7 R5 R3

E'- -O— PG

R8 R6 R4

may be performed by standard procedures known to chemists skilled in the art. This includes reacting compounds with formula VI with a suitable base such as sodium hydride in a suitable solvent such as DMF at a suitable temperature such as 0-60 °C, followed by addition of a compound

R7 R5 R3

E'- -O— PG

R8 R6 R4

After removal of the protecting group by standard methods, the alcohol can be transformed into a suitable leaving group such as the methanesulfonate (CH3SO3 ) group, by reaction with methanesulfonyl chloride in the presence of a suitable base such as triethyl amine, in a suitable solvent such as THF, at a suitable temperature such as 0-25 °C.

Compounds with formula VI are either commercially available or may be prepared by procedures described in the experimental section.

Compounds with formula IV may be prepared according to standard procedures known to chemists skilled in the art as outlined below.

a) Oxidation of a compound

VII

wherein A and R5 - Rl 2 are as described above.

Oxidation of a compound with formula VII may be performed by standard procedures including reaction with a suitable oxidant such as IBX, in a suitable solvent such as THF or acetone, at a suitable temperature, such as reflux, or in DMSO at a suitable temperature, such as room temperature.

Compounds with formula VII may be prepared according to standard procedures known to chemists skilled in the art as outlined below.

Reaction of a compound with formula VI

wherein A and R9 - Rl 2 are as described above, with a compound R7 R5 H

E'- -O— PG

R8 R6 H

wherein R5 - R8 are as described above, and E' is a leaving group such as chloride or bromide, and PG is a suitable protecting group, such as the trimethylsilyl group ((CH₃)₃Si-), under basic conditions.

This includes reacting compounds with formula VI with a suitable base such as sodium hydride in a suitable solvent such as DMF at a suitable temperature such as 0-60 °C, followed by addition of a compound R7 R5 H

E'- -O— PG

R8 R6 H

Followed by removal of the protecting group by standard methods. For a general reference on protecting groups in synthesis, see Greene and Wutts: Protecting groups in organic synthesis. 3^rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0- 471-16019-9.

Compounds with formula IHa, IHb, or IHc may be prepared according to standard procedures known to chemists skilled in the art as outlined below:

a) Deprotection of a compound with formula Villa, VIIIb, or VIIIc, respectively

Villa VIIIb VIIIc wherein n, Rl, R2 and -L-are as described above, and PG is a suitable protecting group, such as the tert-butoxy carbonyl group (Boc). Deprotection may be performed according to procedures known to the skilled person. For a general reference, see Greene and Wutts: Protecting groups in organic synthesis. 3^rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0-471-16019-9.

Compounds with formula Villa, VIIIb, or VIIIc may be prepared according to standard procedures known to chemists skilled in the art as outlined below.

Reaction of a suitably substituted amino piperidine with formula IXa, IXb, or IXc

IXa IXb IXc

wherein n, R2 and -L-are as described above, and PG is a protecting group such as the

Boc group,

with a carboxylic acid chloride RlCOCl or a carboxylic acid RlCOOH. Reaction with a carboxylic acid chloride may be performed by standard procedures known to a person skilled in the art. This includes mixing compounds with formula IXa, IXb, or IXc and carboxylic acid chlorides RlCOCl in a suitable solvent such as acetonitrile or 1 ,2-di-chloroethane at a suitable temperature such as 0-60 °C, in the presence of a suitable base such as diisopropyl- ethyl amine. The base may be immobilized on a solid support such as polystyrene beads.

The reaction of compounds of formula IXa, IXb, or IXc with carboxylic acids is performed by methods known to the skilled chemist, such as reaction in the presence of a carbodiimide coupling reagent such as diisopropyl carbodiimide in the presence of a suitable base such as triethylamine, and in the presence or absence of an additive such as 1-hydroxy-benzotriazole, in a suitable solvent such as 1 ,2-dichloroethane at a suitable temperature such as 0-60 °C.

Compounds with formula IXa, IXb, or IXc are either commercially available, or may be prepared by standard procedures known to the skilled artisan.

For example, IXa where n is 0 and -L-is CH2CH2 is prepared by amination of commercially available JV-Boc-nortropinone by methods described in: Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.

For example, IXb where n is 0 and -L-is CH2CH2 is prepared from 3-benzyl-3-aza- bicyclo[3.2.1]octan-8-one, obtained as described in Lowe, J. A. et al.: J. Med. Chem. 1994, p.2831-2840; followed by in situ de-benzylation and introduction of the Boc protecting group as described in WO06108127; followed by animation by methods described in: Machetti, F. et al: Eur. J. Org. Chem., 2004, p. 2928-2935.

For example, IXc where n is 0 and -L-is CH2CH2 is prepared from 5-oxo-2-aza- bicyclo[2.2.2]octane-2-carboxylic acid tert-bvXy\ ester, obtained as described in Gong,L. et al. Biorg. Med. Chem. Lett. 2003, 3597-3540; followed by amination by methods described in: Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.

For example, IXa where -L-is absent, R2 is Me and n is 1 is prepared by the following procedures: from commercially available JV-BOC piperidone by silyl-enolization as described in van Niel, M.B. et al: J. Med. Chem., 1999, p. 2087-2104; followed by reaction with methyl iodide or another source of an electrophilic methyl group; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935; or from 2-methyl-4-oxo- piperidine-1-carboxylic acid benzyl ester obtained as described in Richards, S. et al.: Bioorg. Med. Chem. Lett. 2006, p. 6241-6245; followed by in situ de-benzylcarbamoylation and introduction of the Boc protecting group by methods described in WO06108127; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928- 2935.

An example of IXa where -L-is absent, R2 is Me and n is 2, is prepared from 3,3-dimethyl-4- oxo-piperidine-1-carboxylic acid tert-butyl ester obtained as described in WO 2005040120; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.

Another example of IXa where -L-is absent, R2 is Me and n is 2, is prepared from 2,6- dimethyl-4-oxo-piperidine-l-carboxylic acid benzyl ester obtained as described in Richards, S. et al.: Bioorg. Med. Chem. Lett. 2006, p. 6241-6245; followed by in situ de- benzylcarbamoylation and introduction of the Boc protecting group by methods described in WO06108127; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935. An example of IXa where -L-is absent, R2 is halogen and n is 1 is prepared by the following procedures: from commercially available JV-BOC piperidone by silyl-enolization as described in van Niel,

M.B. et al: J. Med. Chem., 1999, p. 2087-2104; followed by reaction with a source of electrophilic halogen such as SelectFluor (fluorination), followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935; or from commercially available N-Boc piperidone by silyl-enolization and reaction with NCS

(chlorination) by methods described in Armstrong, A. et al. J. Org. Chem. 2002, p.8610-8617; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935;

An example of of IXa where -L-is CH2CH2, R2 is chlorine and n is 1 is prepared from commercially available JV-Boc-nortropinone by methods described in Armstrong, A. et al. J. Org. Chem. 2002, p.8610-8617; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.

Compounds with formula Va, Vb, or Vc may be prepared according to standard procedures known to a person skilled in the art, as outlined below.

Deprotection of a compound with formula Xa, Xb, or Xc:

wherein A, n, R2 - Rl 2 and -L-are as described above, and PG is a protecting group such as the Boc group.

Deprotection may be performed according to procedures known to the skilled person. For a general reference see Greene and Wutts: Protecting groups in organic synthesis. 3^rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0-471-16019-9.

Compounds with formula Xa, Xb, or Xc may be prepared according to standard procedures known to chemists skilled in the art, as outlined below. a) Reaction of a compound with formula II with a compound with formula XIa, XIb, or XIc under basic conditions.

XIa XIb XIc

wherein n, R2 and -L-are as described above, and PG is a protecting group such as the Boc group.

The reaction of compounds with formula II with a compound with formula XIa, XIb, or XIc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula II and compound with formula XIa, XIb, or XIc in a suitable solvent such as acetonitrile or 2-butanone at a suitable temperature such as 20-80 °C, in the presence of a suitable base such as potassium carbonate or diisopropyl-ethyl amine.

b) Reaction of a compound with formula IV with a compound with formula XIa, XIb, or XIc under reducing conditions.

The reaction of compounds with formula IV with a compound with formula XIa, XIb, or XIc may be performed by standard procedures known to chemists skilled in the art. This includes reacting compounds with formula IV and compound with formula XIa, XIb, or XIc with a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane at a suitable temperature such as 15-30 °C, in the presence or absence of a suitable acid such as acetic acid.

The invention disclosed herein is further illustrated by the following non-limiting examples. Preparation of intermediates

Preparation of the intermediates with structure II

Ia: l-β-Bromo-propyl)-3,4-dihvdro-lH-guinolin-2-one:

Sodium hydride (60% in oil dispersion) (187 mmol) was suspended in DMF (75 rnL). 3,4- Dihydro-2(lH)-quinolinone (170 mmol) was suspended in DMF (100 mL) and added portion wise at 10 °C. The mixture was stirred at room temperature for ca. 90 min., and then poured into a ice-cooled solution of 1,3-dibromopropane in DMF (100 mL) with vigorous stirring. The mixture was stirred for ca. 15 min., and then poured into NaCl (aq., sat.) (800 mL). The aqueous phase was extracted with ethyl acetate (3x300 mL) and the combined organic extracts were dried on MgSO₄. After filtration the solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica using an eluent of 35% ethyl acetate in heptane. Yield = 38%.

¹H NMR (D₆-DMSO): 2.08 (qui, 2H); 2.54 (t, 2H); 2.86 (t, 2H); 3.59 (t, 2H); 4.00 (t, 2H); 7.01 (t, IH); 7.16 (d, IH); 7.20-7.29 (m, 2H).

Ib: 4-(3-Bromo-propyl)-4H-benzo[ 1 ,4] oxazin-3-one:

Prepared as described for compound Ia using 4H-benzo[l,4]oxazin-3-one. Yield = 62%.

¹H NMR (D₆-DMSO): 2.10 (qui, 2H); 3.59 (t, 2H); 4.02 (t, 2H); 4.65 (s, 2H); 6.99-7.10 (m, 3H); 7.23 (d, IH). l-(3-Bromo-propyl)-8-fluoro-3,4-dihvdro-lH-quinolin-2-one 1 c : 3-Chloro-N- (2-fluoro-phenyl)-propionamide

2- Fluoroaniline (60 mmol) was dissolved in 1,2-dichloroethane (50 niL) and pyridine (66 mmol) was added. The flask was placed on a water bath (ca. 15 °C) and 3-chloropropionyl chloride (66 mmol) was added drop wise. Stirred at room temperature for 2h, then the reaction mixture was washed with H₂O and then HCl (2M, aq.). The organics were dried on MgSO₄, filtered and the solvent removed by evaporation. Yield = 88% 1H NMR (D₆-DMSO): 2.91 (t, 2H); 3.88 (t, 2H); 7.12-7.29 (3H); 7.91 (m, IH); 9.87 (br s, IH).

