HK1148275A - Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors - Google Patents

Abstract

The present invention relates to novel compounds, in particular novel imidazo[1,2- a]piridine derivatives according to Formula (I). The compounds according to the invention are positive allosteric modulators of metabotropic receptors- subtype 2 ("mGluR2") which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

Description

Imidazo [1, 2-a ] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors

Technical Field

The present invention relates to novel imidazo [1, 2-a ] pyridine derivatives which are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 ("mGluR 2") and which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

Background

Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays an important role in many physiological functions such as learning and memory as well as sensory perception, synaptic plastic development, motor control, respiration and cardiovascular function regulation. In addition, glutamate is of interest in a variety of different neurological and psychiatric disorders in which an imbalance in glutamatergic neurotransmission exists.

Glutamate mediates synaptic neurotransmission via activation of ionotropic glutamate receptor channels (iglurs) and NMDA, AMPA and kainate receptors that elicit rapid excitatory transmission.

In addition, glutamate activation has a more modulatory role of metabotropic glutamate receptors (mglurs) that contribute to the fine-tuning of synaptic efficacy.

Glutamate activates mglurs via binding to the larger extracellular amino terminal domain of the receptor (referred to herein as the orthosteric binding site). This binding induces changes in the receptor configuration that activate the G protein and intracellular signaling pathways.

The mGluR2 subtype negatively couples adenylate cyclase via activation of the G α i protein, and activation of the G α i protein results in inhibition of glutamate release in the synapse. In the Central Nervous System (CNS), mGluR2 receptors are mainly abundant throughout the cortex, thalamic regions, accessory olfactory bulbs, hippocampus, amygdala, caudate putamen and nucleus accumbens.

Activation of mGluR2 has been shown in clinical trials to be effective in the treatment of anxiety disorders. In addition, potent activation of mGluR2 in a variety of animal models is shown to provide a potential novel therapeutic approach for the treatment of schizophrenia, epilepsy, addiction/drug dependence, Parkinson's disease, pain, sleep disorders, and Huntington's disease.

To date, the majority of available pharmacological tools for targeting mglurs are orthosteric ligands that activate several members of this family, due to their structural analogs of glutamate.

A novel approach to developing selective compounds that act at mglurs is to identify compounds that act by modulating the receptor through allosteric mechanisms by binding to a site other than the highly conserved orthosteric binding site.

Recently, positive allosteric modulators of mglurs have emerged as novel pharmacological entities offering this attractive alternative. A variety of compounds have been described as mGluR2 positive allosteric modulators. WO2004/092135(NPS & Astra Zeneca), WO2004/018386, WO2006/014918 and WO2006/015158(Merck), WO2001/56990(EliLilly) and WO2006/030032 and WO2007/104783(Addex & Janssen Pharmaceutica) describe phenylsulfonamides, acetophenones, indanones, pyridylmethyl sulfonamides and pyridone derivatives, respectively, as mGluR2 positive allosteric modulators. None of the specifically disclosed compounds therein are structurally related to the compounds of the present invention.

These compounds have been shown not to activate the receptor alone. Rather, it enables the receptor to produce a maximal response to a concentration of glutamate that alone induces a minimal response. Mutational analysis has clearly demonstrated that binding of mGluR2 positive allosteric modulators does not occur at the orthosteric site, but rather at an allosteric site located within the seven transmembrane region of the receptor.

Animal data indicate that positive allosteric modulators of mGluR2 have effects in anxiety and psychiatric models similar to those obtained with orthosteric agonists. Allosteric modulators of mGluR2 were shown to be active on fear-enhanced startle and stress-induced anxiety disorder fever models. Furthermore, the compound was shown to be active in the reversal of either ketamine or amphetamine-induced hyperkinesia (hyperkinesia) and the reversal of amphetamine-induced prepulse inhibition disruption in the acoustic startle effect model of schizophrenia (J.Pharmacol.Exp.Ther.2006, 318, 173-185; Psychopharmacology 2005, 179, 271-283).

Recent animal studies further revealed that biphenyl-indanone (BINA), a selective positive allosteric modulator of metabotropic glutamate receptor subtype 2, blocks a hallucinogenic drug model of psychosis, supporting a strategy to target mGluR2 receptors to treat glutamate dysfunction in schizophrenia (mol. pharmacol.2007, 72, 477-.

While positive allosteric modulators enable potentiation of glutamate responses, they have also been shown to potentiate responses to orthosteric mGluR2 agonists such as LY379268 or DCG-IV. This data provides evidence demonstrating another novel therapeutic approach to treat the above mentioned neurological and psychiatric disorders involving mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 and an orthosteric agonist of mGluR 2.

Disclosure of Invention

The present invention relates to compounds having metabotropic glutamate receptor 2 modulator activity, which compounds have the formula (I):

(I)

and stereochemically isomeric forms thereof, wherein

R¹Is C_1-6An alkyl group; c_3-6A cycloalkyl group; a trifluoromethyl group; c substituted by_1-3Alkyl groups: trifluoromethyl, 2, 2, 2-trifluoroethoxy, C_3-7Cycloalkyl, phenyl or via C_1-3Alkyl radical, C_1-3Alkoxy, cyano, halo, trifluoromethyl or trifluoromethoxy substituted phenyl; a phenyl group; through 1 or 2 groups selected from C_1-3Alkyl radical, C_1-3Phenyl substituted with a substituent of the group consisting of alkoxy, cyano, halo, trifluoromethyl and trifluoromethoxy; or 4-tetrahydropyranyl;

R²is cyano, halo, trifluoromethyl, C_1-3Alkyl or cyclopropyl;

R³is a group of formula (a) or (b) or (c) or (d):

R⁴is hydrogen; hydroxy radical C_3-6A cycloalkyl group; a pyridyl group; through one or two C_1-3An alkyl-substituted pyridyl group; a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; warp 1Or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl, hydroxy C_1-3Alkyl, mono-or polyhalo C_1-3Alkyl, cyano, hydroxy, amino, carboxyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy, mono-or polyhalo-C_1-3Alkoxy radical, C_1-3Alkylcarbonyl, mono-and di (C)_1-3Alkyl) amino and morpholinyl; or a phenyl group bearing two adjacent substituents which together form a divalent group of the formula:

-N＝CH-NH-(e)，

-CH ═ CH-NH- (f), or

-O-CH₂-CH₂-NH-(g)；

R⁵Is hydrogen, fluorine, hydroxy C_1-3Alkyl, hydroxy C_1-3Alkoxy, fluoro C_1-3Alkyl, fluoro C_1-3Alkoxy, morpholinyl or cyano;

x is C or N, in which case R⁵Represents an electron pair on N; or

R⁴-X-R⁵Represents a group of formula (h) or (i) or (j):

n is 0 or 1;

q is 1 or 2;

R⁶is C_1-3An alkyl group; c_3-6A cycloalkyl group; hydroxy radical C_2-4An alkyl group; (C)_3-6Cycloalkyl) C_1-3An alkyl group; a phenyl group; a pyridyl group; or phenyl or pyridyl substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3Alkyl, trifluoromethyl and (CH)₂)_m-CO₂H, wherein m is 0, 1 or 2; or

R⁶Is a cyclic group of formula (k):

wherein R is⁸Is hydrogen, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3An alkyl group;

p is 1 or 2;

z is O, CH₂Or CR⁹(OH) wherein R⁹Is hydrogen or C_1-3An alkyl group; or

R⁸And R⁹Form a group-CH₂-CH₂-；

R⁷Is hydrogen, halo or trifluoromethyl;

y is a covalent bond, O, NH, S, SO₂、C(OH)(CH₃)、-CH₂-O-、-O-CH₂-, CHF or CF₂(ii) a Or

R⁶-y is optionally via hydroxy or hydroxy C_1-3Alkyl-substituted morpholinyl, pyrrolidinyl, or piperidinyl; and is

A is O or NH;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (I):

or a stereochemically isomeric form thereof, wherein

R¹Is C_1-6An alkyl group; a trifluoromethyl group; c substituted by_1-3Alkyl groups: trifluoromethyl, 2, 2, 2-trifluoroethoxy, C_3-7Cycloalkyl, phenyl or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; a phenyl group; phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; or 4-tetrahydropyranyl;

R²is cyano, halo, trifluoromethyl, C_1-3Alkyl or cyclopropyl;

R³is a group of formula (a) or (b):

R⁴is hydrogen; a pyridyl group; a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; phenyl substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl, hydroxy C_1-3Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, carboxyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy, polyhalo C_1-3Alkoxy radical, C_1-3Alkylcarbonyl, mono-and di (C)_1-3Alkyl) amino and morpholinyl; or a phenyl group bearing two adjacent substituents which together form a divalent group of the formula:

-N＝CH-NH-(e)，

-CH ═ CH-NH- (f), or

-O-CH₂-CH₂-NH-(g)；

R⁵Is hydrogen, fluorine, hydroxy C_1-3Alkyl, hydroxy C_1-3Alkoxy, fluoro C_1-3Alkyl, fluoro C_1-3Alkoxy or cyano;

x is C or N, in which case R⁵Represents an electron pair on N;

n is 0 or 1;

R⁶is phenyl; a pyridyl group; or phenyl or pyridyl substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl radical, C_1-3Alkoxy, trifluoromethyl and (CH)₂)_m-CO₂H, wherein m is 0, 1 or 2; or

R⁶Is a cyclic group of formula (k):

wherein R is⁸Is hydrogen, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3An alkyl group;

p is 1 or 2;

z is O or CR⁹(OH) wherein R⁹Is hydrogen or C_1-3An alkyl group; or

R⁸And R⁹Form a group-CH₂-CH₂-；

R⁷Is hydrogen, halo or trifluoromethyl;

y is a covalent bond, O, NH, S, SO₂Or CF₂(ii) a Or

A pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (I), wherein

R¹Is C_1-6An alkyl group; a trifluoromethyl group; c substituted by trifluoromethyl or phenyl_1-3An alkyl group; or phenyl;

R²is cyano or halo;

R³is a group of formula (a) or (b):

R⁴is a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; through 1 or 2 groups selected from halogen, polyhalo C_1-3Phenyl substituted with a substituent of the group consisting of alkyl;

R⁵is hydrogen or hydroxy;

x is C or N, in which case R⁵Represents an electron pair on N;

n is 0 or 1;

R⁶is selected from 1 or 2 of C_1-3Pyridyl substituted with a substituent of the group consisting of alkyl;

R⁷is hydrogen or halo;

y is O; or

A pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (I), wherein

R¹Is methyl; ethyl, 1-propyl, trifluoromethyl; 2, 2, 2-trifluoroethyl, 4, 4, 4-trifluorobutyl, phenylmethyl, or phenyl;

R²is cyano;

R³is a group of formula (a) or (b):

R⁴is a pyrimidinyl group; warp beamOne or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro and trifluoromethyl;

R⁵is hydrogen or hydroxy;

x is C or N, in which case R⁵Represents an electron pair on N;

n is 0 or 1;

R⁶is pyridyl substituted with 1 or 2 substituents selected from the group consisting of methyl;

R⁷is hydrogen, fluorine or chlorine;

y is O; or

A pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the invention relates to a compound of formula (I) or a stereochemically isomeric form thereof, wherein said compound is

8-chloro-7- (4-fluoro-4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine (E50),

2- (2- {1- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] -piperidin-4-yl } -phenyl) -propan-2-ol (E65),

7- {4- [2- (1-hydroxy-1-methyl-ethyl) -phenyl ] -piperidin-1-yl } -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E67),

7- (4-fluoro-4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E68),

(cis) -7- [ 3-chloro-4- (4-hydroxy-cyclohexylamino) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E95),

(trans) -7- [ 3-chloro-4- (4-hydroxy-cyclohexylamino) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E96),

(trans) -4- { 2-chloro-4- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] -phenylamino } -1-methyl-cyclohexanol (E100),

4- { 2-chloro-4- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] phenylamino } -cyclohexanol (E101), or

7- (3-chloro-4-cyclopropylamino-phenyl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E105).

As a radical or part of a radical C_1-3Alkyl defines a saturated straight or branched chain hydrocarbon group having 1 to 3 carbon atoms, such as methyl, ethyl, 1-propyl and 1-methylethyl.

As a radical or part of a radical C_1-6Alkyl defines a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl, and the like.

Ring C of representation_3-7Alkyl defines saturated cyclic hydrocarbon radicals having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Halo may be fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

Pharmaceutically acceptable salts are defined to include the non-toxic acid addition salt forms which the compounds of formula (I) are capable of forming and are therapeutically active. Such salts may be obtained by treating the base form of the compound of formula (I) with a suitable acid, for example, an inorganic acid, such as hydrohalic acids, especially hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids; organic acids such as acetic, glycolic, propionic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic and pamoic acids.

Conversely, the salt form can be converted to the free base form by treatment with an appropriate base.

The compounds of formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic basic salt forms by treatment with appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts; alkali and alkaline earth alkali metal salts, especially lithium, sodium, potassium, magnesium and calcium salts; salts with organic bases, such as benzathine (benzathine), N-methyl-D-glucosamine, and altretamine salts; and salts with amino acids such as arginine and lysine.

Conversely, the salt form can be converted to the free acid form by treatment with an appropriate acid.

The term solvate encompasses the solvent addition forms which the compounds of formula (I) are able to form as well as salts thereof. Examples of such solvent addition forms are, for example, hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" as used hereinbefore defines that the compounds of formula (I) may have all possible isomeric forms. Unless otherwise indicated or indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, which mixtures contain all diastereomers and enantiomers of the basic molecular structure. The invention also includes each of the individual isomeric forms of the compounds of formula (I) and salts and solvates thereof which are substantially free, i.e. associated with less than 10%, preferably less than 5%, especially less than 2% and most preferably less than 1% of other isomers (associated with). Thus, when a compound of formula (I) is defined as, for example, (R), it is meant that the compound is substantially free of the (S) isomer. The stereosymmetric center may have an R or S configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis or trans configuration.

According to CAS nomenclature, when there are two stereosymmetric centers of known absolute configuration in a compound, the R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rules) to the lowest-numbered chiral center, i.e., the reference center. The configuration of the second stereocenter of symmetry uses the correlation descriptor [ R ]^*，R^*]Or [ R ]^*，S^*]Is shown in (1), wherein R is^*Always defined as the center of reference, and [ R^*，R^*]Indicates having the same chiral center and [ R ]^*，S^*]Indicating different chiral centers. For example, if the lowest-numbered chiral center in a compound has the S configuration and the second center is R, the stereodescriptor will be specified as S- [ R ]^*，S^*]. When "α" and "β" are used: the position of the substituent with the highest priority on the asymmetric carbon atom in the ring system with the lowest ring number is always arbitrary (arbitrarily) at the "α" position of the single plane (meanplane) defined by the ring system. The position of the substituent with the highest priority on the other asymmetric carbon atom in the ring system (hydrogen atom in the compound of formula (I)) is designated "α" if it is located on the same side of the single plane defined by the ring system as the position of the substituent with the highest priority on the reference atom and "β" if it is located on the other side of the single plane defined by the ring system.

In the framework of the present application, an element, especially when mentioned in connection with the compounds of formula (I), comprises all naturally occurring or synthetically produced isotopes and isotopic mixtures of this element occurring in natural abundance (natural abundance) or in isotopically enriched form. The compound of formula (I) labelled with a radioisotope may comprise a radioisotope selected from the group of isotopes:³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷br and⁸²br is added. The radioisotope is preferably selected from³H、¹¹C and¹⁸and F.

Preparation of

The compounds of the present invention can generally be prepared by a series of steps, each of which is known to those skilled in the art. This compound can be prepared, inter alia, according to the following synthesis.

The compounds of formula (I) may be synthesized as racemic mixtures of enantiomers which can be separated from each other according to resolution methods known in the art. The compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by the alkali metal. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

A. Preparation of the Final Compounds

Experimental method 1

The final compound of formula (I-a) may be prepared according to reaction scheme (1) by reacting an intermediate compound of formula (II) with a compound of formula (III) in a suitable reaction inert solvent (such as 1, 4-dioxane) or mixture of inert solvents (such as 1, 4-dioxane/DMF) in a suitable base (such as K)₂CO₃) Pd complex catalysts (such as Pd (PPh)₃)₄) In the presence of heat (such as heating the reaction mixture at 150 ℃ for 10 minutes under microwave irradiation). In reaction scheme (1), all variables are as defined in formula (I) and W is a group suitable for Pd mediated coupling with alkyl trifluoroborate, such as halo.

Reaction scheme 1

Experimental method 2

The final compounds of formula (I-b) may be prepared according to reaction scheme (2) by reacting an intermediate compound of formula (II) with a compound of formula (IV) in a suitable reaction-inert solvent, such as 1, 4-dioxane, in a suitable base, such as K₃PO₄) Pd complex catalysts (such as) In the presence of heat (such as, for example, at 80 ℃ heating reaction mixture for 12 hours). In reaction scheme (2), all variables are as defined in formula (I) and W is an amine-coupled group suitable for Pd-mediated coupling, such as halo.

Alternatively, the compounds of formula (I-b) may be prepared according to reaction scheme (2) by reacting an intermediate compound of formula (II) with a compound of formula (IV) in a suitable reaction-inert solvent such as 1, 2-dimethoxyethane or acetonitrile in a suitable base such as Cs₂CO₃Or N, N-diisopropylethylamine) under thermal conditions (such as, for example, heating the reaction mixture at 180 ℃ for 45 minutes under microwave irradiation).

Alternatively, the compounds of formula (I-b) may be prepared according to reaction scheme (2) by reacting an intermediate compound of formula (II) with a compound of formula (IV) in a suitable reaction inert solvent such as toluene in the presence of a suitable base such as sodium tert-butoxide, a metal based catalyst, especially a palladium catalyst such as palladium (II) acetate, and a suitable ligand such as 1, 1 ' - [1, 1 ' -binaphthyl ] -2, 2 ' -diylbis [1, 1-diphenyl-phosphine ] (BINAP) for a suitable time to allow the reaction to complete (e.g. 16 hours at 100 ℃ in a sealed tube).

Reaction scheme 2

Experimental method 3

The final compounds of formula (I-c) may be prepared according to reaction scheme (3) by reacting an intermediate compound of formula (II) with a compound of formula (V) in a suitable reaction inert solvent (such as 1, 4-dioxane) or mixture of inert solvents (such as 1, 4-dioxane/DMF) in a suitable base (such as NaHCO₃Or Na₂CO₃Aqueous solution), Pd complex catalyst (such as Pd (PPh)₃)₄) In the presence of heat (such as heating the reaction mixture at 150 ℃ for 10 minutes under microwave irradiation). In reaction scheme (3), all variables are as defined in formula (I) and W is a group suitable for Pd mediated coupling with boronic acids or boronic esters, such as a halo, triflate or pyridinium moiety. R¹⁰And R¹¹May be hydrogen or alkyl, or may together form, for example, a group of the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂A divalent group of (a).

Reaction scheme 3

Experimental method 4

The final compound of formula (I) may be prepared according to reaction scheme (4) by reacting an intermediate compound of formula (VI) with a compound of formula (V-a) in a suitable reaction inert solvent (such as 1, 4-dioxane) or mixture of inert solvents (such as 1, 4-dioxane/DMF) in a suitable base (such as NaHCO₃Or Na₂CO₃Aqueous solution), Pd complex catalyst (such as Pd (PPh)₃)₄) In the presence of heat (such as heating the reaction mixture at 150 ℃ for 10 minutes under microwave irradiation). In reaction scheme (4), all variables are as defined in formula (I) and W is a group suitable for Pd mediated coupling with boronic acids or boronic estersA group, such as a halo group. R¹⁰And R¹¹May be hydrogen or alkyl, or may together form, for example, a group of the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂A divalent group of (a).

Reaction scheme 4

Experimental method 5

The final compounds of formula (I-d) can be prepared according to reaction scheme (5) by reacting an intermediate of formula (VII) with an intermediate compound of formula (VIII). The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as, for example, heating the reaction mixture at 150 ℃ for 50 minutes under microwave irradiation. In reaction scheme (5), all variables are as defined in formula (I).

Reaction scheme 5

Experimental method 6

The final compounds of formula (I-a) can be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (IV) under reductive amination conditions known to those skilled in the art. The reaction is illustrated in reaction scheme (6), wherein all variables are as defined in formula (I). The reaction may be carried out, for example, in the presence of sodium triacetoxyborohydride (sodium triacetoxy borohydrate) in a suitable reaction inert solvent such as 1, 2-dichloroethane at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete.

