HK1191330B - Ethynyl derivatives as positive allosteric modulators of the mglur5 - Google Patents

Description

Ethynyl derivatives as positive allosteric modulators of MGLUR5

The invention relates to ethynyl derivatives of formula I

Wherein

X is N or C-R, wherein R is hydrogen or halogen;

g is N or CH;

provided that at most one of G or X may be nitrogen;

R¹is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R³，R^3’，R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring, with the proviso that m is 0 and n is 1 or 2;

R⁵is hydrogen or lower alkyl;

n is 0, 1 or 2;

m is 0 or 1; provided that n and m are not both 0;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

It has now surprisingly been found that the compounds of the general formula I are Positive Allosteric Modulators (PAM) of the metabotropic glutamate receptor subtype 5(mGluR 5).

In the Central Nervous System (CNS), transmission of stimuli occurs through the interaction of neurotransmitters emitted by neurons with neuroreceptors.

Glutamate is the major excitatory neurotransmitter in the brain and has a unique role in a variety of Central Nervous System (CNS) functions. Glutamate-dependent stimulus receptors fall into two main classes. The first major class, the ionotropic receptors, forms ligand-controlled ion channels. Metabotropic glutamate receptors (mGluRs) belong to the second major class, and also belong to the G-protein coupled receptor family.

Currently, eight distinct members of these mglurs are known, and some of these members even have subtypes. These eight receptors can be subdivided into three subgroups based on their sequence homology, signal transduction mechanisms and agonist selectivity:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group may be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

Other treatable indications in this connection are: restricted brain function resulting from shunt surgery or grafts, poor cerebral blood supply, spinal cord injury, head injury, hypoxia resulting from pregnancy, cardiac arrest and hypoglycemia. Further treatable indications are ischemia, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism (idiophatic parkinsonism) or parkinsonism caused by drugs and conditions which lead to glutamate-deficiency functions, such as, for example, muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction (nicotinoidism), opiate addiction, anxiety, vomiting, dyskinesia and depression.

Disorders that are wholly or partially mediated by mGluR5 are, for example, acute, traumatic and chronic degenerative processes of the nervous system, such as alzheimer's disease, senile dementia, parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychoses such as schizophrenia and anxiety, depression, pain and drug dependence (Expert opin.

One new approach for developing selective modulators is to identify compounds that act through allosteric mechanisms, modulating receptors by binding to sites that differ from the highly conserved orthosteric binding site. Positive allosteric modulators of mGluR5 have recently emerged as novel pharmaceutical entities offering this attractive alternative. Positive allosteric modulators are described, for example, in WO2008/151184, WO2006/048771, WO2006/129199 and WO2005/044797 and in molecular Pharmacology, 40, 333-336, 1991; the Journal of pharmacology and Experimental Therapeutics, Vol 313, No.1, 199-.

Positive allosteric modulators are compounds that do not directly activate the receptor by itself, but rather significantly enhance the agonist-evoked response, increase potency and maximize efficacy. Binding of these compounds increases the affinity of glutamate-site agonists for their extracellular N-terminal binding sites. Positive allosteric modulation is therefore an attractive mechanism to enhance activation of appropriate physiological receptors. Selective positive allosteric modulators of the mGluR5 receptor are rare. Conventional mGluR5 receptor modulators often lack satisfactory water solubility and exhibit poor oral bioavailability. Therefore, there remains a need for compounds that overcome these disadvantages and effectively provide selective positive allosteric modulators of the mGluR5 receptor.

The compounds of formula I are distinguished by valuable therapeutic properties. They may be useful in the treatment or prevention of disorders in which positive allosteric modulators of the mGluR5 receptor are involved.

The most preferred indications for compounds as positive allosteric modulators are schizophrenia and cognition.

The present invention relates to compounds of formula I and their pharmaceutically acceptable salts, to these compounds as pharmaceutically active substances, to processes for their preparation and to their use in the treatment or prevention of disorders in which positive allosteric modulators of the mGluR5 receptor are involved, such as schizophrenia, tuberous sclerosis (tuberosis) and cognition, as well as to pharmaceutical compositions comprising compounds of formula I.

The following definitions of general terms used in the present description apply regardless of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group, including straight or branched carbon chains having from 1 to 4 carbon atoms. Examples of "alkyl" are methyl, ethyl, n-propyl and isopropyl.

The term "alkoxy" denotes the group-O-R ', wherein R' is lower alkyl as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable acid addition salts" encompass salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the present invention are compounds of formula IA

Wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or lower alkyl;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples from this group of compounds are

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

(RS) -1, 5, 5-trimethyl-3- (5- (pyridin-3-ylethynyl) pyridin-2-yl) pyrrolidin-2-one

(RS) -3- (5- ((3-chlorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

(RS) -3-hydroxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

(RS) -3-methoxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

(RS) -1, 3, 5, 5-tetramethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one

(3RS, 3aSR, 6aSR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

(3RS, 3aSR, 6aSR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

(3S, 3aR, 6aR) or (3R, 3aS, 6aS) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

(3RS, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

(3SR, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

(3R, 6S, 7S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one and

(3S, 6R, 7R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

(3RS, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(3SR, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(3R, 6S, 7S) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(3S, 6R, 7R) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(3R, 6S, 7S) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(3S, 6R, 7R) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

(RS) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one

(S) or (R) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one or

(R) or (S) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one.

One embodiment of the present invention are compounds of formula IB

Wherein

X is N or C-R, wherein R is halogen;

R¹is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or lower alkyl;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples from this group of compounds are

(RS) -1, 5, 5-trimethyl-2-oxo-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidine-3-carboxylic acid benzyl ester

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidin-2-one

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one or

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyrimidin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one.

One embodiment of the present invention is a compound of formula IC

Wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or lower alkyl;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples from this group of compounds are

(RS) -3- (6- ((3-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

(RS) -3- (6- ((4-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one or

(RS) -3- (6- (phenylethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one.