Id: 8-Fluoro-3, 4-dihydro-lH-quinolin-2-one

Compound Ic (53 mmol) was mixed well with anhydrous aluminium trichloride (74 mmol) (caution: heating!) in a flask equipped with a washing flask containing NaOH (2M). The resulting melt was heated at 220 °C for 2h, then the melt was cooled and poured into ice- water. The formed precipitate was collected by filtration and dried in vacuo. The crude product was absorbed onto silica gel and purified by flash chromatography on silica using a gradient from 30% ethyl acetate in heptane to 50% ethyl acetate in heptane as eluent. Used without further purification. Yield = 60% 1H NMR (D₆-DMSO): 2.48 (t, 2H); 2.92 (t, 2H); 6.79-7.14 (3H); 10.08 (s, IH). Ie: l-(3-Bromo-propyl)-8-fluoro-3, 4-dihydro-lH-quinolin-2-one

Prepared as described for compound Ia using compound Id. Yield = 70% 1U NMR (D₆-DMSO): 2.26 (qui, 2H); 2.62 (t, 2H); 2.89 (t, 2H); 3.41 (t, 2H); 4.08 (t, 2H); 6.95-7.03 (3H).

l-(3-Bromo-propyl)-7 -fluoro-3 A-dikvdro-lH-quinolin-2-one If: 3-Chloro-N-(3-fluoro-phenyl)-propionamide

Prepared as described for compound Ic using 3-fluoroaniline.

Yield = 87%

¹U NMR (CDCl₃): 2.83 (t, 2H); 3.89 (t, 2H); 6.83 (dt, IH); 7.15 (d, IH); 7.27 (m, IH); 7.43 (br s, IH); 7.50 (m, IH).

Ig: 7-Fluoro-3, 4-dihydro-lH-quinolin-2-one

Prepared as described for compound Id using compound If. Used without further purification. Yield = 90%

¹U NMR (CDCl₃): 2.64 (t, 2H); 2.94 (t, 2H); 6.49 (dd, IH); 6.69 (dt, IH); 7.11 (dd, IH); 7.85 (br s, IH). Ih: l-(3-Bromo-propyl)-7-fluoro-3,4-dihydro-lH-quinolin-2-one

Prepared as described for compound Ia using compound Ig. Yield = 40% 1H NMR (CDCl₃): 2.22 (qui, 2H); 2.45 (t, 2H); 2.87 (t, 2H); 3.48 (t, 2H); 4.05 (t, 2H); 6.71 (dt, IH); 6.81 (dd, IH); 7.11 (dt, IH).

l-(3-Chloro-propyl)-6-fluoro-3,4-dihvdro-lH-quinolin-2-one Ii: l-Hydroxy-3, 4-dihydro-lH-quinolin-2-one

1,2,3,4-Tetrahydro-quinoline (80 mmol) was dissolved in MeOH (500 mL) and Na₂WO₄ • 2

H₂O was added. The mixture was cooled to 5 °C on an ice-water bath, then H₂O₂ (30% aq.)

(25mL, 220 mmol) was added drop wise. Stirred at room temperature for 72h. The solvent was removed by evaporation, the residue was re-dissolved in dichloromethane, dried on MgSO₄, and filtered. The solvent was evaporated and the crude product adsorbed onto silica gel. Purified by flash chromatography on silica using a gradient from 50% ethyl acetate in heptane to ethyl acetate eluent.

Yield = 37%

¹H NMR (CDCl₃): 2.76 (t, 2H); 2.95 (t, 2H); 7.05 (t, IH); 7.16 (d, IH); 7.30 (t, IH); 7.37 (d, IH); 9.19 (s, IH).

Ij : 6-Fluoro-3,4-dihydro-lH-quinolin-2-one

Compound Ii (21 mmol) was dissolved in dichloromethane (100 mL) under an argon atmosphere and cooled to 5 °C. DAST (25 mmol) was added drop wise over a course of ca. 10 min. Stirred for 10 min., then poured onto NaHCCh (aq., sat.) (400 rnL). The phases were separated and the aqueous phase was extracted xl with dichloromethane. The organics were combined, washed with brine, dried on MgSO₄ and filtered. The solvent was removed by evaporation. The crude product was purified by flash chromatography on silica using 50% ethyl acetate in heptane as eluent. The isolated product was recrystallized from ethyl acetate/heptane (ca. 15:85) Yield = 23% 1H NMR (CDCl₃): 2.63 (t, 2H); 2.96 (t, 2H); 6.77-6.92 (3H); 9.68 (br s, IH).

Ik: l-(3-Chloro-propyl)-6-fluoro-3,4-dihydro-lH-quinolin-2-one

Sodium hydride (60% in oil dispersion) (10 mmol) was dissolved in DMSO (50 mL) at 60 °C. Cooled to room temperature, then compound Ij (7 mmol) was added and the mixture was stirred for Ih. l-bromo-3-chloro-propane (33 mmol) was added at once, stirring was continued for Ih. The reaction mixture was poured onto H₂O (250 mL), and the aqueous phase was extracted x2 with diethyl ether. The organic extracts were combined, dried on MgSO₄ and filtered. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica using 50% ethyl acetate in heptane as eluent. Yield = 66% 1H NMR (CDCl₃): 2.13 (qui, 2H); 2.64 (t, 2H); 2.89 (t, 2H); 3.62 (t, 2H); 4.08 (t, 2H); 6.88- 7.04 (3H).

l-(3-Bromo-propyl)-5-fluoro-3,4-dihvdro-lH-quinolin-2-one 11: Diethyl 2-(2-fluoro-6-nitrobenzyl)malonate

Sodium hydride (60% oil dispersion) (112 mmol) was suspended in DMF (110 mL) and THF (50 mL). Diethyl malonate (109 mmol) was dissolved in THF (20 mL) and added drop wise while maintaining the temperature of the reaction mixture below 40 °C, then stirred at ambient temperature for 2h. 2-Fluoro-6-nitro-benzylbromide (107 mmol) was dissolved in DMF (40 mL) and THF (30 mL) and added drop wise while maintaining the temperature of the reaction mixture below 50 °C. Refluxed for 3h, then stirred at ambient temperature for 18h. Poured onto NaCl (aq., sat.) (300 mL), and the aqeuous phase was extracted x2 with ethyl acetate. The combined organic fractions were washed with brine, dried on MgSO₄ and filtered. The solvent was removed under reduced pressure to yield a red oil. Used without further purification.

Im: 3-(2-Fluoro-6-nitrophenyl)propanoic acid

Compound 11 (ca. 106 mmol) was dissolved in glacial acetic acid (100 mL), and HCl (cone.) (50 mL) and H₂O (5OmL) was added. Refluxed for 6h, then stirred at room temperature for 18h. The solvent was evaporated, and the residue was stirred with H₂O (500 mL). The formed precipitate was filtered off and dissolved in NaOH (2M) (400 mL) and EtOH (400 mL). The mixture was refluxed for 40 min., then the solvent volume was reduced to 500 mL and ice (30Og) and HCl (4M) was added to acidic pH. The aqueous phase was extracted x3 with ethyl acetate, and the organic fractions were combined, washed with brine, dried on MgSO₄ and filtered. The crude was obtained as a dark solid and was used without further purification. Yield = 79%

¹H NMR (D₆-DMSO): 2.55 (t, 2H); 3.04 (t, 2H); 7.52-7.65 (2H); 7.82 (d, IH); 12.38 (br s, IH).

In: 5-Fluoro-3,4-dihydro-lH-quinolin-2-one

Compound Im (9,4 mmol) was dissolved in MeOH (125 mL) and Pd/C (10%) (250 mg) and ammonium formate (94 mmol) was added. Refluxed for 45 min., then the mixture was cooled and filtered. The solvent was removed by evaporation, toluene (50 mL) was added, and removed by evaporation. The residue was partitioned between ethyl acetate and brine, the aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried on MgSO₄ and filtered. The solvent was removed by evaporation and the product was used without further purification.

Yield = 96%

¹H NMR (D₆-DMSO): 2.47 (t, 2H); 2.87 (t, 2H); 6.70 (d, IH); 6.77 (m, IH); 7.16 (m, IH).

lo: l-(3-Bromo-propyl)-5-fluoro-3,4-dihydro-lH-quinolin-2-one

Prepared as described for compound Ia using compound In. Yield = 49%

¹H NMR (D₆-DMSO): 2.06 (qui, 2H); 2.57 (t, 2H); 2.87 (t, 2H); 3.58 (t, 2H); 4.00 (m, 2H); 6.91 (m, IH); 7.02 (d, IH); 7.30 (m, IH).

l-(3-Chloro-prop\l)-6, 7 -difiuoro-3 ,4-dϊkvdro-lH-quinolin-2-one Ip: 3-Chloro-N-(3,4-difluoro-phenyl)-propionamide

3,4-Difluoro-phenylamine (250 mmol) was dissolved in ethyl acetate (500 mL) and triethyl amine (300 mmol) was added. 3-Chloropropionyl chloride (275 mmol) was added drop wise while maintaining the temperature below 30 °C. Stirred at room temperature for Ih, then H₂O (250 mL) was added. The phases were separated and the organic phase was washed with brine, dried on MgSO₄, and filtered. The solvent was evaporated to yield the product, which was used without further purification. Yield = 73% Iq: 6, 7-Difluoro-3,4-dihydro-lH-quinolin-2-one

Compound Ip (120 mmol) was mixed well with aluminium trichloride (150 mmol) (caution: heating!) in a flask equipped with a washing flask containing NaOH (2M). The resulting melt was heated at 180 °C for Ih, then the melt was cooled and poured into ice-water and added HCl (12M) (25mL) and dichloromethane (200 mL). Stirred well, the opbtained solid was recovered by filtration and dried. The crude product was recrystallized from ethyl acetate. Yield = 37%

¹H NMR (D₆-DMSO): 2.44 (t, 2H); 2.85 (t, 2H); 6.82 (m, IH); 7.30 (m, IH); 10.14 (br s, IH).

Ir: l-(3-Chloro-propyl)-6, 7 -dijluoro-3 , 4-dihydro-lH-quinolin-2-one

Prepared as described for compound Ik using compound Iq. Purified by flash chromatography on silica using 30% ethyl acetate in heptane as eluent. Yield = 73%

¹H NMR (CDCl₃): 2.13 (qui, 2H); 2.64 (t, 2H); 2.86 (t, 2H); 3.63 (t, 2H); 4.03 (t, 2H); 6.85- 7.06 (2H).

Is: l-(3-Bromo-propyl)-6-methoxy-3,4-dihvdro-lH-quinolin-2-one

Prepared as described for compound Ia using 6-methyxy-3,4-dihydro-l/f-quinolin-2-one.

Purified by flash chromatography on silica using 35 % ethyl acetate in heptane as eluent. Yield = 48% ¹H NMR (D₆-DMSO): 2.05 (qui, 2H); 2.50 (t, 2H); 2.82 (t, 2H); 3.56 (t, 2H); 3.73 (s, 3H); 3.96 (t, 2H); 6.79-6.86 (2H); 7.07 (d, IH).

l-(3-Bromo-propyl)-7-methoxy-3,4-dihvdro-lH-quinolin-2-one It: (E)-3-(4-Methoxy-2-nitro-phenyl)-acrylic acid

4-Methoxy-2-nitro-benzaldehyde (320 mmol) was dissolved in pyridine (500 rnL) and malonic acid (320 mmol) was added. Refluxed for 3h, then the mixture was cooled to room temperature. Ethyl acetate was added and the mixture was rendered acidic with HCl (2M). The phases were separated, the organic phase was washed with HCl (2M), then washed with water and then brine. Dried on MgSO₄ and filtered, the solvent was removed by evaporation.