Reaction scheme 6

Experimental method 7

Alternatively, the final compound of formula (I-a) may be prepared by reacting an intermediate of formula (X) with an intermediate of formula (IV) under alkylation conditions known to those skilled in the art. The reaction is illustrated in reaction scheme (7), wherein all variables are as defined above. The reaction may be carried out, for example, in the presence of a base such as diisopropylethylamine in a suitable reaction solvent (such as DMF) at a suitable temperature such as 120 ℃ for a suitable time to allow the reaction to complete.

Reaction scheme 7

Experimental method 8

The final compounds of formula (I-e) can be prepared by reacting intermediates of formula (XI) under reducing conditions known to those skilled in the art. The reaction is illustrated in reaction scheme (8), wherein all variables are as defined in formula (I). The reaction may be carried out, for example, in the presence of a catalyst such as palladium on activated carbon for a suitable time to ensure completion of the reaction, typically at room temperature and 1 hydrogen pressure for 16 hours. R^1aIs C_1-4Alkyl or trifluoromethyl substituted C_1-4An alkyl group.

Reaction scheme 8

Experimental method 9

The final compound of formula (I-f) mayBy reacting an intermediate of formula (XII) under reducing conditions known to those skilled in the art. This reaction is illustrated in reaction scheme (9), wherein all substituents are as defined in formula (I). The reaction may be carried out in the presence of, for example, sodium borohydride in a suitable solvent such as methanol. The reaction may be carried out at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete. R⁸And p is as R⁶The radicals of the formula (k) in the definitions.

Reaction scheme 9

Experimental method 10

Alternatively, the final compounds of formula (I-f) may be prepared by methods known in the art by treating an intermediate of formula (XIII) under suitable deprotection conditions. In reaction scheme (10), all variables are as defined in formula (I) and PG is a suitable protecting group for the alcohol functional group, such as trimethylsilyl and tert-butyldimethylsilyl.

Reaction scheme 10

Experimental method 11

The final compounds of formula (I-g) can be prepared by methods known in the art according to scheme (11) by reacting an organometallic compound of formula (XIV) with an intermediate compound of formula (XII). The reaction may be carried out in an inert solvent such as THF, diethyl ether or dioxane. The mixture can be stirred at a temperature of between 0 and 100 ℃ for 1 to 48 hours. In reaction scheme (11), all variables are as defined in formula (I).

Reaction scheme 11

Experimental method 12

The final compounds of formula (I-h) can be prepared by methods known in the art by treating the final compounds of formula (I-I) with intermediate compounds of formula (XV). The reaction may be carried out with an alkylating agent (such as methyl iodide) in an inert solvent (such as DMF) in the presence of a base (such as potassium carbonate) under thermal conditions (such as microwave irradiation at 150 ℃ for 10 minutes).

Likewise, the final compounds of formula (I-h) can be prepared according to experimental procedure (12). In reaction scheme (12), all variables are as defined in formula (I); and Z is a suitable leaving group in the alkylation reaction, such as halo, triflate, 4-methylphenylsulfonyl, methylsulfonyl; and R is¹²Is C_1-3Alkyl or mono-or polyhalo C_1-3An alkyl group.

Reaction scheme 12

Experimental method 13

The final compounds of formula (I-j) may be prepared from the intermediate compounds of formula (XVI) by processes known in the art, using methods known to those skilled in the art, via Sandmeyer type reactions. In reaction scheme (13), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-.

Reaction scheme 13

The conversion of the functional groups present in the final compound of formula (I) into other functional groups can be carried out by synthetic methods well known to the person skilled in the art. For example, the ester-containing compound of formula (I) may be hydrolyzed according to methods known in the art.

B. Preparation of intermediate compounds

Experimental method 14

An intermediate compound of formula (II) wherein W represents halo (hence (II-a)) may be prepared by reacting an intermediate compound of formula (XVII) with a suitable halogenating agent, such as phosphorus (V) oxychloride, in a suitable reaction-inert solvent, such as DMF, at moderate to high temperature, such as 110 ℃, for a suitable time, for example 1 hour, to allow the reaction to complete. In reaction scheme (14), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-.

Reaction scheme 14

Experimental method 15

The intermediate compound of formula (XVII) can be prepared according to reaction scheme (15) by reacting the intermediate of formula (XVIII) with the intermediate compound of formula (VIII). The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as, for example, heating the reaction mixture at 160 ℃ for 45 minutes under microwave irradiation. In reaction scheme (15), all variables are as defined in formula (I).

Reaction scheme 15

Experimental method 16

The intermediate compound of formula (XVIII) can be prepared by reacting the intermediate compound of formula (XIX) with a source of ammonia, such as ammonium hydroxide, under thermal conditions, such as, for example, heating the reaction mixture at reflux for 3 hours. In reaction scheme (16), R²As defined in formula (I).

Reaction scheme 16

Experimental method 17

The intermediate compound of formula (XIX) can be prepared according to reaction scheme (17) by reacting the intermediate of formula (XX) with N, N-dimethylformamide dimethyl acetal. The reaction is carried out under thermal conditions (such as heating the reaction mixture under reflux for 2 hours) in a suitable reaction inert solvent (such as methanol). In reaction scheme (17), R²As defined in formula (I).

Reaction scheme 17

The intermediate compounds of formula (XX) are commercially available (R)²CN; c.a.s.5515-16-2) or can be prepared according to reaction methods known to those skilled in the art. Thus, for example, wherein R²Intermediate compounds of formula (XX) which are halo may be prepared according to the procedures described in Chemische belichte (1976), 109(8), 2908-13.

Experimental method 18

Wherein R is²An intermediate compound of formula (II) which is cyano (hence the name (II-b)) may be prepared by methods known in the art from R²Intermediates of formula (II) which are halo groups, therefore referred to as (II-c), are prepared by treatment with copper cyanide. The reaction is carried out in a suitable reaction zoneIn an organic solvent such as acetonitrile under microwave irradiation, for example by heating the reaction mixture for 30 minutes at, for example, 160 ℃. In reaction scheme (18), all variables are as defined for formula (I), halo-can be chloro-, bromo-, or iodo-, and W is as defined for formula (II).

Reaction scheme 18

Experimental method 19

Wherein R is²Intermediate compounds of formula (II) that are halo groups, thus referred to as (II-c), can be prepared according to reaction scheme (19) by reacting an intermediate of formula (XXI) with an intermediate compound of formula (VIII). The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as, for example, heating the reaction mixture at 150 ℃ for 50 minutes under microwave irradiation. In reaction scheme (19), all variables are as defined for formula (I) and W is as defined for formula (II).

Reaction scheme 19

Experimental method 20

An intermediate compound of formula (XXI) can be prepared according to reaction scheme (20) by treating an intermediate of formula (XXII) with an acid such as trifluoroacetic acid. The reaction is carried out in a suitable reaction inert solvent (such as DCM) at room temperature for a time allowing the reaction to complete, for example 2 hours. In reaction scheme (20), all variables are as defined for formula (I), halo-can be chloro-, bromo-, or iodo-, and W is as defined for formula (II).

Reaction scheme 20

Experimental method 21

Intermediate compounds of formula (XXII) can be prepared according to reaction scheme (21) by reacting an intermediate compound of formula (XXIII) with a strong base, such as butyl lithium, and further treating with a halogenating agent, such as iodine. The reaction is carried out in a suitable reaction-inert solvent such as THF at low temperature such as-78 ℃ for a time allowing the reaction to complete, for example 2 hours. In reaction scheme (21), halo-can be chloro-, bromo-, or iodo-, and W is as defined in formula (II). Reaction scheme 21

Experimental method 22

An intermediate compound of formula (XXIV) may be prepared according to reaction scheme (22) by reacting an intermediate compound of formula (XXV) with diphenylmethanimine by heating in a suitable reaction-inert solvent such as toluene in the presence of a suitable base such as sodium tert-butoxide, a metal-based catalyst, especially a palladium catalyst such as palladium (II) acetate, and a suitable ligand such as 1, 1 ' - [1, 1 ' -binaphthalene ] -2, 2 ' -diylbis [1, 1-diphenyl-phosphine ] (BINAP) for a suitable time to allow the reaction to complete (e.g. 16 hours at 100 ℃ in a sealed tube). In reaction scheme (22), all variables are as defined in formula (I).

Reaction scheme 22

Experimental method 23

Wherein R is³Is shown in the formula (I) The intermediate compound of formula (XXV) of the group of formula (b) as defined in (a), hence the name (XXV-a), can be prepared according to reaction scheme (23) by reacting an intermediate compound of formula (XXVI) with a compound of formula (V) in a suitable reaction inert solvent (such as 1, 4-dioxane) or a mixture of inert solvents (such as 1, 4-dioxane/DMF) in a suitable base (such as NaHCO)₃Or Na₂CO₃Aqueous solution), Pd complex catalyst (such as Pd (PPh)₃)₄) In the presence of heat (such as heating the reaction mixture at 150 ℃ for 10 minutes under microwave irradiation). In reaction scheme (23), all variables are as defined for formula (I), and W is as defined for formula (II). R¹⁰And R¹¹As defined in formula (V).

Reaction scheme 23

Experimental method 24

Wherein R is³An intermediate compound of formula (XXV), which is a group of formula (a) as defined in formula (I) wherein n is 0, thus referred to as (XXV-b), may be prepared according to reaction scheme (24) by reacting an intermediate compound of formula (XXVI) with a compound of formula (IV) in a suitable reaction-inert solvent, such as 1, 4-dioxane, in a suitable base, such as K₃PO₄) Pd complex catalysts (such as) In the presence of heat (such as, for example, at 80 ℃ heating reaction mixture for 12 hours). In reaction scheme (24), all variables are as defined in formula (I) and W is an amine-coupled group suitable for Pd-mediated coupling, such as halo.

Alternatively, the compound of formula (XXV-b) may be prepared according to reaction scheme (2) by reacting an intermediate compound of formula (XXVI) with a compound of formula (IV) in a suitable reaction inert solventIn a reagent (such as 1, 2-dimethoxyethane or acetonitrile) in a suitable base (such as Cs)₂CO₃Or N, N-diisopropylethylamine) under thermal conditions (such as, for example, heating the reaction mixture at 180 ℃ for 45 minutes under microwave irradiation).

Alternatively, compounds of formula (XXV-b) may be prepared according to reaction scheme (24) by reacting an intermediate compound of formula (XXVI) with a compound of formula (IV) in a suitable reaction-inert solvent such as toluene in the presence of a suitable base such as sodium tert-butoxide, a metal-based catalyst, especially a palladium catalyst such as palladium (II) acetate, and a suitable ligand such as 1, 1 ' - [1, 1 ' -binaphthyl ] -2, 2 ' -diylbis [1, 1-diphenyl-phosphine ] (BINAP) for a suitable time to allow the reaction to complete (e.g. 16 hours at 100 ℃ in a sealed tube).

Reaction scheme 24

Experimental method 25

Wherein R is³Intermediate compounds of formula (XXV) which are groups of formula (a) as defined in formula (I) wherein n is 1 (hence the name (XXV-c)) may be prepared by reacting an intermediate of formula (XXVII) with an intermediate of formula (IV) under reductive amination conditions known to those skilled in the art. This reaction is illustrated in reaction scheme (25). The reaction may be carried out, for example, in the presence of sodium triacetoxyborohydride in a suitable reaction inert solvent such as 1, 2-chloroethane at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete. In reaction scheme (25), all variables are as defined in formula (I).

Reaction scheme 25

Experimental method 26

The intermediate compound of formula (XXVII) may be prepared by reacting an intermediate of formula (XXVI) using conditions known to those skilled in the art. The reaction is illustrated in reaction scheme (26), wherein all variables are defined as mentioned above. This reaction can be carried out, for example, by first converting an aryl halide of formula (XXVI) (where W ═ halo) to an aryl metal derivative (where W ═ metal, where the metal can be lithium, magnesium, boron or zinc), followed by reaction with a suitable carbonyl source such as DMF. Reaction methods to achieve this reaction are well known to those skilled in the art and include a halogen-metal interchange in the presence of a Grignard reagent (such as isopropyl magnesium chloride) or a strong base (such as BuLi) in a suitable reaction-inert solvent (such as THF, diethyl ether, or toluene, preferably THF) at a temperature between-78 ℃ and room temperature, followed by reaction with a carbonyl source (such as DMF) at a temperature between-78 ℃ and 100 ℃.

Reaction scheme 26

Experimental method 27

The intermediate compounds of formula (IX) can be prepared by reacting an intermediate of formula (XXVIII) with at least a stoichiometric amount of an oxidizing agent under conditions known to those skilled in the art. The reaction may be carried out in the presence of water in a suitable reaction-inert solvent such as THF. The reaction is preferably carried out at moderately elevated temperatures (such as room temperature to 50 ℃). The reaction is continued until the reaction is substantially complete, typically within about 0.5 to 5 hours. Suitable oxidizing agents are well known in the art and include, for example, sodium periodate (NaIO)₄). In reaction scheme (27), all variables are as defined in formula (I).

Reaction scheme 27

Experimental method 28

An intermediate compound of formula (XXVIII) may be prepared by reacting an intermediate of formula (XXIX) with at least a stoichiometric amount of dimethoxymethyl-dimethyl-amine [ C.A.S.4637-24-5 ]. The reaction is preferably carried out in a reaction inert solvent such as 1, 4-dioxane at moderate to high temperatures such as about 100 ℃ to 160 ℃. The reaction is illustrated in reaction scheme (28), wherein all variables are as defined in formula (I).

Reaction scheme 28

Experimental method 29

An intermediate compound of formula (XXIX) may be prepared according to reaction scheme (29) by reacting an intermediate of formula (XXX) with an intermediate of formula (VIII). The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as, for example, heating the reaction mixture at 160 ℃ for 45 minutes under microwave irradiation. In reaction scheme (29), all variables are as defined in formula (I).

Reaction scheme 29

Experimental method 30

An intermediate compound of formula (XXX) may be prepared by reacting an intermediate compound of formula (XXXI) with an ammonia source, such as ammonium hydroxide, under thermal conditions, such as heating the reaction mixture at reflux for 3 hours. In reaction scheme (30), R²Of formula (I)As defined in (1).

Reaction scheme 30

Experimental method 31

The intermediate compounds of formula (XXXI) may be prepared by reacting an intermediate of formula (XXXII) with an intermediate of formula (XXXIII) under Knoevenagel conditions known to those skilled in the art. The reaction is illustrated in scheme 31, wherein all variables are defined as mentioned above.

Reaction scheme 31

Experimental method 32

The intermediate compounds of formula (XXXIV) may be prepared by reducing the carbonyl function present in the intermediate compound of formula (IX) under reducing conditions well known to those skilled in the art. The reaction is illustrated in reaction scheme (32), wherein all variables are as defined in formula (I). The reaction may be carried out, for example, in the presence of sodium triacetoxyborohydride in a suitable reaction-inert solvent such as dichloroethane at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete.

Reaction scheme 32

Experimental method 33

The intermediate compound of formula (X) can be prepared from formula (X)XXIV) intermediates are prepared by converting the hydroxyl groups present in the structure to halogens under reaction conditions known to those skilled in the art. The reaction is illustrated in reaction scheme (33), wherein all variables are defined as mentioned above and halo is chloro, bromo or iodo. The reaction may be carried out, for example, in a halogenating agent such as P (O) Br₃) In the presence of a suitable reaction inert solvent such as DCM or DMF or a mixture of both, at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete.

Reaction scheme 33

Experimental method 34

Intermediate compounds of formula (XXXV) can be prepared according to reaction scheme (34) by reacting R therein²An intermediate of formula (XXVI) which is halo and W is iodo, hence (XXVI-a), is reacted with ammonium hydroxide. The reaction is carried out under thermal conditions (such as, for example, heating the reaction mixture in a sealed vessel at 130 ℃ for 12 hours).

Reaction scheme 34

Experimental method 35

Wherein R is¹Intermediate compounds of formula (II) that are trifluoromethyl and W is halo (hence, (II-d)) may be prepared according to reaction scheme (35) by reacting an intermediate of formula (XXXVI) with a suitable trifluoromethylating agent, such as methyl fluorosulfonyl (difluoro) acetate. The reaction is carried out in a suitable reaction-inert solvent (such as N, N-dimethylformamide) in the presence of a suitable coupling agent (such as cuprous iodide) under thermal conditions (such as, for example, heating the reaction mixture at 160 ℃ for 45 minutes under microwave irradiation) The process is carried out. In reaction scheme (35), all variables are as defined in formula (I).

Reaction scheme 35

Experimental method 36

Intermediate compounds of formula (XXXVI) may be prepared according to reaction scheme (36) by reacting an intermediate of formula (XXXVII) with a suitable halogenating agent, such as N-iodosuccinimide. The reaction is carried out in a suitable reaction-inert solvent such as acetonitrile, for example, by stirring the mixture at room temperature for 3 hours. In reaction scheme (36), all variables are as defined in formula (I).

Reaction scheme 36

Experimental method 37

An intermediate compound of formula (XXXVII) may be prepared by reacting an intermediate compound of formula (XXXVIII) with a suitable halogenating agent, such as phosphorus (V) oxychloride, in a suitable reaction-inert solvent, such as DMF, at moderate to high temperatures, such as 110 c, for a suitable time, for example 1 hour, to allow the reaction to complete. In reaction scheme (37), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-.

Reaction scheme 37

Experimental method 38

Intermediate compounds of formula (XXXVIII) may be prepared according to reaction scheme (38) by reacting an intermediate of formula (XVIII) with chloroacetaldehyde. The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as, for example, heating the reaction mixture at 160 ℃ for 45 minutes under microwave irradiation. In reaction scheme (38), R²As defined in formula (I).

Reaction scheme 38

Experimental method 39

Intermediate compounds of formula (XI) can be prepared by reacting intermediate compounds of formula (XXXIX) as defined in experimental methods 2 and 3. All variables are as defined in formula (I), and halo-can be chloro-, bromo-, or iodo-, and R^1aIs C_1-4Alkyl or trifluoromethyl substituted C_1-4An alkyl group.

Reaction scheme 39

Experimental method 40

The intermediate compounds of formula (XXXIX) may be prepared by reacting an intermediate compound of formula (XL) with an intermediate of formula (XLI) under standard Wittig reaction conditions. The reaction is carried out in a suitable reaction-inert solvent such as THF at a temperature between-78 ℃ and room temperature in the presence of a wittig-type reagent of formula (XLI), for example prepared in situ from an alkyl triphenyl phosphonium halide, and a base such as lithium bis (trimethylsilyl) amide, for a suitable time, such as 1 hour, to allow the reaction to complete. In reaction scheme (40), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-, and R^1aIs C_1-4Alkyl or trifluoromethyl substituted C_1-4An alkyl group.

Reaction scheme 40

Experimental method 41

The intermediate compounds of formula (XL) can be prepared by reacting under standard Weissel-Hank (Vilsmeier-Haack) reaction conditions such as DMF and phosphorus oxychloride (POCl)₃) Prepared by reacting an intermediate compound of formula (XXXVII) at room temperature to 140 ℃ under classical thermal heating or microwave irradiation for a suitable time (e.g. 1 hour) allowing the reaction to complete. In reaction scheme (41), R²As defined in formula (I), and halo-may be chloro-, bromo-, or iodo-.

Reaction scheme 41

Experimental method 42

Alternatively, intermediate compounds of formula (XXXIX) may be prepared by reacting an intermediate of formula (XLII) with a suitable halogenating agent, such as phosphorus (V) oxychloride. The reaction is carried out under microwave irradiation at moderately elevated temperature (such as 130 ℃) for 15 minutes. In reaction scheme (42), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-, and R^1aIs C_1-4Alkyl or trifluoromethyl substituted C_1-4An alkyl group.

Reaction scheme 42

Experimental method 43

Intermediate compounds of formula (XLII) can be prepared according to reaction scheme (43) by reacting an intermediate compound of formula (XXXVIII) with an aldehyde of formula (XLIII). The reaction is carried out in an acidic medium, such as an acetic acid medium, under microwave irradiation at moderately elevated temperature (e.g. 155 ℃) for a suitable period of time, for example 1 hour. In reaction scheme (43), all variables are as defined in formula (I) and R^1aIs C_1-4Alkyl or trifluoromethyl substituted C_1-4An alkyl group.

Reaction scheme 43

Experimental method 44

The intermediate compound of formula (III) may be prepared according to reaction scheme (44) by reacting the intermediate of formula (IV) with potassium (bromomethyl) trifluoroborate. The reaction is carried out in a suitable reaction inert solvent such as acetonitrile under thermal conditions such as heating the reaction mixture for 2 hours at, for example, 80 ℃. In reaction scheme (44), all variables are as defined in formula (I).