One embodiment of the invention is a compound of formula ID

Wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R³，R^3’，R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

R⁵is hydrogen or lower alkyl;

n is 1 or 2;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples from this group of compounds are

(RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) piperidin-2-one

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyridin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

(RS) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one

(RS) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-azepan-2-one

(RS) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-azepan-2-one

(S or R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one or

(R or S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one.

One embodiment of the present invention is a compound of formula IE

Wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy or C (O) O-benzyl;

R³，R^3’，R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or lower alkyl;

R⁵is hydrogen or lower alkyl;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples from this group of compounds are

(RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) piperidin-2-one

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one or

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one.

One embodiment of the present invention is a compound of the formula

Wherein

X is N or C-R, wherein R is hydrogen, methyl or halogen;

g and A are independently N or CH;

with the proviso that at most one of G, A or X may be nitrogen;

q is O, N-R⁹or-CR⁶R^6’-；

R¹Is phenyl or heteroaryl, optionally substituted by halogen, lower alkyl or lower alkoxy;

R²is hydrogen, lower alkyl, hydroxy, lower alkoxy, C (O) O-benzyl, C (O) O-lower alkyl or CONR⁷R⁸；

R³，R^3’，R⁴，R^4’，R⁶，R^6’Independently of one another, hydrogen, lower alkyl, alkoxy, hydroxy or CH₂-lower alkoxy;

or R³And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

r5 is hydrogen, lower alkyl, or may be substituted with R⁴Together form C₃-C₆-a cycloalkyl group;

R⁷，R⁸is independently hydrogen, lower alkyl, or R⁷Can be reacted with R⁸Form C₃-C₆-a cycloalkyl ring;

R⁹is hydrogen or lower alkyl;

n is 0, 1 or 2;

m is 0 or 1;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

The preparation of the compounds of formula I of the present invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the present invention is shown in scheme 1 below. The skills required to carry out the reaction and the purification of the resulting product are known to those skilled in the art. The substituents and indices used in the following description of the process have the meanings given above.

The compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. However, the reaction sequence is not limited to the one shown in the scheme, and the order of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by the methods described in the references cited in the specification or in the examples or by methods known in the art.

The compounds of formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example by process variants comprising:

a) reacting a compound of formula 3

Wherein X¹Is halogen

With a compound of formula 4, with a pharmaceutically acceptable carrier,

to the compound of formula I

Wherein is defined as above, or

b) Reacting a compound of formula 5

Wherein X¹Is halogen

With a compound of formula 2,

to form a compound of formula I

Wherein the compounds obtained are as defined above or, if desired, converted into pharmaceutically acceptable acid addition salts.

The preparation of the compounds of formula I is further described in more detail in schemes 1 to 4 and in examples 1-46.

The acetylenic compounds of formula I can be obtained, for example, by: p-dihalogen disubstituted heterocyclic derivative 1 with an appropriately substituted cyclic amide 2 in the presence of a strong base such as sodium hydride, sodium hexamethyldisilazane (NaHMDS), Lithium Diisopropylamide (LDA), or in an inert solvent such as toluene, DMF, DMSO or THF; or with sodium alkoxides in the corresponding alcohols as solvents to form the corresponding 3-heteroaryllactam derivatives 3. Sonogashira coupling of lactam 3 with appropriately substituted arylacetylene 4 gives the desired ethynyl compounds of general formula I (scheme 1).

The acetylenic compound of formula I can be obtained as follows: for example when R²(iii) COO-benzyl or COO-lower alkyl, by hydrolysis of the ester group using, for example, aqueous sodium hydroxide or (of) potassium hydroxide in a solvent such as methanol or ethanol, followed by decarboxylation of the acid formed to give the compound of formula I, wherein R is²Is hydrogen (scheme 2).

The latter procedure may also be used to modify compounds of formula 3, wherein R²Is an ester to form a compound of formula 3, wherein R²Is hydrogen. Sonogashira coupling of lactam 3 with appropriately substituted arylacetylene 4 gives the desired ethynyl compounds of the general formula I, where R is²Is hydrogen (scheme 3).

Formula I can also be modified in certain cases, for example by first performing a Sonogashira coupling to form the appropriately substituted aryl-or heteroaryl-ethynyl derivative 5, followed by reaction with a lactam of formula 2 using procedures analogous to those described in schemes 1 to 3 (scheme 4).

Biological assays and data:

intracellular Ca²⁺Mobilization assay

Generating a monoclonal HEK-293 cell line stably transfected with cDNA encoding the human mGlu5a receptor; for work with mGlu5 Positive Allosteric Modulators (PAMs), cell lines with low receptor expression levels and low constitutive receptor activity were selected to be able to distinguish agonist activity from PAM activity. Cells were cultured according to standard protocols (Freshney, 2000) in high glucose Dulbecco's Modified Eagle Medium supplemented with 1mM glutamine, 10% (vol/vol) heat-inactivated calf serum, penicillin/streptomycin, 50 μ g/ml hygromycin and 15 μ g/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).

About 24 hours before the experiment, 5x10⁴Cells/well were seeded in poly-D-lysine coated 96-well plates with black/clear bottom. Cells were loaded with 2.5. mu.M Fluo-4AM in loading buffer (1xHBSS, 20mM HEPES) for 1hr at 37 ℃ and washed five times with loading buffer. Cells were transferred to a Functional Drug Screening System 7000(Hamamatsu, Paris, France) and 11 semilog serial dilutions of test compounds at 37 ℃ were added and cells were incubated for 10-30 minutes and fluorescence recorded online. After this pre-incubation step, the cells are added with EC₂₀The agonist L-glutamate at the corresponding concentration (typically about 80 μ M) and the fluorescence is recorded online; to illustrate the day-to-day variation in cellular responsiveness, the EC of glutamate was determined by recording the full dose response curve of glutamate immediately prior to each assay₂₀。

The response was measured as the peak increase in fluorescence minus the baseline (i.e., fluorescence without addition of L-glutamic acid), and the maximum stimulatory effect obtained with saturating concentrations of L-glutamic acid was normalized. Plot with% maximal stimulation using XLfit, a curve fitting program that iteratively plots the data using the Levenburg Marquardt algorithm. The single site competition assay equation used was y ═ a + ((B-a)/(1+ ((x/C) D))), where y is% maximal stimulatory effect, a is minimal y, B is maximal y, and C is EC₅₀X is the log10 of the concentration of competing compound and D is the slope of the curve (Hill Coefficient). From these curves, EC was calculated₅₀(concentration at which half maximal stimulation is achieved), hill coefficient and maximum response expressed as% maximal stimulatory effect obtained with saturating concentrations of L-glutamate.

