UA110246C2 - 5- (phenyl /piridinylethinyl) -2-pyridine / 2- pyrimidinecarboxamides as a modulator of mglur5 - Google Patents

Abstract

The present invention relates to ethynyl derivatives of formula I, wherein Y is N or CR; R is hydrogen, methyl, halogen or nitrile; R is phenyl or pyridinyl which may be substituted by halogen, lower alkyl or lower alkoxy; R / R independently of one another denotes hydrogen lower alkyl substituted with halogen or R 1 can, together with the N atom to which they are attached, form a morpholine ring, piperidine ring or azetidine ring which is not substituted or substituted by one or more substituents selected from lower alkoxy, selected from lower alkoxy, R / R independently represent hydrogen or lower alkyl, or R and R together form a C-cycloalkyl, tetrahydrofuran or oxetane ring, or their pharmaceutically acceptable acid additive salts, racemic mixtures or their corresponding enantiomers and / or enantiomers and / or enantiomers. and / or stereoisomers. The compounds of general formula I have been unexpectedly found to be positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5).

Description

(c) Kk ve m a te M v2 r, SHU v '

EE, And where

M stands for M or C-83;

WZ denotes hydrogen, methyl, halogen or nitrile;

B' denotes phenyl or pyridinyl, which may be substituted by halogen, lower alkyl or lower alkoxy;

B2/A87 independently of each other represent hydrogen, lower alkyl or lower alkyl substituted with halogen, or B? and B? can, together with the M atom to which they are attached, form a morpholine ring, a piperidine ring or an azetidine ring, which are unsubstituted or substituted by one or more substituents selected from lower alkoxy, halogen, hydroxy or methyl;

VUV" independently of each other denote hydrogen or lower alkyl, or B? and B" together form a C3-5-cycloalkyl, tetrahydrofuran or oxetane ring; or their pharmaceutically acceptable acid addition salts, racemic mixtures or their respective enantiomers and/or optical isomers, and/or stereoisomers.

It was unexpectedly found that compounds of the general formula | are positive allosteric modulators (PAMs) of metabotropic glutamate receptors subtype 5 (tasPshA5). (c) sq m a te M in2

Dr. v

IS!

The present invention relates to ethynyl derivatives of the formula

Ge) pu ru ri in the grove

Where is she?

U denotes M or C-B3; and WZ represents hydrogen, methyl, halogen or nitrile;

AB' denotes phenyl or pyridinyl, which may be substituted by halogen, lower alkyl or lower alkoxy;

B2/82 independently of each other represent hydrogen, lower alkyl or lower alkyl substituted with halogen, or B: and B? may, together with the M atom to which they are attached, form a morpholine ring, a piperidine ring or an azetidine ring, which are unsubstituted or substituted by one or more substituents selected from lower alkoxy, halogen, hydroxy or methyl;

BBA" independently of each other denote hydrogen or lower alkyl, or B" and KU together form a C35 cycloalkyl, tetrahydrofuran or oxetane ring; or their pharmaceutically acceptable acid addition salts, racemic mixtures or their respective enantiomers and/or optical isomers and/or stereoisomers.

Now it was unexpectedly found that compounds of the general formula !/| are positive allosteric modulators (PAMs) of metabotropic glutamate receptors subtype 5 (TaichA5).

In the central nervous system (CNS), the transmission of stimuli occurs as a result of the interaction of a neurotransmitter sent by a neuron with a neuroreceptor.

Glutamate is the primary excitatory neurotransmitter in the brain and plays a unique role in various functions of the central nervous system (CNS). Glutamate-dependent stimulating receptors are divided into two main groups. The first main group, namely ionotropic receptors, forms ligand-gated ion channels. Metabotropic glutamate receptors (TAVs) belong to the second main group and, in addition, belong to the family of C-protein coupled receptors.

To date, eight different members of these tai are known, and some of them even have subtypes. According to their sequence homology, signal transmission mechanism and agonist selectivity, these eight receptors can be divided into three subgroups: tA! and ТОИША5 belong to group I, ТОСИШВ2 and ТОоИШВАЗ belong to ІЙ group, and Тичка, and ВАб, таоИШВ7 and ts BA8 belong to PP group.

Metabotropic glutamate receptor ligands belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory impairment, as well as chronic and acute pain

In this regard, other indications for treatment are limited brain function caused by bypass or transplant operations, poor cerebral blood supply, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, and hypoglycemia.

Also treatable conditions are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS 5), AIDS-related dementia, eye injuries, retinopathy, idiopathic parkinsonism or drug-induced parkinsonism, and conditions that lead to glutamate-deficient function such as such as muscle spasms, convulsions, migraines, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.

Disorders mediated in whole or in part by tan receptors are, for example, acute, traumatic and chronic degenerative processes in the nervous system, such as disease

Alzheimer's, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, mental illnesses such as schizophrenia and anxiety, depression, pain and drug addiction (Ehrep Orip. TNeg. Raiepiv (2002), 12, (12)) .

A new direction for the development of selective modulators is the identification of compounds that act by an allosteric mechanism, modulating the receptor by binding to a site other than the highly conserved orthosteric binding site. Positive allosteric modulators of TashA5 receptors have emerged recently as a new pharmaceutical agent that offers this attractive alternative. Positive allosteric modulators were described, for example, in

MO2008/151184, M/O2006/048771, UuO2006/129199 and M/O02005/044797, and in Moscow

Rpaptasaiodu, 40, 333-336, 1991; Tpe uoshtai oi Rpaptasoiodu apa Ehregitepia! Pegareshisv,

My. 313, Mo. 1, 199-206, 2005;

Positive allosteric modulators are compounds that do not directly activate receptors per se, but greatly enhance the agonist-stimulated response, increasing potency and maximal efficacy. Binding of these compounds increases the affinity of agonist glutamate sites on their extracellular M-terminal binding site. Positive allosteric modulation is thus an attractive mechanism for augmenting the corresponding physiological receptor activation. There is a lack of selective positive allosteric modulators of taSH5 receptors.

Conventional tasshA5 receptor modulators often have unsatisfactory water solubility and low bioavailability. Thus, there is a need for compounds that do not have these drawbacks and that are effective selective positive allosteric modulators of ta|shHA5 receptors.

Compounds of the formula | are distinguished by the presence of valuable therapeutic properties. They can be used for the treatment or prevention of disorders associated with positive allosteric modulators of ta|shHA5 receptors.

The best indications for compounds that are positive allosteric modulators are schizophrenia and cognitive processes.

The present invention relates to compounds of formula I and their pharmaceutically acceptable salts as pharmaceutically active substances, methods of their preparation, as well as their use for the treatment or prevention of disorders associated with positive allosteric modulators of TashA5 receptors, such as schizophrenia, tuberous sclerosis and impaired cognitive ability, and as well as pharmaceutical compositions containing compounds of formula I.

The following definitions of common terms used in this specification apply whether the terms are used alone or in combination.

As used herein, the term "lower alkyl" means a saturated, ie, aliphatic, hydrocarbon group comprising a straight or branched carbon chain of 1-4 carbon atoms. Examples of "alkyl" include methyl, ethyl, n-propyl and isopropyl.

The term "halogen-substituted lower alkyl" means an alkyl group, as defined above, in which at least one hydrogen atom is replaced by a halogen atom. The SEZ group is the best.

The term "Alkoxy" refers to the group -O-B', where E" refers to lower alkyl as defined above.

The term "halogen" means fluorine, chlorine, bromine or iodine.

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

One of the embodiments of this invention are compounds of the formula c) dn

DU r and IA de

U stands for M or C-VZ; and WZ represents hydrogen, methyl, halogen or nitrile;

B' denotes phenyl or pyridinyl, which may be substituted by halogen, lower alkyl or lower alkoxy; or their pharmaceutically acceptable acid addition salts, racemic mixtures or their respective enantiomers and/or optical isomers and/or stereoisomers.

The following compounds of formula IA were synthesized:

B-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5- difluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide

B-pyridin-3-ylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(5-fluoropyridin-3-ylethynyl)/pyridine-2 -carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide

5-(2,5-difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)-3-methylpyridine- 2-carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5-difluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 5-( 5-chloropyridin-3-ylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide

C-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide

3-fluoro-5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5-difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridine-3- ilethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide

C-chloro-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide or

C-cyano-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide.

An additional embodiment of this invention are compounds of formula I, where K' denotes phenyl, possibly substituted by halogen, for example, the following compounds:

B-phenylethynylpyridine-2-carboxylic acid tert-butylamide

B-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5- difluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide 5-(4-fluorophenylethynyl) pyrimidine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide

B-m-tolyethynylpyrimidine-2-carboxylic acid tert-butylamide 5-(33-chlorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide 5-(2,5-difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 5-( 3-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 5-(4-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5-difluorophenylethynyl)-3-methylpyridine-2 -carboxylic acid tert-butylmethylamide

Z-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide

3-fluoro-5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(2,5-difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyridine- 2-carboxylic acid cyclobutylmethylamide 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid oxetan-3-ylamide 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide 5- (4-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide 5-(2,5-difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide 5-(3,4-difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide 5- (4-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide 5-(33-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)-amide

B-m-tolylethynylpyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide (2,2-dimethylmorpholin-4-yl)-(5-(3-fluorophenylethynyl)pyridin-2-yl|methanone

15-(2,5-difluorophenylethynyl)pyridin-2-yl1-(2,2-dimethylmorpholin-4-yl)umethanone

15-(3-fluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-4-methylpiperidin-1-yl)umethanone (85)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)-(5 -phenylethynylpyridin-2-ylomethanone (85)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-ylomethanone (85)-I5-(4-fluorophenylethynyl)pyridin-2-ylI -(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone (85)-I5-(3-fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone

C-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)-amide

C-chloro-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide (3,3-difluoroazetidin-1-yl)-(5 -phenylethynylpyrimidin-2-yl)umethanone (3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone (85)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)- (5-phenylethynylpyrimidin-2-yl)umethanone (85)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone (85)-I5-(3- fluorophenylethynyl)pyrimidin-2-yl|-(4-hydroxy-3,3-dimethylpiperidin-1-yl-methanone

3-fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide (85)-3-fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(2,2,2-trifluoro -1- methylethyl)amide

3-cyano-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(3Z-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide (85)- 5-(3-chlorophenylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)-amide (85)-5-(3-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2, 2,2-trifluoro-1-methylethyl)amide (85)-I5-(3-fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (85)-I5- (2,5-difluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-yl)-methanone (85)-15-(3-fluorophenylethynyl)pyrimidin-2-yl|-( 4-hydroxy-2,2-dimethylpiperidin-1-yl-methanone (85)-I(5-(2,5-difluorophenylethynyl)pyrimidin-2-ylI|-(4-hydroxy-2,2-dimethylpiperidin-1- yl)umethanone (85)-3-fluoro-5-(3-fluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone or (85)-I(5- (2,5-difluorophenylethynyl)-3-fluoropyridin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-ylumethanone).