Reaction scheme 44

Experimental method 45

The intermediate compound of formula (IV) can be prepared according to reaction scheme (45) by deprotecting the nitrogen atom in an intermediate compound of formula (XLIV) wherein Q represents a suitable protecting group for the nitrogen atom of the derivative, such as tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl, and methyl, using methods known in the art. For example, if Q represents benzyl, the deprotection reaction can be carried out in a sealed vessel in a suitable reaction-inert solvent (such as an alcohol, i.e., methanol; and 1, 4-cyclohexadiene) in the presence of a suitable catalyst (such as palladium on charcoal) at moderately elevated temperatures (such as 100 ℃). Alternatively, if Q represents alkoxycarbonyl, the deprotection reaction may be carried out by reaction with a suitable acid (such as hydrochloric acid) in a suitable reaction-inert solvent (such as 1, 4-dioxane) at moderate to high temperatures (such as reflux temperature). In reaction scheme (45), all variables are as defined in formula (I).

Reaction scheme 45

Experimental method 46

The intermediate compound of formula (V) may be prepared by methods known in the art by reacting an intermediate of formula (XLV) with a suitable boron source, such as bis (pinacolato) diboron, in the presence of a palladium catalyst, such as [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II), in an inert solvent, such as dichloromethane, in the presence of a suitable salt, such as potassium acetate, at moderately elevated temperature, such as 110 ℃.

Alternatively, compounds of formula (V) may be prepared from formula (XLV) according to halogen-metal interchange methods known in the art and subsequently reacted with an appropriate boron source. Thus, for example, an intermediate compound of formula (XLV) is reacted with an organolithium compound such as n-butyllithium in an inert solvent such as THF at moderate to low temperatures such as-40 ℃, followed by subsequent reaction with an appropriate boron source such as trimethoxyborane. In reaction scheme (46), all variables are as defined in formula (I), and R¹⁰And R¹¹As defined in formula (V).

Reaction scheme 46

Experimental method 47

Intermediate compounds of formula (XLV) can be prepared according to reaction scheme (47) by reacting a halogenated intermediate of formula (XLVI) with a suitable intermediate of formula (XLVII) by methods known in the art of nucleophilic substitution. The reaction is carried out in the presence of a suitable base (such as sodium hydride) in an inert solvent (such as DMF) under classical heating or microwave irradiation heating at moderately elevated temperatures (such as 180 ℃) for a suitable time to ensure completion of the reaction. In reaction scheme (47), all variables are as defined in formula (I), halo can be chloro, bromo, or iodo, and U is a suitable leaving group in the nucleophilic substitution reaction, such as halo or nitro.

Reaction scheme 47

Experimental method 48

Alternatively, compounds of formula (XLV) may be prepared from intermediate aniline-like compounds of formula (XLVIII) via sandmeyer type reactions by methods known in the art according to reaction conditions well known to those skilled in the art. In reaction scheme (48), all variables are as defined in formula (I), and the halo group can be chloro, bromo, or iodo.

Reaction scheme 48

Experimental method 49

Intermediate compounds of formula (XLVIII) can be prepared from intermediate nitro compounds of formula (XLIX) by reducing the nitro group to an amine functional group via methods known in the art, such as catalytic hydrogenation or using tin (II) chloride dihydrate as a reducing agent. In reaction scheme (49), all variables are as defined in formula (I).

Reaction scheme 49

Experimental method 50

Intermediate compounds of formula (XLIX) may be prepared by methods known in the art according to reaction scheme (50) by reacting an intermediate of formula (L) with a suitable intermediate of formula (LI) in the presence of a suitable base such as cesium carbonate in an inert solvent such as tetrahydrofuran, with heating at a suitable temperature and under conventional heating or microwave irradiation for a suitable time to allow the reaction to complete. In reaction scheme (50), all variables are as defined in formula (I), and Y is O or NH.

Reaction scheme 50

Experimental method 51

Wherein R is⁶Intermediate compounds of formula (V) which are cyclic groups of formula (k) (thus referred to as (V-b)) can be prepared by methods known in the art according to reaction scheme (51) by reacting R therein⁶Intermediates of formula (XLV) which are cyclic groups of formula (k) (hence the name (XLV-a)) are prepared by reaction with a suitable boron source according to conditions known in the art, such as those described in reaction scheme (46) above.

Reaction scheme 51

Experimental method 52

In addition, wherein R⁶Compounds of formula (V) which are cyclic groups of formula (k) and Y is NH, thus referred to as (V-c), may be prepared by reacting an intermediate compound of formula (LII) with a cyclic ketone derivative of formula (LIII) according to reaction scheme (52) under reductive amination conditions known to those skilled in the art, using a reducing agent such as sodium triacetoxyborohydride in a suitable reaction inert solvent such as 1, 2-dichloroethane at a suitable temperature (typically room temperature) for a suitable time to allow the reaction to complete. In reaction scheme (52), all variables are as defined in formula (I), and R¹⁰And R¹¹As defined in formula (V).

Reaction scheme 52

Experimental method 53

Wherein R is⁶Intermediate compounds of formula (XLV) which are cyclic groups of formula (k) and Y is NH, hence the name (XLV-a), can be prepared by methods known in the art according to reaction scheme (53) by reacting aniline intermediates of formula (LIV) with cyclic ketone derivatives of formula (LIII) under reductive amination conditions known to those skilled in the art using a reducing agent such as sodium triacetoxyborohydride in a suitable reaction-inert solvent such as 1, 2-dichloroethane at a suitable temperature, typically room temperature, for a suitable time to allow the reaction to complete. In reaction scheme (53), all variables are as defined in formula (I), R¹⁰And R¹¹As defined in formula (V) and halo-may be chloro-, bromo-, or iodo-.

Reaction scheme 53

Experimental method 54

Wherein R is⁶Intermediate compounds of formula (XLV) that are cyclic groups of formula (k) and Y is O, thus referred to as (XLV-b), can be prepared by methods known in the art according to reaction scheme (54) by reacting a phenol intermediate of formula (LV) with a cyclic alcohol of formula (LVI) in the presence of a phosphine such as triphenylphosphine and a suitable coupling agent such as di-tert-butyl azenobu-like coupling such as bis-tert-butyl azelate in an inert solvent such as dichloromethane at moderately low temperatures such as 25 ℃ for, for example, 2 hours. In reaction scheme (54), all variables are as defined for formula (I), and halo-can be chloro-, bromo-, or iodo-.

Reaction scheme 54

Experimental method 55

The intermediate compound of formula (VIII) may be prepared by reacting an intermediate compound of formula (XLII) with a halogenating agent, such as bromine, in an inert solvent, such as 1, 4-dioxane, at moderately low temperatures, such as 0 ℃. In reaction scheme (55), all variables are as defined in formula (I).

Reaction scheme 55

Starting materials of the formulae (V-a), (XIV), (XV), (XXIII), (XXVI), (XXXII), (XXXIII), (XLIII), (XLIIV), (XLVVI), (L), (LI), (LII), (LIII), (LIV), (LV) and (LVI) are compounds which are commercially available or can be prepared according to known reaction methods generally known to the person skilled in the art.

Thus, intermediate compounds of formula (IV) may be used, for example, as Organic Letters 2007, 9(8), 1505; tetrahedron Letters 2000, 41(46), 8853; prepared as described in Toso Kenkyu Hokoku1999, 43, 37 or commercially available.

Thus, the intermediate compound of formula (VIII) may be prepared or may be obtained commercially, for example as described in j.

Thus, the intermediate compounds of formula (XIX) may be used, for example, as intermediates in Synthesis (1984), (9), 768-70; prepared as described in Heterocycles 1986, 24(8), 2111 or commercially available.

Thus, intermediate compounds of formula (XXIII) may be prepared or may be obtained commercially, for example as described in WO 2008051197 a 2.

Thus, intermediate compounds of formula (XLII) may be prepared, for example, as described in Journal of the American chemical Society 1987, 109(25), 7714 and Synthetic Communications2007, 37(4), 599-.

Thus, the intermediate compounds of formulae (LIII), (LIV), (LV) and (LVI) may be prepared according to methods generally known to the person skilled in the art and may thus be prepared, for example, as described in WO2003029209-a 2. In addition, some of these intermediates are commercially available.

Pharmacology of

The compounds provided in the present invention are positive allosteric modulators of metabotropic glutamate receptors, which are, inter alia, positive allosteric modulators of mGluR 2. The compounds of the present invention do not appear to bind to the glutamate recognition site, the orthosteric ligand site, but rather to an allosteric site within the seven transmembrane region of the receptor. The compounds of the invention increase mGluR2 responses in the presence of glutamate or an agonist of mGluR 2. The compounds provided in the present invention are expected to exert effects on receptors by virtue of their ability to increase the response of mGluR2 to glutamate or mGluR2 agonists, thereby enhancing the response of the receptors. Accordingly, the present invention relates to a compound of the invention for use as a medicament, and the use of a compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment or prevention, especially treatment, of a condition (condition) in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, especially positive allosteric modulators thereof. The invention also relates to a compound of the invention or a pharmaceutical composition of the invention for use in the manufacture of a medicament for the treatment or prevention, especially treatment, of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, especially positive allosteric modulators thereof. The invention also relates to a compound of the invention or a pharmaceutical composition of the invention for use in the treatment or prevention, especially treatment, of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, especially positive allosteric modulators thereof.

The invention also relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment, prevention, amelioration, control of risk of or a variety of neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

When the invention is considered to relate to the use of a compound or composition of the invention for the manufacture of a medicament, for example for the treatment of a mammal, it is to be understood that such use is to be interpreted within the scope of, for example, a method of treating a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound or composition of the invention.

Neurological and psychiatric disorders associated with glutamate dysfunction include, inter alia, one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant brain defects, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's diseaseDiseases, muscle spasms and disorders associated with muscle spasms including tremor, epilepsy, convulsions, migraine (migaine) including migraine (migaine headaches), urinary incontinence, substance tolerance, substance withdrawal including, for example, opiates, nicotine, smoking articles, alcohol, benzodiazepinesCocaine, sedatives, hypnotics, and the like), psychosis, schizophrenia, anxiety disorders (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), affective disorders (including depression, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain (including acute and chronic states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.

The condition or disease is in particular a central nervous system disorder selected from the group of anxiety disorders, psychiatric disorders, personality disorders, substance-related disorders, eating disorders, affective disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegenerative disorders, neurotoxicity and ischemia.

The central nervous system disorder is preferably an anxiety disorder selected from the group of agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

The central nervous system disorder is preferably a personality disorder selected from the group of obsessive-compulsive personality disorder and schizophrenia, schizotypal disorder.

The central nervous system disorder is preferably a substance-related disorder selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.

The central nervous system disorder is preferably an affective disorder selected from the group of bipolar disorders (I and II), cyclothymic disorder, depression, dysthymia, major depressive disorder and substance-induced affective disorder.

The central nervous system disorder is preferably migraine.

The central nervous system disorder is preferably epilepsy or a convulsive disorder selected from the group of generalized non-convulsive epilepsy, generalized convulsive epilepsy, petit mal epileptic status, grand mal epileptic status, partial epilepsy with or without conscious impairment, infantile spasms, partial epileptic status, and other forms of epilepsy.

The central nervous system disorder is preferably attention deficit/hyperactivity disorder.

The central nervous system disorder is preferably a cognitive disorder selected from the group of delirium, substance-induced persistent delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, substance-induced persistent dementia and mild cognitive impairment.

Of the disorders mentioned above, the treatment of anxiety, schizophrenia, migraine, depression and epilepsy is particularly important.

Currently, the fourth edition of the american psychiatric society for mental disorders diagnostic and statistics manual (DSM-IV) provides diagnostic tools for identifying the disorders described herein. Those skilled in the art will recognize that there are alternative nomenclature, disease classification, and grading systems for neurological and psychiatric disorders described herein and that they are well established with medical and scientific development.

Since this positive allosteric modulator comprising mGluR2 of the compound of formula (I) enhances the response of mGluR2 to glutamate, this is an advantage of the present method to exploit endogenous glutamate.

Because positive allosteric modulators of mGluR2, including compounds of formula (I), enhance the response of mGluR2 to agonists, it will be appreciated that the present invention relates to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a positive allosteric modulator of mGluR2, including compounds of formula (I), and an mGluR2 agonist.

The compounds of the present invention may be used in combination with one or more other drugs for the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions in which compounds of formula (I) or other drugs may have utility, where the combination of drugs together is safer or more effective than the single drug.

Pharmaceutical composition

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound of the invention, in particular a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a stereochemically isomeric form thereof.

An effective daily amount may range from about 0.01mg to about 10mg per kg of body weight, preferably from about 0.05mg to about 1mg per kg of body weight.

For administration purposes, the compounds of the present invention, especially the compounds of formula (I), their pharmaceutically acceptable salts, solvates and stereochemically isomeric forms thereof, or any subcombination or combination thereof, may be formulated into a variety of pharmaceutical forms. Suitable compositions may be mentioned all compositions which are customarily used for systemic administration of drugs.

To prepare the pharmaceutical compositions of the invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent, which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that the pharmaceutical composition is in a single dosage form suitable for administration, inter alia, orally, rectally, transdermally, parenterally, by injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like may be employed. Oral administration is preferred because of the ease of administration, and tablets and capsules represent the most convenient oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise at least a major portion of sterile water, although the carrier may comprise other ingredients, for example, to aid solubility. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally in minor proportions, of suitable additives of any nature which do not have a significant deleterious effect on the skin. The additive facilitates administration to the skin and/or aids in the preparation of the desired composition. The composition may be administered in a variety of ways, for example in the form of a transdermal patch, in the form of drops (spot-on), in the form of an ointment.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient suitable for the purpose of producing the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are lozenges (including scored or coated lozenges), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like and divided portions thereof.

The precise dosage and frequency of administration will depend on the particular compound of formula (I) used, as is well known to those skilled in the art; the particular condition being treated; the severity of the condition being treated; the age, weight, sex, extent of the condition and general physical condition of the particular patient and other medications that the individual may take. Furthermore, it is apparent that the effective daily amount may be reduced or increased depending on the response of the subject being treated and/or as assessed by the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition should comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight of active ingredient and from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

As already mentioned, the invention also relates to a pharmaceutical composition comprising a compound of the invention and one or more other drugs for the treatment, prevention, control, amelioration or reduction of risk of diseases or conditions in which a compound of formula (I) or other drug may have utility, and to the use of such a composition for the manufacture of a medicament. The invention also relates to combinations of the compounds of the invention with mGluR2 orthoagonists. The invention also relates to such a combination for use as a medicament. The invention also relates to a product containing (a) a compound of the invention, a pharmaceutically acceptable salt or solvate thereof, and (b) an mGluR2 orthosteric agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 allosteric modulators, particularly positive mGluR2 allosteric modulators. The different drugs of the combination or product may be combined into a single formulation with a pharmaceutically acceptable carrier or diluent, or they may each be present in separate formulations with a pharmaceutically acceptable carrier or diluent.

The following examples are intended to illustrate but not limit the scope of the invention.

Chemistry

Several methods of preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise indicated, all starting materials were obtained from the supplier and used without further purification.

Hereinafter, "THF" means tetrahydrofuran; "DMF" means N N-dimethylformamide; "EtOAc" means ethyl acetate; "DCM" means dichloromethane; "BINAP" means 1, 1 '- [1, 1' -binaphthalene]-2, 2' -diylbis [1, 1-diphenyl-phosphine](ii) a "DBU" means 1, 8-diaza-7-bicyclo [5.4.0]Undecene; "NH₄OH "means ammonium hydroxide; "NaHCO₃"means sodium bicarbonate; et₂O "means diethyl ether; "MgSO (MgSO)₄"means magnesium sulfate; "EtOH" means ethanol; "Na₂SO₄"means sodium sulfate; ' CH₃CN "means acetonitrile; "NaH" means sodium hydride; "MeOH" means methanol; "NH₃"means ammonia; "Na₂S₂O₃"means sodium thiosulfate; "AcOH" means acetic acid; et₃N "means triethylamine; "NH₄Cl "means ammonium chloride; "K₂CO₃"means potassium carbonate; "Pd (PPh)₃)₄"means tetrakis (triphenylphosphine) palladium (0); "r.t." means room temperature.

The microwave-assisted reaction was carried out in a single mode reactor: initiator^TMSixty EXP microwave reactor (Biotage AB); or in a multi-mode reactor: MicroSYNTHLabstation (Milestone, Inc.).

Description 1

2- (1-ethoxy-ethylene) -malononitrile (D1)

A mixture of malononitrile (17g, 257.57mmol) and triethyl orthoacetate (45.95g, 283.25mmol) was heated at 95 ℃ for 1.5 hours. The mixture was then evaporated under vacuum to give a solid which was filtered off to give compound D1(34g, 99%) as a yellow solid. This compound was used in the next reaction step without further purification.

Compound D1 is also commercially available, CAS: 5417-82-3.

Description 2

2- (3-dimethylamino-1-methoxy-allylidene) -malononitrile (D2)

To a mixture of D1(34g, 250mmol) in methanol (300ml) was added N, N-dimethylformamide dimethyl acetal (44.68g, 375 mmol). The reaction mixture was heated at reflux for 2 hours. The mixture was then cooled to room temperature and after cooling a dark red solid precipitated. The solid was filtered off, washed with cold methanol and dried under vacuum to give compound D2(16.2g, 38%) as a red solid.

LCMS: MW (theory): 177; [ MH⁺]：178；RT(min)：2.25。

Compound D2 is also commercially available, CAS: 95689-38-6.

Description 3

2-amino-4-methoxy-nicotinonitrile (nicotinonitrile) (D3)

D2(16g, 90.39mmol) was heated to NH under reflux₄Mixture in OH (100ml, 30% in water) for 3 hours. After cooling in an ice bath, a yellow solid precipitated. The solid was filtered off, washed with cold isopropanol and dried under vacuum to give compound D3(10g, 76%) as a white solid.

LCMS: MW (theory): 149; [ MH⁺]：150；RT(min)：0.41。

Compound D3 is also commercially available, CAS: 98651-70-8.

Description 4

Bromo-phenyl-acetaldehyde (D4)

To a solution of phenylacetaldehyde (4.03g, 33.5mmol) in 1, 4-dioxane (1ml) cooled to 0 ℃ was added bromine (1.80ml, 35mmol) dropwise over 15 minutes. The reaction mixture was stirred at 0 ℃ for a further 10 minutes, allowed to warm to room temperature and then stirred for a further 10 minutes. This mixture containing compound D4 (assuming quantitative yield) was used in the next reaction step without further purification.

Compound D4 can also be prepared as described in the following documents: bulletin of the Korean chemical Society 1995, 16(4), 371-.

Description 5

7-hydroxy-3-phenyl-imidazo [1, 2-a ] pyridine-8-carbonitrile (D5)

A mixture of compound D3(2g, 13.41mmol) and D4(6.69g, 33.5mmol) in EtOH (10ml) was subjected to microwave heating at 160 ℃ for 45 minutes. The reaction mixture was cooled to room temperature and then diluted with DCM, causing a solid to precipitate. The solid obtained was filtered off, washed thoroughly with DCM and dried under vacuum to give compound D5(2.65g, 84%) as a pale yellow solid.

LCMS: MW (theory): 235; [ MH⁺]: 236; RT (min): 1.63 (method 21).

Description 6

7-chloro-3-phenyl-imidazo [1, 2-a ] pyridine-8-carbonitrile (D6)

A mixture of compound D5(2.3g, 9.77mmol) and phosphorus (V) oxychloride (50ml) was heated at 120 ℃ for 5 hours. After cooling to room temperature, the solvent was evaporated under vacuum. The residue obtained is carefully poured into crushed ice and NaHCO₃(saturated aqueous solution). EtOAc was then added and the mixture was stirred for 2 hours until complete hydrolysis of the remaining phosphoryl chloride occurred. The organic layer was then separated, washed with brine and dried (Na)₂SO₄) And the solvent was evaporated under vacuum to give a residue which was treated with Et₂A precipitate formed after O. The solid was filtered off and dried under vacuum to give compound D6(0.82g, 33%) as a yellow solid.

LCMS: MW (theory): 253; [ MH⁺]: 254; RT (min): 3.44 (method 1).

MP: and (5) decomposing.

Description 7

(Phenylpiperidinylmethyl) potassium trifluoroborate (D7)

To a solution of potassium (bromomethyl) trifluoroborate (0.1g, 0.5mmol) in CH₃To a solution of CN (1ml) was added 4-phenylpiperidine (0.241g, 1.5 mmol). The reaction mixture was heated at 80 ℃ for 2 hours. After cooling, the solvent was evaporated under vacuum to give a residue which was Et-dried₂And precipitating after O treatment. The solid was filtered off and dried under vacuum to give compound D7(0.108g, 89%).