In and with PAM test Compound Pre-incubation period (i.e., at application of EC)₂₀Prior to the concentration of L-glutamate) indicates agonist activity, and the absence of this signal indicates lack of agonist activity. In the addition of EC₂₀A decrease in the signal observed after the concentration of L-glutamate is indicative of the inhibitory activity of the test compound.

In the following table, the prepared compounds 1 to 46 are shown together with the corresponding results (EC)₅₀In nM).

List of examples:

the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, may be used for the aqueous injection solutions of the water-soluble salts of the compounds of formula (I), but in general this is not essential. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain additional other therapeutically valuable substances.

As mentioned before, medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, and processes for the preparation of these medicaments are also an object of the present invention, said processes comprising: bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

As also mentioned previously, the use of a compound of formula (I) for the preparation of a medicament useful in the prevention and/or treatment of the diseases listed above is also an object of the present invention.

The dosage can vary within wide limits and will of course be fitted to the individual requirements in each particular case. In general, an effective dose for oral or parenteral administration is 0.01-20 mg/kg/day, with a dose of 0.1-10 mg/kg/day being preferred for all indications mentioned. Accordingly, the daily dose for an adult having a body weight of 70kg is 0.7-1400 mg/day, preferably 7-700 mg/day.

Preparation of pharmaceutical compositions comprising the compounds of the invention:

example A

Tablets having the following composition were prepared in a conventional manner:

example 1

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

Step 1: (RS) -3- (5-iodo-pyridin-2-yl) -1, 5, 5-trimethyl-pyrrolidin-2-one

A solution of 2-fluoro-5-iodopyridine (260mg, 1.17mmol) and 1, 5, 5-trimethyl-pyrrolidin-2-one (148mg, 1.17mmol) in 6ml of dry toluene was purged with argon and cooled to-4 ℃. A1M solution (2.33ml, 2.33mmol) of sodium hexamethyldisilazide (NaHMDS) in toluene was added dropwise to maintain the temperature below 0 deg.C. The red solution was stirred at 0 ℃ for 2h and quenched by the addition of 5ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (400mg) was taken up in ethyl acetate and adsorbed onto 5g of silica gel loaded onto a 20g pre-packed flash column. After elution with a 0% to 75% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 145mg (38%) of the title compound as a yellow viscous oil, MS: 331.0(M + H)⁺)。

Step 2: (RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

A solution of (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one (140mg, 0.42mmol), ethynylbenzene (65.0mg, 69.9. mu.l, 0.64mmol), triethylamine (129mg, 177. mu.l, 1.27mmol), bis (triphenylphosphine) palladium (II) chloride (17.9mg, 25.4. mu. mol) and triphenylphosphine (3.34mg, 12.7. mu. mol) in 4ml of THF was purged with argon. Copper (I) iodide (2.42mg, 12.7. mu. mol) was then added and the reaction was heated at 60 ℃ for 3 h. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was taken up in ethyl acetate and adsorbed onto 3g of silica gel loaded onto a 20g pre-packed flash column. After elution with a 0% to 65% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 103mg (72%) of the title compound as an amorphous yellow solid, MS: 305.2(M + H) M/e⁺)。

Example 2

(RS) -1, 5, 5-trimethyl-3- (5- (pyridin-3-ylethynyl) pyridin-2-yl) pyrrolidin-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one (example 1, step 1) and 3-ethynyl-pyridine as an amorphous yellow solid, MS: 306.2(M + H) M/e⁺)。

Example 3

(RS) -3- (5- ((3-chlorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one (example 1, step 1) and 3-ethynyl-3-chloro-benzene as a yellow viscous oil, MS: 339.1, 341.1(M + H)⁺)。

Example 4

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 1, step 2, starting from (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one (example 1, step 1) and 1-ethynyl3-fluoro-benzene to give the title compound as a yellow viscous oil, MS: 323.3(M + H)⁺)。

Example 5

(RS) -1, 5, 5-trimethyl-2-oxo-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidine-3-carboxylic acid benzyl ester

Step 1: (RS) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester

In a flame-dried 50ml three-neck flask, 1.27g (10.0mmol) of 5, 5-dimethylpyrrolidin-2-one are dissolved in 10ml of dry THF under an argon atmosphere. After cooling to-75 ℃, a 2M solution of lithium diisopropylamide in THF (10.5ml, 10.5mmol) was added dropwise to maintain the temperature below-73 ℃. The solution was stirred at-75 ℃ for 1 h. A solution of dibenzyl carbonate (2.72g, 11.0mmol) in 5ml of THF was then added dropwise at-75 deg.C, allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by the addition of 5ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was loaded onto a 50g pre-filled flash chromatography column. After elution with a 10% to 70% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 1.07g (41%) of the title compound as a light yellow oil, MS: 262.2(M + H)⁺)。

Step 2: (RS) -1, 5, 5-trimethyl-2-oxo-3- (5- (phenylethynyl) pyrimidin-2 yl) -pyrrolidine-3-carboxylic acid benzyl ester

Benzyl (RS) -1, 5, 5-trimethyl-2-oxopyrrolidine-3-carboxylate (206mg,787. mu. mol) in 4ml of dry DMF was purged with argon and cooled to 0 ℃. Then a 60% suspension of sodium hydride (31.5mg, 0.79mmol) was added and the mixture was stirred at room temperature for 40 minutes, thereby forming a white suspension. Followed by the addition of 2-chloro-5- (phenylethynyl) pyrimidine (CAS: [1051388-40-9]]) (130mg, 606. mu. mol), the mixture was stirred at 80 ℃ for 30 minutes and then quenched by addition of 1ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (440mg, yellow oil) was taken up in ethyl acetate, adsorbed onto 3g of silica gel and loaded onto a 20g pre-packed flash column. After elution with a 10% to 60% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 212mg (80%) of the title compound as a light yellow waxy solid, MS: 440.3(M + H) M/e⁺)。