Yield = 64%

¹H NMR (D₆-DMSO): 3.89 (s, 3H); 6.49 (d, IH); 7.33 (dd, IH); 7.58 (d, IH); 7.72 (d, IH);

7.93 (d, IH); 12.57 (br s, IH).

Iu: (E)-3-(4-Methoxy-2-nitro-phenyl)-acrylic acid methyl ester

Compound It (178 mmol) was dissolved in MeOH (500 mL) and HCl/ether (sat.) (250 mL) was added. Stirred at room temperature for 18h, then then solvent was evaporated and the residue was dissolved in etyl acetate. A similar volume ice-water was added and the mixture was adjusted to pH 10 with NaOH (2M). The phases were separated and the aqueous phase was extracted with ethyl acetate, the organic fractions were combined, dried on MgSO₄ and filtered. The solvent was removed by evaporation.

Yield = 91% 1H NMR (CDCl₃): 3.82 (s, 3H); 3.91 (s, 3H); 6.30 (d, IH); 7.16 (dd, IH); 7.50 (d, IH); 7.58

(d, IH); 8.04 (d, IH). Iv: 3-(2-Amino-4-methoxy-phenyl)-propionic acid methyl ester

Compound Iu (148 mmol) was dissolved in EtOH (700 mL) and Raney Nickel (1Og) was added. Stirred under a hydrogen atmosphere for 72h, then the reaxtion mixture was filtered and the solvent was removed by evaporation. The crude was purified by flash chromatography on silica using 50 % ethyl acetate in heptane as eluent. Yield = 67%

Iw: 7-Methoxy-S, 4-dihydro-lH-quinolin-2-one

Compound Iv (88 mmol) and potassium hydroxide (89 mmol) was refuxed in MeOH (500 mL) for Ih, the reaction mixture was cooled and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and water, the phases were separated and the organic phase was dried on MgSO₄ and filtered. The solvent was evaporated to yield the product. Yield = 96%

¹H NMR (CDCl₃): 2.62 (t, 2H); 2.90 (t, 2H); 3.77 (s, 3H); 6.34 (d, IH); 6.52 (dd, IH); 7.05 (d, IH); 8.19 (br s, IH).

Ix: l-(3-Bromo-propyl)- 7-methoxy-3, 4-dihydro- lH-quinolin-2-one

Prepared as described for compound Ia using compound Iw. Purified by flash chromatography on silica using 35 % ethyl acetate in heptane as eluent. Yield = 38%

¹H NMR (D₆-DMSO): 2.07 (qui, 2H); 2.51 (t, 2H); 2.78 (t, 2H); 3.59 (t, 2H); 3.76 (s, 3H); 3.99 (t, 2H); 6.69 (dd, IH); 6.69 (d, IH); 7.12 (d, IH). Iy: 7-Fluoro-4H-benzo[ 1 , 4]oxazin-3-one

3-Fluoro-6-nitrophenol (134 mmol) was dissolved in EtOH (250 mL) and Pd/C (5%) (2g) was added. Hydrogenated at room temperature for 3h in a Parr apparatus under 3 bar H₂. The catalyst was filtered off and the solvent removed by evaporation. The residue was dissolved in DMF (200 mL) and chloroacetylchloride (209 mmol) was added with stirring. Stirred at room temperature for 18h, then K2CO3 (360 mmol) was added and stirring was continued another 24h. Evaporated, the residue was partitioned between H₂O and ethyl acetate. The phases were separated and the organic phase was dried on MgSO₄ and filtered, and the solvent was removed by evaporation. The obtained solid was recrystallized from warm ethyl acetate. The mother liquor was concentrated and purified by flash chromatography on silica using 40 % ethyl acetate in heptane as eluent. The product fractions were combined. Yield = 80% 1H NMR (D₆-DMSO): 4.58 (s, 2H); 6.80 (m, IH); 6.86-6.90 (2H); 10.72 (br s, IH).

Iz: 4-(3-Chloro-propyl)- 7-fluoro-4H-benzo [ 1 , 4]oxazin-3-one

Prepared as described for compound Ik using compound Iy. Purified by flash chromatography on silica using 30% ethyl acetate in heptane as eluent. Yield = 86%

¹H NMR (CDCl₃): 2.15 (qui, 2H); 2.63 (t, 2H); 4.08 (t, 2H); 4.60 (s, 2H); 6.72-6.80 (2H); 7.00 (m, IH). 2a: 4-(3-Bromo-propyl)-6-fluoro-4H-benzo [ 1 ,4] oxazin-3-one

Prepared as described for compound Ia using 6-fluoro-2H-l,4-benzoxazin-3(4H)-one. Purified by flash chromatography on silica using 35% ethyl acetate in heptane as eluent. Yield = 60%

¹H NMR (D₆-DMSO): 2.09 (qui, 2H); 3.59 (t, 2H); 3.99 (t, 2H); 4.64 (s, 2H); 6.84 (dt, IH); 7.03 (dd, IH); 7.19 (dd, IH).

4-(3-Chloro-propyl)-6, 7-difluoro-4H-benzo [ 1 ,4] oxazin-3-one 2b: 6, 7-Difluoro-4H-benzo[ 1,4] oxazin-3-one

Prepared as described for compound Iy using 4,5-difluoro-2-nitrophenol. Purified by flash chromatography on silica using 40% ethyl acetate in heptane as eluent. Yield = 70% 1H NMR (D₆-DMSO): 4.59 (s, 2H); 6.70 (dd, IH); 7.15 (dd, IH); 10.77 (br s, IH).

2c: 4-(3-Chloro-propyl)-6, 7-difluoro-4H-benzo[ 1 ,4] oxazin-3-one

Prepared as described for compound Ik using compound 2b. Purified by flash chromatography on silica using 30% ethyl acetate in heptane as eluent. Yield = 82%

¹H NMR (CDCl₃): 2.15 (qui, 2H); 3.64 (t, 2H); 4.05 (t, 2H); 4.61 (s, 2H); 6.85 (m, IH); 6.94 (m, IH). 2d: 4-(3-Bromo-propyl)-6-chloro-4H-benzo [ 1 ,4] oxazin-3-one

Prepared as described for compound Ia using 6-chloro-2H-l,4-benzoxazin-3(4H)-one. Purified by flash chromatography on silica using 35% ethyl acetate in heptane as eluent. Yield = 52%

¹H NMR (D₆-DMSO): 2.10 (qui, 2H); 3.59 (t, 2H); 4.01 (t, 2H); 4.67 (s, 2H); 7.00-7-08 (2H); 7.33 (m, IH).

2e: 4-(3-Bromo-propyl)-6-methyl-4H-benzo [ 1 ,4] oxazin-3-one

Prepared as described for compound Ia using 6-methyl-2H-l,4-benzoxazin-3(4H)-one.

Purified by flash chromatography on silica using 35% ethyl acetate in heptane as eluent. Yield = 63%

¹H NMR (D₆-DMSO): 2.11 (qui, 2H); 2.29 (s, 3H); 3.59 (t, 2H); 4.00 (t, 2H); 4.58 (s, 2H); 6.81 (dd, IH); 6.89 (d, IH); 7.06 (dd, IH).

4-(3-Chloro-propyl)-6-methoxy-4H-benzo[ 1,4] oxazin-3-one 2f : 6-Methoxy-4H-benzo[ 1 , 4] oxazin-3-one

Prepared as described for compound Iy using 4-methoxy-2-nitrophenol. Used without further purification. Yield = 100% 1H NMR (D₆-DMSO): 3.68 (s, 3H); 4.48 (s, 2H); 6.45-6.51 (2H); 10.62 (br s, IH). 2g: 4-(3-Chloro-propyl)-6-methoxy-4H-benzo [ 1 , 4]oxazin-3-one

Prepared as described for compound Ia using compound 2m and l-bromo-3-chloropropane. Purified by flash chromatography on silica using 25% ethyl acetate in heptane as eluent. Yield = 75%

¹H NMR (CDCl₃): 2.19 (qui, 2H); 3.65 (t, 2H); 3.82 (s, 3H); 4.10 (t, 2H); 4.56 (s, 2H); 6.55 (dd, IH); 6.68 (d, IH); 6.93 (d, IH).

2h: 4-(3-Bromo-propyl)-4H-benzofl,4Jthiazin-3-one

Prepared as described for compound Ia using (2H)l,4-benzothiazin-3(4H)-one. Purified by flash chromatography on silica using 35% ethyl acetate in heptane as eluent. Yield = 14%

¹H NMR (D₆-DMSO): 2.07 (qui, 2H); 3.50 (s, 2H); 3.52 (t, 2H); 4.08 (t, 2H); 7.06 (dt, IH); 7.28-7.26 (2H); 7.42 (dd, IH).

2i: 4-β-Bromo-propyl)-7-chloro-4H-benzofl,4Jthiazin-3-one

Prepared as described for compound Ia using 7-chloro-4H-benzo[l,4]thiazin-3-one. Purified by flash chromatography on silica using 35% ethyl acetate in heptane as eluent. Yield = 65% ¹H NMR (D₆-DMSO): 2.06 (qui, 2H); 3.51 (t, 2H); 3.54 (s, 2H); 4.07 (t, 2H); 7.35 (m, 2H); 7.54 (m, IH).

2j: 3-(3-Chloro-propyl)-3H-benzoxazol-2-one

Sodium hydride (60% in oil dispersion) (155 mmol) was washed with diethyl ether under an argon atmosphere, then suspended in DMF (75 mL). 3H-Benzoxazol-2-one (148 mmol) was dissolved in DMF (150 mL) and added drop wise to the slurry. After stirring for ca. 30 min. the mixture was homogenous and was then cooled to -5 °C on an acetone-ice bath. 1-Bromo- 3-chloropropane (296 mmol) was dissolved in DMF (50 mL) and added drop wise to the cold solution. The reaction mixture was allowed to come to room temperature and stirring was continued for 18h. Poured into H₂O, the aqueous phase was extracted x3 with ethyl acetate.

The combined organic fractions were washed x2 with NH₄Cl (aq., sat.) dried on MgSO₄ and the solvent was removed by evaporation to yield an oil which solidified on standing. The obtained solid was washed with diethyl ether and dried in vacuo. The product was udes without further purification.

Yield = 54%

¹H NMR (D₆-DMSO): 2.16 (qui, 2H); 3.71 (t, 2H); 3.96 (t, 2H); 7.14 (t, IH); 7.24 (t, IH);

7.29-7.36 (2H).

4c: 4-(3-Chloro-propyl)-4H-benzofl,4Jthiazin-3-one:

Was prepared analogously to compound 2h using l-bromo-3-chloro-propane Yield = 12% 1H NMR (D₆-DMSO): 1.98 (qui, 2H); 3.50 (s, 2H); 3.65 (t, 2H); 4.09 (t, 2H); 7.07 (m, IH); 7.29-7.36 (2H); 7.43 (m, IH). 4d: (rac)-4-(3-Chloro-propyl)-l-oxo-l,4-dihvdro-2H-l ⁴-benzo[l,4]thiazin- 3-one:

Compound 4c (21 mmol) was dissolved in methanol (10 mL), sodium periodate (22 mmol) was suspended in water (3 mL) and added. Stirred for 3 days at room temperature, then partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase extracted x2 with ethyl acetate. The organic fractions were combined, washed with brine, then dried on MgSO₄, filtered and evaporated. The obtained crude product was stirred with ethyl acetate and heptane (1:1) (6mL) with caused separation of the product as a white solid. Dried in vacuo. Yield = 44%

¹H NMR (D₆-DMSO): 1.94-2.08 (2H); 3.67 (t, 2H); 4.10-4.41 (4H); 7.30 (m, IH); 7.57 (m, IH); 7.69 (m, IH); 7.85 (m, IH).