An additional embodiment of this invention are compounds of formula I, where KE! denotes pyridinyl, optionally substituted with halogen, for example, the following compounds

B-pyridin-3-ylethynylpyridine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 5-(5-fluoropyridin-3-ylethynyl)/pyridine-2 -carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 5 -(5-chloropyridin-3-ylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide

Zo 5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide (85)-5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1 - methylethyl)amide of 5-(2-chloropyridin-4-ylethynyl)pyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (8)- or (5)-5-(2 -chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide or (5)- or (K)-5-(2-chloropyridin-4-ylethynyl)/pyridine -2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide.

One additional object of this invention is compounds of formula 1-1 in mode I where

U stands for M or C-B83; and WZ represents hydrogen, methyl, halogen or nitrile;

B' denotes phenyl or heteroaryl, which may be substituted by halogen, lower alkyl or lower alkoxy;

B2/82 independently of each other denote hydrogen, lower alkyl, lower alkyl,

BO substituted by halogen or СНо-lower alkoxy, or B: and B? can, together with the M atom to which they are attached, form a morpholine ring, a piperidine ring or an azetidine ring, which are unsubstituted or substituted by lower alkoxy, halogen, hyroxy or methyl;

BB independently of each other denote hydrogen, lower alkyl or CH»-lower alkoxy, or KK" and KU together form a C35 cycloalkyl, tetrahydrofuran or oxetane ring; or their pharmaceutically acceptable acid-addition salts, racemic mixtures, or their respective enantiomers and/ or optical isomers and/or stereoisomers.

Another object of this invention are compounds of formula 1-2

Go) pu re and ru ri in the garden

I-2 where

U denotes M or C-B3; and WZ represents hydrogen, methyl, halogen or nitrile;

B' denotes phenyl or heteroaryl, which may be substituted by halogen, lower alkyl or lower alkoxy;

B2/B2 independently of each other denote hydrogen, lower alkyl or СНо-lower alkoxy, or K2 and K?7 form, together with the M atom to which they are attached, a ring with -(CHg)g,zm-, - (CHg )2-MA»-СНе- or -(СНг)2-ОО-СНо-, which is unsubstituted or substituted by lower alkoxy, hydroxy or methyl; where there is a? represents hydrogen or lower alkyl;

BB independently of each other denote hydrogen, lower alkyl or CH»-lower alkoxy, or KK" and KU together form a C3-5-cycloalkyl, tetrahydrofuran or oxetane ring; or their pharmaceutically acceptable acid-addition salts, racemic mixtures, or their respective enantiomers and/or optical isomers and/or stereoisomers.

Preparation of compounds of the formula | according to this invention can be carried out by sequential or convergent synthesis. The syntheses of the compounds of the invention are shown in Scheme 1 below.

The skills required to carry out the reactions and purify the resulting products are known to specialists in this area. The placeholders and subscripts used in the following description of the processes have the meanings indicated above.

Compounds of formula I may be prepared by the methods set forth below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for individual stages of the reaction are known to a person skilled in the art. The sequence of reactions is not limited to that depicted in the diagrams, but, depending on the starting materials and their reactivity,

The sequence of reaction stages can be freely changed. The starting materials are either commercially available or can be obtained by methods similar to those described below, by methods described in the references given in the description or in the examples, or by methods known in the art.

The compounds of the formula I according to the present invention and their pharmaceutically acceptable salts can be obtained by methods known from the state of the art, for example, various variants of the method described below, which includes: a) the interaction of the compound of the formula

DU V

4 ra: b with a suitable compound of the formula

B'-Nai! 7 with the formation of a compound of the formula ri in 4 v' where the substituents are as described above, or p) the interaction of a compound of the formula iv' 1 ry rli B

Hg C with a suitable compound of formula 4

Kk 4 with the formation of a compound of the formula

M rei o ri v de pr y c) the interaction of the compound of formula (6) rel rli 4 and 9 with a suitable compound of formula 4 'puav, nm sv"

I and 2 with the formation of a compound of the formula

Mary J

DU in de 1 dk and where the substituents are as described above, or, if necessary, conversion of the obtained compounds into pharmaceutically acceptable acid-addition salts.

Preparation of compounds of the formula | also described in more detail in schemes 1, 2 and 3 and in examples 1-68.

Scheme 1 tk 1. the base of the huniga, g:

M | g TVTY, dioxane, 4 p.m. 9 th and M 2 u i in: room. temperature of schizy KE deyre or (COMPOSITION, DMF (cat) donu in

SNaSsS, 4-6 h., ET 1 2 i) 2, pyridine, SNeSi", 4-16 h., KT Z 2. Bis-rVI-RYAST, EBM, '

TRR, Sy, DMF, 2-4 p.m., OB r tes M or A, p--- - well ni riv 7 more I di 4 I

Ethynylpyridine or ethynylpyrimidine compound of the formula | can be prepared, for example, by reacting 5-bromopyridine-2-carboxylic acid or 5-bromopyrimidine-2-carboxylic acid 1 with a suitable amine 2 in the presence of a base such as Hunig's base and a peptide coupling reagent such as TVTI in solvent such as dioxane, or by obtaining ip 5 and the corresponding anhydride chloride with oxalyl chloride and DMF (cat.) in a solvent such as dichloromethane, followed by interaction with amine 2 in the presence of a base such as pyridine. Bonding according to Sonogashira of 5-bromopyridine-2-carboxylic acid amide or 5-bromopyrimidine-2-carboxylic acid amide C with a suitable substituted arylacetylene 4 leads to obtaining the desired ethynyl compounds of the general formula I (Scheme 1). The introduction of the K7 substituent can also be implemented at different stages of the synthesis sequence by alkylation of the corresponding intermediate compounds, where K2 is H.

Scheme 2 of the battle 1Bis-prr)-Rag s, Ov'v o pud EM, TRR, Si, DMF, mich Ar: m re 2-1B h, 70 s GO

GO In -i in no where and I shi

Z y x 5 B 2. bis-prri-RYAPS, ЭМ, St

TRE, Sy, TVAR, DMF, o vu 1 jud., 70 s / mov p2

ШУ----Ш2Ш0ТЗ0-- r sew r'-vi tya 7

The ethynylpyridine or ethynylyrimidine compound of the formula !/ can be obtained by Sonogashira coupling of 5-bromopyridine-2-carboxylic acid amide or 5-bromopyrimidine-2-carboxylic acid amide C with ethynyltrimethylsilane 5 to give the corresponding 5-trimethylsilanylethynyl derivative 6. Binding according to Sonogashira with IP 5 and desilylation of compound 6 and a suitable aryl halide 7 leads to the formation of the desired ethynylpyridine or ethynylpyrimidine compounds of formula I (Scheme 2). Introduction of the substitute B? can also be carried out at different stages of the synthesis sequence by alkylating the corresponding intermediate compounds in which B2-H.

Scheme Z

1.1) bis-Krr)-RY ST,

EM, TRR, Sy, o DmF, 2-16 h, 70 S a rev / Mo and She: ii saponification (SHON) Meito and Me yav ----БШ2Ш2Ш25-- ШЧО nm

Ve -y s in: 4 prs-yai

B e 2

WITH

2. base x uniga, and vu

TVTI, dioxane, 4 p.m. M Shi room winter temperature in:

Zh-Schshchshshchshchshchshchshchshchshchshchshchshchshchshchshchiszhchye | and. rI or p(SOost, DdmMf (cat. - 4

Snessia tod KO ria

Ii 2, pyridine, SNa Si»

A-4 p.m., CT

In general, the sequence of steps used for the synthesis of compounds of formula I may also be varied in some cases, for example by first carrying out the coupling by

Sonogashira of 5-bromopyridine-2-carboxylic acid methyl ester or 5-bromopyrimidine-2g-carboxylic acid methyl ester 8 and a suitable substituted arylacetylene 4, followed by saponification with a base such as PON to give the corresponding acid 9.

Reaction of the appropriate acid 9 with a suitable amine 2 in the presence of a base such as a base

Hunig, and a peptide binding reagent such as TVTI in a solvent such as dioxane, or preparation of the corresponding anhydride chloride with oxalyl chloride and DMF (cat.) in a solvent such as dichloromethane, followed by interaction with amine 2 in the presence of a base , such as pyridine, leads to obtaining ethynyl compounds of the general formula I! (scheme 3). Introduction of the substitute K? can be implemented at different stages of the synthesis sequence by alkylation of the corresponding intermediate compounds, where K2-H.

Preferably, a compound of formula I as described above, as well as a pharmaceutically acceptable salt thereof, is used for the treatment or prevention of psychosis, epilepsy, schizophrenia, disease

Alzheimer's, cognitive impairment and memory impairment, chronic and acute pain, limited brain function due to bypass or transplant, poor cerebral blood flow, spinal cord injury, head injury, pregnancy-induced hypoxia, cardiac arrest and hypoglycemia, ischemia, Huntington's chorea , amyotrophic lateral sclerosis (ALS 5), AIDS-related dementia, eye injury, retinopathy, idiopathic or drug-induced parkinsonism, muscle spasms, convulsions, migraine, urinary incontinence, gastrointestinal reflux disorders, liver damage, or drug- or disease-induced liver failure, Martin-Bell syndrome, Down syndrome, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, particularly bulimia or anorexia, and depression, especially for the treatment and prevention of acute and/or or chronic neurological disorders, anxiety, treatment of chronic and acute pain, urinary incontinence and obesity.

The best indications are schizophrenia and cognitive disorders.

The present invention also relates to the use of a compound of formula I as described above, as well as

From its pharmaceutically acceptable salt, for the manufacture of a medicinal product, preferably for the treatment and prevention of the aforementioned diseases.

Biological analysis and data:

Analysis of intracellular Ca mobilization?

A monoclonal cell line HEK-293 was stably transfected with cDNA encoding human toiysba receptors; to work with positive allosteric modulators (PAMs) toii5 selected cell lines with a low level of expression and low constitutive activity of receptors in order to differentiate the activity of agonists from the activity of PAMs.

Cells were cultured according to standard protocols (Egezppeu, 2000) in Dulbecco's modified Eagle's medium with high glucose supplemented with 1 mM glutamine, 1095 (vol./06.) heat-inactivated bovine serum, penicillin/streptomycin, 50 μg/ml hydromycin and 15 μg/ml blasticidin (all cell culture reagents and antibiotics produced by Ipmigodep, Vazei, Zm/ygepapa).

Approximately 24 hours before the experiment, 5x1027 cells/well were seeded into coated poly-O-

lysine black 9b-well tablets with a transparent bottom. Cells were plated with 2.5 µM Risho-4AM in plating buffer (1xHB5Z5, 20 mM NEREZF) for 1 h at 37°C and washed 5 times with plating buffer. , Egapse) and added 11 semi-logarithmic dilutions of the tested compounds at 37 "С and the cells were incubated for 10-30 minutes with online recording of fluorescence. After this pre-incubation stage, the agonist I-glutamate was added to the cells at a concentration corresponding to ESho (usually about 80 µM) with online recording of fluorescence; in order to calculate diurnal changes in the corresponding response of the cells, ECo of glutamate was determined immediately before each experiment by recording the complete dose-response curve for glutamate.