Example 6

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidin-2-one

To a solution of (RS) -benzyl 1, 5, 5-trimethyl-2-oxo-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidine-3-carboxylate (example 5, step 2) (205mg, 0.47. mu. mol) in 3ml of ethanol was added a 1N sodium hydroxide solution (933. mu.l, 0.94 mmol). After stirring at room temperature for 1.5h, the pH was neutralized by addition of 1N HCl and the solvent was evaporated in vacuo. The residue (165mg, yellow oil) was loaded onto a 20g pre-packed flash column. After elution with a 15% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 94mg (66%) of the title compound as a pale yellow crystalline solid, MS: 306.2(M + H) M/e⁺)。

Example 7

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: (RS) -3- (5-bromo-pyrimidin-2-yl) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester

Using chemistry similar to that described in example 5, step 2, from (RS) -benzyl 1, 5, 5-trimethyl-2-oxopyrrolidine-3-carboxylate (example 5, step 1) and 5-bromo-2-chloropyrimidine the title compound was obtained as a colorless viscous oil, MS: 420.1, 418.2(M + H) M/e⁺)。

Step 2: (RS) -3- (5-bromo-pyrimidin-2-yl) -1, 5, 5-trimethyl-pyrrolidin-2-one

Using chemistry similar to that described in example 6, the title compound was obtained from (RS) -3- (5-bromo-pyrimidin-2-yl) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester as a crystalline white solid, MS: 284.0, 286.0(M + H)⁺)。

And step 3: (RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one and 1-ethynyl-3-fluoro-benzene as a crystalline white solid, MS: 324.2(M + H)⁺)。

Example 8

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: 2-chloro-5- (4-fluoro-phenylethynyl) -pyrimidine

A solution of 2-chloro-5-iodopyrimidine (600mg, 2.5mmol), 1-ethynyl-4-fluorobenzene (330mg, 2.75mmol), triethylamine (556mg, 761. mu.l, 5.49mmol) and bis (triphenyl-phosphine) palladium (II) chloride (175mg, 250. mu. mol) in 7ml THF was purged with argon. Copper (I) iodide (23.8mg, 125. mu. mol) was then added and the reaction was heated at room temperature for 2 h. The dark solution was filtered and the solid was washed with THF. The residue was taken up in ethyl acetate and adsorbed onto 3g of silica gel loaded onto a 50g pre-packed flash column. After elution with a 0% to 20% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 505mg (87%) of the title compound as a crystalline light yellow solid, MS: 233.1, 235.1(M + H)⁺)。

Step 2: 3- [5- (4-fluoro-phenylethynyl) -pyrimidin-2-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3- Carboxylic acid benzyl ester

Using chemistry similar to that described in example 5, step 2, starting from (RS) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester (example 5, step 1) and 2-chloro-5- (4-fluoro-phenylethynyl) -pyrimidine to give the title compound as a light yellow viscous oil, MS: 458.3(M + H)⁺)。

And step 3: (RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 6, starting from 3- [5- (4-fluoro-phenylethynyl) -pyrimidin-2-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester to obtain the title compound as a white waxy solid, MS: 324.2(M + H)⁺)。

Example 9

(RS) -3- (6- ((3-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: 3-chloro-6- (3-fluoro-phenylethynyl) -pyridazine

Using chemistry similar to that described in example 8, step 1, the title compound was obtained from 3-chloro-6-iodopyridazine and 1-ethynyl-3-fluorobenzene as a crystalline light yellow solid, MS: 233.1, 235.0(M + H)⁺)。

Step 2: (RS) -3- [6- (3-fluoro-phenylethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine -3-Carboxylic acid benzyl ester

The procedure used was as described in example 5,similar chemistry is described in step 2, from (RS) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester (example 5, step 1) and 3-chloro-6- (3-fluoro-phenylethynyl) -pyridazine the title compound was obtained as a yellow gum, MS: 458.3(M + H)⁺)。

And step 3: (RS) -3- (6- ((3-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 6, starting from (RS) -3- [6- (3-fluoro-phenyl-ethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester to give the title compound as a colorless viscous oil, MS: 324.2(M + H)⁺)。

Example 10

(RS) -3- (6- ((4-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: 3-chloro-6- (4-fluoro-phenylethynyl) -pyridazine

Using chemistry similar to that described in example 8, step 1, the title compound was obtained from 3-chloro-6-iodopyridazine and 1-ethynyl-4-fluorobenzene as a crystalline light yellow solid, MS: 233.1, 235.1(M + H)⁺)。

Step 2: (RS) -3- [6- (3-fluoro-phenylethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine -3-Carboxylic acid benzyl ester

Using chemistry similar to that described in example 5, step 2, the title compound was obtained from (RS) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester (example 5, step 1) and 3-chloro-6- (4-fluoro-phenylethynyl) -pyridazine as a yellow viscous oil, MS: 458.3(M + H)⁺)。

And step 3: (RS) -3- (6- ((3-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 6, starting from (RS) -3- [6- (4-fluoro-phenyl-ethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester to give the title compound as a colorless viscous oil, MS: 324.2(M + H)⁺)。

Example 11

(RS) -3- (6- (phenylethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: 3-chloro-6- (phenylethynyl) -pyridazine

Using chemistry similar to that described in example 8, step 1, the title compound was obtained from 3-chloro-6-iodopyridazine and 1-ethynyl-benzene as a crystalline light yellow solid, MS: 215.2, 217.2(M + H)⁺)。

Step 2: (RS) -3- [6- (phenylethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3- Carboxylic acid benzyl ester