4e: l-f3-Chloro-propyl)-3-methyl-l,3-dihvdro-benzoimidazol-2-one

l-(3-Chloro-propyl)-l,3-dihydro-benzoimidazol-2-on (24 mmol), potassium t-butoxide (48 mmol) were combined in dry THF (100 mL) and MeI (118 mmol) was added. Stirred at room temperature for Ih, then the mixture was poured onto water and extracted x3 with ethyl acetate. The combined organic extracts were dried on MgSO₄, filtered and evaporated. Used without further purification. Yield = 98%

¹H NMR (CDCl₃): 2.23 (qui, 2H); 3.41 (s, 3H); 3.57 (t, 2H); 4.04 (t, 2H); 6.96 (m, IH); 7.05- 7.14 (3H). 4f: 3-(3-Hvdroxy-propyl)-3H-benzothiazol-2-one

Sodium hydride (60 % in mineral oil) (58 mmol) was suspended in DMF (100 mL), and benzothiazolone (53 mmol) was added. The reaction mixture was stirred for Ih at room temperature, then a solution of 3-bromo-l-propanol (58 mmol) in DMF (20 mL) was added dropwise. Stirred at ambient temperature over night, the reaction mixture was diluted with water and extracted with ethyl acetate x3. The organic fractions were combined, washed with brine x3, dried on MgSO₄, filtered and evaporated.The crude was purifϊrd by flash chromatography on silica using ethyl acetate / heptane (1 :1) as rthe eluent, to yield the product as an oil. Yield = 86%

¹H NMR (CDCl₃): 1.95 (qui, 2H); 3.11 (br, IH); 3.63 (m, 2H); 4.12 (t, 2H); 7.11-7.20 (2H); 7.33 (t, IH); 7.44 (d, IH).

4g: 3-(3-Bromo-propyl)-3H-benzothiazol-2-one

Compound 4f (15 mmol) and carbon tetrabromide (18 mmol) was dissolved in acetonitrile (100 mL) at room temperature, under an atmosphere of N₂. To this mixture was added PS- triphenylphosphine (14.5 g, 1.53 mmol/g loading). The mixture was stirred at room temperature for 2h. To the mixture was added trirthylamine (7.2 mmol), and stirring was continued for Ih. After this the reaction mixture was filtered and evaporated, and the crude product was purified on silica using 20% ethyl acetate /heptane as eluent. Yield = 79% 1H NMR (CDCl₃): 2.33 (qui, 2H); 3.48 (t, 2H); 4.12 (t, 2H); 7.15-7.22 (2H); 7.35 (t, IH); 7.45 (d, IH). 4h: 3-Oxo-3,4-dihvdro-2H-ctuinoxaline-l-carboxylic acid tert-butyl ester

3,4-Dihydro-lH-quinoxalin-2-one (67 mmol) was dissolved in dry THF (150 mL), then di- tert-butyl-dicarbonate (142 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated and purified on silica using 30% ethyl acetate in heptane as eluent. Yield = 55%

¹H NMR (CDCl₃): 1.55 (s, 9H); 4.39 (s, 2H); 6.92 (m, IH); 7.00-7.14 (2H); 7.64 (m, IH); 9.41 (br, IH).

4i: 4-(3-Chloro-propyl)-3-oxo-3,4-dihvdro-2H-auinoxaline-l-carboxylic acid tert-butvl ester

Sodium hydride (60 % in mineral oil) (41 mmol) was suspended in dry THF (20 mL) and a solution of compound 4h (37 mmol) in dry THF (60 mL) was added dropwise. Stirred for Ih at room temperature, then l-bromo-3-chloro-propane (74 mol) dissolved in dry THF (20 mL) was added dropwidse. The reaction mixture was stirred at reflux over night. Poured onto water and extracted x3 with ethyl acetate, the organic extracts were combined, dried on MgSO₄, filtered and evaporated. The crude was purified on silica using 25% ethyl acetate in heptane as eluent. Yield = 83%

¹H NMR (CDCl₃): 1.53 (s, 9H); 2.17 (qui, 2H); 3.64 (t, 2H); 4.11 (t, 2H); 4.37 (s, 2H), 7.05- 7.23 (3H); 7.64 (m; IH). Preparation of the intermediates with structure IXa

4j: (lS,3R,5R)-3-Hvdroxy-8-aza-bicvclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

O Nortropine (78 mmol) was dissolved in dry THF (250 mL), and di-tert-butyl-dicarbonate (82 mmol) was added. Stirred at ambient temperature for Ih. The solvent was removed by evaporation and the resisue recrystallized from ethyl acetate/heptane. The product was collected and dried in vacuo. Yield = 80% 1H NMR (D₆-DMSO): 1.38 (s, 9H); 1.61 (m, 2H); 1.70-1.93 (4H); 2.12 (m, 2H); 3.91 (br; IH); 3.99 (br, 2H); 4.58 (s, IH).

4k; flSJSJW-S-flJ-Dioxo-lJ-dihvdro-isoindol^-vDS-aza-bicvclofSJ.lloctane-S- carboxylic acid tert-butyl ester

Compound 4j (59 mmol) and phthalimide (88 mmol) was dissolved in dry THF (600 mL).

The mixture was cooled to 15 ⁰C, then triphenylphosphine (94 mmol) was added. The mixture was stirred for 15 minutes, then diisopropyl azodicarboxylate (100 mmol) was added dropwise during 20 minutes, while keeping the temperature at 10-15 ⁰C. The reaction mixture was allowed to come to room temperature and was stirred for 2h, then the solvent was removed by evaporation and the crude product was purified on silica using 30% ethyl acetate in heptane as eluent. Yield = 25% ¹H NMR (D₆-DMSO): 1.48 (s, 9H); 1.59 (m, 2H); 1.73 (m, 2H); 1.97 (m, 2H); 2.42 (m, 2H); 4.13 (br, 2H); 4.55 (hep, IH); 7.80-7.87 (4H).

41: ( 1 S,3 S,5R)-3-Amino-8-aza-bicvclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Compound 4k (15 mmol) was dissolved in ethanol (125 mL), and hydrazine hydrate (22.5 mmol) was added, and the mixture was refluxed for 3h. The reaction mixture was cooled on ice and filtered, then the solution was evaporated and the crude product was purified on silica using an eluent of ethyl acetate/ethanol/triethylamine (70:25:5). Yield = 75%

¹H NMR (D₆-DMSO): 1.22 (m, 2H); 1.40 (s, 9H); 1.58 (m, 2H); 1.66 (m, 2H); 1.80 (m, 2H); 2.99 (hep, IH); 3.32 (br); 4.00 (br, 2H).

Preparation of the intermediates with structure IHa, IHb, or IHc

4m: (rac)-3-Methyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester

NaH (60 w% in mineral oil) (75 mmol) was suspended in dry THF ( 200 mL), and a solution of Boc-piperidone in dry THF ( 150 mL) was added dropwise at room temperature. The reaction mixture was stirred for Ih at this temperature, then methyl iodide (75 mmol) was added. The reaction mixture was refluxed overnight, then diluted with water and extracted x3 with ethyl acetate. The combined organic extracts were washed with brine and dried on MgSO₄, filtered and evaporated. The crude product was purified twice on silica using 10% ethyl acetate in heptane as eluent,as by-products were difficult to separate completely. Yield = 16% ¹H NMR (CDCl₃): 1.03 (d, 3H); 1.48 (s, 9H); 2.34-2.58 (3H); 2.84 (br, IH); 3.25 (m, IH); 4.06-4.35 (2H).

4n: (rac)-(cis/trans)-4-Amino-3-methyl-piperidine-l-carboxylic acid tert-butyl ester

Compound 4m (13 mmol) was dissolved in MeOH (30 niL) and ammonium formate (75 mmol) and sodium cyanoborohydrate (14 mmol) was added followed by molecular sieves, (3A) (Ig). The reaction mixture was stirred for 3h at ambient temperature, then it was filtered and the solvent evaporated. The residue was purified on silica, using as eluent a gradient of ethyl acetate/ethanol/triethylamine (70:26:4) to ethyl acetate/ethanol /triethylamine (80:16:4) to yield the product as a mixture of stereoisomers as determined by NMR. Yield = 60%

4o : (rac)-(cis/trans)-3-Methyl-4-phenylacetylamino-piperidine-l-carboxylic acid tert-butyl ester

Compound 4n (5 mmol) was dissolved in dry THF (60 mL) and triethylamine (7 mmol) was added. The reaction mixture was cooled to 0 ⁰C, and phenyl acetylchloride (7 mmol) was added dropwise. Stirred at room temperature fro Ih, then the reaction was filtered and the solvent removed by evaporation. The crude product was purified on silica using as eluent a gradient of 30% ethyl acetate in heptane to 100% ethyl acetate to yield the product as a mixture of stereoisomers as determined by NMR. Yield = 49% 4p: (rac)-(cis/trans)-N-β-Methyl-piperidin-4-yl)-2-phenyl-acetamide

Compound 4o (2 mmol) was dissolved in MeOH (6 mL) and HCl in ether (2M) (5 mmol) was added. Stirred at room temperature over night, then the solvents were evaporated and the residue was diluted with ice water. Ammonia in water (25w%) was added until the pH was slightly basic (pH 8-10), then the mixture was extracted with ethyl acetate x3. The organics were combined, dried on MgSO₄, filtered and evaporated. Teh crude product was purified on silica using an eluent of ethyl acetate/ ethanol/triethylamine (92:4:4). The product was obtained as a mixture of stereoisomers as determined by NMR Yield = 76%

Preparation of the intermediates with structure Va, b or c:

2k: 4- [3-(4-Amino-piperidin- l-vD-propyl] -4H-benzo [ 1 ,4] oxazin-3-one

Compound Ib (18 mmol) and piperidin-4-yl-carbamic acid tert-hvXy\ ester (18 mmol) was dissolved in MeCN (50 mL) and K₂CO₃ (20 mmol) was added. Stirred at 80°C for 18h, then cooled and poured into H₂O. The aqueous phase was extracted x2 with ethyl acetate and the combined organic extracts were dried on MgSO₄ and filtered. The solvent was removed under reduced pressure to yield an oil which was purified by flash chromatography on silica using 50% ethyl acetate in heptane as eluent. The obtained product was dissolved in dichloromethane and TFA/H₂O (95:5) (15mL) was added. After 20 min. more H₂O was added and the solution was added NaOH (2M) to pH ca. 12. The aqueous phase was extracted x3 with ethyl acetate, the organic fractions were combined, dried on MgSO₄ and the solvent was removed by evaporation to yield the product as an oil. Yield = 50%

¹H NMR (D₆-DMSO): 1.36 (m, 2H); 1.66 (m, 2H); 1.75 (m, 2H); 1.88 (t, 2H); 2.29 (t, 2H); 2.72 (m, IH); 2.79 (m, 2H); 2.84 (t, 2H); 3.44 (m, 2H); 3.88 (t, 2H); 6.99 (t, IH); 7.14-7.28 (3H).