Responses were measured as the peak increase in fluorescence minus the basal level (ie, fluorescence without addition of I-glutamate), normalized to the maximal stimulatory effect obtained with saturating concentrations of I-glutamate. Graphs were constructed as a percentage of maximum stimulation using the XI curve approximation program, which iteratively constructs data graphs using the Levenberg-Marquardt algorithm. The equation of one-point competitive analysis was used in 5 A (B-AM 1 (x/C)O))), where y denotes 95 of the maximum stimulated effect, A denotes the minimum of y, B denotes the maximum of y, C denotes ESvo, x denotes 0910 concentration of the competing compound and ХО indicates the slope of the curve (Hill's coefficient). From these curves, the ECs (concentration at which half the maximum stimulation was achieved), the Hill coefficient, as well as the maximum response at 95% of the maximum stimulation effect obtained for saturating concentrations of I -glutamate were calculated.

Positive signals obtained during preincubation with RAM test compounds (that is, before the introduction of ES5 concentration of I-glutamate) were indicative of agonistic activity, the absence of such signals demonstrated the absence of agonistic activity. The decrease in the signal observed after the introduction of EC50 concentration of I-glutamate was indicative of the inhibitory activity of the test compound.

The table below shows the obtained compounds 1-68 with the corresponding test results of 1-68 (ESvov NM).

List of examples: tai5RAM Fo o pe cho I 4 | ru of 5-phenylethynylpyridine-2-carboxylic acid 49 115 d-tert-butylamide o ve 2 | ru | 5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide o

J

And 5-(3-fluorophenylethynyl)pyridine-2-

From -x carboxylic acid tert- 16 64 butylmethylamide

E o te Ro 5-(4-fluorophenylethynyl)pyridine-2-4 de her carboxylic acid tert- 18 83 butylmethylamide

E o) according to Cho:

E | | 5-(2,5-difluorophenylethynyl)-pyridine-2g-carboxylic acid tert- 12 42 butylmethylamide

E o) p Cho: t i B-pyridin-3-ylethynylpyridin-2- carb of carboxylic acid tert- 72 70 2 y

M" butylmethylamide -

Gee)

Me c

A 1 5-(5-chloropyridine-Z-ilethynyl)-7xx to pyridine-2-carboxylic acid tert-17Z" butylmethylamide ---

SI o) by:

And 5-(5-fluoropyridin-3-ylethynyl)-mch" of pyridine-2-carboxylic acid tert- 62 79

Butylmethylamide -

Eh oh us pops

AM 5-(4-fluorophenylethynyl)pyrimidine-2-127 and carboxylic acid tert-butylamide

E c) / es ro 4 5-(3-fluorophenylethynyl)pyrimidine-2-7 carboxylic acid tert-butylamide 36 VI

E o i 5-(4-fluorophenylethynyl)pyrimidine-2-11 r DM of carboxylic acid tert-34 butylmethylamide

E c) es yam! 5-(Z-fluorophenylethynyl)pyrimidine-2- 12 4 carboxylic acid tert- 23 55 butylmethylamide

E c) adj

М B-m-tolylethynylpyrimidine-2-

Zhzh-8 13 57 carboxylic acid tert-butylamide Sh 83 c) es

M. a. - - - . in. 14 r, 5-(3 chlorophenylethynyl)pyrimidine 2. 144 95 carboxylic acid tert-butylamide (c) c) gshn

E r 5-(2,5-difluorophenylethynyl)-dO of pyrimidine-2-carboxylic acid 35 32 tert-butylmethylamide

E c)

WITH

Ah! 5-(5-chloropyridine-3-ylethynyl)-16 c ho pyrimidine-2-carboxylic acid 58 27

Tert-butylmethylamide (c) c) tert-butylmethylamide

E c)

M x seams; 5-(4-fluorophenylethynyl)-3- 18 g of methylpyridine-2-carboxylic acid 76 71 tert-butylmethylamide

E c) pe Ya

Е Ж 5-(2,5-difluorophenylethynyl)-3- 19 doO of methylpyridine-2-carboxylic acid C 23 tert-butylmethylamide

E c) and at ro | 5-(5-chloropyridin-3-ylethynyl)-3-s dO of methylpyridine-2-carboxylic acid 102 26 " p tert-butylmethylamide (c) c)

M Ya

IA 1 Z-fluoro-5-(3-fluorophenylethynyl)-21 sv and pyridine-2-carboxylic acid tert- 18 54 butylmethylamide

E c)

M 0 , , p | Z-fluoro-5-(4-fluorophenylethynyl)-22 p,E pyridine-2-carboxylic acid tert- 32 65 butylmethylamide

E c) pe Ya

ЕЖ 5-(2,5-difluorophenylethynyl)-3-23 doO and fluoropyridine-2-carboxylic acid 10 С8 tert-butylmethylamide

E c) and at ro | 5-(5-chloropyridin-3-ylethynyl)-3- 24 s dO and fluoropyridine-2-carboxylic acid 11 23 " r tert-butylmethylamide (c) о вх;

And, | 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid 32 56 cyclobutylmethylamide

E o (c) 5-(3-fluorophenylethynyl)pyridine-2-26 2 carboxylic acid oxetan-3-43 ylamide

E c) (c) 1 5-(3-fluorophenylethynyl)pyridin-2-27 2 carboxylic acid methyl-(3-24 53 methyloxetan-3-yl)amide

E o (in c and 5-(4-fluorophenylethynyl)pyridin-2- 28 carboxylic acid methyl-(3- 37

I methyloxetane-3-yl)amide

E c) (c)

E | | 5-(2,5-difluorophenylethynyl)-pyridin-29 d-x 2g-carboxylic acid methyl-(3-21 45 methyloxetan-3-yl)amide

E o (in what t 5-(3,4-difluorophenylethynyl)-pyridino- rac of 2-carboxylic acid methyl-(3- 50

E I methyloxetan-3-yl)amide

E c) in 1 5-(3-fluorophenylethynyl)pyridine-2-

From 4 carboxylic acid methyl-(1-17 43 methylcyclopropyl)amide

Oh, whore PD

And 5-(4-fluorophenylethynyl)pyridin-2-32 zhd 4 carboxylic acid methyl-(1-24 59 methylcyclopropyl)amide

E about

M E where in the village

Av 5-(3-chlorophenylethynyl)pyridine-2-

C3 du carboxylic acid methyl-(1- C3 37 trifluoromethylcyclopropyl)amide (c) o

MME

B-m-tolylethynylpyridin-2-34 to carboxylic acid methyl-(1-2746 trifluoromethylcyclopropyl)amid o

M ia (2,2-dimethylmorpholin-4-yl)-(5-(3- sxO fluorophenylethynyl)pyridin-2- 46 57 yl|Imethanone

E about

M

E | I 15-(2,5-difluorophenylethynyl)pyridin-36 shkhO 2-yl|-(2,2-dimethylmorpholin-4-56 44 yl)umethanone

E about

MU M

I - (5-(3-fluorophenylethynyl)pyridin-2-374-yl|-(4-hydroxy-4-methyl-7938-piperidin-1-yl)umethanone

E o g e i (85)-(4-hydroxy-2,2-38 de -4 o) dimethylpiperidin-1-yl)-(5-28 57 phenylethynylpyridin-2-yl)umethanone o g e fa (85)-( 4-hydroxy-3,3- 39 de -4 (o) dimethylpiperidin-1-yl)-(5- 35 58 phenylethynylpyridin-2-yl)umethanone c) pe fa (85)-I5-(4-fluorophenylethynyl)- , aa (c) pyridin-2-yl|-(4-hydroxy-3,3- 93 37 dimethylpiperidin-1-yl)umethanone

E about

MU M

(85)-(5-(3-fluorophenylethynyl)-41 Es o pyridin-2-yl|-(4-hydroxy-3,3-72 45 dimethylpiperidin-1-yl)umethanone

E c) pe eva

IA 1 Z-fluoro-5-(3-fluorophenylethynyl)-42 s P pyridine-2-carboxylic acid Z 35 methyl-(1-methylcyclopropyl)amide

E oh le: oh, and. its 3-chloro-5-phenylethynylpyridine-2-43 desa carboxylic acid tert-36 butylmethylamide

Ii M E mov E . . . .

Y. m Y is 5-(3-fluorophenylethynyl)pyrimidine-2-44 s carboxylic acid methyl-(1-42 trifluoromethylcyclopropyl)amide

E c) and 45 Ii m ee (3,3-difluoroazetidin-1-yl)-(5-vo BI 4 E phenylethynylpyrimidin-2-yl)methanone o va 46 | AM (3,3-dimethylpiperidin-1-yl)-(5-BO B9 - phenylethynylpyrimidin-2-yl)methanone o a (85)-(4-hydroxy-2,2-dimethyl-47 de 2 o piperidin-1 -yl)-(5-phenylethynyl-57 pyrimidin-2-yl)umethanone o ! SE (85)-(4-hydroxy-3,3-dimethyl- 48 de M (in; piperidin-1-yl)-(5-phenylethynyl- 43 55 pyrimidin-2-yl)umethanone o

M has (85)-I(5-(3-fluorophenylethynyl)-43 SHU o pyrimidin-2-yl|-(4-hydroxy-3,3-48 dimethylpiperidin-1-yl)umethanone

E c) (c)

Mach be Z-fluoro-5-phenylethynylpyridine-2- 50 ru Sak. carboxylic acid methyl-(3-40 67 and methyloxetan-3-yl)amide 7 E

(85)-3-fluoro-5-phenylethynylpyridine-51 and 2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)amide

In line 7, 3-cyano-5-phenylethynylpyridin-2-52 de 4 s of carboxylic acid tert-34 butylmethylamid o ME che t and E 5-(5-chloropyridin-3-ylethynyl)-p. . ru of pyridine-2-carboxylic acid 53 sh methyl-(1-trifluoromethyl- 44 97 cyclopropyl)amide (0) c)

Ma y 5-(2-chloropyridin-4-ylethynyl)-

BA Y B of pyridine-2-carboxylic acid 37 oku» sv (2,2,2-trifluoro-1,1-dimethylethyl)-

M. amide c)

Ma in 5-(5-chloropyridine-3-ylethynyl)-

BB I 1 ee of pyridine-2-carboxylic acid 37 63 scoli methyl-(2,2,2-trifluoro-1,1-

There is dimethylethyl)amide c)

Eyche Ru, 5-(Z-chlorophenylethynyl)pyridin-2-56 zhd 4 E carboxylic acid methyl-(2,2,2-22 29 w trifluoro-1,1-dimethylethyl)amide c) me u (85) -5-(2-chloropyridine-4- 57 ce Biletinyl)/pyridine-2-carbon 22 to

Cy acids (2,2,2-trifluoro-1-

M" methylethyl)amide c) hey 5-(2-chloropyridin-4-ylethynyl)-

Pyrimidine-2-carboxylic acid 57 30 sy (2,2,2-trifluoro-1,1-dimethylethyl)-

M» amide 9) : E Spiga! hey motuche po

M (K) or (5)-5-(2-chloropyridin-4-ylethynyl)upyridin-2-carboxylic acid (2,2,2-trifluoro-1-

IS .