LCMS: MW (theory): 281; [ M ] A^-]：242；RT(min)：2.64。

Description 8

2-bromo-4, 4, 4-trifluoro-butyraldehyde (D8)

To a mixture of 4, 4, 4-trifluorobutanal (5g, 39.68mmol) in 1, 4-dioxane (5ml) cooled to 0 ℃ was added dropwise bromine (2.24ml, 43.65 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours. The resulting reaction mixture was filtered through a pad of celite and NaHCO₃The filtrate was washed (saturated aqueous solution). The organic layer was separated and dried (MgSO)₄) And evaporated in vacuo to give compound D8(6.2g, 76%), D8 was used in the next reaction step without further purification.

¹H-NMR(CDCl₃)：9.46(s，1H)；4.48(t，J＝6.5Hz，1H)；3.26-3.13(m，1H)；2.74-2.60(m，1H)。

Description 9

7-hydroxy-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D9)

Compounds D3(3.31g, 22.19mmol) and D8(6.2g, 21.86 mmol) were reacted with¹H-NMR calculated purity 72%) in EtOH (10ml) was subjected to microwave heating at 150 ℃ for 40 min. After cooling to room temperature, the solvent was evaporated under vacuum. With Et₂The residue obtained was treated with O and a solid precipitated out. The solid obtained was filtered off, washed with EtOAc and dried under vacuum to give compound D9(1g, 18%).

LCMS: MW (theory): 241, a first electrode and a second electrode; [ MH⁺]：242；RT(min)：1.06。

Description of the preferred embodiments 10

7-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D10)

A mixture of compound D9(1g, 4.148mmol) and phosphorus (V) oxychloride (2ml) was subjected to microwave heating at 130 ℃ for 15 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. Followed by NaHCO₃The residue obtained was treated (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. By column chromatography (silica gel; Et)₂O as eluent (eluent)) purified the crude product. The desired fractions were collected and evaporated in vacuo to yield compound D10(0.6g, 56%) as a yellow solid.

LCMS: MW (theory): 259; [ MH⁺]: 260 of a nitrogen atom; RT (min): 2.66 (method 16).

Description of the preferred embodiments 11

2, 4-dibromo-nicotinonitrile (nicotinonitrile) (D11)

To a commercially available 4-methoxy-2-oxo-1, 2-dihydro-3-pyridinecarbonitrile (95.47g, 333mmol) [ C.A. S.21642-98-8]To a solution in acetonitrile (670ml) was added phosphorus (V) oxybromide (250g, 166mmol) in portions. The resulting suspension was heated at 60 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and washed with NaHCO₃Washed (saturated aqueous solution) and dried (MgSO)₄) And evaporated under vacuum. The crude product obtained was wet-milled (tributed) with diisopropyl ether to give compound D11(34.5g, 79%) as a white solid.

Gcms (ei): MW (theory): 262; [ M-2H ]⁺]：260；RT(min)：9.67。

Description of the preferred embodiments 12

2-amino-4-bromo-nicotinonitrile (nicotinonitrile) (D12)

Heating Compound D11(32g, 122.2mmol) in NH at 100 ℃ in a PARR pressure vessel₄OH (200ml) and THF (200ml) for 12 hours. After cooling, EtOAc was added. The organic layer was separated, washed with brine and dried (Na)₂SO₄) And evaporated under vacuum. The residue obtained was wet milled with DCM. The solid obtained is filtered off. The filtrate was evaporated in vacuo to give compound D12(6.5g, 26.8%) as a white solid.

LCMS: MW (theory): 197; [ MH⁺]: 198; RT (min): 1.14 (method 1).

Description 13

7-bromo-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D13)

A mixture of compound D12(2g, 10.1mmol) and D8(2.898g, 14.14mmol) in EtOH (10ml) was subjected to microwave heating at 150 ℃ for 40 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. The obtained residue was diluted with EtOAc and washed with water. The organic layer was separated and washed with water, then 1M HCl (aq), dried (MgSO)₄) And evaporated under vacuum. The crude product obtained was wet-milled with diethyl ether to give compound D13(1.5g, 48.8%).

LCMS: MW (theory): 303; [ MH⁺]: 304; RT (min): 2.48 (method 14).

Description 14

4- (4-bromo-3-fluoro-phenoxy) -2-methyl-pyridine N-oxide (D14)

To a mixture of 4-bromo-3-fluorophenol (6g, 31.41mmol) in DMF (20ml) was added NaH (0.81g, 56mmol, 60% in mineral oil) at room temperature. The resulting reaction mixture was stirred for 10 minutes, followed by addition of 4-nitro-2-methylpyridine N-oxide (5.6g, 36.12 mmol). The resulting solution was subjected to microwave heating at 180 ℃ for 1 hour. The mixture was cooled to room temperature and extracted with EtOAc and H₂And (4) diluting with oxygen. The layers were separated and the aqueous layer was extracted twice with EtOAc. Drying (Na)₂SO₄) The combined organic extracts were evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) was purified. The desired fractions were collected and evaporated under vacuum to give compound D14(3.61g, 39%) as a dark orange solid.

LCMS: MW (theory): 297; [ MH⁺]: 298; RT (min): 2.54 (method 12)。

Description of the preferred embodiments 15

2-fluoro-4- (2-methyl-pyridin-4-yloxy) -boronic acid (D15)

To a solution of compound D14(1.05g, 3.52mmol) in a mixture of 1, 4-dioxane (9ml) and DMF (4ml) was added bis (pinacolato) diboron (2.68g, 10.56mmol) and potassium acetate (1.035g, 10.56 mmol). The resulting mixture was degassed using a nitrogen stream and [1, 1' -bis (diphenylphosphino) ferrocene was added thereto]Palladium (II) dichloride (0.115g, 0.141 mmol). The reaction mixture was subsequently heated at 110 ℃ for 3 hours. The mixture was cooled to room temperature and washed with H₂Diluted O and extracted twice with EtOAc. The combined organic layers were evaporated in vacuo to give compound D15(0.87g, quantitative) as a dark brown oil, which was used in the next reaction step without further purification.

LCMS: MW (theory): 247; [ MH⁺]: 248; RT (min): 2.22 (method 22).

Description 16

2, 3-dichloro-4-iodo-pyridine (D16)

The reaction was carried out under a nitrogen atmosphere. To a solution of n-butyllithium (27.6mL, 69mmol, 2.5M in hexanes) in anhydrous Et₂To a solution in O (150ml) cooled at-78 ℃ was added 2, 2, 6, 6-tetramethylpiperidine (11.64ml, 69mmol) dropwise. The resulting reaction mixture was stirred at-78 ℃ for 10 minutes and then a solution of 2, 3-dichloropyridine (10g, 67.57mmol) in dry THF (75ml) was added dropwise. The mixture was stirred at-78 ℃ for 30 minutesAnd then a solution of iodine (25.38g, 100mmol) in dry THF (75ml) was added. The mixture was allowed to warm to room temperature overnight, over Na₂S₂O₃(saturated aqueous solution) quenched and extracted twice with EtOAc. With NaHCO₃The combined organic extracts were washed (saturated aqueous solution) and dried (Na)₂SO₄) And evaporated under vacuum. The crude residue was precipitated with heptane, filtered off and dried to give compound D16(8.21g, 44%) as a pale cream solid.

LCMS: MW (theory): 273; [ MH⁺]: not ionizing; RT (min): 2.73 (method 21).

Description of the preferred embodiments 17

3-chloro-4-iodo-pyridin-2-ylamine (D17)

Compound D16(6g, 21.9mmol) was heated at 129 ℃ in NH₄Mixture in OH (12ml, 11N) for 12 hours. After cooling, DCM was added and the organic layer was separated, washed with brine and dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) was purified. The desired fractions were collected and evaporated under vacuum to give compound D17(2.88g, 52%) as a white solid.

LCMS: MW (theory): 254; [ MH⁺]: 255; RT (min): 2.22 (method 22).

Description 18

2-bromo-pentanal (D18)

Within 15 minutes, the process is carried outTo a solution of valeraldehyde (4.27g, 49.57mmol) in 1, 4-dioxane (1ml) cooled to 0 ℃ was added bromine (2.46ml, 49.57mmol) dropwise. The reaction mixture was stirred at 0 ℃ for a further 10 minutes, allowed to warm to room temperature and stirred for a further 10 minutes. Followed by NaHCO₃(saturated aqueous solution) quench the mixture and use Et₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) And evaporated in vacuo to give compound D18(6g, 30%), and D18 was used in the next reaction step without further purification.

Compound D18 can also be prepared as described in the following documents: helvetica Chimicaacta 1949, 3235-38.

Description 19

8-chloro-7-iodo-3-propyl-imidazo [1, 2-a ] pyridine (D19)

To a mixture of compound D17(0.76g, 2.98mmol) in EtOH (8ml) was added compound D18(2.55g, 15.5 mmol). The reaction mixture was subjected to microwave heating at 150 ℃ for 45 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was treated with DCM. The obtained precipitate was filtered off and dried to give compound D19 as a light cream solid (0.7g, 73%).

LCMS: MW (theory): 320, a first step of mixing; [ MH⁺]: 321; RT (min): 2.55 (method 23).

Description 20

8-chloro-7-iodo-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine (D20)

To compound D17(0.507g,1.992mmol) in EtOH (7ml) was added compound D8(0.817g, 3.985 mmol). The reaction mixture was subjected to microwave heating at 150 ℃ for 30 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was then dissolved in DCM and NaHCO₃(saturated aqueous solution) washing. The organic layer was separated and dried (Na)₂SO₄) And the solvent was evaporated under vacuum. The residue obtained was purified by column chromatography (silica gel; up to 6% DCM/EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D20(0.5g, 69.6%) as a yellow solid.

LCMS: MW (theory): 360; [ MH⁺]: 361; RT (min): 2.31 (method 15).

Description of the preferred embodiments 21

7-hydroxy-imidazo [1, 2-a ] pyridine-8-carbonitrile (D21)

To a mixture of compound D3(2g, 13.404mmol) in EtOH (5ml) was added chloroacetaldehyde (1.58g, 20.11 mmol). The reaction mixture was subjected to microwave heating at 150 ℃ for 45 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. Followed by Et₂The residue obtained was treated with O and a solid precipitated. The solid obtained was filtered off, washed with EtOAc and dried under vacuum to give compound D21(1.5g, 70%).

LCMS: MW (theory): 159; [ MH⁺]：160；RT(min)：0.21。

Description of the preferred embodiments 22

7-chloro-imidazo [1, 2-a ] pyridine-8-carbonitrile (D22)

A mixture of compound D21(1.5g, 9.425mmol) and phosphorus (V) oxychloride (3.5ml) was subjected to microwave heating at 130 ℃ for 15 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. With NaHCO₃The residue obtained was treated (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. By column chromatography (silica gel; Et)₂O as eluent) was purified. The desired fractions were collected and evaporated in vacuo to yield compound D22(1.6g, 95%) as a yellow solid.

LCMS: MW (theory): 177; [ MH⁺]：178；RT(min)：1.45。

MP: and (5) decomposing.

Description 23

7-chloro-3-iodo-imidazo [1, 2-a ] pyridine-8-carbonitrile (D23)

To compound D22(0.5g, 2.81mmol) in CH₃To the mixture in CN (5ml) was added N-iodosuccinimide (0.696g, 3.o9 mmol). The reaction mixture was stirred at room temperature for 3 hours. After cooling, the solvent was evaporated under vacuum. With Na₂S₂O₃The residue was treated with aqueous (2N) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. The crude product was purified by column chromatography (silica gel; heptane/EtOAc 1: 1 as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D23(0.7g, 82%) as a brown solid.

LCMS: MW (theory): 303; [ MH⁺]: 304; RT (min): 2.14 (method 17).

Description 24

7-chloro-3-trifluoromethyl-imidazo [1, 2-a ] pyridine-8-carbonitrile (D24)

To a mixture of compound D23(0.2g, 0.659mmol) in DMF (3ml) were added methyl fluorosulfonyl (difluoro) acetate (0.633g, 3.295mmol) and copper (I) iodide (0.63g, 3.295 mmol). The reaction mixture was subjected to microwave heating at 160 ℃ for 45 minutes. After cooling, the solvent was evaporated under vacuum. The crude product was purified by column chromatography (silica gel; heptane/EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D24(0.1g, 62%) as a yellow solid.

LCMS: MW (theory): 259; [ MH⁺]: 260 of a nitrogen atom; RT (min): 2.56 (method 16).

Description 25

7-hydroxy-3- (4, 4, 4-trifluoro-but-1-enyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D25)

To a mixture of compound D21(0.25g, 1.57mmol) in AcOH (3ml) was added 4, 4, 4-trifluorobutanal (1.38g, 10.99 mmol). The reaction mixture was subjected to microwave heating at 155 ℃ for 45 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. Followed by NaHCO₃The residue was treated (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. The crude product was purified by column chromatography (silica gel; DCM/MeOH 0.5% as eluent). The desired fractions were collected and evaporated in vacuo to give compound D25(0.1g, 24%) as an oil.

LCMS: MW (theory): 267; [ MH⁺]: 268; RT (min): 2.16 (method 24).

Description 26

7-chloro-3- (4, 4, 4-trifluoro-but-1-enyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D26)

A mixture of compound D25(0.1g, 0.374mmol) and phosphorus (V) oxychloride (1.5ml) was subjected to microwave heating at 130 ℃ for 15 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. With NaHCO₃The residue was treated (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. The crude product was purified by column chromatography (silica gel; DCM/MeOH 0.5% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D26(0.85g, 80%) as a yellow solid.

LCMS: MW (theory): 285; [ MH⁺]：286；RT(min)：2.85。

MP：158℃。

Description 27

7- (4-phenyl-piperidin-1-yl) -3- (4, 4, 4-trifluoro-but-1-enyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D27)

To a mixture of compound D26(0.12g, 0.42mmol) in DMF (3ml) was added 4-phenylpiperidine (0.081g, 0.504mmol) and Et₃N (0.064g, 0.63 mmol). The reaction mixture was subjected to microwave heating at 150 ℃ for 45 minutes. After cooling to room temperature, the solvent is evaporated under vacuum and taken up with NH₄The obtained residue was treated with Cl (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) And evaporated under vacuum. From postThe crude product was purified by chromatography (silica gel; heptane/EtOAc 7: 3 as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D27(0.12g, 70%) as a yellow oil.

LCMS: MW (theory): 410; [ MH⁺]: 411; RT (min): 3.49 (method 17).

Description of the preferred embodiments 28

4- [2- (1-hydroxy-1-methyl-ethyl) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester (D28)

To 4- (2-methoxycarbonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (2.6g, 8.14mmol) [ C.A.S.732275-95-5]To a solution in THF (150ml) cooled at 0 deg.C under nitrogen was added dropwise methylmagnesium bromide (1.4M solution in toluene/THF) (17.443ml, 24.421mmol) and the resulting reaction mixture was stirred at 45 deg.C for 2 hours. After cooling in an ice bath, the mixture was carefully quenched with saturated aqueous ammonium chloride solution and subsequently extracted with EtOAc. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum to give D28(2.77g, 69%).

LCMS: MW (theory): 319; [ MH⁺]: 320, a first step of mixing; RT (min): 3.01 (method 20).

Description 29

2- (2-piperidin-4-yl-phenyl) -propan-2-ol (D29)

A solution of intermediate D28(27g, 5.636mmol) and potassium hydroxide (2.433g, 43.357mmol) in isopropanol (13.5ml) and water (27ml) was subjected to microwave heating at 180 ℃ for 60 minutes. Cooling to room temperatureAfter that, the mixture was washed with water and sodium chloride (saturated aqueous solution). The organic phase was dried (Na)₂SO₄) And the solvent was evaporated under vacuum. By column chromatography (silica; up to 10% DCM/MeOH (NH)₃) As eluent) to purify the crude product. The desired fractions were collected and evaporated in vacuo to give compound D29(1.041g,%) as a yellow solid.

M.P.：219.5℃。

LCMS: MW (theory): 220, 220; [ M ] A⁺]: 220, 220; RT (min): 1.29 (method 11).

Description of the preferred embodiments 30

(4-bromo-2-chloro-phenyl) -cyclopropyl-amine (D30)

To a stirred solution of 4-bromo-2-chloroaniline [ c.a.s.38762-41-3] (1g, 4.843mmol) in AcOH (19mL) and MeOH (10mL) at room temperature under a nitrogen atmosphere was added dropwise (1-ethoxycyclopropyloxy-trimethylsilane [ c.a.s.27374-25-0] (1.199mL, 5.57mmol), then the reaction mixture was refluxed at 67-69 ℃ for 3 hours, then the mixture was concentrated under vacuum to give intermediate D30'.

In another flask, NaBH was added₄(0.366g, 9.687mmol) was suspended in THF (10mL) and cooled to 5 ℃. Subsequently, BF was added dropwise₃·Et₂O complex (1.228ml, 9.687 mmol). The reaction mixture obtained is reacted in N₂Stirred under an atmosphere at 5 ℃ for 1 hour. Subsequently, a solution of D30' in THF (5mL) was added dropwise to the mixture over 20 minutes at 5-10 ℃. After stirring at room temperature for 5 hours, stirring at reflux temperature for 2 hours and subsequent removal of THF by distillation, the mixture was cooled to room temperature and poured into water. With Et₂And O extracting the obtained mixture. The organic layer was washed with water and dried (Na)₂SO₄) Followed by removal of volatile components under vacuum. By column chromatography (silica)Gluing; heptane/EtOAc 99: 1 as eluent) was purified. The desired fractions were collected and evaporated under vacuum to give intermediate D30(0.390g, 32.6%).

Description 31

[ 2-chloro-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -cyclopropyl-amine (D31)

Bis (pinacolato) diboron (0.643g, 2.531mmol) and potassium acetate (0.466g, 4.746mmol) were added to a solution of intermediate D30(0.390g, 1.582mmol) in 1, 4-dioxane (2ml) and DMF (0.5 ml). The mixture was degassed and then [1, 1' -bis (diphenylphosphino) -ferrocene ] -dichloropalladium (II) -DCM complex (1: 1) (0.0348g, 0.0475mmol) was added. The reaction mixture was heated at 150 ℃ for 10 minutes under microwave irradiation. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was evaporated under vacuum. The crude residue was purified by column chromatography (silica gel; heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D31(0.269g, 49%).

GCMS: MW (theory): 293; [ M ] A⁺]：293；RT(min)：12.7。

Description 32

[4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl ] - [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl ] -amine (D32)

4- (tert-butyl-dimethyl-silanyloxy) -cyclohexanone (1.72ml, 6.85mmol) [ C.A.S.55145-45-4]、4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]A mixture of dioxolan-2-yl) -phenylamine (1g, 4.56mmol) and sodium triacetoxyborohydride (1.44g, 6.85mmol) in DCM (25ml) was stirred at room temperature for 1 day. Followed by NH₄The mixture was washed with Cl (saturated aqueous solution). The organic layer was collected and dried (MgSO)₄) And evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; up to 5% heptane/EtOAc as eluent). The desired fractions were collected and evaporated under vacuum to give intermediate D32-a (trans) (0.566g, 31%) and D32-b (cis) (1.089g, 61%).

Description 33

(4-bromo-2-chloro-phenyl) - (1, 4-dioxa-spiro [4.5] dec-8-yl) -amine (D33)

A mixture of 4-bromo-2-chloro-phenylamine (6g, 29.06mmol), 1, 4-cyclohexanedione monoethylketal (6.908g, 43.59mmol) and sodium triacetoxyborohydride (9.239g, 43.59mmol) in DCE (100ml) and acetic acid (0.2ml) was stirred at room temperature for 2 days. The mixture was then filtered through a pad of celite and washed with dichloromethane. With NaHCO₃The filtrate was washed with (saturated aqueous solution) and sodium chloride (saturated aqueous solution), and dried (Na)₂SO₄) And evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; DCM/EtOAc 4: 1 as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D33(8.57g, 85%).

Description 34

4- (4-bromo-2-chloro-phenylamino) -cyclohexanone (D34)

Intermediate D33(4g, 11.539mmol), p-toluenesulfonic acid (21.949mg, 0.115mmol) in H were heated at 110 ℃ under microwave irradiation₂Mixture of O (6ml) and acetone (3ml) for 45 min. After cooling to room temperature, the reaction mixture was diluted with DCM and washed with saturated aqueous NaCl solution, dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; up to 0.1% DCM/MeOH (NH)₃) As eluent) purification of the reaction mixture. The desired fractions were collected and evaporated in vacuo to yield intermediate D34(2.17g, 62%) as a white solid.