21: 1 - [3 -(4-Amino-piperidin- 1 -yl)-propyl] -3 ,4-dihydro- 1 H-quino lin-2-one

Prepared as described for compound 2k using compound Ia. Yield = 35% 1H NMR (D₆-DMSO): 1.36 (m, 2H); 1.65 (m, 2H); 1.74 (m, 2H); 1.88 (m, 2H); 2.28 (m, 2H); 2.70 (m, IH); 2.78 (m, 2H); 2.83 (m, 2H); 3.88 (m, 2H); 6.99 (t, IH); 7.15-7.28 (3H).

General procedures for the preparation of compounds with formula I

Examples:

2m: N-{l-[3-(2-Oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2-phenyl- acetamide

A suspension of diisopropylamino methyl-polystyrene (20 mg, 3.67 mmol/g) in 0.5 mL of a stock solution of l-[3-(4-amino-piperidin-l-yl)-propyl]-3,4-dihydro-lH-quinolin-2-one (21) (0.1 mmol/mL) in acetonitrile was cooled to 0⁰C. 0.5 mL of a stock solution of phenylacetyl chloride (0.1 mmol/mL) was added. The reaction mixture was shaken at 0 ⁰C for 30 min and then at room temperature for 16 h. The reaction mixture was filtered and solvent was removed under reduced pressure. The crude product was purified by prep. LC-MS. LC/MS: m/z = 406,6 (MH+), retention time = 0,72; method C.

The following were prepared analogously:

2n: N-{l-[3-(2-Oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-vH-acetamide

Prepared from 21 and acetyl chloride. LC/MS: m/z = 330 (MH+); retention time = 0,49; method C.

2o: 3-Methyl-N-{l-[3-(2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- butyramide

Prepared from 21 and 3-methyl-butyryl chloride.

LC/MS: m/z = 372,3 (MH+); retention time = 0,66; method C.

2p: Cvclobutanecarboxylic acid {l-[3-(2-oxo-3, 4-dihvdro-2H-quinolin-l-yl)-propyl]- Oweridin-4-vH-amide

N O

Prepared from 21 and cyclobutanecarbonyl chloride

LC/MS: m/z = 370,2 (MH+); retention time = 0,61; method C.

2q: 2-(4-Chloro-phenyl)-N-{l-[3-(2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4- vH-acetamide

Prepared from 21 and (4-chloro-phenyl)-acetyl chloride. LC/MS: m/z = 440,2 (MH+); retention time = 0,83; method C.

2r: 2-Cvclopentyl-N-{l-f3-f2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propylJ-piperidin-4-yl}- acetamide

Prepared from 21 and cyclopentyl-acetyl chloride. LC/MS: m/z = 398,3 (MH+); retention time = 0,76; method C.

2s: 2-Ethyl-N-{l-[3-(3-oxo-2,3-dihvdro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-vH- butyramide

Prepared from 2k and 2-ethyl-butyryl chloride. LC/MS: m/z = 388,4 (MH+); retention time = 0,68; method C. 2t: 2-(4-Methoxy-phenyl)-N^~ -{ l-[3-(3-oxo-2 ,3-dihvdro-benzo [ 1 ,4) ^} oxazin-4-yl) -propyl] - piperidinA-yli-acetamide

Prepared from 2k and (4-methoxy-phenyl)-acetyl chloride. LC/MS: m/z = 438,4 (MH+); retention time = 0,72; method C.

2u: 2-β-Chloro-phenyl)-N-{l-f3-β-oxo-2,3-dihvdro-benzofl,4Joxazin-4-yl)-propylJ- piperidin-4-vH-acetamide

Prepared from 2k and (3-chloro-phenyl)-acetyl chloride.

LC/MS: m/z = 442,4 (MH+); retention time = 0,82; method C.

2v: 2-(3-Methoxy-phenyl)-N^~ -{ l-[3-(3-oxo-2 ,3-dihvdro-benzo [ 1 A) ^} oxazin-4-yl) -propyl] - piperidin-4-yl}-acetam,ide

Prepared from 2k and (3-methoxy-phenyl)-acetyl chloride.

LC/MS: m/z = 438,4 (MH+); retention time = 0,73; method C. 2w: 2-Cvclohexyl-N-{ 1- [3-(2-oxo-3 ,4-dihvdro-2H-quinolin- l-vD-propyl] -piperidin-4-yl}- acetamide

0.4 mL of a stock solution of l-[3-(4-amino-piperidin-l-yl)-propyl]-3,4-dihydro-lH-quinolin- 2-one (21) (0.125 mmol/niL) in DMF and 0.4 mL of a stock solution of cyclohexyl- acetic acid (0.125 mmol/mL) in DMF were combined, and 0.22 mL of a stock solution of HOBt, EDC HCl and DIPEA, 0.25M in each in DMF was added to the reactor. The reactors were heated at 80 °C for 16h with gentle shaking. The reactions were filtered and evaporated, then the crude products were purified by prep. LC-MS. LC/MS: m/z = 412,4 (MH+), retention time = 0,85; method C.

The following was prepared analogously:

2x: 2-(3,4-Dichloro-phenyl)-N-{l-[3-(2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin- 4-vH-acetamide

Prepared from 21 and 3,4-dichloro-phenylacetic acid. LC/MS: m/z = 474,6 (MH+); retention time = 0,93; method C. 2y: N- { 1- [3-(3-Oxo-2 ,3-dihvdro-benzo [ 1 A) ^} oxazin-4-yl) -propyl) ^] -piperidin-4-yl}- isobutyramide

^\ ,,CL

^ N ^O

A suspension of TBD-methyl polystyrene (0.33 mmol) was added to 1 ml of a stock solution of 4-amino-piperidine-l-carboxylic acid tert-bvXy\ ester (0.1 mmol/mL) in 1,2-dichloroethane. Isobutyryl chloride (0.11 mmol) was added to the reactors and the reactions were shaken over night at room temperature.

Tris-(2-aminoethyl)amine polystyrene (0.33 mmol) was added to the reactors, and the reactions were shaken for 120 min. The reaction mixtures were filtered into a deep well plate. TFA (2.5 mmol) was added and the reactions were shaken for 120 min at room temperature. The intermediate was purified by SCX (The SCX-column was preconditioned with a 10% solution of AcOH in MeOH, the sample directly loaded, the loaded columns were washed with MeOH and acetonitrile, and the intermediate was then eluted with 4 M NH3 in MeOH).

The solvent was removed under reduced pressure and the residue was dissolved in DMF (200

L). 4-(3-bromo-propyl)-4/f-benzo[l,4]oxazin-3-one (Ib) (0.045 mmol) and DIPEA (0.225 mmol) were added. The reactors were shaken for 90 min at room temperature and then placed in an oven at 50 ⁰C over night. The reactions were purified by prep. LC-MS. LC/MS: m/z = 360,1 (MH+), retention time = 0,90; method B.

The following were prepared analogously: 2z: N-{ 1- [3-(6-Methoxy-2-oxo-3 ,4-dihvdro-2H-quinolin- l-vD-propyl] -piperidin-4-yl}- isobutyramide

Prepared from Is, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and isobutyryl chloride.

LC/MS: m/z = 388,5 (MH+), retention time = 0,91; method B.

3a: 2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-methoxy-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl}-acetam,ide

Prepared from Ix, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and (3,4-dimethoxy- phenyl)-acetyl chloride.

LC/MS: m/z = 496,6 (MH+), retention time = 1,05; method B.

3b: N-{l-[3-(6-Chloro-3-oxo-2,3-dihvdro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-2- (3,4-dimethoxy-phenyl)-acetamide

Prepared from 2d, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride. LC/MS: m/z = 502,5 (MH+), retention time = 0,77; method A. 3c: N- { l-[3-(6-Methyl-3-oxo-2 ,3-dihvdro-benzo [ 1 ,4) ^} oxazin-4-yl) -propyl) '-piperidin-4-ylϊ- propionamide

Prepared from 2e, 4-amino-piperidine-l-carboxylic acid tert-bvXy\ ester and n-propionyl chloride.

LC/MS: m/z = 360,1 (MH+), retention time = 0,93; method B.

3d: Cvclopropanecarboxylic acid { l-[3-(6-methyl-3-oxo-2 ,3-dihvdro-benzo [ 1 A) ^]oxazin-4-yl)- propyl] -piperidin-4-yli-amide

Prepared from 2e, 4-amino-piperidine-l-carboxylic acid tert-bvXy\ ester and cyclopropanoyl chloride.

LC/MS: m/z = 372,4 (MH+), retention time = 0,63; method A.

3e: 2-(3 A-Dimethoxy-phenyl)-N-{ l-[3-(6-fluoro-3-oxo-2,3-dihvdro-benzo[ 1 A] oxazin-4-yl)- propyl] -piperidin-4-vH-acetamide

Prepared from 2a, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride. LC/MS : m/z = 486,6 (MH+), retention time = 1 ; method B. 3f: 2-Benzo[ 1 ,3] dioxol-5-yl-N-{ l-[3-(6-fluoro-3-oxo-2 ,3-dihvdro-benzo[ 1 ,4] oxazin-4-yl)- propylJ-piperidin-4-ylϊ-acetamide

Prepared from 2a, 4-amino-piperidine-l-carboxylic acid tert-bvXy\ ester and benzo [ 1 ,3 ]dioxo 1-5 -yl-acetyl chloride. LC/MS: m/z = 470,5 (MH+), retention time = 1,04; method B.

3g: N-{l-[3-(7-Chloro-3-oxo-2,3-dihvdro-benzo[l,4]thiazin-4-yl)-propyl]-piperidin-4-vH- isobutyramide

Prepared from 2i, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and isobutyryl chloride.

LC/MS: m/z = 410,4 (MH+), retention time = 0,77; method A.

3h:N-{ 1- [3-(3-Oxo-2 ,3-dihvdro-benzo [ 1 A) Hhiazin-4-yl) -propyl) ^] -piperidin-4-yl}- yroyionamide

Prepared from 2h, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and n-propionyl chloride.

LC/MS: m/z = 362,5 (MH+), retention time = 0,88; method B.

3i: 2-(3-Methoxy-phenyl)-N-{l-[3-(3-oxo-2,3-dihvdro-benzo[l,4]thiazin-4-yl)-propyl]-

Oweridin-4-vH-acetamide

Prepared from 2h, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and (3-methoxy- phenyl)-acetyl chloride. LC/MS : m/z = 454,3 (MH+), retention time = 1,11; method B.

3j: N-{l-[3-(3-Oxo-2,3-dihvdro-benzo[l,4]thiazin-4-yl)-propyl]-piperidin-4-vH- isobutyramide

Prepared from 2h, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and isobutyryl chloride. LC/MS: m/z = 376,1 (MH+), retention time = 0,61; method A.

3k: N-{l-f3-(3-Oxo-2,3-dihvdro-benzofl,4Jthiazin-4-yl)-propylJ-piperidin-4-ylϊ-2-phenyl- acetamide

Prepared from 2h, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and benzoyl chloride. LC/MS: m/z = 424,1 (MH+), retention time = 0,74; method A. 31: 2-(3-Methoxy-phenyl)-N-{l-[3-(2-oxo-benzooxazol-3-yl)-propyl]-piperidin-4-yl}- acetamide

Prepared from 2j, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3-methoxy- phenyl)-acetyl chloride.