M «i, methylethyl)amide - sa s ss

M

(o) And Spiga! m TE

Fi Mun s shy-x7O 7, (5) or (K)-5-(2-chloropyridin-4-ov ilethynyl)upyridin-2-carbonate acid (2,2,2-trifluoro-1-pe " and, methylethyl)amide according to o

(85)-5-(3-Chlorophenylethynyl)-61 de and Y of pyridine-2-carboxylic acid 61 83 o (2,2,2-trifluoro-1-methylethyl)amide c) me u ( 85)-5-(Z-chlorophenylethynyl)-in A 1 Y of pyridine-2-carboxylic acid 25 z5 s 4 methyl-(2,2,2-trifluoro-1-methylethyl)amide (in) ge and (85)- I(5-(3-fluorophenylethynyl)-63 g 4 (in pyridin-2-yl|-(4-hydroxy-2,2- 40 45

And dimethylpiperidin-1-yl)umethanone o

M M

E I (85)-I5-(2,5-difluorophenylethynyl)-64 DU o pyridin-2-yl|-(4-hydroxy-2,2- 34 42 dimethylpiperidin-1-yl)umethanone

IS

(in)

Fi (85)-I5-(3-fluorophenylethynyl)- 65 zhd 2 (in pyrimidin-2-yl|-(4-hydroxy-2,2- 149 55

Dimethylpiperidin-1-yl)umethanone is (85)-(5-(2,5-difluorophenylethynyl)-4-pyrimidin-2-yl|-(4-hydroxy-2,2-101 49 dimethylpiperidine) -1-yl)umethanone

IS

(c) he and (85)-III-fluoro-5-(3-fluorophenyl-67 de a: o ethynyl)pyridin-2-yl|-(4-hydroxy-2,2- 54 57

And dimethylpiperidin-1-yl-methanone o

M M

Е И, (85)-(5-(2,5-difluorophenylethynyl)-3- dO and o fluoropyridin-2-yl|-(4-hydroxy-2,2- 46 54 dimethylpiperidin-1-yl-methanone)

IS

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicinal products, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be carried out rectally, for example, in the form of suppositories, or parenterally,

for example, in the form of solutions for injections.

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers to obtain pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.; depending on the nature of the active substance, no carrier, however, is usually required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Adjuvants, such as alcohols, polyols, glycerin, vegetable oils, etc., can be used for aqueous injection solutions based on water-soluble salts of compounds of formula (I), but, as a rule, are not necessary.

Suitable carriers for suppositories are, for example, natural or solidified oils, waxes, fats, semi-liquid or liquid polyols, etc.

In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, flavors, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned earlier, medicinal products containing a compound of formula (I) or its pharmaceutically acceptable salts and a therapeutically inert excipient are also an object of the present invention, as well as a method of preparing such medicinal products, which includes the introduction of one or more compounds of the formula And or their pharmaceutically acceptable salts and, if necessary, one or more other therapeutically valuable substances, in a galenic dosage form together with one or more therapeutically inert carriers.

As also mentioned earlier, the use of compounds of formula (I) for the preparation of medicinal products for the prevention and/or treatment of the above-mentioned diseases is also an object of this invention.

The dosage can vary widely and, of course, must meet individual requirements in each specific case. In general, an effective dosage for oral or parenteral administration is in the range of 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all the indications described. The daily dose for an adult weighing 70 kg, respectively, is in the range of 0.7-1400 mg per day, better, from 7 to 700 mg per day.

Preparation of pharmaceutical compositions containing compounds according to the invention:

Example A

Tablets of the following composition were obtained in the usual way: ooomtablezh.id////111111111Ї1 o Polyvinylpyrrolidone.//////77777771111111111111111111111111111111111111Ї11118

Experimental section:

Example 1

B-Phenylethynylpyridine-2-carboxylic acid tert-butylamide (6) an and ho

Stage 1: 5-Bromopyridine-2-carboxylic acid tert-butylamide 6) where

Vg -4

5-Bromopicolinic acid (200 mg, 0.99 mmol) was dissolved in dioxane (2 mL) and base was added

Huniga (520 μl, 2.97 mmol, 3 eq.), TVTI (350 mg, 1.09 mmol, 1.1 eq.), and tert-butylamine (124 μl, 1.19 mmol, 1.2 eq.) at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted with a saturated solution

ManHsCOz and twice a small volume of dichloromethane. The crude product was purified by flash chromatography by loading the dichloromethane layers directly onto a silica gel column and eluting with an ethyl acetate/heptane gradient from 0:100 to 50:50. The desired 5-bromopyridine-2-carboxylic acid tert-butylamide (235 mg, yield 92950) was obtained as a colorless oil, Me: m/e - 257.0/259.0 (MAN).

Stage 2: 5-Phenylethynylpyridine-2-carboxylic acid tert-butylamide c)

Ma s and y

Bis(triphenylphosphine)palladium(i!) dichloride (31 mg, 44.7 μmol, 0.05 equiv.) was dissolved in 2 ml

DMF (230 mg, 894 μmol), 5-bromopyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and phenylacetylene (183 mg, 196 μL, 1.79 mmol, 2 equiv) were added at room temperature. Triethylamine (272 mg, 374 μL, 2.68 mmol, 3 eq.), triphenylphosphine (7 mg, 26.8 μmol, 0.03 eq.), and copper(I) iodide (5 mg, 26.8 μmol, 3 eq.) were added. 0.03 equiv.) and the mixture was stirred for 2 hours at 70 "C. The reaction mixture was cooled, extracted with a saturated solution

ManHsCOz and twice a small volume of dichloromethane. The crude product was purified by flash chromatography loading the dichloromethane layers directly onto a silica gel column and eluting with an ethyl acetate/heptane gradient from 0:100 to 100:0. The desired 5-phenylethynylpyridine-2-carboxylic acid tert-butylamide (174 mg, 70 95 yield) was obtained as a light yellow precipitate, Me: m/e xx 279.1 (Ma-NU).

Example 2 5B-Phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide c)

Me c

5B-Phenylethynylpyridine-2-carboxylic acid tert-butylamide (Example 1, stage 2) (74 mg, 266 μmol) was dissolved in DMF (1 mL) and cooled to 0-5 °C. Mann (55905) (14 mg, 319 μmol, 1.2 equiv.) and the mixture was stirred for 30 minutes at 0-5 "С. Iodomethane (22 μl, 346 μmol, 1.3 equiv) was added and the mixture was then stirred for 1 hour at room temperature.

2 The reaction mixture was evaporated and treated with a saturated solution of ManHCO3 and extracted twice with a small volume of SNeSi. The organic layers were immediately loaded onto a silica gel column and the crude material was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide (48 mg, yield 62 95) was obtained as a light yellow precipitate, M: t/e - 293.0 (M.N).

Example C of 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide c)

Ma s

A ho

IS

Stage 1: 5-Bromopyridine-2-carboxylic acid tert-butylmethylamide

Vg -4

The title compound was obtained as a white precipitate, M5: m/e - 271.2/273.2 (MaANU), using a method similar to that described in Example 2 from 5-bromopyridine-2-carboxylic acid tert-butylamide (Example 1, stage 1) and iodomethane.

Stage 2: 5-Trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide 6) / m. c r what c4 5

The title compound was obtained as a yellow precipitate, Me: m/e - 289.2 (MAN), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2-carboxylic acid tert-butylmethylamide (Example 3, stage 1) and ethynyltrimethylsilane.

Stage 3: 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide c) / Ma s r ho

IS

B-Trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide (Example 3, stage 2) (60 mg, 0.2 mmol) was dissolved in DMF (1 mL). 1-Fluoro-3-iodobenzene (74 mg, 0.33 mmol, 1.6 eq.), EVM (87 μl, 0.62 mmol, 3 eq.), bis(triphenylphosphine)palladium(II) dichloride (7 mg, 10.4 μmol, 0.05 equiv.) and medicin iodide) (0.4 mg, 2 μmol, 0.01 equiv.) in a nitrogen atmosphere and the mixture was heated to 70 °C. TVAE 1M in THF was added dropwise (230 μl, 0.23 mmol, 1.1 equiv.) for 20 minutes at 70 "С. The reaction mixture was stirred for 30 minutes at 70 "C and evaporated to dryness in the presence of the sorbent IsoYsheF. The crude product was purified using flash chromatography on a 20 g silica gel column, eluting with a mixture of heptane/ethyl acetate 100:0 -» 70:30. The desired 5-( 3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide (64 mg, yield 9995) was obtained as a colorless oil, Me: m/e - 311.5 (MAN).

Example 4 5-(4-Fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide c) / mass

IS

The title compound was obtained as a light yellow precipitate, M5: m/e - 311.5 (MaANU), using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyridine-2-carboxylic acid tert -butylmethylamide (Example 3, stage 2) and 1-fluoro-4-iodobenzene.

Example 5

Zo 5-(2,5-Difluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide (c) / ma s e - s

IS

The title compound was obtained as a light yellow precipitate, Me: t/e - 329.1

(MaANU), using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide (Example 3, stage 2) and 1,4-difluoro-2-iodobenzene.

Example 6 5B-Pyridin-3-ylethynylpyridine-2-carboxylic acid tert-butylmethylamide 6) / m. c r Y 2

M

Eat with

The title compound was obtained as a light yellow precipitate, Me: m/e - 2941 (MaANU, using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide ( Example 3, stage 2) and 3-iodopyridine.

Example 7 5-(5-Chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide (c) / mass r Y 2

M

Eat with

SI

The title compound was obtained as a white precipitate, MO: m/e - 328.1/330.0 (MaANU, using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide (Example 3, stage 2) and 33-chloro-5-iodopyridine.

Example 8 5-(5-Fluoropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide (c) / mass r Y 2

M

It is with y

The title compound was obtained as a white precipitate, M5: m/e - 312.2 (MANU, using a method similar to that described in Example 3, stage 3, 3 5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide (Example 3, stage 2) and C3-fluoro-5-iodopyridine.

Example 9 5-(4-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide i) / iiK

M dk

IS

Stage 1: 5-Bromopyrimidine-2-carboxylic acid tert-butylamide 6) det

Vg M

Z 5-Bromopyrimidine-2-carboxylic acid (1 g, 4.93 mmol) was suspended in dichloromethane (10 mL) and DMF (20 µL). Oxalyl chloride (520 μl, 5.91 mmol, 1.2 equiv.) was added dropwise at room temperature and the mixture was stirred for 16 hours. The reaction mixture was then cooled to 0-"C and pyridine (480 μl, 5.91 mmol, 1.2 equiv.) and tert-butylamine (621 μl, 5.91 mmol, 1.2 equiv.) were added dropwise at 0 -5 7 C. The mixture was stirred for 4 hours at room temperature.

The reaction mixture was extracted with a saturated solution of ManHsSose and dichloromethane. The organic layers 5 were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The desired 5-bromopyrimidine-2-carboxylic acid tert-butylamide (960 mg, 76 95 yield) was obtained as a light yellow precipitate, Me: m/e - 258.0/259.9 (MAN).