Description 35

4- [ 2-chloro-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenylamino ] -cyclohexanone (D35)

Bis (pinacolato) diboron (2.028g, 7.984mmol) and potassium acetate (1.469g, 14.97mmol) were added to a solution of intermediate D34(1.51g, 4.99mmol) in 1, 4-dioxane (4ml) and DMF (1 ml). The mixture was degassed and then [1, 1' -bis (diphenylphosphino) -ferrocene ] -dichloropalladium (II) -DCM complex (1: 1) (0.110g, 0.15mmol) was added. The reaction mixture was heated at 150 ℃ for 10 minutes under microwave irradiation. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was evaporated under vacuum. The crude residue was purified by column chromatography (silica gel; up to 10% heptane/EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D35(1.09g, 62.4%).

LCMS: MW (theory): 349; [ MH⁺]: 350 of (a); RT (min): 3.46 (method 16).

Description 36

7- [ 3-chloro-4- (4-oxo-cyclohexylamino) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2a ] pyridine-8-carbonitrile (D36)

To a mixture of compound D10(0.25g, 0.963mmol) in 1, 4-dioxane (4ml) under nitrogen atmosphere was added compound D35(0.404g, 1.156mmol), Pd (PPh)₃)₄(0.111g, 0.0963mmol) and finally NaHCO₃(1ml, saturated aqueous solution). The reaction mixture was subjected to microwave heating at 150 ℃ for 10 minutes. After cooling, the mixture was filtered through a pad of celite and the pad was washed with EtOAc. The combined filtrates were washed with NaCl (saturated aqueous solution). The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum and purified by column chromatography (silica gel; from up to 10% DCM/MeOH (NH)₃) Starting as eluent) was purified. The desired fractions were collected and evaporated under vacuum to give intermediate compound D36(0.419g, 97%).

LCMS: MW (theory): 446; [ MH⁺]: 447 (c); RT (min): 3.06 (method 17).

Description 37

4- (4-bromo-2-chloro-phenylamino) -cyclohexanol (D37)

To a stirred mixture of intermediate D34(2g, 5.288mmol) in MeOH (40ml) at-78 deg.C was added sodium borohydride (220mg, 5.816 mmol). The mixture was allowed to warm to room temperature step by step and stirred for a further 16 hours. Subsequently, the resulting mixture was quenched with a saturated aqueous ammonium chloride solution, washed with sodium chloride (saturated aqueous solution), and dried (Na)₂SO₄) Filtered and evaporated under vacuum. By circular chromatography (silica; up to 5% DCM/MeOH (NH)₃) As eluent) was purified. Collecting the desired fraction and purifying it inEvaporation in vacuo gave D37-a (trans) (0.380g, 23.6%) and D37-b (cis) (0.710g, 44%).

D37-a (reverse)

M.P.＞300℃

LCMS: MW (theory): 303; [ MH⁺]: 304; RT (min): 4.17 (method 12).

D37-b (shun)

M.P.＞300℃

LCMS: MW (theory): 303; [ MH⁺]: 304; RT (min): 2.93 (method 18).

Description D38

(trans) -4- [ 2-chloro-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenylamino ] cyclohexanol (D38)

Bis (pinacolato) diboron (0.947g, 3.729mmol) and potassium acetate (0.686g, 6.992mmol) were added to a solution of intermediate D37-a (0.710g, 2.331mmol) in 1, 4-dioxane (5 ml). Degassing the mixture and subsequently adding [1, 1' -bis (diphenylphosphino) -ferrocene]Dichloropalladium (II) -DCM complex (1: 1) (0.051g, 0.0699 mmol). The reaction mixture was heated at 150 ℃ for 10 minutes under microwave irradiation. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) was purified. The desired fractions were collected and evaporated in vacuo to give a colourless oily residue which crystallized to give the intermediate trans-D38 (0.950g) as a white solid.

LCMS: MW (theory): 351, a step of; [ MH⁺]: 352; RT (min): 3.09 (method 18).

Description 39

2, 3-dichloro-4- (4 '-fluoro-4' -phenyl) -piperidinyl-pyridine (D39)

D16(2g, 7.302mmol), 4-fluoro-4-phenylpiperidine hydrochloride (2.048g, 9.493mmol) [ C.A.S.1056382-25-2 ] were heated at 110 ℃ in a sealed tube]And a mixture of DMF (5.055ml, 29.209mmol) in acetonitrile (10ml) for 16 h. Followed by NaHCO₃(saturated aqueous solution) the mixture was treated. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. The crude product is purified by column chromatography (silica gel; heptane/DCM from 4: 1 up to 1: 4 as eluent). The desired fractions were collected and evaporated under vacuum to give compound D39(0.88g, 37%) as a white solid.

LCMS: MW (theory): 324, respectively; [ MH⁺]: 325; RT (min): 5.08 (method 2).

Description 40

2-amino-3-chloro-4- (4 '-fluoro-4' -phenyl) -piperidinyl-pyridine (D40)

To a previously degassed, stirred solution of compound D39(0.88g, 2.709mmol) in toluene (14ml) were added sodium tert-butoxide (0.496g, 3.842mmol), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthalene (0.269g, 0.433mmol), tris (dibenzylideneacetone) dipalladium (0) (0.161g, 0.176mmol) and benzophenone imine (0.559ml, 3.328 mmol). The reaction mixture was heated at 80 ℃ for 16 hours in a sealed tube. Subsequently, hydroxylamine hydrochloride (1.116g, 16.06mmol) and triethylamine (2.4ml, 17.219mmol) in MeOH (14ml) were added and then stirred for 5 hours. With NaHCO₃The reaction mixture was diluted (saturated aqueous solution). The residue was dissolved in DCM. The resulting precipitated solid was filtered off and dried under vacuum to give 0.3g D40. The mother liquor was evaporated under vacuum. The residue obtained was purified by column chromatography (silica gel; up to 20% DCM/AcOEt as eluent). The desired fractions were collected and evaporated under vacuum to give D40(0.270 g). The total amount of D40 is 570 mg.

LCMS: MW (theory): 305; [ MH⁺]: 306; RT (min): 4.55 (method 6).

Description 41

2, 3-dichloro-pyridine-4-carbaldehyde (D41)

To a solution of 2, 3-dichloropyridine (10g, 67.57mmol) [ C.A.S.2402-77-9]To a cooled solution at-78 ℃ under a nitrogen atmosphere in anhydrous THF (200ml) was added n-butyllithium (37.165ml, 74mmol, 2M in hexanes) dropwise. The resulting reaction mixture was stirred at-78 ℃ for 20 minutes. Anhydrous DMF (6.28ml, 81.087mmol) was then added dropwise. After stirring at-78 ℃ for 15 min, the mixture was warmed to room temperature, quenched with water and extracted with DCM. Drying (Na)₂SO₄) The organic extracts were combined and evaporated under vacuum. The crude residue was purified by short hollow column chromatography (DCM as eluent). The desired product fractions were collected and evaporated in vacuo to give a residue which was further purified by column chromatography (silica; up to 50% DCM/heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D41(4.15g, 34.9%) as a white solid.

GCMS＝RT(min)：7.9。

Description 42

2- [4- (2, 3-dichloro-pyridin-4-ylmethyl) -piperazin-1-yl ] -pyrimidine (D42)

A solution of 2-piperazin-1-yl-pyrimidine hydrochloride (1.132g, 4.773mmol) in DCE (25ml) was added to D41(0.7g, 3.977mmol), sodium triacetoxyborohydride (1.264g, 5.966mmol) and acetic acid (0.4 ml). The resulting mixture was stirred at room temperature for 1 day. Subsequently DMF (5ml) was added and the reaction was stirred at room temperature for a further 16 h. Followed by NaHCO₃The reaction mixture was diluted (saturated aqueous solution) and extracted with DCM. Drying (MgSO)₄) The organic layer was evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; up to 4% DCM/MeOH as eluent). The desired fractions were collected and evaporated under vacuum to give intermediate compound D42(0.865g, 67%) as a white solid.

LCMS: MW (theory): 323; [ MH⁺]: 324, respectively; RT (min): 4.18 (method 1).

Description 43

3-chloro-4- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -pyridin-2-ylamine (D43)

To a previously degassed, stirred solution of compound D42(0.835g, 2.575mmol) in toluene (16ml) were added sodium tert-butoxide (0.351g, 3.657mmol), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthalene (0.257g, 0.412mmol), tris (dibenzylideneacetone) dipalladium (0) (0.153g, 0.167mmol) and benzophenone imine (0.532ml, 3.168 mmol). The reaction mixture was heated at 80 ℃ for 16 hours in a sealed tube. Subsequently, after cooling, a solution of 1N HCl (40ml) and THF (40ml) was added and the mixture was stirred for 1 hour. The resulting water-soluble mixture was then washed with EtOAc. With NaHCO₃Basified aqueous layer with (saturated aqueous solution) and diluted withAnd (4) extracting the EtOAc. Drying (MgSO)₄) The organic layer was evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; up to 2% DCM/MeOH as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D43(0.607g, 77%) as a yellow solid.

M.P.：185℃。

LCMS: MW (theory): 304; [ MH⁺]: 305; RT (min): 3.03 (method 1).

Description 44

2, 3-dichloro-4- [3 ' H-spiro [2 ' -benzofuran-1, 4 ' -piperidinylmethyl) -pyridine (D44)

Spiro [ isobenzofuran-1 (3H), 4' -piperidine]A solution of hydrochloride salt (0.155g, 0.818mmol) in DCE (2ml) was added to D41(0.12g, 0.682mmol), sodium triacetoxyborohydride (0.159g, 0.75mmol) and acetic acid (0.4 ml). The resulting mixture was stirred at room temperature for 1 day. With NaHCO₃The reaction mixture was diluted (saturated aqueous solution) and extracted with DCM. Drying (MgSO)₄) The organic layer was evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; up to 6% DCM/AcOEt as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D44(0.15g, 63%) as a white solid.

LCMS: MW (theory): 348; [ MH⁺]: 349; RT (min): 4.33 (method 13).

Description 45

2-amino-3-chloro-4- [3 ' H-spiro [2 ' -benzofuran-1, 4 ' -piperidinylmethyl) -pyridine (D45)

To a previously degassed stirred solution of compound D44(0.154g, 0.429mmol) in toluene (3ml) were added sodium tert-butoxide (0.059g, 0.61mmol), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthalene (0.043g, 0.0687mmol), tris (dibenzylideneacetone) dipalladium (0) (0.0255g, 0.0279mmol) and benzophenone imine (0.0886ml, 0.528 mmol). The reaction mixture was heated at 80 ℃ for 16 hours in a sealed tube. Subsequently, after cooling, a solution of 1N HCl (40ml) and THF (40ml) was added and the mixture was stirred for 1 hour. The resulting water-soluble mixture was then washed with EtOAc. With NaHCO₃The aqueous layer was basified (saturated aqueous solution) and extracted with EtOAc. Drying (MgSO)₄) The organic layer was evaporated under vacuum. The crude product obtained was purified by column chromatography (silica gel; up to 2% DCM/MeOH as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D45(0.1g, 71%) as a yellow solid.

LCMS: MW (theory): 329 of the formula (I); [ MH⁺]: 330; RT (min): 3.13 (method 4).

Description 46

7- {4- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexylamino ] -phenyl } -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (D46)

To a mixture of compound D13(0.048g, 0.158mmol) in 1, 4-dioxane (2ml) under a nitrogen atmosphere was added compound D32-a (0.082g, 0.19mmol), Pd (PPh)₃)₄(9.15g, 0.00792mmol) and NaHCO₃(0.5ml, saturated aqueous solution). The reaction mixture was subjected to microwave heating at 150 ℃ for 10 minutes. After cooling, the mixture was washed with DCM. The organic layer was separated and dried (Na)₂SO₄) And is in factThe residue was evaporated under air and purified by column chromatography (silica gel; starting with up to 6% DCM/EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D46(0.06g, 72%).

LCMS: MW (theory): 528 of the raw material; [ MH⁺]: 529; RT (min): 3.18 (method 15).

Description 47

2-chloro-3-nitro-4 (4' -phenylpiperidine) pyridine (D47)

To 2, 4-dichloro-3-nitro-pyridine (2g, 10.363mmol) [ CAS No.5975-12-2]To a solution of acetonitrile (40ml) cooled at 0 ℃ were added triethylamine (2.873ml, 20.727mmol) and phenylpiperidine (1.671mg, 10.363mmol) [ CAS No.771-99-3]. The resulting mixture was stirred at 0 ℃ for 1.5 hours. Then NaHCO is added₃(saturated aqueous solution). The resulting aqueous solution was extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. The residue was purified by column chromatography (silica gel; starting from up to 20% DCM/heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D47(2.67g, 81%) as a yellow solid.

M.P.：131.0℃。

LCMS: MW (theory): 317; [ MH⁺]: 318; RT (min): 4.57 (method 1).

Description 48

2-amino-3-nitro-4- (4' -phenylpiperidine) pyridine (D48)

A mixture of intermediate D47(1.5g, 4.72mmol) in ammonium hydroxide (40ml) was heated at 140 ℃ for 16 hours in a PARR reactor vessel. The solvent was then evaporated under vacuum. The residue was purified by column chromatography (silica gel; starting from up to 2% DCM/MeOH as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D48(0.4g, 28.4%) as a solid.

M.P.：205.6℃。

LCMS: MW (theory): 298; [ MH⁺]: 299; RT (min): 4.01 (method 1).

Description 49

8-Nitro-7- (4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine (D49)

A mixture of intermediate D48(0.4g, 1.341mmol) and D8(2g, 9.757mmol) in EtOH (2ml) was subjected to microwave heating at 150 ℃ for 50 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) was purified. The desired fractions were collected and evaporated under vacuum. The residue was wet milled with diisopropyl ether to give intermediate D49(130g, 24%) as an orange oil.

LCMS: MW (theory): 404; [ MH⁺]: 405; RT (min): 4.51 (method 1).

Description 50

7- (4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-8-ylamine (D50)

To intermediate D49(0.075g, 0.185mmol) in EtOH (0.6mL), H₂To a mixture of O (0.1ml) and HCl (0.1ml) was added iron (103.6mg, 1.855mmol) portionwise. The mixture was heated at 80 ℃ for 1 hour. After cooling, the mixture was filtered through a pad of celite and washed with DCM. Followed by NaHCO₃The filtrate was washed (saturated aqueous solution). The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; from up to 2% DCM/MeOH (NH)₃) Starting as eluent) was purified. The desired fractions were collected and evaporated under vacuum to give compound D50(0.057g, 82%).

LCMS: MW (theory): 374; [ MH⁺]: 375; RT (min): 5.13 (method 19).

Description 51

4- (2-benzyloxy-3-fluoro-phenyl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (D51)

To 1, 2, 3, 6-tetrahydro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -pyridine-1-carboxylic acid tert-butyl ester (0.75g, 2.426mmol) [ CAS 375853-82-0](Synthesis as described in WO 2004072025A 220040826) in 1, 4-dioxane (7ml) and K₂CO₃To a solution of a saturated aqueous solution (3.5ml) was added 2-benzyloxy-1-bromo-3-fluoro-benzene (1.023mg, 3.638mmol) [1036724-55-6 mmol ]]. The resulting solution was degassed using a nitrogen stream and Pd (PPh) was added thereto₃)₄(0.14g, 0.121 mmol). The reaction was then subjected to microwave heating at 150 ℃ for 10 minutes in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with water and washed with EtOAc. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. Purification by column chromatography (silica; starting from up to 100% heptane/DCM as eluent)And (4) residue. The desired fractions were collected and evaporated under vacuum to give intermediate D51(0.727g, 78%).

Description 52

4- (3-fluoro-2-hydroxy-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (D52)

In H-CUBE^TMA solution of intermediate D51(0.727g, 1.896mmol) in EtOH (40ml) was hydrogenated under perhydro at 80 ℃ and a flow rate of 1.5ml/min using a Pd/C10% column (CatCart 70 mm). The solvent was evaporated under vacuum to give intermediate compound D52(0.56g, 100%).

Description 53

2-fluoro-6-piperidin-4-yl-phenol (D53)

Intermediate D52(3.067g, 7.852mmol) was dissolved in a mixture of trifluoroacetic acid (5ml) in DCM (5 ml). The resulting solution was stirred at room temperature for 30 minutes. Followed by careful addition of Na₂CO₃(saturated aqueous solution) and the resulting water-soluble mixture was washed with a DCM/n-BuOH 1: 3 mixture. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum to give intermediate compound D53(0.37g, 100%).

LCMS: MW (theory): 195; [ MH⁺]: 196 parts by weight; RT (min): 0.36 (method 16).

Description 54

7- [4- (3-fluoro-2-hydroxy-phenyl) -piperidin-1-yl ] -3- (2, 2, 2-trifluoro-ethyl) imidazo [1, 2-a ] pyridine-8-carbonitrile (D54)

Compound D10(0.31g, 1.194mmol), D53(0.349g, 1.79mmol), N-diisopropylethylamine (0.416ml, 2.388mmol) was added to CH₃The mixture in CN (3ml) was subjected to microwave heating at 180 ℃ for 10 minutes in a sealed tube. The mixture was cooled to room temperature and Na was added₂CO₃Diluted (saturated aqueous) and washed with DCM. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. The residue was treated with DCM. The obtained solid was collected to obtain intermediate compound D54(0.32g, 64%).

LCMS: MW (theory): 418; [ MH⁺]: 419; RT (min): 4.05 (method 2).

Example 1

3-phenyl-7- (4-phenyl-piperidin-1-ylmethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E1)

To compound D6(0.15g, 0.593mmol) and K₂CO₃To a mixture (0.35g, 2.55mmol) in 1, 4-dioxane (4ml) and DMF (1.5ml) was added compound D7(0.237g, 0.85 mmol). The resulting mixture was degassed using a nitrogen stream and Pd (PPh) was added thereto₃)₄(0.098g, 0.085 mmol). The reaction mixture was then subjected to microwave heating at 150 ℃ for 10 minutes in a sealed tube. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under vacuum. The obtained residue was purified by preparative reverse phase HPLC to give compound E1(0.072g, 31%).

¹H NMR(500MHz，CDCl₃)δppm 1.74-1.83(m，2H)，1.83-1.90(m，2H)，2.32(td，J＝11.6，2.6Hz，2H)，2.55(tt，J＝11.9，3.8Hz，1H)，2.99(br.d，J＝11.3Hz，2H)，3.86(s，2H)，7.18-7.22(m，2H)，7.22-7.25(m，2H)，7.28-7.34(m，2H)，7.44-7.51(m，1H)，7.51-7.58(m，4H)，7.78(s，1H)，8.43(d，J＝7.2Hz，1H)。

Example 2

7- (4-pyrimidin-2-yl-piperazin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E2)

Compound D10(0.1g, 0.38mmol), 1- (2-pyrimidinyl) piperazine dihydrochloride (0.101g, 0.50mmol), N-diisopropylethylamine (0.21ml, 1.2mmol) in CH₃The mixture in CN (5ml) was subjected to microwave heating at 180 ℃ for 45 minutes in a sealed tube. The mixture was then cooled to room temperature and the solvent was evaporated under vacuum. The residue obtained is subsequently dissolved in DCM and NaHCO₃(saturated aqueous solution) washing. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) to purify the crude product. The desired fractions were collected and evaporated in vacuo to yield compound E2(0.089g, 60%) as a yellow solid.

¹H NMR(500MHz，CDCl₃)δppm 3.67(q，J＝10.1Hz，2H)，3.71-3.76(m，4H)，4.02-4.10(m，4H)，6.57(t，J＝4.6Hz，1H)，6.65(d，J＝7.8Hz，1H)，7.53(s，1H)，7.94(d，J＝7.8Hz，1H)，8.35(d，J＝4.9Hz，1H)。

Example 3

7- (4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E3)

Compound D10(0.1g, 0.38mmol), 4-phenylpiperidine (0.073g, 0.45mmol), N-diisopropylethylamine (0.21ml, 1.2mmol) in CH₃The mixture in CN (5ml) was subjected to microwave heating at 180 ℃ for 45 minutes in a sealed tube. The mixture was then cooled to room temperature and the solvent was evaporated under vacuum. The residue obtained is subsequently dissolved in DCM and NaHCO₃(saturated aqueous solution) washing. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) to purify the crude product. The desired fractions were collected and evaporated in vacuo to give a prepurified fraction which was further purified by preparative reverse phase HPLC to give compound E3(0.102g, 70%) as a yellow solid.