LC/MS: m/z = 424,1 (MH+), retention time = 1,02; method B.

3m: N-{ 1- [3-(8-Fluoro-2-oxo-3 ,4-dihvdro-2H-quinolin- l-vD-propyl] -piperidin-4-yl}- propionamide

Prepared from Ie, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and n-propionyl chloride.

LC/MS: m/z = 362,5 (MH+), retention time = 0,87; method B.

3n: 2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-fluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl}-acetam,ide

Prepared from Ih, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride. LC/MS : m/z = 484,4 (MH+), retention time = 1 ,03; method B. 3o: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- propionamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and n-propionyl chloride.

LC/MS: m/z = 380,6 (MH+), retention time = 0,94; method B.

3p: N-{1- [3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-vH- isobutyramide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and isobutyryl chloride.

LC/MS: m/z = 394,2 (MH+), retention time = 0,66; method A.

3q: N-{l-[3-(6, 7-Difluoro-3-oxo-2,3-dihvdro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-vH- isobutyramide

Prepared from 2c, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and isobutyryl chloride. LC/MS: m/z = 396,2 (MH+), retention time = 0,96; method B.

3r: N- { l-[3-(7-Fluoro-3-oxo-2 ,3-dihvdro-benzo/ 1 A) ^} oxazin-4-yl) -propyl) '-piperidin-4-ylϊ- propionamide

Prepared from Iz, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and n-propionyl chloride.

LC/MS: m/z = 364,6 (MH+), retention time = 0,85; method B.

3s: 2-(3 ,4-Dimethoxy-phenyl)-N-{ l-[3-(7-fluoro-3-oxo-2 ,3-dihvdro-benzo[ 1 ,4] oxazin-4-yl)- propyl] -piperidin-4-vH-acetamide

Prepared from Iz, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride. LC/MS : m/z = 486,5 (MH+), retention time = 1,01; method B.

3t: N-/l-f3-f7-Fluoro-3-oxo-2,3-dihvdro-benzofl,4Joxazin-4-yl)-propylJ-piperidin-4-yl}-2- thiophen-2-yl-acetamide

Prepared from Iz, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and thiophen-2-yl- acetyl chloride. LC/MS: m/z = 432,5 (MH+), retention time = 1,01; method B.

3u: 2-Benzo[ 1 ,3] dioxol-5-yl-N-{ l-[3-(7-fluoro-3-oxo-2 ,3-dihvdro-benzo[ 1 ,4] oxazin-4-yl)- propyl] -piperidin-4-vH-acetamide

Prepared from Iz, 4-amino-piperidine-l-carboxylic acid tert-hvXy\ ester and benzo[l,3]dioxol-

5-yl-acetyl chloride.

LC/MS: m/z = 470,5 (MH+), retention time = 1,06; method B.

3v: N- { 1- [3-(7-Fluoro-3-oxo-2 ,3-dihvdro-benzo [ 1 A) ^} oxazin-4-yl) -propyl) ^] -piperidin-4-yl}- butyramide

Prepared from Iz, 4-amino-piperidine-l-carboxylic acid tert-bvXy\ ester and n-butyryl chloride. LC/MS : m/z = 378,5 (MH+), retention time = 0,92; method B.

3w: N-{l-[3-(5-Fluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-vH- propionamide

Prepared from lo, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and n-propanoyl chloride.

LC/MS: m/z = 362,4 (MH+), retention time = 0,9; method B.

3x: 2-(3,4-Dimethoxy-phenyl)-N-{l-f3-(5-βuoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)- propyl] -piperidin-4-vH-acetamide

Prepared from lo, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride. LC/MS: m/z = 484,4 (MH+), retention time = 1,04; method B.

3y: N-{ 1- [3-(5-Fluoro-2-oxo-3 ,4-dihvdro-2H-quinolin- l-vD-propyl] -piperidin-4-yl}- butyramide

Prepared from lo, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and n-butyryl chloride. LC/MS: m/z = 376,4 (MH+), retention time = 0,95; method B. 3z: N-I l-[3-(3-Oxo-2 ,3-dihvdro-benzo/ 1 A) ^] oxazin-4-yl) -propyl) '-piperidin-4-ylϊ-acetamide

Prepared from Ib, 4-amino-piperidine-l-carboxylic acid tert-butyi ester and acetyl chloride. LC/MS: m/z = 332,2 (MH+), retention time = 0,8; method B.

4a: Cvclopropanecarboxylic acid /l-f3-β-oxo-2,3-dihvdro-benzofl,4Joxazin-4-yl)-propylJ- piperidin-4-vH-amide

Prepared from Ib, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and cyclopropanoyl chloride.

LC/MS: m/z = 358,4 (MH+), retention time = 0,88; method B.

4b: N-{l-f3-(3-Oxo-2,3-dihvdro-benzofl,4Joxazin-4-yl)-propylJ-piperidin-4-ylϊ-2-phenyl- acetamide

Compound 2k (17 mmol) was dissolved in dry THF (60 mL) and triethylamine (26 mmol) was added. The mixture was cooled to 5 °C and phenylacetyl chloride (19 mmol) was added drop wise. The mixture was stirred at room temperature for Ih. The crude mixture was filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica with gradient elution from 80 % ethyl acetate in heptane (+ 5 v% triethylamine) to 5% EtOH in ethylacetate (+ 5v% triethylamine). Yield = 64% LC/MS: m/z = 408,5 (MH+), retention time = 1,0; method B.

4q: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2-(3- methoxy-phenvD-acetamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3-methoxy- phenyl)-acetyl chloride. LC/MS: m/z = 472.6 (MH+), retention time = 1.15; method B.

4r: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- acetamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and acetyl chloride. LC/MS: m/z = 366.6 (MH+), retention time = 0.55; method A.

4s: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2- (3,4-dimethoxy-phenyl)-acetamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and (3,4-dimethoxy- phenyl)-acetyl chloride.

LC/MS: m/z = 502.5 (MH+), retention time = 0.75; method A. 4t: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2- phenyl-acetamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and phenyl-acetyl chloride.

LC/MS: m/z = 442.5 (MH+), retention time = 0.8; method A.

4u: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-3- methyl-butyramide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and 3-methyl-butyryl chloride.

LC/MS: m/z = 408.5 (MH+), retention time = 0.74; method A.

4v: Cvclopropanecarboxylic acid {l-[3-(6, 7-difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)- propyll -piperidin-4-yli-amide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and cyclopropanoyl chloride. LC/MS: m/z = 392.7 (MH+), retention time = 0.64; method A. 4w: 2-Benzo[l,3]dioxol-5-yl-N-{l-[3-(6, 7-difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl}-acetam,ide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and benzo[l,3]dioxol- 5-yl-acetyl chloride.

LC/MS: m/z = 486.6 (MH+), retention time = 1.1; method B.

4x: N-{1- [3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2- thiophen-2-yl-acetamide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and thiophen-2-yl- acetyl chloride.

LC/MS: m/z = 448.4 (MH+), retention time = 1.06; method B.

4y: N-{l-[3-(6, 7-Difluoro-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)-propyl]-piperidin-4-vH- butyramide

Prepared from Ir, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and n-butyryl chloride. LC/MS: m/z = 394.5 (MH+), retention time = 0.97; method B. 4z: (rac)-N-S(lS.3S.5R)-8-[3-(1.3-Dioxo-2.3-dihvdro-lH-llambda*4*-benzo[1.41thiazin-4- vD-propyll -8-aza-bicvclo [3.2.1 loct-3-yl}-isobutyramide

Prepared from 4d, (lS,3S,5R)-3-Amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester and isobutyryl chloride .

LC/MS: m/z = 418.8 (MH+), retention time = 0.86; method B.

5a: N-I(IS, 3S,5R)-8-[3-(3-Methyl-2-oxo-2,3-dihvdro-benzoimidazol-l-yl)-propyl] -8-aza- bicvclo [3.2.11 oct-3-yli-propionamide

Prepared from 4e, (lS,3S,5R)-3-Amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester and n-propionyl chloride.

LC/MS: m/z = 371.4 (MH+), retention time = 0.87; method B.

5b : N-KlS, 3 S.5R)-8-[3-(2-Oxo-benzooxazol-3-yl)-propyll-8-aza-bicvclo[3.2.1 loct-3-yli- isobutyramide

Prepared from 2j, (lS,3S,5R)-3-Amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester and isobutyryl chloride . LC/MS: m/z = 372.4 (MH+), retention time = 0.89; method B. 5c: N-{l-[3-(2-Oxo-benzothiazol-3-yl)-propyll-piperidin-4-yl}-isobutyramide

Prepared from 4g, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and isobutyryl chloride . LC/MS: m/z = 362.4 (MH+), retention time = 0.91; method B.

5&. N-/aS.3S.5R)-8-f3-f7-Methoxy-2-oxo-3.4-dihvdro-2H-quinolin-l-yl)-propyl]-8-aza- bicvclo[3.2.11 oct-3-yl}-propionamide

Prepared from Ix, (lS,3S,5R)-3-Amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester and n-propionyl chloride. LC/MS: m/z = 400.3 (MH+), retention time = 0.95; method B.

5e: N-{l-[3-(2-Oxo-3,4-dihvdro-2H-quinoxalin-l-yl)-propyl]-piperidin-4-yl}-propionamide

Prepared from 4i, 4-amino-piperidine-l-carboxylic acid tert-butyl ester and n-propionyl chloride. The intermediate product obtained from the procedure as described for 2y, was added TFA (2.5 mmol) the reaction was shaken for 120 min at room temperature, before it was evaporated to dryness to yield the title compound. LC/MS: m/z = 345.4 (MH+), retention time = 0.82; method B. 5f: (rac)-N-{(3S.4S)-3-Methyl-l-r3-(3-oxo-2.3-dihvdro-beDzori.41oxazin-4-yl)-propyl1- piperidin-4-vU-2-phenyl-acetamide

Compound 4p (1.7 mmol) and Ib (1.9 mmol) were dissolved in acetonitrile, and K2CO3 (2.8 mmol) was added. The reaction mixture was re fluxed for 4h, then it was filtered and the solvent removed by evaporation. The crude product was purified on silica using an eluent of 5% triethylamine in ethyl acetate to obtain the product. The product iso meres separated into the racemic cis and recemic trans diastereomers. The title compound (racemic trans diatereomer) eluted as the last product and was obtained in 17% yield. LC/MS: m/z = 422.3 (MH+), retention time = 1.03; method B.

¹H NMR (CDCl₃): 0.82 (d, 3H); 1.28 (m, IH); 1.38 (m, IH); 1.71 (t, 2H); 1.82 (m, 2H); 1.91 (m, IH); 1.99 (dt, IH); 2.37 (t, 2H); 2.81 (m, 2H); 6.97-7.07 (4H); 7.25-7.40 (5H).

Abbreviations: DMF = JV,JV-dimethyl formamide

THF = tetrahydrofurane

DAST = Diethylaminosulfur trifluoride

DMSO = dimethylsulfoxide

TFA = trifluoroacetic acid DIEA/DIPEA= N,JV-diisopropyl-JV-ethyl amine

IBX = l-hydroxy-l,2-benziodoxol-3(lH)-one 1-oxide

HOBt= 1-hydroxybenzotriazole

NCS = JV-Chloro succinimide

EDC HCl =l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride AcOH = acetic acid

Boc = te/t-butylcarbonyloxy Reagents used for the preparation of compounds Ia - 4b

Name CAS no. Supplier Catalog no.