Stage 2: 5-Iodopyrimidine-2-carboxylic acid tert-butylamide (c) es

Xa 5B-Bromopyrimidine-2-carboxylic acid tert-butylamide (Example 9, stage 1) (950 mg, 3.68 mmol) was dissolved in dioxane (10 mL). (2.2 g, 14.7 mmol, 4 equiv.), midixI iodide) (66 mg, 0.74 mmol, 0.2 equiv.) and trans-M,M-dimethylcyclohexane-1,2-diamine ( CA5 67579-81-1) (105 mg, 0.74 mmol, 0.2 equiv.) and the mixture was stirred for 16 hours at 100 "C. The reaction mixture was extracted with saturated Mansoze solution and twice with ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a 20 g silica gel column, eluting with heptane/ethyl acetate 100:0 -» 0:100. The desired 5-iodopyrimidine-2-carboxylic acid tert-butylamide (870 mg , yield 7895) was obtained as a yellow precipitate, Me: t/e - 306.0 (MN).

Stage 3: 5-(4-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide i) / nn

AM

2

IS

The title compound was obtained as a yellow precipitate, M: m/e - 298.4 (M.H), using a method similar to that described in Example 1, stage 2, from 5-iodopyrimidine-2-carboxylic acid tert -butylamide (Example 9, stage 2) and 1-ethynyl-4-fluorobenzene.

Example 10 5-(3-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide i) / es

AM d-

IS

The title compound was obtained as a yellow precipitate, M: m/e - 298.5 (MAN), using a method similar to that described in Example 1, stage 2, from 5-iodopyrimidine-2-carboxylic acid tert-butylamide (Example 9, stage 2) and 1-ethynyl-3-fluorobenzene.

Example 11 5-(4-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide i) / i

AM d-

IS

Stage 1: 5-Bromopyrimidine-2-carboxylic acid tert-butylmethylamide i) dO

Vg M

The compound indicated in the title was obtained as a white precipitate, MO: t/e - 272.2/214 1

(MaANU), using a method similar to that described in Example 9, stage 1, with 5-bromopyrimidine-2-carboxylic acid and tert-butylmethylamine.

Stage 2: 5-Iodopyrimidine-2-carboxylic acid tert-butylmethylamide i) / es

Ha

The title compound was obtained as a white precipitate, M: m/e - 319.9 (M.--NU), using a method similar to that described in Example 9, stage 2, from 5-bromopyrimidine-2-carbon acid tert-butylmethylamide (Example 11, stage 1).

Stage 3: 5-(4-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide and) den

Her ki d-

IS

The title compound was obtained as a yellow precipitate, M: m/e - 312.3 (MAN), using a method similar to that described in Example 1, stage 2, from tert-butylmethylamide 5-iodopyrimidine-2-carboxylic acid (Example 11, stage 2) and 1-ethynyl-4-fluorobenzene.

Example 12 5-(3-Fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 6) / C

AM d- y

The title compound was obtained as a light brown precipitate, M: m/e - 312.2 (MaANU), using a method similar to that described in Example 1, stage 2, from 5-iodopyrimidine-2-carboxylic acid tert -butylmethylamide (Example 11, stage 2) and 1-ethynyl-3-fluorobenzene.

Example 13

B-m-Tolylethynylpyrimidine-2-carboxylic acid tert-butylamide i) иКиС

AM d-

The title compound was obtained as an orange oil, Me: m/e - 294.0 (MaANU, using a method similar to that described in Example 1, stage 2, from 5-iodopyrimidine-2-carboxylic acid tert-butylamide ( Example 9, stage 2) and 1-ethynyl-3-methylbenzene.

Example 14 5-(3-Chlorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide 6) / i

AM to

SI

From the compound indicated in the title, it was obtained in the form of a light yellow precipitate, Me: t/e -

314.0/316.0 (M--NU), using a method similar to that described in Example 1, stage 2, with

B-iodopyrimidine-2-carboxylic acid tert-butylamide (Example 9, stage 2) and 1-chloro-3-ethynylbenzene.

Example 15 5-(2,5-Difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 6) / C e M d-

IS

Stage 1: 5-Trimethylsilanylethynylpyrimidine-2-carboxylic acid tert-butylmethylamide i) / is z sho 5

The title compound was obtained as an orange precipitate, M5: m/e - 290.1 (MaANU, using a method similar to that described in Example 1, stage 2, from 5-iodopyrimidine-2-carboxylic acid tert-butylmethylamide ( Example 11, stage 2) and ethynyltrimethylsilane.

Stage 2: 5-(2,5-Difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 6) / i

E M d-

IS

The title compound was obtained as a light yellow precipitate, M5: m/e - 312.3 (MaANU, using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyrimidine-2-carboxylic acid tert- butylmethylamide (Example 15, stage 1) and 1,4-difluoro-2-iodobenzene.

Example 16 5-(5-Chloropyridin-3-ylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide 6) and

She m d-

M and -

SI

The title compound was obtained as a light yellow precipitate, Me: te - 329.0/331.2 (M--NU), using a method similar to that described in Example 3, stage 3, with

B-trimethylsilanylethynylpyrimidine-2-carboxylic acid tert-butylmethylamide (Example 15, stage 1) and 3-chloro-5-iodopyridine.

Example 17 5-(3-Fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide

/ ma s i d-

IS

Stage 1: 5-Bromo-3-methylpyridine-2-carboxylic acid tert-butylmethylamide i) dO

Hg 4

The title compound was obtained as a yellow oil, M: m/e - 285.0/286.9 (MANU), using a method similar to that described in Example 9, stage 1, from 5-bromo-3-methylpicolin acid and tert-butylmethylamine.

Stage 2: 5-(3-Fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide 6) / mass

IS

The title compound was obtained as a yellow precipitate, Me: m/e - 325.3 (MH), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-methylpyridine-2-carbon tert-butylmethylamide acid (Example 17, stage 1) and 1-ethynyl-3-fluorobenzene.

Example 18 5-(4-Fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide i) / ma s r d-x

IS

The title compound was obtained as a yellow precipitate, M: m/e - 325.3 (MAN), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-methylpyridine-2-carbon tert-butylmethylamide acid (Example 17, stage 1) and 1-ethynyl-4-fluorobenzene.

Example 19 5-(2,5-Difluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide i) / ma s

E - d-

IS

Stage 1: 3-Methyl-5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide i) / ma s r zv shdhO y x

The title compound was obtained as a brown precipitate, M: m/e - 303.0 (MANNU), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-methylpyridine-2-carbon tert-butylmethylamide acid (Example 17, stage 1) and ethynyltrimethylsilane.

Stage (2: 5-(2,5-Difluorophenylethynyl)-3-methylpyridine-2-carboxylic acid /-tert-butylmethylamide and) shop and

Uh-d-

IS

The title compound was obtained as a white precipitate, M5: m/e - 343.1 (M.-NU), using a method similar to that described in Example 3, stage 3, with 3-methyl-5-trimethylsilanylethynylpyridine- 2-carboxylic acid tert-butylmethylamide (Example 19, stage 1) and 1,4-difluoro-2-iodobenzene.

Example 20 5-(5-Chloropyridine-3-ylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide i) / ma Os r d-

M and I

SI

The title compound was obtained as a yellow precipitate, M5: m/e - 342.1/344.0 (MANNU), using a method similar to that described in Example 3, stage 3, with 3-methyl-5-trimethylsilanylethynylpyridine -2-carboxylic acid tert-butylmethylamide (Example 19, stage 1) and 3-chloro-5-iodopyridine.

Example 21

C-Fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 6) / m s

where d-

IS

Stage 1: 5-Bromo-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide i) te

ALL THAT

The title compound was obtained as a light yellow oil, M5: m/e - 288.9/290.9 (M--NU), using a method similar to that described in Example 9, stage 1, with

B-bromo-3-fluoropicolinic acid and tert-butylmethylamine.

Stage 2: 3-Fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide 6) / m s

where d-

IS

The title compound was obtained as a yellow oil, Me: m/e - 329.0 (MANNU),

using a method similar to that described in Example 1, stage 2, from tert-butylmethylamide 5-bromo-3-fluoropyridine-2-carboxylic acid (Example 21, stage 1) and 1-ethynyl-3-fluorobenzene.

Example 22

3-Fluoro-5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide i) / m. Os p - Y

IS

The title compound was obtained as a light yellow precipitate, Me: m/e - 329.1 (MANNU), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-fluoropyridine-2 -carboxylic acid tert-butylmethylamide (Example 21, stage 1) and 1-ethynyl-4-fluorobenzene.

Example 23 5-(2,5-Difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide i) / m. Os

E - E d-

IS

Stage 1: 3-Fluoro-5-trimethylsilanylethynylpyridine-2-carboxylic acid tert-butylmethylamide i) / ma s

DE zv --O 5

The title compound was obtained as a light yellow precipitate, Me: m/e - 307.3 (MANU), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-fluoropyridine-2 -carboxylic acid tert-butylmethylamide (Example 21, stage 1) and ethynyltrimethylsilane.

Stage 2: 5-(2,5-Difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide i) / me s

And where to

IS

The title compound was obtained as a light yellow precipitate, Me: m/e - 347.0 (MANU), using a method similar to that described in Example 3, stage 3, from 3-fluoro-5-trimethylsilanylethynylpyridine-2 -carboxylic acid tert-butylmethylamide (Example 23, stage 1) and 1,4-difluoro-2-iodobenzene.

Example 24 5-(5-Chloropyridin-3-ylethynyl)-3-fluoropyridin-2-carboxylic acid tert-butylmethylamide) / me s dit

MO 7 and »

SI

The title compound was obtained as a white precipitate, M5: m/e - 346.0/348.0 (MANNU), using a method similar to that described in Example 3, stage 3, with 3-fluoro-5-trimethylsilanylethynylpyridine -2-carboxylic acid tert-butylmethylamide (Example 23, stage 1) and 3-chloro-5-iodopyridine.

Example 25 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid cyclobutylmethylamides) i,

SHI r shdhE

IS

Stage 1: 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid iv) c; d.s

IS

The title compound was obtained as a light yellow precipitate, Me: m/e - 239.8 (M-NU, using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2-carboxylic acid of methyl ether and 1-ethynyl-3-fluorobenzene with subsequent saponification of GION.

Stage 2: 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid cyclobutylamide

IS

The title compound was obtained as a white precipitate, M5: m/e - 295.1 (Mae-NU, using a method similar to that described in Example 1, stage 1, with 5-(3-fluorophenylethynyl)pyridine- 2-carboxylic acid (Example 25, stage 1) and cyclobutanamine.

Stage 3: 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid cyclobutylmethylamides) i,

AI r dk

IS

The title compound was obtained as a light yellow oil, M: p/e - 309.1 (MANU, using a method similar to that described in Example 2, from 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid cyclobutylamide (Example 25, stage 2) and iodomethane.

Example 26 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid oxetan-3-ylamide o (c) m. Zh,

And d 2

IS

The title compound was obtained as a yellow precipitate, M5: m/e - 297.2 (MH), using a method similar to that described in Example 1, stage 1, with 5-(3-fluorophenylethynyl)/pyridine-2 -carboxylic acid (Example 25, stage 1) and oxetane-3-amine hydrochloride.

Example 27 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide about C in; r dkh y

Stage 1: 5-Bromopyridine-2-carboxylic acid (3-methyloxetan-3-yl)amide that is

In 4

The title compound was obtained as a light yellow precipitate, Me: te - 2711/2731 (MANNU), using a method similar to that described in Example 1, stage 1, with

B-bromopyridine-2-carboxylic acid and C-methyloxetane-3-amine.