Using chemistry similar to that described in example 5, step 2, the title compound was obtained from (RS) -1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester (example 5, step 1) and 3-chloro-6- (phenylethynyl) -pyridazine as a light yellow oil, MS: 440.2(M + H) M/e⁺)。

And step 3: (RS) -3- (6- (phenylethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Using chemistry similar to that described in example 6, starting from (RS) -3- [6- (phenylethynyl) -pyridazin-3-yl]-1, 5, 5-trimethyl-2-oxo-pyrrolidine-3-carboxylic acid benzyl ester to obtain the title compound as a yellow waxy solid, MS: 306.3(M + H)⁺)。

Example 12

(RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) piperidin-2-one

Step 1: 3 to 1 mixture of 6, 6-dimethyl-piperidin-2-one and 3, 3-dimethyl-piperidin-2-one:

to 9.97g (88.9mmol) of 2, 2-dimethylcyclopentanone was added 70ml of 98% formic acid with stirring. To the clear solution was added 15.1g (133mmol) of hydroxylamine-O-sulfonic acid in portions to maintain the temperature at 15-20 ℃ using an ice bath. After stirring for 5 minutes, the white suspension became a clear solution. The mixture was then refluxed for 4h (100 ℃) and allowed to cool overnight. The resulting yellow solution was concentrated in vacuo. The light orange resinous residue is taken up in 30ml of water, 40ml of 1N sodium hydroxide solution and 100ml of chloroform and stirred vigorously until completely dissolved. The pH of the aqueous phase was adjusted to 8 by adding 25% NaOH solution. The organic phase was separated. The aqueous phase was extracted five times with 30ml of chloroform. The combined organic phases were washed with 10ml of water. The combined organic phases were concentrated in vacuo to give 9.9g of a pale orange semi-solid, which was purified by chromatography on silica gel (ethyl acetate/methanol 9: 1). The fractions containing both isomers were collected to yield 4.72g (41.8%) of a white solid, which was used directly in the next step.

Step 2: 1, 6, 6-trimethyl-piperidin-2-one

To a solution of a 3: 1 mixture of 3, 3-dimethylpiperidin-2-one and 6, 6-dimethylpiperidin-2-one (4.72g, 37.1mmol) in 60ml of THF was added a 60% suspension of sodium hydride (1.93g, 48.2 mmol). The gray reaction mixture was stirred at room temperature for 30 minutes. Methyl iodide (3.02ml, 48.2mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and worked up with ethyl acetate/water (worked up). The orange oil was chromatographed on a pre-packed 70g silica column. After elution with a 50% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 2.46g (47%) of the title compound as a light yellow solid; and 0.91g (17%) of the isomeric 1, 3, 3-trimethyl-piperidin-2-one as a yellow oil.

Step 2: (RS) -5-iodo-1 ', 6 ', 6 ' -trimethyl-3 ', 4 ', 5 ', 6 ' -methylhydro-1 ' H- [2, 3 ']Bipyridine-2' -one

Using chemistry similar to that described in example 1, step 1, the title compound was obtained from 1, 6, 6-trimethyl-piperidin-2-one and 2-fluoro-5-iodopyridine as a colorless viscous oil, MS: 345.1(M + H) M/e⁺)。

And step 3: 5(RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) piperidin-2-one

Using chemistry similar to that described in example 1, step 2, from (RS) -5-iodo-1 ', 6 ', 6 ' -trimethyl-3 ', 4 ', 5 ', 6 ' -tetrahydro-1 ' H- [2, 3 ']Bipyridin-2' -one and 3-ethynyl-pyridine to give the title compound as a light yellow viscous oil, MS: 319.2(M + H)⁺)。

Example 13

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Using chemistry similar to that described in example 1, step 2, from (RS) -5-iodo-1 ', 6 ', 6 ' -trimethyl-3 ', 4 ', 5 ', 6 ' -tetrahydro-1 ' H- [2, 3 ']Bipyridin-2' -one and 1-ethynyl-3-fluoro-benzene gave the title compound as a light yellow viscous oil, MS: 337.2(M + H)⁺)。

Example 14

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyridin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Using chemistry similar to that described in example 1, step 2, from (RS) -5-iodo-1 ', 6 ', 6 ' -trimethyl-3 ', 4 ', 5 ', 6 ' -tetrahydro-1 ' H- [2, 3 ']Bipyridin-2' -one and 1-ethynyl-4-fluoro-benzene gave the title compound as a light yellow waxy solid, MS: 337.2(M + H)⁺)。

Example 15

(RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) piperidin-2-one

Step 1: (RS) -1, 6, 6-trimethyl-2-oxo-piperidine-3-carboxylic acid benzyl ester

The title compound was obtained as light yellow oil from 1, 6, 6-trimethyl-piperidin-2-one and dibenzyl carbonate using chemistry similar to that described in example 5, step 1.

Step 2: (RS) -1, 6, 6-trimethyl-2-oxo-3- (5-phenylethynyl-pyrimidin-2-yl) -piperidine-3-carboxylic acid Benzyl ester

The title compound was obtained as a yellow oil from (RS) -1, 6, 6-trimethyl-2-oxo-piperidine-3-carboxylic acid benzyl ester and 2-chloro-5- (phenylethynyl) pyrimidine (CAS: [1051388-40-9]) using chemistry similar to that described in example 5, step 2.

And step 3: (RS) -1, 6, 6-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) piperidin-2-one

Using chemistry similar to that described in example 6, the title compound was obtained from (RS) -1, 6, 6-trimethyl-2-oxo-3- (5-phenylethynyl-pyrimidin-2-yl) -piperidine-3-carboxylic acid benzyl ester as a light yellow solid, MS: 320.2(M + H) M/e⁺)。

Example 16

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Step 1: (RS) -1, 6, 6-trimethyl-2-oxo-3- (5- ((4-fluorophenyl) ethynyl) -pyrimidin-2-yl) -piper ine Pyridine-3-carboxylic acid benzyl ester

The title compound was obtained as an orange oil from (RS) -1, 6, 6-trimethyl-2-oxo-piperidine-3-carboxylic acid benzyl ester and 2-chloro-5- (4-fluoro-phenylethynyl) -pyrimidine (example 8, step 1) using chemistry similar to that described in example 5, step 2.