3,4-Dihydro-2(lH)-quinolinone 553-03-7 ALDRICH 415936

4H-Benzo[l,4]oxazin-3-one 5466-88-6 ALDRICH 383503

1,3-Dibromopropane 109-64-8 ALDRICH 12,590-3

Piperidin-4-yl-carbamic acid tert-butyl ester

73874-95-0 ALDRICH 54,093-5 2-Bromo-pyridin-3-ylamine 39856-58-1 ALFA L19839

3 -Chloropropyl acetate 628-09-1 ALDRICH 166561

Triethylphosphonoacetate 867- 13-0 ALDRICH T6,130-l

2- Fluoroaniline 348-54-9 ALDRICH F3401

3-Chloropropionyl chloride 625-36-5 ALDRICH C69128 3 -Fluoroaniline 372-19-0 FLUOROCHEM 1438

1,2,3,4-Tetrahydroquinoline 635-46-1 ALDRICH T15504

Na₂WO₄ * 2 H₂O 10213-10-2 ALDRICH 14304

DAST 38078-09-0 ALDRICH 23,525-3

2-Fluoro-6-nitrobenzyl bromide 1958-93-6 ALFA L16240 3-Fluoro-6-nitrophenol 446-36-6 ALDRICH 23,324-2

Chloroacetyl chloride 79-04-9 ALDRICH 14,449-3

3,4-Difluoro-phenylamine 3863-11-4 ALDRICH 27,023-7

3-Chloropropionyl chloride 625-36-5 ALDRICH C6,912-8

6-Fluoro-2H- 1 ,4-benzoxazin-3(4H)-one 398-63-0 ALDRICH 557412

6-Methyxy-3,4-dihydro-lH-quinolin-2-one

54197-64-7 APOLLO OR9941

4-Methoxy-2-nitro-benzaldehyde 22996-21 -0 THREEB-MED 3B-16876 4 , 5 -Difluoro -2-nitropheno 1 APOLLO PC 2779 6-Chloro-2/f- 1 ,4-benzoxazin-3(4H)-one OAKWOOD 12230 6-Methyl-2H- 1 ,4-benzoxazin-3(4H)-one

39522-26-4 ALDRICH 475467 4-Methoxy-2-nitrophenol 1568-70-3 ALDRICH 387711 l-Bromo-3-chloropropane 109-70-6 ALDRICH B62404

(2H)l,4-Benzothiazin-3(4H)-one 5325-20-2 ALDRICH 175277 7-Chloro-4H-benzo[l,4]thiazin-3-one

5333-05-1 ALDRICH 54,358-6

3H-Benzooxazol-2-one 59-49-4 ALDRICH 157058 te/t-butyl-4-amino- 1 -piperidinecarboxylate

87120-72-7 ALDRICH 640042

IBX 61717-82-6 SYNTECH M1551

N-Boc-nortropinone 185099-67-( SIGMA 15515

1-Hydroxybenzotriazol 2592-95-2 ABCR AV21700

1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

25952-53-8 ALDRICH 16,146-2 diisopropylaminomethyl-polystyrene (PS-DIEA)

ALDRICH 538736 ALDRICH 538736

Nortropine 538-09-02-03 E-Merck 8.14892.0025

Benzothiazolone 934-34-9 Tyger Sci B50440 triphenylphosphine-polystyrene (PS-triphenylphosphine)

Senn Chemicals Lot 7746-AA/l

Pharmacological Testing

Calcium²⁺ flux assay for human Ml-mACh receptor stably expressed in CHO-Kl cells.

A. Stable cell lines. Standard molecular cloning techniques (Maniatis et al. Molecular Cloning, A Laboratory Manual (1989)) were used to generate a cell line of Chinese hamster ovary (CHO-Kl) cells stably expressing human muscarinic Ml receptor (Ml-mAChR). The cDNA encoding the Ml-mAChR corresponds to the sequence published in NCBI Genbank Nucleotide database, accession number Y00508. The cell line was grown in F- 12 Kaighn's medium with L- Glutamine (Gibco), 10% FetalClone I serum (HyClone), 1% penicillin and streptavidine, and 0.5 μg/ml G418 (Gibco).

B. Methods

CHO-Kl cells stably expressing human Ml-mAChR receptor were plated in growth medium at a density of 18.000 cells/well in clear-bottomed, cell-culture coated 96-well plates (Corning, Costar #3904) and grown for 48 hrs at 37°C in the presence of 5% CO₂. Before assay, the cells were washed with 2x100 μl of assay buffer (Hanks' balanced salt solution with Ca²⁺ and Mg²⁺(Gibco) containing 20 mM HEPES, pH 7.4. The cells were incubated with a calcium-sensitive fluorescent dye, Calcium assay kit R8033 (100 μl /well, half concentration relative to manufacturers instruction, Molecular Devices Inc) with 2.5 mM Probenecid (Sigma) for 50 minutes at 37°C and followed by 10 min at room temperature. Calcium flux was measured using a FLIPR³⁸⁴ fluorometric imaging plate reader (Molecular Devices Inc). The cells are periodically excited by 488 nm light and emitted fluorescent light passed through a 510-570 nm filter and detected by a cooled CCD camera (Sullivan et al., 1999). The FLIPR³⁸⁴ apparatus allows multiple liquid additions by computer-controlled liquid-handling hardware. Test compounds were diluted from 2 mM stock solutions in 100% DMSO in assay buffer, and then added to cells (25 μl to 100 μl in well). 10 different concentrations were tested for each compound. Fluorescence readout was measured for 5 minutes starting just prior to compound addition. C. Data analysis

The fluorescence readout was calculated as max-min response, i.e. maximum fluorescence reading after and before liquid addition. The fluorescence max-min data were normalized to yield responses for no stimulation (buffer) and full stimulation (1 μM acetylcholine) of 0% and 100% stimulation, respectively. Data were collected from at least three independent experiments. Concentration-response data were fitted to the four-parameter logistic equation to estimate compound potency (EC50) and efficacy (E_max) (Motulsky and Christopoulos, 2004). In this assay, common muscarinic agonists yielded potency/efficacy of:

E. Sullivan, E. M. Tucker, and I. L. Dale. Measurement of [Ca2+] using the Fluorometric Imaging Plate Reader (FLIPR). Methods. MoI Biol 114:125-133, 1999.

Harvey Motulsky, Arthur Christopoulos, Fitting Models to Biological Data Using Linear and Nonlinear Regression (A Practical Guide to Curve Fitting), ISBN: 0195171802, Oxford University, 2004.

Results of the experiments showed that the majority of the compounds of the invention had EC50 values of <50nM, many compounds <20nM and some had EC50 values <10nM.

Furthermore the majority of the tested compounds exhibited E_max stimulation values of >80%, many even >95%.

Claims

1. A Compound according to Formula I

wherein

G is a mono- or bicyclic heterocyclic group selected from:

Rl is Ci^ alkyl, C₃-₅ cycloalkyl, Ci^ alkyl-C₃.₇ cycloalkyl wherein each Ci^ alkyl, C₃.₅ cycloalkyl and C3.7 cycloalkyl may be optionally substituted with C1-6 alkyl-Cδ-io aryl_> Ce- 1₀ aryl, Ci^ alkyl-heteroaryl, or heteroaryl, and wherein each Ci-β alkyl-Cβ-io aryl, Cβ-io aryl, Ci^ alkyl-heteroaryl, or heteroaryl, may be optionally substituted with a halogen,- OH; Gr-6 thioalkoxy,^" CNrCf-^ alkyl r Ct^Talkbxy;^~or^"

Rl is C ₁ -₆ alkyl substituted with halogen or C|_₆ alkoxy,

-L- is CH₂CH₂ or CH₂CH₂CH₂ or absent,

he asterisk * denotes the attachment point of the group G,

RECTIFIED SHEET (RULE 91) ISA/EP R2 is independently selected from halogen and Ci^ alkyl,

n is an integer selected from O, 1 and 2,

R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci^ thioalkoxy, CN, Ci -6 alkyl and d-β alkoxy;

R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF₃, Ci_-6 alkyl and C i-₆ alkoxy, and

Rl 3 is H or C^ alkyl,

2. A compound according to claim 1, wherein n is 0 and -L-is absent.

3. A compound according to any one of the preceding claims, wherein R3, R4, R5, R6, R7 and R8 are all hydrogen.

4. A compound according to any one of the preceding claims, wherein Rl is selected from Cι-₆ alkyl or Ci^ alkyl-Cβ-io aryl.

5. A compound according to any one of the preceding claims, wherein R9, RlO, Rl 1 and R12 are all hydrogen.

6. A compound according to any one of claims 1-4, wherein at least one of R9, RlO, Rl 1 and Rl 2 is not hydrogen.

RECTIFIED SHEET (RULE 91) ISA/EP

7. A compound according to any one of claims 1-4, wherein at least one of R9, RlO, Rl 1 and Rl 2 is halogen.

8. A compound according to any one of claims 1-4, wherein at least one of R9, RlO, Rl 1 and R12 is C^ alkoxy.

9. A compound according to claim 1 , represented by the formula Ib

wherein

G is a mono- or bicyclic heterocyclic group selected from:

Rl is Ci alkyl, C^ alkyl, Cs-s cycloalkyl, Cf-β alkyl-C3-7 cycloalkyl wherein each Ci alkyl. C4-6 alkyl, C₃.₅ cycloalkyl and C₃.₇ cycloalkyl may be optionally substituted with Cβ-io aryl or heteroaryl, and wherein each C₆-io aryl or heteroaryl, may be optionally substituted with a halogen, OH, C ₁-₆ thioalkoxy, CN, C|-6 alkyl or Ci_-6 alkoxy; or

Rl is Ci alkyl or C₄^ alkyl are substituted with halogen or Ci^ alkoxy,

RECTIFIED SHEET (RULE 91) ISA/EP -L- is CH₂CH₂ or CH₂CH₂CH₂ or absent,

the asterisk * denotes the attachment point of the group G,

R2 is independently selected from halogen and Ci_-6 alkyl,

n is an integer selected from 0, 1 and 2,

R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Cι-₆ thioalkoxy, CN, Ci^ alkyl and Ci_-6 alkoxy;

A is a biradical selected from: O, CH₂, S, OCH₂, CH₂CH₂, SCH₂, SOCH₂, N-Ci^ alkyl and NRl 3CH₂,

R9 and Rl 2 are independently selected from H, halogen, CN, CF₃, Ci-β alkyl and

alkoxy, and

Rl 3 is H or Cu₆ alkyl,

10. A compound according to claim 9, wherein n is 0 and -L-is absent.

11. A compound according to any one of claims 9-10, claims wherein R3, R4, R5, R6, R7 and R8 are all hydrogen.

12. A compound according to any one of claims 9-11, wherein R9 and Rl 2 are both hydrogen.

13. A compound according to any one of claims 9-11, wherein at R9 and/or Rl 2 are not hydrogen.

RECTIFIED SHEET (RULE 91) ISA/EP

14. A compound according to any one of claims 1-13, wherein the compound is selected from:

N-{l-[3-(2-Oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2-pheny.l- _ acetamide