Stage 2: 5-Bromopyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide c) with gu

She

In 4

The title compound was obtained as a white precipitate, M5: m/e - 285.0/286.9 (MANNU), using a method similar to that described in Example 2, from 5-bromopyridine-2-carboxylic acid (3Z -methyloxetan-3-yl)iamide (Example 27, stage 1) and iodomethane.

Stage 3: 5-(3-Fluorophenylethynyl)/pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amid o c a. r d-

IS

The title compound was obtained as a brown oil, M5: m/e - 325.3 (M-

NU), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2g-carboxylic acid methyl-(3-methyloxetan-3-ylamide (Example 27, stage 2) and 1-ethynyl-3-fluorobenzene .

Example 28 5-(4-Fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide) c and; r d-kh

IS

The title compound was obtained as a yellow oil, Me: m/e - 325.3 (M-NU), using a method similar to that described in Example 1, stage 2, from methyl 5-bromopyridine-2-carboxylic acid -(3-methyloxetane-3-ylamide (Example 27, stage 2) and 1-ethynyl-4-fluorobenzene.

Example 29 5-(2,5-Difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide and a.

E - shd-

IS

Stage 1: 5-Trimethylsilanylethynylpyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide c) c and; r chi -h! m

The title compound was obtained as a yellow precipitate, M5: m/e - 303.2 (M-NU), using a method similar to that described in Example 1, stage 2, from methyl 5-bromopyridine-2-carboxylic acid -(3-methyloxetane-3-ylamide (Example 27, stage 2) and ethynyltrimethylsilane.

Stage 2: 5-(2,5-Difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide and a.

E - shd-

IS

The title compound was obtained as a yellow oil, Me: m/e - 343.1 (MH), using a method similar to that described in Example 3, stage 3, from 5-trimethylsilanylethynylpyridine-2-carboxylic acid methyl-( 3-methyloxetan-3-yl)amide (Example 29, stage 1) and 1,4-difluoro-2-iodobenzene.

Example 30 5-(3,4-Difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amides) c y; p

E 4

IS

The title compound was obtained as a yellow oil, Me: m/e - 343.3 (MH), using a method similar to that described in Example 3, stage 3, from 5-

trimethylsilanylethynylpyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide (Example 29, stage 1) and 1,2-difluoro-4-iodobenzene.

Example 31 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide

GF) M. a. r sho

IS

Step 1: 5-Bromopyridine-2-carboxylic acid (1-methylcyclopropyl)amide

IF) HM.

Vg -4

The title compound was obtained as a colorless oil, M5: m/e - 255.0/257.0 (M--NU), using a method similar to that described in Example 1, stage 1, with

B-bromopyridine-2-carboxylic acid and 1-methylcyclopropanamine hydrochloride.

Step 2: 5-Bromopyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide

IF) HM.

Hg 4

The title compound was obtained as a colorless oil, M5: m/e - 269.1/271.1 (Manet), using a method similar to that described in Example 2, from 5-bromopyridine-2-carboxylic acid (1 -methylcyclopropyl)amide (Example 31, stage 1) and iodomethane.

Stage C: 5-(3-Fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide c)

AJ r to

IS

The title compound was obtained as a yellow oil, Me: m/e - 309.0 (M-NU), using a method similar to that described in Example 1, stage 2, from methyl 5-bromopyridine-2-carboxylic acid -(1-methylcyclopropyl)uamide (Example 31, stage 2) and 1-ethynyl-3-fluorobenzene.

Example 32 5-(4-Fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide

IF) M. and; p

IS

The title compound was obtained as a yellow oil, Me: m/e - 309.4 (M-NU), using a method similar to that described in Example 1, stage 2, from methyl 5-bromopyridine-2-carboxylic acid -(1-methylcyclopropyl)uamide (Example 31, stage 2) and 1-ethynyl-4-

From fluorobenzene.

Example 33 5-(3-Chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide

Zo

M Her and

ME

GA 1 ee p

IF)

Stage 1: 5-Bromopyridine-2-carboxylic acid (1-trifluoromethylcyclopropyl)amide

M. Y

IS

In 4

The title compound was obtained as a white precipitate, M5: m/e - 308.9/311.0 5 (MaNU), using a method analogous to that described in Example 1, stage 1, from 5-bromopyridine-2- carboxylic acid and 1-(trifluoromethyl)cyclopropanamine.

Stage 2: 5-Bromopyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amides)

E du

IS

In 4

The title compound was obtained as a colorless oil, M5: m/e - 323.0/325.1 (MaNU, using a method similar to that described in Example 2, from 5-bromopyridine-2-carboxylic acid (1- trifluoromethylcyclopropyl)amide (Example 33, stage 1) and iodomethane.

Stage C: 5-(3-Chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide

M Her R iz M E

And 1 in to a

The title compound was obtained as a brown oil, Me: m/e - 379.2/381.2 (M-NU), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2 -carboxylic acid methyl-(1-trifluoromethylcyclopropyl)uamide (Example 33, stage 2) and 1-ethynyl-3-chlorobenzene.

Example 34

B-m-Tolylethynylpyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide c)

IS

M

F g r E St

The title compound was obtained as a brown oil, M5: m/e - 359.0 (M-

NU), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2g-carboxylic acid methyl-(1-trifluoromethylcyclopropylamide (Example 33, stage 2) and 1-ethynyl-3-methylbenzene.

Example 35 (2,2-Dimethylmorpholin-4-yl)-(5-(3-fluorophenylethynyl)pyridin-2-yl|methanone

(in)

M - - where to

IS

The title compound was obtained as a yellow precipitate, M: m/e - 339.3 (M.N), using a method similar to that described in Example 1, stage 1, from 5-(3-fluorophenylethynyl)pyridine- 2-carboxylic acid (Example 25, stage 1) and 22-dimethylmorpholine.

Example 36

15-(2,5-Difluorophenylethynyl)pyridin-2-yl|-(2,2-dimethylmorpholin-4-yl)umethanone (c)

E d So to

IS

Stage 1: (5-Bromopyridin-2-yl)-(2,2-dimethylmorpholin-4-yl)umethanone (c)

SE

-- So

Ve

The title compound was obtained as a colorless oil, M5: m/e - 299.2/301.1 (M-NU), using a method similar to that described in Example 1, stage 1, with

B-bromopyridine-2-carboxylic acid and 2,2-dimethylmorpholine.

Stage 2: (2,2-Dimethylmorpholin-4-yl)-(5-trimethylsilanylethynylpyridin-2-yl)umethanone (c) renez y- So zv s y |! h

The title compound was obtained as a yellow oil, M5: m/e - 317.1 (M-NU), using a method similar to that described in Example 1, stage 2, from (5-bromopyridin-2-yl) -(2,2-dimethylmorpholin-4-yl)methanone (Example 36, stage 1) and ethynyltrimethylsilane.

Stage 3: (5-(2,5-Difluorophenylethynyl)pyridin-2-yl|-(2,2-dimethylmorpholin-4-yl)umethanone (c) ee

E ra So dO

R

The title compound was obtained as a yellow oil, Me: m/e - 357.1 (MAN), using a method similar to that described in Example 3, step 3, from (2,2-dimethylmorpholin-4-yl) -(5-trimethylsilanylethynylpyridin-2-yl)umethanone (Example 36, stage 2) and 1,4-difluoro-2-iodobenzene.

Example 37

I5-(3-Fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-4-methylpiperidin-1-yl)-methanone

(c) a; d to o

IS

Stage 1: 1-(5-Bromopyridine-2-carbonyl)/piperidin-4-one and)

Vg 4 o

The title compound was obtained as a white precipitate, M5: m/e - 283.0/285.0 (MaANU, using a method similar to that described in Example 1, stage 1, from 5-bromopyridine-2-carboxylic acid and piperidin-4-one hydrochloride.

Stage 2: (5-Bromopyridin-2-yl)-(4-hydroxy-4-methylpiperidin-1-yl)methanone (c)

Bg -4 o 1-(5-Bromopyridine-2-carbonyl)piperidin-4-one (Example 37, stage 1) (135 mg, 0.48 mmol) was dissolved in THF (3 ml) and the mixture was cooled to 0-5 "C. 3M methylmagnesium bromide (190 μl, 0.57 mmol, 1.2 equiv.) was added dropwise at 0-5 7C and the mixture was stirred for 2 hours at 0-5 76.

The reaction mixture was extracted with a saturated solution of MNACI and twice with ethyl acetate. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a 20 g silica gel column, eluting with a mixture of heptane/ethyl acetate 100:0 -» 0:100. The desired (5-bromopyridin-2-yl)-(4-hydroxy-4-methylpiperidin-1-ylumethanone) (35 mg, 25 95 yield) was obtained as a colorless oil, Me: m/e - 299.2/3011 (MAN ).

Stage 3: (5-(3-Fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-4-methylpiperidin-1-yl)umethanone (c) a; d sa o

IS

The title compound was obtained as a brown oil, M5: m/e - 339.3 (M-

NU, using a method similar to that described in Example 1, stage 2, with (5-bromopyridin-2-yl)-(4-hydroxy-4-methylpiperidin-1-yl)umethanone (Example 37, stage 2) and 1- ethynyl-3-fluorobenzene.

Example 38.

Stage 1: (K5)-(5-Bromopyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone and)

Vg 4 o

The compound indicated in the title was obtained as a white precipitate, MO: t/e - 314 4 (MaeNU,, with

Using a method similar to that described in Example 9, stage 1, with 5-bromopyridine-2-

carbonyl chloride and (K5)-2,2-dimethylpiperidin-4-ol (SAZ 937681-12-4).

Stage 2: (K5)-(4-Hydroxy-2,2-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-yl)umethanone c) and d to c);

The title compound was obtained as a white precipitate, M5: m/e - 335.4 (M-NU), using a method similar to that described in Example 1, stage 2, from (H5)-(5-bromopyridine) - 2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (Example 38, stage 1) and phenylacetylene.

Example 39 (n85)-(4-Hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-yl)y-methanone c) two and where c);

Stage 1: (K5)-(5-Bromopyridin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-methanone (c)

Be -4 c)

The title compound was obtained as a white precipitate, M5: m/e - 314.2 (M-NU), using a method similar to that described in Example 1, stage 1, from 5-bromopyridine-2-carboxylic acid and (K5)-3,3-dimethylpiperidin-4-ol (SAZ 373603-88-4).

Stage 2: (K5)-(4-Hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-yl)umethanone c) rve d zh c);

The title compound was obtained as a colorless oil, M5: m/e - 335.4 (M-

NU, using a method similar to that described in Example 1, stage 2, with (H5)-(5-bromopyridin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-ylumethanone) (Example 39, stage 1 ) and phenylacetylene.

Example 40 (85)-I(5-(4-Fluorophenylethynyl)pyridin-2-ylI|-(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone (c) oda and dk c)

IS

The title compound was obtained as a light yellow precipitate, Me: m/e - 353.3 (M-NU), using a method similar to that described in Example 1, stage 2, from (H85)-(5- bromopyridin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone (Example 39, stage 1) and 1-ethynyl-4-fluorobenzene.