¹H NMR(400MHz，CDCl₃)δppm 1.87-2.00(m，2H)，2.00-2.09(m，2H)，2.74-2.87(m，1H)，3.31(td，J＝12.6，2.3Hz，1H)，3.66(q，J＝9.8Hz，2H)，4.22(br.d，J＝13.2Hz，2H)，6.65(d，J＝7.9Hz，1H)，7.21-7.28(m，3H)，7.30-7.38(m，2H)，7.51(s，1H)，7.89(d，J＝7.6Hz，1H)。

Example 4

7- [ 2-fluoro-4- (2-methyl-pyridin-4-yloxy) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E4)

To a mixture of compound D10(0.24g, 0.98mmol) in 1, 4-dioxane (2ml) under a nitrogen atmosphere was added compound D15(0.483g, 1.96mmol), Pd (PPh)₃)₄(0.045g, 0.039mmol) and NaHCO₃(2ml, saturated aqueous solution). Make contraryThe mixture should be subjected to microwave heating at 150 ℃ for 10 minutes. After cooling, the mixture was filtered through a pad of celite and washed with dioxane. The filtrate is evaporated in vacuo and purified by column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) purification of the residue. The desired fractions were collected and evaporated under vacuum to give compound E4(0.039g, 9%).

¹H NMR(400MHz，CDCl₃)δppm 2.57(s，3H)，3.82(q，J＝9.7Hz，2H)，6.81(dd，J＝5.8，2.3Hz，1H)，6.85(d，J＝2.1Hz，1H)，7.00(dd，J＝10.9，2.3Hz，1H)，7.05(dd，J＝8.3，2.3Hz，1H)，7.10(dd，J＝7.2，1.6Hz，1H)，7.63(t，J＝8.3Hz，1H)，7.84(s，1H)，8.26(d，J＝7.2Hz，1H)，8.46(d，J＝5.8Hz，1H)。

Example 21

1- (8-chloro-3-propyl-imidazo [1, 2-a ] pyridin-7-yl) -4-phenyl-piperidin-4-ol (E21)

To a stirred solution of compound D19(0.3g, 0.94mmol) in toluene (10ml) were added 4-hydroxy-4-phenylpiperidine (0.166g, 0.95mmol), palladium (II) acetate (0.011g, 0.047mmol), sodium tert-butoxide (0.23g, 2.35mmol) and BINAP (0.0437g, 0.071 mmol). The reaction mixture was heated at 100 ℃ for 16 hours in a sealed tube. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was evaporated under vacuum. By column chromatography (silica; up to 2% DCM/MeOH (NH)₃) As eluent) was purified. The desired fractions were collected and evaporated in vacuo to give E21(0.014g, 4%) as a pale yellow solid.

¹H NMR(500MHz，CDCl₃)δppm 1.04(t，J＝7.2Hz，3H)，1.87(br.s.，1H)，1.73-1.82(m，2H)，1.88-1.94(m，2H)，2.39(td，J＝13.3，4.9Hz，2H)，2.77(t，J＝7.5Hz，2H)，3.33(td，J＝11.8，2.0Hz，2H)，3.36-3.43(m，2H)，6.81(d，J＝7.2Hz，1H)，7.28-7.32(m，1H)，7.33(s，1H)，7.40(t，J＝7.7Hz，2H)，7.56-7.61(m，J＝8.1，1.2Hz，2H)，7.79(d，J＝7.5Hz，1H)。

Example 28

7- (4-phenyl-piperidin-1-yl) -3- (4, 4, 4-trifluoro-butyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E28)

A mixture of compound D27(0.12g, 0.292mmol) in EtOAc (10mL) was hydrogenated at room temperature in the presence of 10% palladium on activated carbon (0.002g, 0.02 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The mixture was then filtered through a pad of celite and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (silica gel; heptane/EtOAc 1: 1 as eluent) and subsequently by preparative reverse phase HPLC to give compound E28(0.02g, 17%) as a yellow solid.

¹H NMR(500MHz，CDCl₃)δppm 1.94(qd，J＝12.1，3.8Hz，2H)，1.98-2.07(m，4H)，2.15-2.27(m，2H)，2.79(tt，J＝12.1，3.8Hz，1H)，2.88(t，J＝7.5Hz，2H)，3.29(td，J＝12.7，2.3Hz，2H)，4.18(br.d，J＝13.0Hz，2H)，6.61(d，J＝7.8Hz，1H)，7.21-7.26(m，3H)，7.29(s，1H)，7.31-7.36(m，2H)，7.79(d，J＝7.8Hz，1H)。

Example 29

7- (4-phenyl-piperidin-1-yl) -3-trifluoromethyl-imidazo [1, 2-a ] pyridine-8-carbonitrile (E29)

To a mixture of compound D24(0.08g, 0.326mmol) in DMF (3ml) was added 4-phenylpiperidine (0.058g, 0.358mmol) and Et₃N (0.05g, 0.489 mmol). The reaction mixture was subjected to microwave heating at 150 ℃ for 45 minutes. After cooling, the solvent was evaporated under vacuum. The crude product was pre-purified by column chromatography (silica gel; heptane/EtOAc 1: 1 as eluent) and subsequently by preparative radial chromatography. The desired fractions were collected and evaporated in vacuo to give a yellow oil which was treated with isopropanol to give a precipitate which was filtered off and dried to give compound E29(0.005g, 4%).

¹H NMR(400MHz，CDCl₃)δppm 1.85-2.00(m，2H)，2.02-2.12(m，2H)，2.84(tt，J＝12.0，3.8Hz，1H)，3.36(td，J＝12.7，2.3Hz，2H)，4.29(dt，J＝13.2，2.0Hz，2H)，6.72(d，J＝7.9Hz，1H)，7.21-7.28(m，3H)，7.30-7.38(m，2H)，7.82(d，J＝1.2Hz，1H)，8.03(d，J＝7.9Hz，1H)。

Example 36

8-chloro-7- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -3- (2, 2, 2-trifluoro-ethyl) imidazo [1, 2-a ] pyridine (E36)

A mixture of compound D43(0.51g, 1.673mmol) and D8(0.686g, 3.347mmol) in EtOH (8ml) was subjected to microwave heating at 150 ℃ for 50 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. The residue obtained is dissolved in NaHCO₃(saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum and purified by column chromatography (silica gel; from up to 1% DCM/MeOH (NH)₃) Starting and then up to 2% DCM/MeOH as eluent) purification of the residue. The desired fractions were collected and evaporated under vacuum to give a residue which was wet milled with diisopropyl ether to give a cream-colored solidCompound E36(0.40g, 58%) of (v/v).

¹H NMR(500MHz，CDCl₃)δppm 2.56-2.63(m，4H)，3.74(q，J＝10.1Hz，2H)，3.78(s，2H)，3.82-3.88(m，4H)，6.49(t，J＝4.9Hz，1H)，7.21(d，J＝6.9Hz，1H)，7.67(s，1H)，7.94(d，J＝6.9Hz，1H)，8.31(d，J＝4.6Hz，2H)。

Example 50

8-chloro-7- (4-fluoro-4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine (E50)

To a mixture of compound D40(0.56g, 1.831mmol) and DMF (0.638ml, 3.663mmol) in iPrOH (8ml) was added D8(0.751g, 3.663 mmol). The resulting mixture was subjected to microwave heating at 150 ℃ for 50 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. The residue obtained was purified by column chromatography (silica gel; up to 20% DCM/EtOAc as eluent). The desired fractions were collected and evaporated under vacuum. Prepared by preparative supercritical fluid technique (pyridine 20 mm; mobile phase, isocratic 85% CO)₂15% MeOH) to give compound E50(221g, 29%).

¹H NMR(500MHz，CDCl₃)δppm 2.15(br.t，J＝11.8Hz，2H)，2.33(td，J＝13.6，4.9Hz，1H)，2.42(td，J＝13.6，4.9Hz，1H)，3.31(br.t，J＝11.8Hz，2H)，3.44-3.52(m，2H)，3.71(q，J＝9.8Hz，2H)，6.87(d，J＝7.2Hz，1H)，7.31-7.36(m，1H)，7.39-7.45(m，2H)，7.46-7.50(m，2H)，7.60(s，1H)，7.91(d，J＝7.2Hz，1H)。

Example 51

8-chloro-7- (4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine (E51)

A solution of intermediate D50(0.05g, 0.134mmol) in 12N hydrochloric acid was stirred at room temperature for 10 minutes. Subsequently, after cooling to 0 ℃, NaNO was slowly added₂(0.184mg, 2.671mmol) followed by the addition of CuCl (104.024mg, 0.14 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction was heated at 80 ℃ for a further 90 minutes, cooled and poured into NH₄OH∶H₂O1: 1 mixture and subsequent extraction with DCM. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum. The residue was purified by column chromatography (silica gel; starting with up to 10% DCM/EtOAc as eluent). The desired fractions were collected and evaporated under vacuum. The obtained residue was wet-milled with diisopropyl ether to give E51(19mg, 36%) as a brown solid.

¹H NMR(400MHz，CDCl₃)δppm 1.93-2.09(m，4H)，2.69(tt，J＝11.3，4.6Hz，1H)，2.95(td，J＝11.6，2.9Hz，2H)，3.66(br.d，J＝11.6Hz，2H)，3.70(q，J＝9.8Hz，2H)，6.82(d，J＝7.5Hz，1H)，7.20-7.26(m，1H)，7.28-7.32(m，2H)，7.32-7.38(m，2H)，7.59(s，1H)，7.88(d，J＝7.5Hz，1H)。

Example 61

7- [4- (3-fluoro-2-methoxy-phenyl) -piperidin-1-yl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E61)

To a suspension of intermediate D54(0.090g, 0.215mmol) and potassium carbonate (0.054mg, 0.43mmol) in DMF (1ml) was added methyl iodide (0)037mg, 0.258 mmol). The resulting reaction mixture was heated at 150 ℃ for 10 minutes under microwave irradiation. After cooling to room temperature, water was added and the resulting water-soluble mixture was extracted with EtOAc. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum. The residue was purified by column chromatography (silica gel; starting with up to 25% DCM/EtOAc as eluent). The desired fractions were collected and evaporated under vacuum. The obtained residue was wet-milled with diisopropyl ether to give E61(7.8mg, 8.4%) as a solid.

¹H NMR(400MHz，CDCl₃)δppm 1.82-2.04(m，4H)，3.24(tt，J＝11.7，4.1Hz，1H)，3.34(td，J＝12.9，2.8Hz，2H)，3.66(q，J＝9.9Hz，2H)，3.96(d，J＝1.8Hz，3H)，4.21(br.d，J＝12.9Hz，2H)，6.65(d，J＝7.9Hz，1H)，6.93-7.05(m，3H)，7.51(s，1H)，7.90(d，J＝7.6Hz，1H)。

Example 65

2- (2- {1- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] -piperidin-4-yl } -phenyl) -propan-2-ol (E65)

To a stirred solution of compound D20(0.4g, 1.11mmol) in toluene (13ml) were added D29(0.365g, 1.664mmol), palladium (II) acetate (0.0126g, 0.0555mmol), cesium carbonate (0.904g, 2.774mmol) and BINAP (0.0518g, 0.0832 mmol). The reaction mixture was heated at 100 ℃ for 16 hours in a sealed tube. The reaction mixture was then charged with an amount of cesium carbonate (0.05 eq) and BINAP (0.075 eq) and heating was continued at 100 ℃ for an additional 16 hours. Thereafter, an additional amount of cesium carbonate (0.05 eq) and BINAP (0.075 eq) were added and the reaction was heated at 80 ℃ for 2 days. The mixture was then cooled to room temperature, filtered through a pad of celite, and the filtrate was evaporated under vacuum. The residue obtained is purified by column chromatography (silica; from 100: 0 to 50: 50 DCM/EtOAc). The desired fractions were collected and evaporated under vacuum. The obtained residue was wet-milled with diethyl ether to give E65(0.195g, 39%).

¹H NMR(500MHz，CDCl₃)δppm 1.72(s，6H)，1.81(s，1H)，1.91(br.d，J＝11.8Hz，2H)，2.08(qd，J＝12.7，3.5Hz，2H)，2.92-3.02(m，2H)，3.64(d，J＝11.6Hz，2H)，3.70(q，J＝9.8Hz，2H)，3.81(tt，J＝11.8，3.8Hz，1H)，6.82(d，J＝7.5Hz，1H)，7.13-7.22(m，1H)，7.30(t，J＝7.4Hz，1H)，7.43(d，J＝7.8Hz，1H)，7.49(d，J＝7.5Hz，1H)，7.58(s，1H)，7.88(d，J＝7.5Hz，1H)。

Example 67

7- {4- [2- (1-hydroxy-1-methyl-ethyl) -phenyl ] -piperidin-1-yl } -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E67)

Compound D10(0.23g, 0.62mmol), D29(0.163g, 0.744mmol) and N, N-diisopropylethylamine (0.162ml, 0.93mmol) in CH₃The mixture in CN (10ml) was subjected to microwave heating in a sealed tube at 160 ℃ for 60 minutes. The reaction mixture was again charged with D29(0.0598g, 0.44 equiv.) and N, N-diisopropylethylamine (0.054ml, 0.5 equiv.) and irradiated at 160 ℃ for an additional 45 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. By column chromatography (silica; up to 3% DCM/MeOH (NH)₃) As eluent) to give compound E67(0.212g, 77%).

¹H NMR(500MHz，DMSO-d₆)δppm 1.57(s，6H)，1.76-1.92(m，4H)，3.20-3.29(m，2H)，3.91-4.00(m，1H)，4.14(q，J＝11.0Hz，2H)，4.20(br.d，J＝13.6Hz，2H)，5.07(s，1H)，7.00(d，J＝7.8Hz，1H)，7.11(t，J＝7.2Hz，1H)，7.19(t，J＝7.4Hz，1H)，7.31(d，J＝7.5Hz，1H)，7.39(d，J＝7.5Hz，1H)，7.40(s，1H)，8.51(d，J＝7.8Hz，1H)。

Example 68

7- (4-fluoro-4-phenyl-piperidin-1-yl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E68)

Reacting compound D10(0.626g, 0.250mmol), 4-fluoro-4-phenylpiperidine [ C.A.S.1056382-25-2](0.1234g, 0.689mmol), N-diisopropylethylamine (0.161mg, 1.252mmol) in CH₃The mixture in CN (5ml) was subjected to microwave heating at 150 ℃ for 25 minutes in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue obtained is subsequently dissolved in DCM and NaHCO₃(saturated aqueous solution) washing. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. By column chromatography (silica; up to 10% DCM/MeOH (NH)₃) As eluent) to give compound E68(0.065g, 24.5%).

¹H NMR(500MHz，CDCl₃)δppm 2.14-2.24(m，2H)，2.29(td，J＝13.9，4.6Hz，1H)，2.36(td，J＝13.9，4.9Hz，1H)，3.63(td，J＝13.0，2.6Hz，2H)，3.67(q，J＝9.8Hz，2H)，4.03(ddd，J＝12.7，2.3Hz，2H)，6.69(d，J＝7.8Hz，1H)，7.31-7.36(m，1H)，7.37-7.45(m，4H)，7.54(s，1H)，7.94(d，J＝7.8Hz，1H)。

Example 91

7- [4- (4-hydroxy-cyclohexylamino) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E91, trans)

To a stirred solution of intermediate D46(0.060g, 0.113mmol) in THF (3ml) at room temperature under a nitrogen atmosphere was added tetramethylammonium fluoride (1.0M solution in toluene/THF) (0.170g, 0.17mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 16 h. Subsequently, the solvent was evaporated under vacuum. The obtained residue was dissolved in DCM and the resulting solution was washed with water. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum. By column chromatography (silica; from up to 2% DCM/MeOH (NH)₃) Starting as eluent) was purified. The desired fractions were collected and evaporated under vacuum to give E91(0.016g, 34%) as a yellow solid.

¹H NMR(400MHz，CDCl₃)δppm 1.19-1.35(m，2H)，1.38-1.55(m，3H)，1.99-2.12(m，2H)，2.13-2.24(m，2H)，3.27-3.44(m，1H)，3.67-3.75(m，1H)，3.76(q，J＝9.8Hz，2H)，3.90(br.s.，1H)，6.69(d，J＝8.8Hz，2H)，7.07(d，J＝7.2Hz，1H)，7.58(d，J＝8.8Hz，2H)，7.72(s，1H)，8.13(d，J＝7.4Hz，1H)。

Example 95 and example 96

7- [ 3-chloro-4- (4-hydroxy-cyclohexylamino) -phenyl ] -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E95, cis) (E96, trans)

To a stirred mixture of intermediate D36(0.419g, 0.938mmol) in MeOH (40ml) at 0 deg.C was added sodium borohydride (0.039mg, 1.031 mmol). The mixture was allowed to warm to room temperature step by step and stirred for 30 minutes. The resulting mixture was then evaporated under vacuum. The obtained residue was dissolved in AcOEt, washed with sodium chloride (saturated aqueous solution), and dried (Na)₂SO₄) Is filtered and mixed inEvaporate under vacuum. The residue obtained was purified by column chromatography (silica gel; up to 20% DCM/EtOAc as eluent). The desired fractions were collected and evaporated under vacuum to give E95 (cis) (0.05g, 11.9%) and E96 (trans) (0.075g, 17.8%).

E95, cis

¹H NMR(400MHz，CDCl₃)δppm 1.37(br.s.，1H)，1.70-1.92(m，8H)，3.48-3.57(m，1H)，3.77(q，J＝9.9Hz，2H)，3.98(br.s.，1H)，4.69(br.d，J＝7.6Hz，1H)，6.79(d，J＝9.0Hz，1H)，7.05(d，J＝7.2Hz，1H)，7.60(dd，J＝9.3，2.1Hz，1H)，7.62(s，1H)，7.75(s，1H)，8.15(d，J＝7.2Hz，1H)。

E96, trans

¹H NMR(400MHz，CDCl₃)δppm 1.26(br.s.，1H)，1.30-1.42(m，2H)，1.42-1.54(m，2H)，2.03-2.13(m，2H)，2.20(br.d，J＝12.0Hz，2H)，3.35-3.47(m，1H)，3.70-3.80(m，1H)，3.77(q，J＝9.7Hz，2H)，4.51(br.d，J＝7.2Hz，1H)，6.79(d，J＝8.6Hz，1H)，7.04(d，J＝7.2Hz，1H)，7.59(dd，J＝8.6，2.1Hz，1H)，7.62(d，J＝2.1Hz，1H)，7.75(s，1H)，8.16(d，J＝7.2Hz，1H)。

Examples 98 and 100

4- { 2-chloro-4- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] -phenylamino } -1-methyl-cyclohexanol (E100, trans) and (E98, cis)

To a solution of intermediate D36(0.238g, 0.449mmol) in THF (50ml) cooled at-78 ℃ under a nitrogen atmosphere was added methylmagnesium bromide (1.4M solution in toluene/THF) (0.352ml, 0.493mmol) dropwise and the resulting reaction mixture was stirred for 10 min. The reaction is then carried outThe mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was then charged with methylmagnesium bromide (1.4M solution in toluene/THF) (0.801ml, 0.572 mmol). The reaction was heated at 60 ℃ for 3 hours. After cooling in an ice bath, the mixture was carefully quenched with saturated aqueous ammonium chloride solution and subsequently extracted with EtOAc. Drying the combined organic phases (Na)₂SO₄) And the solvent was evaporated under vacuum. The residue was purified by column chromatography (silica gel; starting from DCM/EtOAc 1: 1 as eluent). The desired fractions were collected and evaporated under vacuum to give E98 (cis) (0.021g) as a cream solid and E100 (trans) (0.052g) as a white solid.