Step 2: (RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Using chemistry similar to that described in example 6, the title compound was obtained from (RS) -1, 6, 6-trimethyl-2-oxo-3- (5- ((4-fluorophenyl) ethynyl) -pyrimidin-2-yl) -piperidine-3-carboxylic acid benzyl ester as a light grey solid, MS: 338.2(M + H) with M/e⁺)。

Example 17

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Step 1: 2-chloro-5- (3-fluoro-phenylethynyl) -pyrimidine

Using chemistry similar to that described in example 8, step 1, the title compound was obtained from 2-chloro-5-iodopyrimidine and 1-ethynyl-3-fluorobenzene as a yellow solid, MS: 233.0M/e, 234.9(M + H)⁺)。

Step 2: (RS) -1, 6, 6-trimethyl-2-oxo-3- (5- ((3-fluorophenyl) ethynyl) -pyrimidin-2-yl) -piper ine Pyridine-3-carboxylic acid benzyl ester

Using similar chemistry to that described in example 5, step 2, the title compound was obtained as a yellow oil from (RS) -1, 6, 6-trimethyl-2-oxo-piperidine-3-carboxylic acid benzyl ester and 2-chloro-5- (3-fluoro-phenylethynyl) -pyrimidine (example 8, step 1).

And step 3: (RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 6, 6-trimethylpiperidin-2-one

Using chemistry similar to that described in example 6, the title compound was obtained from (RS) -1, 6, 6-trimethyl-2-oxo-3- (5- ((3-fluorophenyl) ethynyl) -pyrimidin-2-yl) -piperidine-3-carboxylic acid benzyl ester as a light brown solid, MS: 338.2(M + H) with M/e⁺)。

Example 18

(RS) -3-hydroxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

The title compound was obtained as a by-product in the synthesis of example 1 as a light brown oil, MS: 321.2(M + H)⁺)。

Example 19

(RS) -3-methoxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

Using chemistry similar to that described in example 12, step 2, the title compound was obtained from (RS) -3-hydroxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one (example 18) and methyl iodide as a light yellow oil, MS: m/e-335.2 (M + H)⁺)。

Example 20

(RS) -1, 3, 5, 5-tetramethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

Step 1: (RS) -3- (5-iodo-pyridin-2-yl) -1, 3, 5, 5-tetramethyl-pyrrolidin-2-one

Using similar chemistry to that described in example 12, step 2, the title compound was obtained from (RS) -3- (5-iodo-pyridin-2-yl) -1, 5, 5-trimethyl-pyrrolidin-2-one (example 1, step 1) and methyl iodide as a white solid, MS: 345.0(M + H)⁺)。

Step 2: (RS) -1, 3, 5, 5-tetramethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodo-pyridin-2-yl) -1, 3, 5, 5-tetramethyl-pyrrolidin-2-one (example 20, step 1) and phenylacetylene as a light brown oil, MS: 319.1(M + H) M/e⁺)。

Example 21

(RS) -3- (3-fluoro-5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one

Step 1: (RS) -3- (3-fluoro-5-iodo-pyridin-2-yl) -1, 5, 5-trimethyl-pyrrolidin-2-one

The procedure is as described in example 1, step 1Similar chemistry as above, from 2, 3-difluoro-5-iodopyridine and 1, 5, 5-trimethyl-pyrrolidin-2-one the title compound was obtained as a light brown solid, MS: 349.0(M + H)⁺)。

Step 2: (RS) -3- (3-fluoro-5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidine -2-ketones

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (3-fluoro-5-iodo-pyridin-2-yl) -1, 5, 5-trimethyl-pyrrolidin-2-one (example 21, step 1) and 1-ethynyl-3-fluorobenzene as a light brown oil, MS: 319.1(M + H) M/e⁺)。

Example 22

(RS) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one

Step 1: (RS) -3- (5-iodo-pyridin-2-yl) -1-methyl-azepan-2-one

Using chemistry similar to that described in example 1, step 1, the title compound was obtained from 2-fluoro-5-iodopyridine and 1-methyl-azepan-2-one as a light yellow solid, MS: 331.0(M + H)⁺)。

Step 2: (RS) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodo-pyridin-2-yl) -1-methyl-azepan-2-one (example 22, step 1) and phenylacetylene as an orange solid, MS: 305.1(M + H) M/e⁺)。

Example 23

(RS) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-azepan-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodo-pyridin-2-yl) -1-methyl-azepan-2-one (example 22, step 1) and 1-ethynyl-4-fluoro-benzene as a light yellow solid, MS: m/e 323.1(M + H)⁺)。

Example 24

(RS) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-azepan-2-one

Using similar chemistry to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodo-pyridin-2-yl) -1-methyl-azepan-2-one (example 22, step 1) and 1-ethynyl-3-fluoro-benzene as a light brown solid, MS: m/e 323.1(M + H)⁺)。

Example 25

(S or R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one

The title compound was prepared by isolation of (RS) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one (example 22) using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) as a light yellow oil, MS: 305.1(M + H) M/e⁺)。

Example 26

(R or S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one

The title compound was prepared by isolation of (RS) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -azepan-2-one (example 22) using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) as a light yellow oil, MS: 305.1(M + H) M/e⁺)。

Example 27

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one

Step 1: (3RS, 3aSR, 6aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-hexahydro-cyclopenta [ b] Pyrrol-2-ones

Using chemistry similar to that described in example 1, step 1, starting from 2-fluoro-5-iodopyridine and cis-1-methyl-hexahydro-cyclopenta [ b ]]Pyrrol-2-one (CAS 169688-72-6) the title compound was obtained as a yellow oil, MS: 342.9(M + H) M/e⁺)。

Step 2: (3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopentadiene And [ b ]]Pyrrol-2-ones

Using chemistry similar to that described in example 1, step 2, starting from (3RS, 3aSR, 6aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-hexahydro-cyclopenta [ b [ -b ]]Pyrrol-2-one (example 27, step 1) and phenylacetylene gave the title compound as a brown oil, MS: 317.1(M + H) M/e⁺)。