Example 41 (85)-I(5-(3-Fluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone

(in)

Rava d dk c)

IS

The title compound was obtained as a yellow oil, M5: m/e - 353.3 (M-NU), using a method similar to that described in Example 1, stage 2, from (H5)-(5-bromopyridine- 2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)umethanone (Example 39, stage 1) and 1-ethynyl-3-fluorobenzene.

Example 42

3-Fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amides) le vya d de E

IS

Stage 1: 5-Bromo-3-fluoropyridine-2-carboxylic acid (1-methylcyclopropyl)amide and) to

ALL of the compounds indicated in the title were obtained as a white precipitate, with t/e - ,; ,; (o; and bi M: tu/ 2731/2751 (MANU), using a method similar to that described in Example 1, stage 1, with 5-bromo-3-fluoropyridine-2-carboxylic acid and 1-methylcyclopropanamine hydrochloride.

Stage 2: 5-Bromo-3-fluoropyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide and)

To

The VE compound indicated in the title was obtained as a white precipitate, with t/e - ,; ,; (o; and bi M5: tu/ 286.9/288.9 (MaANU, using a method similar to that described in Example 2, from 5-bromo-3-fluoropyridine-2-carboxylic acid (1-methylcyclopropyl)luamide (Example 42, stage 1) and iodomethane.

Stage C: 3-Fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amides) le vy d de E

IS

The title compound was obtained as a yellow oil, Me: m/e - 327.3 (M-NU), using a method similar to that described in Example 1, stage 2, from 5-bromo-3-fluoropyridine-2 -carboxylic acid methyl-(1-methylcyclopropyl)amide (Example 42, stage 2) and 1-ethynyl-3-fluorobenzene.

Example 43

C-Chloro-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide c) lek d de (o)

Stage 1: 5-Bromo-3-chloropyridine-2-carboxylic acid tert-butylmethylamides)

Goa

Ve-4 SI

The title compound was obtained as a yellow oil, M: m/e - 304.9/307.0 (MANNU), using a method similar to that described in Example 1, stage 1, from 5-bromo-3-chloropyridine -2-carboxylic acid and tert-butylmethylamine.

Stage 2: 3-Chloro-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide c) whether and where (o)

The title compound was obtained as an orange precipitate, Me: m/e - 327.1/329.0 (M-NU), using a method similar to that described in Example 1, stage 2, with 5-bromo-3 -chloropyridine-2-carboxylic acid tert-butylmethylamide (Example 43, stage 1) and phenylacetylene.

Example 44 5-(3-Fluorophenylethynyl)pyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide (c)

IS

M

IN,

AM E d-

IS

Stage 1: 5-Bromopyrimidine-2-carboxylic acid (1-trifluoromethylcyclopropyl)amide

M. Y

Ve a

The title compound was obtained as a yellow precipitate, Me: m/e - 310.0/312.0 (MaANU, using a method similar to that described in Example 1, stage 1, from 5-bromopyrimidine-2-carboxylic acid and 1-(trifluoromethyl)cyclopropanamine.

Stage 2: 5-Bromopyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amides)

And lions

IS

Ve a

The title compound was obtained as a white precipitate, MO: m/e - 324.0/326.1 (MANU), using a method similar to that described in Example 2, from 5-bromopyrimidine-2-carboxylic acid (1 -trifluoromethylcyclopropyl)amide (Example 44, stage 1) and iodomethane.

Stage C: 5-(3-Fluorophenylethynyl)pyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide

M Her and ka dy ru AM E xx

IS

The compound indicated in the title was obtained as a brown precipitate, Me: m/e - 364.1 (M-

NU, using a method similar to that described in Example 1, stage 2, from 5-bromopyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)uamide (Example 44, stage 2) and 1-ethynyl-3-fluorobenzene.

Example 45 (3,3-Difluoroazetidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanones) direct

AM

2 E

Stage 1: 5-Phenylethynylpyrimidine-2-carboxylic acid iv) cher ru AM o

The title compound was obtained as a white precipitate, M5: m/e - 222.8 (M-NU, using a method similar to that described in Example 25, stage 1, from 5-bromopyrimidine-2-carboxylic acid.

Stage 2: (3,3-Difluoroazetidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)methanone iv) rom.

AM

2 E

The title compound was obtained as a brown precipitate, M: t/e - 300.2 (MaANU), using a method similar to that described in Example 1, stage 1, from 5-phenylethynylpyrimidine-2-carboxylic acid (Example 45 , stage 1) and 3,3-difluoroazetidine hydrochloride.

Example 46 (3,3-Dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanones) chr AM xx

The title compound was obtained as an orange oil, Me: m/e - 320.4 (MaANU, using a method similar to that described in Example 1, stage 1, from 5-phenylethynylpyrimidine-2-carboxylic acid (Example 45, stage 1) and 3,3-dimethylpiperidine.

Example 47 (85)-(4-Hydroxy-2,2-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone c) a

AM and Fr

Stage 1: (K5)-(5-Bromopyrimidin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)-methanone and)

In AM Fr

The title compound was obtained as a white precipitate, M5: m/e - 315.2 (M-NU), using a method similar to that described in Example 9, stage 1, from 5-bromopyrimidine-2-carboxylic acid and (K5)-2,2-dimethylpiperidin-4-ol (SAZ 937681-12-4).

Stage 2: (K5)-(4-Hydroxy-2,2-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone c) a

Am you and

The title compound was obtained as a white precipitate, M5: m/e - 336.2 (M-NU, using a method similar to that described in Example 1, stage 2, with (H5B)-(5-bromopyrimidine- 2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-ylomethanone (Example 47, stage 1) and phenylacetylene.

Example 48 (85)-(4-Hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)-methanone b)

SS dm and o

Stage 1: (K5)-(5-Bromopyrimidin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-methanone (c)

Vg a iv)

The title compound was obtained as a white precipitate, M5: m/e - 315.4 (M--NU), using a method similar to that described in Example 1, stage 1, from 5-bromopyrimidine-2-carboxylic acid and (K5)-3,3-dimethylpiperidin-4-ol (SAZ 373603-88-4).

Stage 2: (K5)-(4-Hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone c) ve

AM you and

The title compound was obtained as a brown precipitate, M: m/e - 336.2 (M-

NU, using a method similar to that described in Example 1, stage 2, with (H5)-(5-bromopyrimidin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-ylumethanone) (Example 48, stage 1 ) and phenylacetylene.

Example 49 (85)-(5-(3-Fluorophenylethynyl)pyrimidin-2-yl|-(4-hydroxy-3,3-dimethylpiperidin-1-ylumethanone)

(c) vve

AM si o

IS

The title compound was obtained as a light yellow precipitate, MO: m/e - 354.3 (M-NU), using a method similar to that described in Example 1, stage 2, from (H85)-(5- bromopyrimidin-2-yl)-(4-hydroxy-3,3-dimethylpiperidin-1-ylumethanone) (Example 48, step 1) and 1-ethynyl-3-fluorobenzene.

Example 50

C-Fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(C-methyloxetan-3-yl)amido o c c

Where is it?

Stage 1: 3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid iv) more; and d-

The title compound was obtained as a yellow precipitate, M5: m/e - 239.8 (M-NU), using a method similar to that described in Example 25, stage 1, from 5-bromo-3-fluoropyridine-2 -carboxylic acid.

Stage 2: 3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid (3-methyloxetan-3-yl)amide about C a; -d de E

The title compound was obtained as a light yellow precipitate, Me: m/e - 311.2 (MANNU), using a method similar to that described in Example 1, stage 1, with 3-fluoro-5-phenylethynylpyridine-2 -carboxylic acid (Example 50, stage 1) and 3-methyloxetane-3-amine.

Stage 3: 3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide about sg c. d de E

The title compound was obtained as a light yellow semisolid,

M: t/e - 325.4 (MaANU), using a method similar to that described in Example 2, with 3-fluoro-5-phenylethynylpyridine-2-carboxylic acid (3-methyloxetane-3-ylamide (Example 50, stage 2 ) and iodomethane.

Example 51 (85)-3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)amide

Lee E

M schi in a: p

Stage 1: (K5)-3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide 7 E

M u

ESSAY

YO to

The title compound was obtained as a light yellow precipitate, Me: m/e - 337.1 (MANNU), using a method similar to that described in Example 1, stage 1, with 3-fluoro-5-phenylethynylpyridine-2 -carboxylic acid (Example 50, stage 1) and (85)-1,1,1-trifluoropropan-2-amine hydrochloride.

Stage 2: (K5)-3-Fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)amide o E

Masses: St

The title compound was obtained as a light yellow oil, Me: m/e - 351.3 (MaNU), using a method similar to that described in Example 2, from (H5)-3-fluoro-5-phenylethynylpyridine- 2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide (Example 51, stage 1) and iodomethane.

Example 52

C3-Cyano-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide

GF) M.; d - M

Stage 1: 3-Bromofuro!Y3,4-b|pyridine-5, 7-dione c)

M

J

Ve o

A suspension of 5-bromopyridine-2,3-dicarboxylic acid (700 mg, 2.85 mmol) in acetic anhydride (0.88 mL, 9.39 mmol, 3.3 equiv.) was heated at 80 °C for 10 min and then refluxed for 1 hour. Acetic anhydride was evaporated under vacuum.

The resulting precipitate was triturated with hexane to give 3-bromofuroyl3,4-b|pyridine-5,7-dione (510 mg, 7995) as a gray-white precipitate.

Stage 2: 5-Bromopyridine-2,3-dicarboxylic acid 2-isopropyl ether (6) ХУ p:

VI where iv) iv)

Ma(SiO4)2 (235 mg, 1.053 mmol, 1, 2 eq.) and the reaction mixture was stirred for 5 min at this temperature. Then isopropanol (b ml) was added and the reaction mixture was stirred at 25 "C for 16 hours. Volatile components were removed under vacuum and the resulting residue was dissolved in EAs (30 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Mag50O, filtered and evaporated under vacuum. The crude material obtained in this way was purified by column chromatography over normal silica gel (30-5095 BEUAs/hexane) to give 5-bromopyridine-2,3-dicarboxylic acid 2-isopropyl ether (210 mg, 83.195) as a light brown precipitate, MO : t/e - 286.0 (M-NU).

Stage 3: 5-Bromo-3-cyanopyridine-2-carboxylic acid isopropyl ether c) ura d " Zm

To a solution of 5-bromopyridine-2,3-dicarboxylic acid 2-isopropyl ether (630 mg, 2.187 mmol) in pyridine (8 ml) at 0 "C was added methanesulfonyl chloride (0.34 ml, 4.37 mmol, 2 equiv.) and the reaction mixture was stirred for 1 hour at 25 "С. Then gaseous MH3 was passed through the reaction mixture at 0 "C and stirred at 25 "C for 30 minutes. Excess MH3 was evaporated under vacuum. The reaction mixture was cooled to 0 °C, fresh methanesulfonyl chloride (1.35 mL, 17.49 mmol, 8 equiv) was added dropwise to the mixture and stirring was continued at 25 °C for an additional 16 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO 3 (20 mL) and extracted with EtOAc (2x40 mL). The combined organic layers were dried over anhydrous Mag5O4 and evaporated under reduced pressure to dryness. The resulting crude material was purified by column chromatography over normal silica gel (1095 EtOAc in hexane) to give 5-bromo-3-cyanopyridine-2-carboxylic acid isopropyl ether (320 mg, 54965) as a yellow oil.