N-{ 1 -[3-(2-Oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl } -acetamide

3-Methyl-N-{ 1 -[3-(2-oxo-3 ,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-yl } - butyramide

Cyclobutanecarboxylic acid { l-[3-(2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]- piperidin-4-y 1 } -amide

2-(4-Chloro-phenyl)-N-{ 1 -[3-(2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4- yl} -acetamide

2-Cyclopentyl-N- { 1 - [3 -(2-oxo-3 ,4-dihydro-2H-quinolin- 1 -yl)-propyl]-piperidin-4-y 1 } - acetamide

2-Ethyl-N-{l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- butyramide

2-(4-Methoxy-phenyl)-N- { 1 -[3-(3-oxo-2,3-dihydro-benzo[ 1 ,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -acetamide

2-(3-Chloro-phenyl)-N- { 1 -[3-(3-oxo-2,3-dihydro-benzo[ 1 ,4]oxazin-4-yl)-propyl]- piperidin-4-yl } -acetamide

2-(3-Methoxy-phenyl)-N-{l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl } -acetamide

RECTIFIED SHEET (RULE 91) ISA/EP 2-Cyclohexyl-N-{ l-[3-(2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- acetamide

2-(3,4-Dichloro-ρhenyl)-N_r{J-[H2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]- piperidin-4-yl } -acetamide

N-{l-[3-(6-Methoxy-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- isobutyramide

2-(3,4-Dimethoxy-phenyl)-N-{ l-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl } -acetamide

N-{ 1 -[3-(6-Chloro-3-oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-2- (3 ,4-dimethoxy-phenyl)-acetamide

N-{l-[3-(6-Methyl-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- propionamide

Cyclopropanecarboxylic acid { l-[3-(6-methyl-3-oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)- propyl]-piperidin-4-yl } -amide

2-(3,4-Dimethoxy-phenyl)-N-{ l-[3-(6-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl } -acetamide

2-Benzo[l,3]dioxol-5-yl-N-{l-[3-(6-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propyl]-piperidin-4-yl } -acetamide

N-{ l-[3-(7-Chloro-3-oxo-2,3-dihydro-benzo[l,4]thiazin-4-yl)-propyl]-piperidin-4-yl}- isobutyramide

RECTIFIED SHEET (RULE 91) ISA/EP N-{ l-[3-(3-Oxo-2,3-dihydro-benzo[l,4]thiazin-4-yl)-propyl]-piperidin-4-yl}- propionamide

2-(3-Methoxy-phenyl)-N-{ l-[3-(3-oxo-2,3-dihydro-benzo[l,4]thiazin-4-yl)-propyl]τ piperidin-4-yl}-acetamide

N-{l-[3-(3-Oxo-2,3-dihydro-benzo[l,4]thia2in-4-yl)-propyl]-piperidin-4-yl}- isobutyramide

N-{ l-[3-(3-Oxo-2,3-dihydro-benzo[l ,4]thiazin-4-yl)-propyl]-piperidin-4-yl}-2-phenyl- acetamide

2-(3-Methoxy-phenyl)-N-{l-[3-(2-oxo-benzooxazol-3-yl)-propyl]-piperidin-4-yl}- acetamide

N-{l-[3-(8-Fluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- propionamide

2-(3,4-Dimethoxy-phenyl)-N-{l-[3-(7-fluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl]-piperidin-4-yl } -acetamide

N-{l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- propionamide

N-{l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- isobutyramide

N- { 1 - [3 -(6,7-Difluoro-3 -oxo-2 , 3 -dihydro-benzo[ 1 ,4]oxazin-4-yl)-propy 1] -piperidin-4-yl } - isobutyr amide

N-{ l-[3-(7-Fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4-yl}- propionamide

RECTIFIED SHEET (RULE 91) ISA/EP 2-(3,4-Dimethoxy-phenyl)-N-{ 1 -[3-(7-fluoro-3-oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)- propyl]-piperidin-4-yl } -acetamide

2-Benzo[l,3]dioxol-5-yl-N-{l-[3-(7-fluoro-3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)- propy 1] -piperidin-4-y 1 } -acetamide

N-{l-[3-(5-Fluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- propionamide

N-{1 -[3-(5-Fluoro-2-oxo-3,4-dihydro-2H-quinolin-l -yl)-propyl]-piperidin-4-yl}- butyramide

N-{ 1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-acetamide

Cyclopropanecarboxylic acid { l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -amide

N-{1 -[3-(3-Oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-piperidin-4-yl}-2-phenyl- acetamide

N-{8-[3-(3-Oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-8-aza-bicyclo[3.2.1]oct-3- y 1 } -2-phenyl-acetamide

N-{2-[3-(3-Oxo-2,3-dihydro-benzo[l ,4]oxazin-4-yl)-propyl]-2-aza-bicyclo[2.2.2]oct-5- RECTIFIED SHEET (RULE 91) ISA/EP yl } -2-pheny 1-acetamide

N-IS-tS^S-Oxo^.S-dihydro-benzofl^oxazin-^yO-propyll-S-aza-bicyclofa^.lJoct-S- yl } -2-phenyl-acetamide

rac-N-{2-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4- y 1 } -2-phenyl-acetamide

rac-N-{3-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]-piperidin-4- yl } -2-phenyl-acetamide

N-{l-[3-(2-Oxo-3,4-dihydro-2H-quinoxalin-l-yl)-propyl]-piperidin-4-yl}-2-phenyl- acetamide

N-{l-[3-(4-Methyl-2-oxo-3,4-dihydro-2H-quinoxalin-l-yl)-propyl]-piperidin-4-yl}-2- phenyl-acetamide

N-{l-[3-(l,3-Dioxo-2,3-dihydro-lH-lλ⁴-benzo[l,4]thiazin-4-yl)-propyl]-piperidin-4-yl}- 2-phenyl-acetamide

2-Phenyl-N-{ 1 -[3-( 1 , 1 ,3-trioxo-2,3-dihydro- 1 H- 1 λ⁶-benzo[ 1 ,4]thiazin-4-yl)-propyl]- piperidin-4-yl } -acetamide

N-{l-[3-(2-Oxo-benzothiazol-3-yl)-propyl]-piperidin-4-yl}-2-phenyl-acetamide

N-{l-[3-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-l-yl)-propyl]-piperidin-4-yl}-2- phenyl-acetamide

N-{l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}-2-(3- methoxy-phenyl)-acetamide

RECTIFIED SHEET (RULE 91) ISA/EP N-{l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- acetamide

N-{_^l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-y_l)-propyl]-piperidin-4-yl}j-2- (3,4-dimethoxy-phenyl)-acetamide

N- { 1 -[3-(6,7-Difluoro-2-oxo-3 ,4-dihydro-2H-quinolin- 1 -y l)-propyl]-piperidin-4-yl } -2- phenyl-acetamide

N-ll-tS-CβJ-Difluoro^-oxoO^-dihydro^H-quinolin-l-yO-propyll-piperidin^-ylJO- methyl-butyramide

Cyclopropanecarboxylic acid { 1 -[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yl)- propyl]-piperidin-4-yl } -amide

2-Benzo[l ,3]dioxol-5-yl-N-{ 1 -[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)- propyl] -piperidin-4-yl } -acetamide

N-{ 1 -[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin- 1 -yI)-propyl]-piperidin-4-yl}-2- thiophen-2-yl-acetamide

N-{l-[3-(6,7-Difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]-piperidin-4-yl}- butyramide

(rac)-N-{(lS,3S_}5R)-8-[3-(l,3-Dioxo-2,3-dihydro-lH-llambda*4*-benzo[l,4]thiazin-4- y l)-propyl]-8-aza-bicyclo [3.2.1 ]oct-3 -y 1 } -isobutyramide

N-{(lS,3S,5R)-8-[3-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-l-yl)-propyl]-8-aza- bicyclo [3.2.1] oct-3 -y 1 } -propionamide

RECTIFIED SHEET (RULE 91) ISA/EP N-{ l-[3-(2-Oxo-benzothiazol-3-yl)-propyl]-piperidin-4-yl}-isobutyramide

N-fClS^S.SR^S-tS-CT-Methoxy^-oxo-S^-dihydro^H-quinolin-l-yO-propyll-δ-aza- bicyclo[3.2.1 ]oct-3-yl } -propionamide

N-{l-[3-(2-Oxo-3,4-dihydro-2H-quinoxalin-l-yl)-propyl]-piperidin-4-yl}-propionamide

(rac)-N-{(3S,4S)-3-Methyl-l-[3-(3-oxo-2,3-dihydro-benzo[l,4]oxazin-4-yl)-propyl]- piperidin-4-yl} -2-phenyl-acetamide

or a pharmaceutically acceptable addition salt thereof.

IS. A compound as defined in any one of claims 1 to 14, for use as a medicament.

16. A compound as defined in any one of claims 1 to 14, for use in the treatment of schizophrenia.

17. A compound as defined in any one of claims 1 to 14, for use in the treatment of cognitive impairment such as mild cognitive impairment and cognitive impairment associated with schizophrenia.

18. A compound as defined in any one of claims 1 to 14, for use in the treatment of cognitive impairment associated with a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic- induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; .post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

RECTIFIED SHEET (RULE 91) ISA/EP

19. A compound as defined in any one of claims 1 to 14, for use in the treatment of cognitive impairment associated with a cognition disorder such as Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug^related_^dementia^ dementia associated _with_ intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment.

20. A compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for use in the treatment of schizophrenia.

21. A compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for use in the treatment of cognitive impairment such as mild cognitive impairment and cognitive impairment associated with schizophrenia.

22. A compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for use in the treatment of cognitive impairment associated with a condition or disease selected from the group consisting of a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic-induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a

RECTIFIED SHEET (RULE 91) ISA/EP specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

23. A compound as defined in any one of claims I to 14, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for use in the treatment of cognitive impairment associated with a condition or disease selected from the group consisting of a cognition disorder such as Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment.

24. A method of treating a mammal suffering from schizophrenia, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutical acceptable salt thereof.

25. A method according to Claim 24, wherein the compound of formula I and/or Ib according to any one of claims 1-14, or pharmaceutically acceptable salts thereof, is administered in combination with a neuroleptic agent such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

26. A method of treating a mammal suffering from cognitive impairment, such as mild cognitive impairment and cognitive impairment associated with schizophrenia, which method comprises administering an effective amount of a compound of any one of claims 1 to 14, or a pharmaceutical acceptable salt thereof.

27. A method of treating a mammal suffering from cognitive impairment associated with a condition or disease selected from the group consisting of a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the

RECTIFIED SHEET (RULE 91) ISA/EP delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic-induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance- induced psychotic disorder, for example psychosis_^ induced, by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder, which method comprises administering an effective amount of a compound of any one of claims 1 to 14, or a pharmaceutical acceptable salt thereof.

28. A method of treating a mammal suffering from cognitive impairment associated with a condition or disease selected from the group consisting of a cognition disorder such as Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment, which method comprises administering an effective amount of a compound of any one of claims 1 to 14, or a pharmaceutical acceptable salt thereof.

29. A compound according to formula I and/or Ib as defined in any one of claims 1-14 or a pharmaceutically acceptable salts thereof, for use according to claim 16 in combination with a neuroleptic agent such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 and one or more pharmaceutically acceptable carriers, diluents and excipients.

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