Example 28

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one

By (3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b]Pyrrol-2-one (example 27) Using a chiral column (Chiralpak AD with heptaneIsopropanol 60: 40 as solvent) the title compound was prepared as a pale yellow oil, MS: 317.1(M + H) M/e⁺)。

Example 29

(3RS, 3aSR, 6aSR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

Using chemistry similar to that described in example 1, step 2, starting from (3RS, 3aSR, 6aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-hexahydro-cyclopenta [ b [ -b ]]Pyrrol-2-one (example 27, step 1) and 1-ethynyl-4-fluoro-benzene gave the title compound as a light brown oil, MS: m/e-335.1 (M + H)⁺)。

Example 30

(3RS, 3aSR, 6aSR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

Using chemistry similar to that described in example 1, step 2, starting from (3RS, 3aSR, 6aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-hexahydro-cyclopenta [ b [ -b ]]Pyrrol-2-one (example 27, step 1) and 1-ethynyl-3-fluoro-benzene gave the title compound as a light brown oil, MS: m/e-335.1 (M + H)⁺)。

Example 31

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

By (3RS, 3aSR, 6aSR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-hexahydro-cyclopenta [ b [ ]]Isolation of pyrrol-2-one (example 30) using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) the title compound was prepared as a light yellow oil, MS: m/e-335.1 (M + H)⁺)。

Example 32

(3S, 3aR, 6aR) or (3R, 3aS, 6aS) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one

By (3RS, 3aSR, 6aSR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-hexahydro-cyclopenta [ b [ ]]Isolation of pyrrol-2-one (example 30) using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) the title compound was prepared as a light yellow oil, MS: m/e-335.1 (M + H)⁺)。

Example 33

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyrimidin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one

Use and example 5 and exampleSimilar chemistry as described in example 6, starting from cis-1-methyl-hexahydro-cyclopenta [ b]Pyrrol-2-one (CAS 169688-72-6) instead of 5, 5-dimethylpyrrolidin-2-one the title compound was obtained as a white solid, MS: 318.1(M + H)⁺)。

Examples 34 and 35

(3RS, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one and (3SR, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

Step 1: (3RS, 5SR, 6SR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one and 7: 1-mixtures of (3SR, 5SR, 6SR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one

Using chemistry similar to that described in example 1, step 1, the title compound mixture was obtained from 2-fluoro-5-iodopyridine and racemic cis-octahydro-1-methyl-2H-indol-2-one (CAS 116725-60-1) as a yellow solid, MS: 357.1(M + H) M/e⁺)。

Step 2: (3RS, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one And (3SR, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

Using chemistry similar to that described in example 1, step 2, a 7: 1-mixture of (3RS, 6SR, 7SR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one and (3SR, 6SR, 7SR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one (example 34, step)Step 1) and phenylacetylene to give the title compound (3RS, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one (147mg, major isomer, extra compound) as a light brown solid, MS: 331.2(M + H) M/e⁺) And the minor isomer (3SR, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one (22mg) was obtained as a brown gum, MS: 331.2(M + H) M/e⁺)。

Examples 36 and 37

(3R, 6S, 7S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one and (3S, 6R, 7R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one

Preparation of (3R, 6S, 7S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one (56mg, colourless gum), MS: 331.2(M + H) M/e⁺) And (3S, 6R, 7R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one, (62mg, light yellow gum), MS: 331.2(M + H) M/e⁺)。

Examples 38 and 39

(3RS, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one and (3SR, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

The title compound (3RS, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl) -was obtained from a 7: 1-mixture of (3RS, 3aSR, 7aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one and (3SR, 3aSR, 7aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one (example 34, step 1) and 3-fluorophenylacetylene using similar chemistry as described in examples 34 and 35, step 2]-1-methyl-octahydro-indol-2-one (187mg, major isomer, extra compound) as a yellow oil, MS: 349.3(M + H)⁺) And the minor isomer (3SR, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl is obtained]-1-methyl-octahydro-indol-2-one (25mg) as a light brown gum, MS: 349.3(M + H)⁺)。

Examples 40 and 41

(3R, 6S, 7S) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one and (3S, 6R, 7R) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

By racemisation of (3RS, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl]Isolation of (1-methyl-octahydro-indol-2-one (example 38) Using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) to prepare (3R, 6S, 7S) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indol-2-one (66mg, colorless gum), MS: 349.3(M + H)⁺) (3S, 6R, 7R) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indol-2-one (63mg, colorless gum), MS: 349.3(M + H)⁺)。

Examples 42 and 43

(3R, 6S, 7S) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one and (3S, 6R, 7R) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one

Step 1: (3RS, 6SR, 7SR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indole -2-keto §

The title compound was obtained from a 7: 1-mixture of (3RS, 3aSR, 7aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one and (3SR, 3aSR, 7aSR) -3- (5-iodo-pyridin-2-yl) -1-methyl-octahydro-indol-2-one (example 34, step 1) and 4-fluorophenylacetylene using chemistry similar to that described in example 34, step 2, racemic (3RS, 6SR, 7SR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indol-2-one (189mg, major isomer, extra compound) as a light brown oil, MS: 349.3(M + H)⁺). The minor isomers are not separated.