E98 (shun)

¹H NMR(400MHz，CDCl₃)δppm 1.27(br.s.，1H)，1.33(s，3H)，1.49-1.67(m，4H)，1.71-1.81(m，2H)，2.05-2.15(m，2H)，3.51-3.60(m，1H)，3.75(q，J＝9.9Hz，2H)，4.50(br.d，J＝7.4Hz，1H)，6.76(d，J＝8.6Hz，1H)，6.92(d，J＝6.9Hz，1H)，7.37(dd，J＝8.6，2.1Hz，1H)，7.49(d，J＝2.1Hz，1H)，7.70(s，1H)，7.95(d，J＝6.9Hz，1H)。

E100 (inverse)

M.P.：205.1℃

¹H NMR(400MHz，CDCl₃)δppm 1.14(br.s.，1H)，1.30(s，3H)，1.51-1.64(m，2H)，1.62-1.73(m，2H)，1.73-1.81(m，2H)，1.93-2.03(m，2H)，3.29-3.40(m，1H)，3.75(q，J＝9.9Hz，2H)，4.45(br.d，J＝7.9Hz，1H)，6.75(d，J＝8.6Hz，1H)，6.92(d，J＝7.2Hz，1H)，7.37(dd，J＝8.6，2.1Hz，1H)，7.48(d，J＝2.1Hz，1H)，7.70(s，1H)，7.95(d，J＝6.9Hz，1H)。

Example 101

4- { 2-chloro-4- [ 8-chloro-3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridin-7-yl ] phenylamino } -cyclohexanol (E101)

To a mixture of compound D20(0.480g, 0.934mmol) in 1, 4-dioxane (2ml) under nitrogen atmosphere was added compound D38(0.394g, 1.12mmol), Pd (PPh)₃)₄(0.00539g, 0.0467mmol) and NaHCO₃(1ml, saturated aqueous solution). The reaction mixture was subjected to microwave heating at 150 ℃ for 10 minutes. After cooling, the mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was washed with NaCl (saturated aqueous solution). The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum and purified by column chromatography (silica gel; from up to 1% DCM/MeOH (NH)₃) Start and then DCM/EtOAc 7: 3 as eluent) purify the residue. The desired fractions were collected and evaporated under vacuum to give compound E101(0.240g, 56.1%).

¹H NMR(500MHz，CDCl₃)δppm 1.31-1.40(m，2H)，1.43-1.53(m，2H)，1.47(s，1H)，2.08(br.d，J＝10.4Hz，2H)，2.21(br.d，J＝11.6Hz，2H)，3.33-3.43(m，1H)，3.71-3.78(m，1H)，3.75(q，J＝9.8Hz，2H)，4.37(br.d，J＝7.8Hz，1H)，6.76(d，J＝8.7Hz，1H)，6.92(d，J＝6.9Hz，1H)，7.37(dd，J＝8.4，2.0Hz，1H)，7.49(d，J＝2.3Hz，1H)，7.70(s，1H)，7.96(d，J＝7.2Hz，1H)。

Example 105

7- (3-chloro-4-cyclopropylamino-phenyl) -3- (2, 2, 2-trifluoro-ethyl) -imidazo [1, 2-a ] pyridine-8-carbonitrile (E105)

To a mixture of compound D13(0.150g, 0.321mmol) in 1, 4-dioxane (2ml) under nitrogen atmosphere was added compound D31(0.113g, 3.85mmol), Pd (PPh)₃)₄(0.0185g, 0.016mmol) and NaHCO₃(0.5ml, saturated aqueous solution). The reaction mixture was subjected to microwave heating at 150 ℃ for 10 minutes. After cooling, the mixture was filtered through a pad of celite and washed with 1, 4-dioxane. The filtrate is evaporated in vacuo and purified by column chromatography (silica; up to 10% DCM/MeOH (NH)₃) As eluent) purification of the residue. The desired fractions were collected and evaporated under vacuum to give compound E105(0.017g, 13.9%).

¹H NMR(400MHz，CDCl₃)δppm 0.61-0.67(m，2H)，0.84-0.90(m，2H)，2.50-2.58(m，1H)，3.78(q，J＝9.9Hz，2H)，5.03(br.s.，1H)，7.06(d，J＝7.2Hz，1H)，7.21(d，J＝8.6Hz，1H)，7.60(d，J＝2.1Hz，1H)，7.63(dd，J＝8.6，2.1Hz，1H)，7.76(s，1H)，8.16(d，J＝7.4Hz，1H)。

Example 123

8-chloro-7- (4-spiro- [3- (2, 3-dihydro-benzofuran) ] piperidin-1-ylmethyl) -3- (2, 2, 2-trifluoro-ethyl) imidazo [1, 2-a ] pyridine (E123)

A mixture of D45(0.1g, 0.303mmol) and D8(0.124g, 0.606mmol) in EtOH (2ml) was subjected to microwave heating at 150 ℃ for 50 minutes. After cooling to room temperature, the solvent was evaporated under vacuum. The residue obtained is dissolved in NaHCO₃(saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) And evaporated under vacuum. The residue obtained is purified by column chromatography (silica; starting from up to 3% DCM/MeOH). The desired fractions were collected and evaporated in vacuo to give a residue which was wet milled with diisopropyl ether to give compound E123(0.059g, 44.7%) as a white solid.

¹H NMR(500MHz，CDCl₃)δppm 1.78(br.d，J＝11.8Hz，2H)，1.99(td，J＝13.0，4.6Hz，2H)，2.57-2.67(m，2H)，2.83(br.d，J＝11.3Hz，2H)，3.73(q，J＝9.9Hz，2H)，3.81(s，2H)，5.08(s，2H)，7.13-7.18(m，1H)，7.19-7.24(m，2H)，7.24-7.31(m，2H)，7.66(s，1H)，7.93(d，J＝6.9Hz，1H)。

Table 1: a compound prepared according to formula (I)

Physical and chemical data

General procedure for Waters MS instruments (TOF, ZQ, SQD, Platform)

HPLC measurements were performed using HP 1100 from Agilent Technologies containing a pump with degasser (quaternary or binary), autosampler, column oven, diode multi-bank detector (DAD) and column as described in the corresponding methods below. The flow from the column was split to the MS spectrometer. The MS detector was configured with either electrospray ionization source or ESCI dual ionization source (electrospray and atmospheric pressure chemical ionization). Nitrogen was used as the nebulizer gas. The source temperature was maintained at 140 ℃. Data acquisition was performed using MassLynx-Openlynx software.

General method for Agilent MS instruments (MSD)

HPLC measurements were performed using HP 1100 from Agilent Technologies containing a binary pump with degasser, autosampler, column oven, diode multi-set detector (DAD) and column as described in the corresponding method below. The flow from the column was split to the MS spectrometer. The MS detector was configured with an ESCI dual ionization source (electrospray and atmospheric pressure chemical ionization). Nitrogen was used as the nebulizer gas. The source temperature was maintained at 100 ℃. Data acquisition was performed using chemstation-Agilent Data Browser software.

General method for Waters MS instruments (Acquity-SQD)

UPLC measurements were performed using an Acquity system from Waters containing a sampler manager (sampler organiser), a binary pump with degasser, a four-tube column oven, a diode multi-set detector (DAD) and a column as described in the corresponding method below. Column flow was used without diverting to the MS detector. The MS detector was configured with an ESCI dual ionization source (electrospray and atmospheric pressure chemical ionization). Nitrogen was used as the nebulizer gas. The source temperature was maintained at 140 ℃. Data acquisition was performed using MassLynx-Openlynx software.

Method 1

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1 ml/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol), to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes up to 9.0 minutes. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired in positive ionization mode only by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillary needle voltage was 2.5kV and the injection cone voltage was 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 2

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 0.8 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), 6.0 min to 100% B, held to 6.5 min and equilibrated to initial conditions at 7.0 min until 9.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired in positive ionization mode by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The injection cone voltage for the positive ionization mode was 20V and 50V and the negative ionization mode was 30V.

Method 3

In addition to the general method: reverse phase UPLC was performed on a BEH-C18 column (1.7 μm, 2.1 × 50mm) from Waters at 60 ℃ at a flow rate of 0.8mL/min without diverting to the MS detector. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), to 20% A, 80% B in 6.3 minutes, to 100% B in 6.85 minutes, held until 7.50 minutes and equilibrated to initial conditions at 7.75 minutes until 9.0 minutes. The injection volume is 0.5. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 4

In addition to the general method: reverse phase UPLC was performed on a BEH-C18 column (1.7 μm, 2.1 × 50mm) from Waters at 60 ℃ at a flow rate of 0.8mL/min without diverting to the MS detector. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1) to 20% a, 80% B in 4.9 minutes, to 100% B in 5.3 minutes, held until 5.8 minutes and equilibrated to initial conditions at 6.0 minutes until 7.0 minutes. The injection volume is 0.5. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 5

This method was used for purity/concentration validation (CLND) in beese after SFC isolation. After this, we verified the purity in Toledo using the S6009S6001 method.

Method 6

In addition to the general method: reverse phase UPLC was performed on a HSS-T3 column from Waters (1.8 μm, 2.1 × 50mm) at 60 ℃ at a flow rate of 0.8mL/min without shunting to the MS detector. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1) to 20% a, 80% B in 6.3 minutes, to 100% B in 6.85 minutes, held until 7.50 minutes and equilibrated to initial conditions at 7.75 minutes until 9.0 minutes. The injection volume is 0.5. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 7

In addition to the general method: reverse phase HPLC was performed on an Xbridge-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0mL/min without diverting to the MS detector. The gradient conditions used were: 95% A (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), to 100% B in 6.5 minutes, held until 7.0 minutes and equilibrated to initial conditions at 7.3 minutes until 9.0 minutes. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 8

In addition to the general method: reverse phase HPLC was performed on a Sunfire-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 2.5% B (acetonitrile), 2.5% C (methanol) to 50% B, 50% C in 6.5 minutes, held until 7.0 minutes and equilibrated to initial conditions at 7.3 minutes until 9.0 minutes. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle voltage for positive ionization mode was 2.5kV and for negative ionization mode 2.9 kV. The voltage of the sample injection cone in the positive ionization mode and the negative ionization mode is 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 9

In addition to the general method: reverse phase HPLC was performed on a Sunfire-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0mL/min without diverting to the MS detector. The gradient conditions used were: 95% A (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), up to 100% B at 6.5 minutes, held until 7.0 minutes and equilibrated to initial conditions at 7.3 minutes up to 9.0 minutes. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 10

In addition to the general method: reverse phase HPLC was performed on a Sunfire-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0mL/min without diverting to the MS detector. The gradient conditions used were: 95% A (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), to 100% B in 5.0 minutes, held until 5.15 minutes and equilibrated at 5.30 minutes to initial conditions until 7.0 minutes. The injection volume is 2. mu.l. Low resolution mass spectra (SQD detector; quadrupole) were acquired in positive ionization mode by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The injection cone voltage for the positive ionization mode was 20V and 50V and the negative ionization mode was 30V.

Method 11

In addition to one general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 0.8 mL/min. The gradient conditions used were: 90% A (1g/L ammonium bicarbonate solution), 5% B (acetonitrile), 5% C (methanol) to 50% B and 50% C in 6.0 minutes to 100% B at 6.5 minutes and equilibrated to initial conditions at 7.0 minutes up to 9.0 minutes. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired in positive ionization mode only by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillary needle voltage in positive ionization mode was 2.5kV and the injection cone voltage was 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 12

In addition to the general method: reverse phase HPLC was performed on an Eclipse Plus-C18 column (3.5 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1.0mL/min without diverting to the MS detector. The gradient conditions used were: 95% A (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), to 100% B in 5.0 minutes, held until 5.15 minutes and equilibrated at 5.30 minutes to initial conditions until 7.0 minutes. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 13

In addition to the general method: reverse phase HPLC was performed on a Sunfire-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 2.5% B (acetonitrile), 2.5% C (methanol) to 50% B, 50% C in 5.0 minutes, held until 5.15 minutes and equilibrated to initial conditions at 5.3 minutes until 7.0 minutes. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired by scanning from 100 to 750 in 0.5 seconds using a 0.3 second search dwell time. The capillary needle voltage for positive ionization mode was 2.5kV and for negative ionization mode 2.9 kV. The voltage of the sample injection cone in the positive ionization mode and the negative ionization mode is 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 14

In addition to the general method: reverse phase HPLC was performed on a Sunfire-C18 column (2.5 μm, 2.1X 30mm) from Waters at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.20 min, in 3.5 min to 100% B, held until 3.65 min and equilibrated to initial conditions at 3.8 min until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupole, MSD) were acquired in electrospray mode by scanning from 100 to 1000 in 0.99 seconds with 0.30 step size and 0.10 minutes peak width. The capillary needle voltage was 1.0kV and the fragment voltage for positive and negative ionization mode was 70V.

Method 15

In addition to the general method: reverse phase UPLC was performed on a BEH-C18 column (1.7 μm, 2.1 × 50mm) from Waters at 60 ℃ at a flow rate of 0.8mL/min without diverting to the MS detector. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, to 20% A, 80% B in 3.5 min, to 100% B in 3.8 min, held until 4.15 min and equilibrated to initial conditions at 4.3 min until 5.0 min. The injection volume is 0.5. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 16

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 0.8 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, in 3.0 min to 100% B, held until 3.15 min and equilibrated to initial conditions at 3.3 min until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The injection cone voltage for the positive ionization mode was 20V and 50V and the negative ionization mode was 30V.

Method 17

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol), held for 0.2 min, in 3.5 min to 50% B, 50% C, held until 3.65 min and equilibrated at 3.8 min to initial conditions until 5.0 min. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle voltage for positive ionization mode was 2.5kV and for negative ionization mode 2.9 kV. The voltage of the sample injection cone in the positive ionization mode and the negative ionization mode is 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 18

In addition to the general method: reverse phase HPLC was performed on an Eclipse Plus-C18 column (3.5 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, within 3.0 min to 100% B, held until 3.15 min and equilibrated at 3.3 min to initial conditions until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (quadrupole, MSD) were acquired in electrospray mode by scanning from 100 to 1000 in 0.99 seconds with 0.30 step size and 0.10 minutes peak width. The capillary needle voltage was 1.0kV and the fragment voltage for positive and negative ionization mode was 70V.

Method 19

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol), to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes up to 9.0 minutes. The injection volume is 2. mu.l. High resolution mass spectra (time of flight, TOF) were acquired by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle voltage for positive ionization mode was 2.5kV and for negative ionization mode 2.9 kV. The voltage of the sample injection cone in the positive ionization mode and the negative ionization mode is 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 20

In addition to the general method: reverse phase UPLC was performed on a BEH-C18 column (1.7 μm, 2.1 × 50mm) from Waters at 60 ℃ at a flow rate of 0.8mL/min without diverting to the MS detector. The gradient conditions used were: 95% a (0.5g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, to 20% a, 80% B in 3.5 min, to 100% B in 3.8 min, held until 4.15 min and equilibrated to initial conditions at 4.3 min until 5.0 min. The injection volume is 0.5. mu.l. Low resolution mass spectra (quadrupoles, SQD) were acquired by scanning from 100 to 1000 in 0.1 seconds using an interchannel delay of 0.08 seconds. The capillary needle voltage was 3 kV. The voltage of the sample injection cone in the positive ionization mode is 20V and the voltage in the negative ionization mode is 30V.

Method 21

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, in 3.5 min to 100% B, held until 3.65 min and equilibrated to initial conditions at 3.8 min until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra were acquired by scanning from 100 to 1000 in 0.5 seconds using a dwell time of 0.1 seconds (single quadrupole, ZQ detector). The capillary needle voltage was 3 kV. The injection cone voltage for the positive ionization mode was 20V and 50V and the negative ionization mode was 20V.

Method 22

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.20 min, in 3.5 min to 100% B, held until 3.65 min and equilibrated to initial conditions at 3.8 min until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (single quadrupole, MSD detector) were acquired in electrospray mode by scanning from 100 to 1000 in 0.99 seconds with 0.30 step size and 0.10 minutes peak width. The capillary needle voltage was 1.0kV and the fragment voltage for positive and negative ionization mode was 70V.

Method 23

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 1.0 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol), held for 0.2 min, in 3.5 min to 50% B, 50% C, held until 3.65 min and equilibrated at 3.8 min to initial conditions until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra were acquired by scanning from 100 to 750 in 1.5 seconds using a dwell time of 0.3 seconds (single quadrupole, Platform detector). The capillary needle voltage was 3 kV. The injection cone voltage for the positive ionization mode was 30V and 70V and the negative ionization mode was 30V.

Method 24

In addition to the general method: reverse phase HPLC was performed on an XDB-C18 cartridge (1.8 μm, 2.1X 30mm) from Agilent at 60 ℃ at a flow rate of 0.8 mL/min. The gradient conditions used were: 90% A (0.5g/L ammonium acetate solution), 10% B (acetonitrile/methanol mixture, 1/1), held for 0.2 min, in 3.0 min to 100% B, held until 3.15 min and equilibrated to initial conditions at 3.3 min until 5.0 min. The injection volume is 2. mu.l. Low resolution mass spectra (single quadrupole, MSD detector) were acquired in electrospray mode by scanning from 100 to 1000 in 0.99 seconds with 0.30 step size and 0.10 minutes peak width. The capillary needle voltage was 1.0kV and the fragment voltage for positive and negative ionization mode was 70V.

Table 2: physicochemical data for some compounds (nd not determined)

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						1	nd	392	393	5.32	1
2	239	387	388	3.34	1
						3	nd	384	385	4.41	1
4	nd	426	427	4.11	1
						5	126.8-131	412	413	5.13	1
6	161	344	345	4.73	1
						7	nd	392	393	5.08	1
8	201.1	360	361	3.93	1
						9	159	368	369	4.28	1
10	nd	378	379	5.01	1
						11	181.8	368	369	4.25	1
12	150	330	331	4.39	1
						13	nd	408	409	4.03	1
14	194.4	375	376	4.41	1
						15	148.2	345	346	4.31	1
16	265	346	347	3.55	1
						17	nd	426	427	4.02	1
18	nd	354	355	3.91	1

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						19	231.4	361	362	4.07	1
20	220	379	380	4.64	1
						21	nd	369	370	4.17	1
22	176.4	347	348	3.56	1
						23	nd	333	334	3.13	1
24	nd	340	341	3.55	1
						25	197.6	372	373	3.92	1
26	nd	316	317	3.98	1
						27	nd	398	399	4.74	1
28	128.5	412	413	4.9	1
						29	nd	370	371	4.68	1
30	272.1	400	401	3.64	1
						31	139.3	402	403	4.45	1
32	＞300	452	453	4.80	1
						33	186.5	420	421	4.65	2
34	＞300	415	416	4.15	1
						35	154.8	425	426	4.9	1
36	161.4	410	411	3.8	1
						37	156.9	444	445	4.7	1

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						38	181.2	432	433	3.7	1
Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						39	nd	435	436	4.5	1
40	145	416	417	4.6	1
						41	161.1	425	426	5.1	1
42	Decomposition of	407	408	5.1	1
						43	196	444	445	3.7	1
44	152	416	417	4.9	1
						45	nd	432	433	3.9	1
46	150.2	426	427	4.8	1
						47	267	414	415	5.1	1
48	145.4	370	371	5.0	1
						49	nd	342	343	4.5	1
50	220.7	411	412	5.2	1，5，6
						51	263.1	393	394	4.9	1
52	nd	421	422	4.2	1
						53	Decomposition of	400	401	4.0	1
54	155.4	442	443	4.1	2

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						55	Decomposition of	373	374	4.0	1
56	Decomposition of	401	402	3.7	1
						57	nd	469	470	4.3	1
58	212.9	412	413	4.4	2
						59	Decomposition of	428	429	3.8	1
60	Decomposition of	401	402	3.7	1
						61	nd	432	433	4.6	1
62	289.8	418	419	3.8	3
						63	189.3	451	452	4.3	7
64	213.9	373	374	5.2	1
						65	234.7	451	452	4.7	8
66	174.4	421	422	3.8	4
						67	227.5	442	443	3.4	4
68	214	402	403	4.4	1
						69	nd	432	433	4.4	8
70	Decomposition of	420	421	5.0	1
						71	195.6	409	410	5.0	1
72	nd	427	428	4.8	1
						73	234.1	454	455	4.4	1

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						74	163	411	412	4.7	1
75	277.2	412	413	4.6	1
						76	Decomposition of	411	412	4.8	1
Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						77	177.9	411	412	4.6	1
78	176	411	412	4.7	1
						79	173.4	409	410	4.6	1
80	174.3	393	394	4.7	1
						81	102.7	421	422	4.1	1
82	143.2	451	452	4.4	1
						83	Decomposition of	437	438	3.0	1
84	nd	419	420	5.2	1
						85	Decomposition of	405	406	4.8	1
86	nd	423	424	4.1	1
						87	Decomposition of	393	394	4.7	1
88	nd	357	358	4.7	1
						89	161.6	462	463	4.4	1
90	Decomposition of	435	436	4.2	1

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						91	137.5	414	415	3.4	1
92	230.7	434	435	4.3	1
						93	155	414	415	3.6	1
94	202.6	462	463	4.4	1
						95	nd	448	449	4.1	2
96	123.7	448	449	4.1	1
						97	nd	463	464	3.3	4
98	nd	471	472	4.7	8
						99	149.7	443	444	4.6	9
100	205.1	471	472	4.7	8
						101	183.1	457	458	4.3	8
102	nd	449	450	3.3	4
						103	210.2	449	450	3.1	4
104	nd	463	464	3.5	4
						105	nd	390	391	4.5	1
106	nd	374	375	4.2	1
						107	Decomposition of	384	385	4.8	1
108	Decomposition of	404	405	4.9	1
						109	Decomposition of	393	394	5.1	1

Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						110	Decomposition of	420	421	4.2	1
111	nd	400	401	3.4	1
						112	174	442	443	3.3	4
113	Decomposition of	425	426	4.8	1
						114	207.1	425	426	4.7	1
Compound numbering	Melting Point (. degree.C.)	MW (theory)	[MH+]	RT(min)	LCMS method
						115	198.7	426	427	4.7	1
116	252.5	396	397	4.35	2
						117	Decomposition of	395	396	4.04	2
118	nd	430	431	4.55	2
						119	nd	464	465	4.57	2
120	nd	407	408	4.75	2
						121	Decomposition of	469	470	4.22	2
122	nd	406	407	2.77	4
						123	164.2	435	436	4.63	9
124	nd	451	452	3.07	20
						125	Decomposition of	434	435	4.17	12

n.d. means not determined.