By racemisation of (3RS, 6SR, 7SR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl]Isolation of (1-methyl-octahydro-indol-2-one (example 42) Using a Chiral column (Reprosil Chiral NR with heptane: ethanol 60: 40 as solvent) to prepare (3R, 6S, 7S) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indol-2-one (78mg, light yellow gum), MS: 349.3(M + H)⁺) (3S, 6R, 7R) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl]-1-methyl-octahydro-indol-2-one (75mg, light yellow gum), MS: 349.3(M + H)⁺)。

Example 44

(RS) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one

Using chemistry similar to that described in example 1, step 2, the title compound was obtained from (RS) -3- (5-iodopyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one (example 1, step 1) and 2-chloro-4-ethynyl-pyridine (CAS945717-09-9) as a light yellow oil, MS: 340.3/342.4(M + H)⁺)。

Example 45

(S) or (R) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one

By (RS) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl]1, 5, 5-trimethyl-pyrrolidin-2-one (example 44) the title compound was prepared by isolation using a chiral column (Chiralpak AD with heptane: isopropanol 60: 40 as solvent), yellow solid, MS: 340.4/342.4(M + H)⁺)。

Example 46

(R) or (S) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one

By (RS) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl]Isolation of-1, 5, 5-trimethyl-pyrrolidin-2-one (example 44) using a chiral column (Chiralpak AD with heptane: isopropanol 60: 40 as solvent) the title compound was prepared as a light yellow solid, MS: 340.4/342.4(M + H)⁺)。

Claims (10)

1. A compound of formula I

The formula I is

Wherein

X is N or C-R, wherein R is hydrogen or halogen;

g is N or CH;

provided that at most one of G or X may be nitrogen;

R¹is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, C_1-4Alkyl, hydroxy, C_1-4Alkoxy or C (O) O-benzyl;

R³，R^3’，R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or C_1-4An alkyl group;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or C_1-4An alkyl group;

n is 1;

m is 0;

or a pharmaceutically acceptable acid addition salt, a racemic mixture, or the corresponding enantiomer thereof.

2. A compound according to claim 1 of formula IA,

wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, C_1-4Alkyl, hydroxy, C_1-4Alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or C_1-4An alkyl group;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or C_1-4An alkyl group;

or a pharmaceutically acceptable acid addition salt, a racemic mixture, or the corresponding enantiomer thereof.

3. A compound according to any one of claims 1 or 2 of formula IA,

the compound is

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one,

(RS) -1, 5, 5-trimethyl-3- (5- (pyridin-3-ylethynyl) pyridin-2-yl) pyrrolidin-2-one,

(RS) -3- (5- ((3-chlorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one,

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyridin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one,

(RS) -3-hydroxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one,

(RS) -3-methoxy-1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one,

(RS) -1, 3, 5, 5-tetramethyl-3- (5- (phenylethynyl) pyridin-2-yl) pyrrolidin-2-one,

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3RS, 3aSR, 6aSR) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3RS, 3aSR, 6aSR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3R, 3aS, 6aS) or (3S, 3aR, 6aR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3S, 3aR, 6aR) or (3R, 3aS, 6aS) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-hexahydro-cyclopenta [ b ] pyrrol-2-one,

(3RS, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one,

(3SR, 6SR, 7SR) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one,

(3R, 6S, 7S) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one, and (3S, 6R, 7R) -1-methyl-3- (5-phenylethynyl-pyridin-2-yl) -octahydro-indol-2-one,

(3RS, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(3SR, 6SR, 7SR) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(3R, 6S, 7S) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(3S, 6R, 7R) -3- [5- (3-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(3R, 6S, 7S) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(3S, 6R, 7R) -3- [5- (4-fluoro-phenylethynyl) -pyridin-2-yl ] -1-methyl-octahydro-indol-2-one,

(RS) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one,

(S) or (R) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one, or

(R) or (S) -3- [5- (2-chloro-pyridin-4-ylethynyl) -pyridin-2-yl ] -1, 5, 5-trimethyl-pyrrolidin-2-one.

4. A compound of formula IB according to claim 1,

wherein

X is N or C-R, wherein R is halogen;

R¹is phenyl or pyridyl, which is optionally substitutedHalogen substitution;

R²is hydrogen, C_1-4Alkyl, hydroxy, C_1-4Alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or C_1-4An alkyl group;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or C_1-4An alkyl group;

or a pharmaceutically acceptable acid addition salt, a racemic mixture, or the corresponding enantiomer thereof.

5. A compound of formula IB according to any one of claims 1 or 4,

the compound is

(RS) -1, 5, 5-trimethyl-2-oxo-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidine-3-carboxylic acid benzyl ester,

(RS) -1, 5, 5-trimethyl-3- (5- (phenylethynyl) pyrimidin-2-yl) pyrrolidin-2-one,

(RS) -3- (5- ((3-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one,

(RS) -3- (5- ((4-fluorophenyl) ethynyl) pyrimidin-2-yl) -1, 5, 5-trimethylpyrrolidin-2-one, or

(3RS, 3aSR, 6aSR) -1-methyl-3- (5-phenylethynyl-pyrimidin-2-yl) -hexahydro-cyclopenta [ b ] pyrrol-2-one.

6. A compound according to claim 1 of formula IC,

wherein

R¹Is phenyl or pyridyl, optionally substituted with halogen;

R²is hydrogen, C_1-4Alkyl, hydroxy, C_1-4Alkoxy or C (O) O-benzyl;

R⁴，R^4’，R⁶，R^6’independently of one another, hydrogen or C_1-4An alkyl group;

or R⁶And R⁴May form C together with the carbon atom to which they are attached_4-6-a cycloalkyl ring;

R⁵is hydrogen or C_1-4An alkyl group;

or a pharmaceutically acceptable acid addition salt, a racemic mixture, or the corresponding enantiomer thereof.

7. A compound according to any one of claims 1 or 6 of formula IC,

wherein the compound is

(RS) -3- (6- ((3-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one,

(RS) -3- (6- ((4-fluorophenyl) ethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one, or

(RS) -3- (6- (phenylethynyl) pyridazin-3-yl) -1, 5, 5-trimethylpyrrolidin-2-one.

8. A process for the preparation of a compound of formula I as claimed in claim 1, which process comprises:

a) reacting a compound of formula 3

Wherein X¹Is halogen

With a compound of formula 4, with a pharmaceutically acceptable carrier,

to the compound of formula I

Wherein is as defined in claim 1, or

b) Reacting a compound of formula 5

Wherein X¹Is halogen

With a compound of formula 2,

to form a compound of formula I

Wherein the definition is as described in claim 1, or, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt.

9. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a therapeutically active carrier.

10. Use of a compound according to any one of claims 1-7 for the manufacture of a medicament for the treatment of schizophrenia or cognitive diseases.