D. Examples of pharmacology

The compounds provided in the present invention are positive allosteric modulators of mGluR 2. The compounds appear to potentiate glutamate responses by binding to allosteric sites rather than glutamate binding sites. When the compound of formula (I) is present, mGluR2 is concentrated in glutamic acidThe degree of reaction increases. The compounds of formula (I) are expected to exert a substantial effect on this receptor by virtue of their ability to enhance the function of mGluR 2. Use of a compound of the formula (I), described below and suitable for identifying a positive allosteric modulator, and more specifically, a compound of the formula (I)³⁵S]The properties of the compound on mGluR2 as measured by the GTP γ S binding assay are shown in table 3.

[³⁵S]GTP γ S binding assays

[³⁵S]The GTP γ S binding assay is a functional membrane-based assay for studying the function of a G protein-coupled receptor (GPCR), thereby measuring the non-hydrolyzable form of GTP [ 2]³⁵S]GTP γ S (labelled γ radiation)³⁵Guanosine 5' -triphosphate of S). The G protein alpha subunit catalyzes the exchange of guanosine 5' -diphosphate (GDP) by Guanosine Triphosphate (GTP) and upon activation of the GPCR by an agonist, i.e., absorption³⁵S]GTP γ S, which is and cannot be cleaved to continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley&Sons, Inc.). Radioactivity [ alpha ]³⁵S]The amount of GTP γ S absorbed is a direct measure of the activity of the G protein and thus the agonist activity can be determined. The mGluR2 receptor is preferentially coupled to the G.alpha.i protein (preferential coupling for this method), and therefore it is widely used to study receptor activation of mGluR2 receptor in recombinant cell lines and tissues (Schaffhauser et al, 2003; Pinkerton et al, 2004; Mutel et al, (1998) Journal of neurochemistry.71: 2558-64; Schaffhauser et al, (1998) Molecular Pharmacology 53: 228-33). The inventors herein describe the use of membranes derived from cells transfected with the human mGluR2 receptor and employed by Schaffhauser et al ((2003) molecular Pharmacology 4: 798-³⁵S]GTP γ S is combined with assays to probe the Positive Allosteric Modulation (PAM) properties of the compounds of the invention.

Membrane preparation

CHO cells were cultured to pre-confluency (pre-confluency) and stimulated with 5mM butyrate for 24 hours, followed by washing with PBS, and then collected by knife-coating in homogenization buffer (50mM Tris-HCl buffer, pH 7.4, 4 ℃). The lysate was homogenized briefly (15s) using an ultra-turrax homogenizer. The homogenate was centrifuged at 23500 Xg for 10 min and the supernatant discarded. The pellet was resuspended in 5mM Tris-HCl (pH 7.4) and centrifuged again (30000 Xg, 20min, 4 ℃). The final pellet was resuspended in 50mM HEPES (pH 7.4) and stored in the appropriate aliquot at-80 ℃ prior to use. The protein concentration was determined by the Bradford method (Bio-Rad USA) with bovine serum albumin as a standard.

[³⁵S]GTP γ S binding assays

Measurement of mGluR2 positive allosteric modulatory activity of test compounds in membranes containing human mGluR2 was performed using frozen membranes that were thawed and briefly homogenized before being placed in 96-well microtiter plates (15. mu.g/assay well, 30 min, 30 ℃) in increasing concentrations (0.3nM to 50. mu.M) of positive allosteric modulator and minimal predetermined concentrations of glutamic acid (PAM assay) or assay buffer without added glutamic acid (50mM HEPES, pH 7.4, 100mM NaCl, 3mM MgCl, 100. mu.M)₂50 μ M GDP, 10 μ g/ml saponin). For PAM assays, membranes were incubated with EC₂₅Pre-incubation with glutamic acid at a concentration, EC₂₅Concentration i.e.the concentration which produces 25% of the maximal response glutamate and is found according to published data (Pin et al, (1999) Eur. J. Pharmacol.375: 277-294). Addition [ 2]³⁵S]After a total reaction volume of 200. mu.l of GTP γ S (0.1nM, f.c.), the microtitre plate is briefly shaken and re-incubated to allow the [ 2], [ after activation ]³⁵S]GTP γ S incorporation (30 min, 30 ℃). The microtubes were rapidly vacuum filtered through glass fiber filter disks (Unifilter 96-well GF/B filter disks, Perkin-Elmer, Downers Grove, USA) by using a 96-well microtubes cell harvester (Filtermate, Perkin-Elmer, USA), and then washed with 300. mu.l ice-cold wash buffer (Na₂PO₄.2H₂O 10mM，NaH₂PO₄.H₂O10 mM, pH 7.4) to stop the reaction. The filters were then air-dried and 40. mu.l of liquid scintillation cocktail (Microscint-O) was added to each well, and the membrane bound versions [ 2], [ 2] were measured in a 96-well scintillation disk reader (Top-Count, Perkin-Elmer, USA)³⁵S]GTP γ S. Determination of nonspecific value in the presence of cold 10. mu.M GTP³⁵S]GTP γ S binding. Each data point of each curveDuplicate samples were used and were run at 11 concentrations at least once.

Data analysis

Generation of EC in addition Using Prism GraphPad software (GraphPad Inc, San Diego, USA)₂₅mGluR2 agonist glutamate concentration-response curves representative of the compounds of the invention to determine Positive Allosteric Modulation (PAM). The curve was fitted to a four parameter rogues equation (Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC)₅₀-X) slope) to determine EC₅₀The value is obtained. EC (EC)₅₀The concentration of compound that is half of the maximal potentiation of the glutamate response. This is calculated by subtracting the maximum response of glutamate in the presence of a fully saturating concentration of positive allosteric modulator from the response of glutamate in the absence of a positive allosteric modulator. The concentration that produced half the maximal effect was then calculated as EC₅₀。

Table 3: pharmacological data for the Compounds of the invention

Compound numbering	GTPγS-hR2 PAMpEC50
		1	6.29
2	6.07
		3	6.91
4	6.16
		5	6.97
6	6.81
		7	6.75
8	6.50
		Compound numbering	GTPγS-hR2 PAMpEC50
9	6.50
		10	6.40
11	6.37

Compound numbering	GTPγS-hR2 PAMpEC50
		12	6.30
13	6.23
		14	6.19
15	6.01
		16	6.00
17	5.95
		18	5.88
19	5.64
		20	n.c.
21	n.c.
		22	n.c.
23	n.c.
		24	n.c.
25	n.c.
		26	n.c.
27	6.53
		28	6.88
29	6.11
		30	6.38
31	7.09
		32	7.09
33	7.21

Compound numbering	GTPγS-hR2 PAMpEC50
		34	6.35
35	6.22
		36	n.c.
37	5.52
		38	n.c.
39	5.86
		40	5.89
41	6.36
		42	6.25
43	n.c.
		44	6.49
45	n.c.
		46	5.76
47	6.64
		Compound numbering	GTPγS-hR2 PAMpEC50
48	7.03
		49	6.17
50	6.71
		51	6.80
52	6.56
		53	5.87

Compound numbering	GTPγS-hR2 PAMpEC50
		54	6.62
55	5.96
		56	6.19
57	6.32
		58	7.01
59	6.43
		60	6.28
61	7.43
		62	6.78
63	6.41
		64	5.81
65	6.75
		66	6.55
67	6.84
		68	7.03
69	8.01
		70	6.57
71	6.74
		72	6.67
73	5.98
		74	6.77
75	6.43

Compound numbering	GTPγS-hR2 PAMpEC50
		76	6.57
77	6.98
		78	6.66
79	6.59
		80	6.73
81	6.28
		82	7.35
83	6.17
		84	6.52
85	6.12
		86	5.50
Compound numbering	GTPγS-hR2 PAMpEC50
		87	6.51
88	6.35
		89	6.56
90	6.17
		91	5.95
92	6.15
		93	5.87
94	6.76
		95	6.73

Compound numbering	GTPγS-hR2 PAMpEC50
		96	6.53
97	6.22
		98	6.31
99	6.20
		100	6.90
101	6.81
		102	6.07
103	6.03
		104	5.98
105	6.85
		106	5.2
107	6.63
		108	6.34
109	6.56
		110	5.67
111	5.98
		112	6.17
113	6.81
		114	6.85
115	6.67
		116	6.76
117	6.16

Compound numbering	GTPγS-hR2 PAMpEC50
		118	7.20
119	7.24
		120	6.80
121	5.68
		122	6.26
123	n.c.
		124	6.1
125	5.75

n.c. means EC that cannot be calculated₅₀。

EC was not calculated in the case where the concentration-response curve did not reach the level of the plateau region₅₀The value is obtained. By definition, the EC of a compound₅₀The value is the concentration required to reach 50% of the maximum reaction of the compound.

All compounds are at a predetermined EC₂₅Positive allosteric modulation (GTP γ S-PAM) was determined by testing in the presence of the mGluR2 agonist glutamate at concentration. The values shown are the average of duplicate values from the 11-concentration response curve of at least one experiment. All compounds except compounds No. 20 to 26, the largest of which is not available, showed pEC from 5.6 (weak activity) to 7.2 (very high activity) exceeding 5.0₅₀The value is obtained. Estimation of pEC for a Single experiment₅₀The error in the determination of the values is about 0.3 log units.

E. Composition examples

As used throughout this example, "active ingredient" refers to the final compound of formula (I), its pharmaceutically acceptable salts, its solvates, and its stereochemically isomeric forms.

Typical examples of formulations of the present invention are as follows:

1. pastille

5 to 50mg of active ingredient

Dicalcium phosphate 20mg

Lactose 30mg

Talc 10mg

Magnesium stearate 5mg

Potato starch to make up 200mg

In this example, the active ingredient may be replaced by the same amount of any of the compounds of the present invention, in particular the same amount of any of the exemplified compounds.

2. Suspension liquid

Aqueous suspensions are prepared for oral administration so as to contain, per 1ml, 1 to 5mg of one of the active compounds, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol and the balance 1ml of water.

3. Injection preparation

Parenteral compositions are prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol in water.

4. Ointment

Active ingredient 5 to 1000mg

Stearyl alcohol 3g

Lanolin 5g

White Vaseline (White petroleum) 15g

Water complement 100g

In this example, the active ingredient may be replaced by the same amount of any of the compounds of the present invention, in particular the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious to those skilled in the art that the invention as described may be varied in many ways.

Claims (22)

1. A compound having the formula (I),

or a stereochemically isomeric form thereof, wherein

R¹Is C_1-6An alkyl group; c_3-6A cycloalkyl group; a trifluoromethyl group; c substituted by_1-3Alkyl groups: trifluoromethyl, 2, 2, 2-trifluoroethoxy, C_3-7Cycloalkyl, phenyl or via C_1-3Alkyl radical, C_1-3Alkoxy, cyano, halo, trifluoromethyl or trifluoromethoxy substituted phenyl; a phenyl group; through 1 or 2 groups selected from C_1-3Alkyl radical, C_1-3Phenyl substituted with a substituent of the group consisting of alkoxy, cyano, halo, trifluoromethyl and trifluoromethoxy; or 4-tetrahydropyranyl;

R²is cyano, halo, trifluoromethyl, C_1-3Alkyl or cyclopropyl;

R³is a group of formula (a) or (b) or (c) or (d):

R⁴is hydrogen; hydroxy radical C_3-6A cycloalkyl group; a pyridyl group; through one or two C_1-3An alkyl-substituted pyridyl group; a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; phenyl substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl, hydroxy C_1-3Alkyl, mono-or polyhalo C_1-3Alkyl, cyano, hydroxy, amino, carboxyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy, mono-or polyhalo-C_1-3Alkoxy radical, C_1-3Alkylcarbonyl, mono-and di (C)_1-3Alkyl) amino and morpholinyl; or a phenyl group bearing two adjacent substituents which together form a divalent group of the formula:

-N＝CH-NH- (e)，

-CH ═ CH-NH- (f), or

-O-CH₂-CH₂-NH- (g)；

R⁵Is hydrogen, fluorine, hydroxy C_1-3Alkyl, hydroxy C_1-3Alkoxy, fluoro C_1-3Alkyl, fluoro C_1-3Alkoxy, morpholinyl or cyano;

x is C or N, in which case R⁵Represents an electron pair on N; or

R⁴-X-R⁵Represents a group of formula (h) or (i) or (j):

n is 0 or 1;

q is 1 or 2;

R⁶is C_1-3An alkyl group; c_3-6A cycloalkyl group; hydroxy radical C_2-4An alkyl group; (C)_3-6Cycloalkyl) C_1-3An alkyl group; a phenyl group; a pyridyl group; or a phenyl or pyridyl group substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3Alkyl, trifluoromethyl and (CH)₂)_m-CO₂H, wherein m is 0, 1 or 2; or

R⁶Is a cyclic group of formula (k):

wherein R is⁸Is hydrogen, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3An alkyl group;

p is 1 or 2;

z is O, CH₂Or CR⁹(OH)，R⁹Is hydrogen or C_1-3An alkyl group; or

R⁸And R⁹Form a group-CH₂-CH₂-；

R⁷Is hydrogen, halo or trifluoromethyl;

y is a covalent bond, O, NH, S, SO₂、C(OH)(CH₃)、-CH₂-O-、-O-CH₂-, CHF or CF₂(ii) a Or

R⁶Y is optionally via hydroxy or hydroxy C_1-3Alkyl-substituted morpholinyl, pyrrolidinyl, or piperidinyl; and is

A is O or NH;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, having formula (I):

or a stereochemically isomeric form thereof, wherein

R¹Is C_1-6An alkyl group; a trifluoromethyl group; c substituted by_1-3Alkyl groups: trifluoromethyl, 2, 2, 2-trifluoroethoxy, C_3-7Cycloalkyl, phenyl or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; a phenyl group; phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; or 4-tetrahydropyranyl;

R²is cyano, halo, trifluoromethyl, C_1-3Alkyl or cyclopropyl;

R³is a group of formula (a) or (b):

R⁴is hydrogen; a pyridyl group; a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; phenyl substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl, hydroxy C_1-3Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, carboxyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy, polyhalo C_1-3Alkoxy radical, C_1-3Alkylcarbonyl, mono-and di (C)_1-3Alkyl) amino and morpholinyl; or a phenyl group bearing two adjacent substituents which together form a divalent group of the formula:

-N＝CH-NH- (e)，

-CH ═ CH-NH- (f), or

-O-CH₂-CH₂-NH- (g)；

R⁵Is hydrogen, fluorine, hydroxy C_1-3Alkyl, hydroxy C_1-3Alkoxy, fluoro C_1-3Alkyl, fluoro C_1-3Alkoxy or cyano;

x is C or N, in which case R⁵Represents an electron pair on N;

n is 0 or 1;

R⁶is phenyl; a pyridyl group; or a phenyl or pyridyl group substituted with 1 or 2 substituents selected from the group consisting of: halogen radical, C_1-3Alkyl radical, C_1-3Alkoxy, trifluoromethyl and (CH)₂)_m-CO₂H, wherein m is 0, 1 or 2; or

R⁶Is a cyclic group of formula (k):

wherein R is⁸Is hydrogen, C_1-3Alkyl radical, C_1-3Alkoxy, hydroxy C_1-3An alkyl group;

p is 1 or 2;

z is O or CR⁹(OH) wherein R⁹Is hydrogen or C_1-3An alkyl group; or

R⁸And R⁹Form a group-CH₂-CH₂-；

R⁷Is hydrogen, halo or trifluoromethyl;

y is a covalent bond, O, NH, S, SO₂Or CF₂(ii) a Or

A pharmaceutically acceptable salt or solvate thereof.

3. A compound according to claim 1 or a stereochemically isomeric form thereof, wherein

R¹Is C_1-6An alkyl group; a trifluoromethyl group; c substituted by trifluoromethyl or phenyl_1-3An alkyl group; or phenyl;

R²is cyano or halo;

R³is a group of formula (a) or (b):

R⁴is a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; through 1 or 2 groups selected from halogen, polyhalo C_1-3Phenyl substituted with a substituent of the group consisting of alkyl;

R⁵is hydrogen or hydroxy;

x is C or N, in which case R⁵Represents an electron pair on N;

n is 0 or 1;

R⁶is selected from 1 or 2 of C_1-3Pyridyl substituted with a substituent of the group consisting of alkyl;

R⁷is hydrogen or halo;

y is O; or

A pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, wherein

R¹Is methyl; ethyl, 1-propyl, trifluoromethyl; 2, 2, 2-trifluoroethyl, 4, 4, 4-trifluorobutyl, phenylmethyl, or phenyl;

R²is cyano;

R³is a group of formula (a) or (b):

R⁴is a pyrimidinyl group; through one or two C_1-3Alkyl-substituted pyrimidinyl; a phenyl group; phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro and trifluoromethyl;

R⁵is hydrogen or hydroxy;

x is C or N, in which case R⁵Representing electricity on NA sub-pair;

n is 0 or 1;

R⁶is pyridyl substituted with 1 or 2 substituents selected from the group consisting of methyl;

R⁷is hydrogen, fluorine or chlorine;

y is O; or

A pharmaceutically acceptable salt or solvate thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

6. A compound according to any one of claims 1 to 4 for use as a medicament.

7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.

8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment or prevention of a central nervous system disorder selected from the group of: anxiety disorders, psychiatric disorders, personality disorders, substance-related disorders, eating disorders, affective disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegenerative disorders, neurotoxicity and ischemia.

9. The use according to claim 8, wherein the central nervous system disorder is anxiety disorder selected from the group of agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, Post Traumatic Stress Disorder (PTSD), social phobia and other phobias.

10. Use according to claim 8, wherein the central nervous system disorder is a psychiatric disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

11. Use according to claim 8, wherein the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder and schizophrenia, schizotypal disorder.

12. The use according to claim 8, wherein the central nervous system disorder is a substance-related disorder selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.

13. Use according to claim 8, wherein the central nervous system disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.

14. Use according to claim 8, wherein the central nervous system disorder is an affective disorder selected from the group of bipolar disorders (I and II), cyclothymic disorder, depression, dysthymia, major depression and substance-induced affective disorder.

15. The use according to claim 8, wherein the central nervous system disorder is migraine.

16. The use of claim 8, wherein the central nervous system disorder is epilepsy or a convulsive disorder selected from the group of generalized non-convulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without conscious impairment, infantile spasms, partial status epilepticus, and other forms of epilepsy.

17. The use of claim 8, wherein the childhood disorder is attention deficit/hyperactivity disorder.

18. The use according to claim 8, wherein the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persistent delirium, dementia due to HIV disease, dementia due to huntington's disease, dementia due to parkinson's disease, dementia of the alzheimer's type, substance-induced persistent dementia and mild cognitive impairment.

19. The use according to claim 8, wherein the central nervous system disorder is selected from the group of anxiety, schizophrenia, migraine, depression and epilepsy.

20. Use of a compound according to any one of claims 1 to 4 in combination with an orthosteric agonist of mGluR2 for the manufacture of a medicament for the treatment or prevention of a condition according to any one of claims 7 to 19.

21. Use of a compound according to any one of claims 1 to 4 for the treatment or prevention of a central nervous system disorder selected from the group of: anxiety disorders, psychiatric disorders, personality disorders, substance-related disorders, eating disorders, affective disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegenerative disorders, neurotoxicity and ischemia.

22. A method for treating or preventing a central nervous system disorder selected from the group consisting of: anxiety disorders, psychiatric disorders, personality disorders, substance-related disorders, eating disorders, affective disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegenerative disorders, neurotoxicity and ischemia.