Stage 4: 5-Bromo-3-cyanopyridine-2-carboxylic acid (iv)

In 4 B

Lithium hydroxide monohydrate (32.75 mg, 0, 78 mmol, C equiv.). The reaction mixture was stirred for 2 hours at 25 "C. The mixture was acidified with a 2N aqueous solution of NOSI (pH 5) and extracted with EAs (2x15 ml). The combined organic layers were dried over anhydrous Mag25O4 and evaporated under reduced pressure to dryness to obtain 5-

From bromo-3-cyanopyridine-2-carboxylic acid (45 mg, 7695) as a yellow precipitate, which was used in the next step without further purification.

Stage 5: 5-Bromo-3-cyanopyridine-2-carboxylic acid tert-butylmethylamide c) dO

Hg 4 BO

To a solution of 5-bromo-3-cyanopyridine-2-carboxylic acid (100 mg, 0.44 mmol) in dichloromethane (5 ml) at 0 "С was added OIREA (0.226 ml, 1.32 mmol, 3 equiv.), methyl -tert-butylamine (0.079 mL, 0.661 mmol, 1.5 equiv.) and NVTI (250 mg, 0.661 mmol, 1.5 equiv.). The reaction mixture was stirred at 25 "C for 14 hours. The solvent was removed in vacuo and the resulting crude residue was purified by column chromatography over normal silica gel (10-2095 Es in hexane) to give tert-butylmethylamide 5-bromo-3-cyanopyridine-2-carboxylic acid (85 mg, 6595) as a colorless oil.

Stage 6: 3-Cyano-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide c)

Ge as dOtek

The title compound was obtained as a light brown precipitate, M: t/e -

318.0 (M-NU), using a method similar to that described in Example 1, stage 2, with tert-butylmethylamide 5-bromo-3-cyanopyridine-2-carboxylic acid (Example 52, stage 2) and phenylacetylene.

Example 53 5-(5-Chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide c)

IS

M. / E

IA Te dYYA

MO 7 and 2 (o)

The title compound was obtained as a light yellow precipitate, Me: te - 380.3/382.3 (M-NU), using a method similar to that described in Example 1, stage 2, with 5-bromopyridine-2 -carboxylic acid methyl-(1-trifluoromethylcyclopropyl)uamide (Example 33, stage 2) and 3-chloro-5-ethynylpyridine.

Example 54 5-(2-Chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide

I E le o, r E sh

And that

Stage 1: 5-Bromopyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide

M. I. and Gu" g

In 4

The title compound was obtained as a colorless oil, M5: m/e - 3112/3132 (MANNU), using a method similar to that described in Example 1, stage 1, with

B-bromopyridine-2-carboxylic acid and 1,1,1-trifluoro-2-methylpropan-2-amine.

Stage 2: 5-(2-Chloropyridin-4-ylethynyl)/upyridin-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (c)

ME

- oh

J-E E

ZhdZhshchyV

SI St" and

Ma

The title compound was obtained as a yellow oil, M: m/e - 368.4/370.4 (M-NU, using a method similar to that described in Example 3, stage 3, with 5-bromopyridine-2- carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (Example 54, stage 1) and 2-chloro-4-trimethylsilanylethynylpyridine.

Example 55 5-(5-Chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide c)

E with "o, y:

DV

SI and n-

M

Stage 1: 5-(5-Chloropyridine-3-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide

DI E le U, ro E do

SI and n-

M

The compound indicated in the title was obtained as a white precipitate, MO: m/e - 368.3/370.4 (M-

NU), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (Example 54, stage 1) and C -chloro-5-ethynylpyridine.

Stage 2: 5-(5-Chloropyridin-3-ylethynyl)/upyridin-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide 9 E

That in

IA) in b

SI and l

M

The title compound was obtained as a white precipitate, MO: m/e - 382.3/384.3 (MANNU), using a method similar to that described in Example 2, from 5-(5-chloropyridin-3-ylethynyl )upiridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (Example 55, stage 1) and iodomethane.

Example 56 5-(3-Chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide

M L and 5 ME

IA 1 in si p

Stage 1: 5-(3-Chlorophenylethynyl)/pyridine-2-carboxylic acid/(2,2,2-trifluoro-1,1-dimethylethyl)amide (c)

ME

- oh

Zh-E E si p

The title compound was obtained as a light yellow precipitate, Me: m/e - 367.3/369.3 (M-NU), using a method similar to that described in Example 1, stage 2, from 5-bromopyridine -2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (Example 54, stage 1) and 3-chlorophenylacetylene.

Step 2: 5-(3-Chlorophenylethynyl)/pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide

M L and with ME

IA 1 in si p

The title compound was obtained as a light yellow oil, M5: m/e - 381.4/383.3 (MANNU), using a method similar to that described in Example 2, from 5-(3-chlorophenylethynyl)pyridine -2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (Example 56, stage 1) and iodomethane.

Example 57

(85)-5-(2-Chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide

E and -a ro E

WITH.

AND

M. 2

Stage 1: (K5)-5-Bromopyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amides)

Huh

IS

Be -4

The title compound was obtained as a colorless oil, M5: mp - 2972/2992. (M--NU), using a method similar to that described in Example 1, stage 1, with

B-bromopyridine-2-carboxylic acid and (K5)-1,1,1-trifluoropropan-2-amine.

Stage 2: (K5)-5-(2-Chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide

And E and: "I, - E sl

M. a

The title compound was obtained as a light yellow precipitate, Me: te - 354.3/356.3 (M-NU), using a method similar to that described in Example 3, stage 3, from (85)-5 -bromopyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide (Example 57, stage 1) and 2-chloro-4-trimethylsilanylethynylpyridine.

Example 58 5-(2-Chloropyridin-4-ylethynyl)pyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (c)

M E u,

M ER sl

AND

M. a

Stage 1: 5-Bromopyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide (c)

IS

IS

Ve a

The title compound was obtained as a light yellow precipitate, Me: te - 3122/3142 (MANNU), using a method similar to that described in Example 1, stage 1, with

B-bromopyrimidine-2-carboxylic acid and 1,1,1-trifluoro-2-methylpropan-2-amine.

Step 2: 5-(2-Chloropyrimidine-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide

E and, ru AM E

SI and

AND

M.

The title compound was obtained as a brown precipitate, Me: m/e - 369.3/371.2 (M-NU), using a method similar to that described in Example 3, stage 3, with 5-

From bromopyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)iamide (Example 58,

stage 1) and 2-chloro-4-trimethylsilanylethynylpyridine.

Example 59 (8)- or (5)-5-(2-Chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide a: chiral a chiral

EE E

M

- MA | t "u, - E to no or -

SI same: t si st y

M. - M. w-

The title compound, white precipitate, M: m/e - 354.3/356.3 (МН), was obtained by the separation of (H5)-5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid ( 2,2,2-trifluoro-1-methylethyl)amide (Example 57) using a chiral column (Kergozviei spiga! ME with a mixture of heptane:isopropanol 80:20 as a solvent).

Example 60 (5)- or (K)-5-(2-Chloropyridin-4-ylethynyl)upyridin-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amido r bal a : r val m : and i- "U, | - MO shE still -e or that

SI s de SI sh- ay

M. sh-e M. --

The compound indicated in the title, white precipitate, M: m/e - 354.3/356.3 (Ma-NU), was obtained by separation of (H5)-5-(2-chloropyridin-4-ylethynyl)pyridine-2-carbon acid (2,2,2-trifluoro-1-methylethyl)amide (Example 57) using a chiral column (Kergozbii spiga! ME with a mixture of heptane:isopropanol 80:20 as a solvent).

Example 61 (85)-5-(3-Chlorophenylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amides)

E y -a ro E si s

The title compound was obtained as a light yellow precipitate, Me: te - 353.3/355.3 (M-NU), using a method similar to that described in Example 1, stage 2, from (85)-5 -bromopyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide (Example 57, stage 1) and 3-chlorophenylacetylene.

Example 62 (85)-5-(3-Chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)amide 9 E

That and

GA ee si sv

The title compound was obtained as a colorless oil, M: m/e - 367.3/369.2 (M.--NU), using a method similar to that described in Example 2, from (85)-5- (3-chlorophenylethynyl)/pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide (Example 61) and iodomethane.

Example 63 (85)-I(5-(3-Fluorophenylethynyl)pyridin-2-ylI|-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone

(c) ovi d

E sp

The title compound was obtained as a light yellow precipitate, Me: m/e - 353.4 (MaNU), using a method similar to that described in Example 1, stage 1, from 5-(3-fluorophenylethynyl)pyridine- 2-carboxylic acid (Example 25, stage 1) and (H85)-2,2-dimethylpiperidin-4-ol (СА5 937681-12-4).

Example 64 (85)-I(5-(2,5-Difluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanones) and

E - J's)

IS

The title compound was obtained as a light yellow precipitate, Me: m/e - 371.4 (M-NU), using a method similar to that described in Example 1, stage 2, from (H85)-(5- bromopyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-ylumethanone) (Example 38, stage 1) and 2,5-difluorophenylacetylene.

Example 65 (85)-(5-(3-Fluorophenylethynyl)pyrimidin-2-ylI-(4-hydroxy-2,2-dimethylpiperidin-1-ylumethanone) (c) ha

AM with (in)

Stage 1: (K5)-(5-Bromopyrimidin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (c)

You r o

The title compound was obtained as a white precipitate, MO: m/e - 314.4/316.3 (MaANU, using a method similar to that described in Example 1, stage 1, from 5-bromopyrimidine-2-carboxylic acid and (K5)-2,2-dimethylpiperidin-4-ol (SAZ 937681-12-4).

Stage 2: (K5)-(5-(3-Fluorophenylethynyl)pyrimidin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (c) ha

AM

The title compound was obtained as a light yellow precipitate, MO: m/e - 354.4 (M-NU), using a method similar to that described in Example 1, stage 2, from (H85)-(5- bromopyrimidin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-ylumethanone) (Example 65, step 1) and

C-fluorophenylacetylene.

Example 66 (85)-I(5-(2,5-Difluorophenylethynyl)pyrimidin-2-yl|-(4-hydroxy-2,2-dimethylpiperidine-1-

From il)umethanon iv) ha

E. M. and o

IS

The title compound was obtained as a yellow precipitate, M: m/e - 372.4 (M-NU, using a method similar to that described in Example 1, stage 2, with (H5B)-(5-bromopyrimidine- 2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-ylomethanone (Example 65, stage 1) and 2,5-difluorophenylacetylene.

Example 67 (85)-III-Fluoro-5-(3-fluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (c) and d

E dk E (6)

Stage 1: (K5)-(5-Bromo-3-fluoropyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone (c) "in a: o

The title compound was obtained as a yellow oil, M: m/e - 331.2/333.2 (MANNU), using a method similar to that described in Example 1, stage 1, from 5-bromo-3-fluoropyridine -2-carboxylic acid and (K5)-2,2-dimethylpiperidin-4-ol (СА5 937681-12-4).

Stage 2: (K5)-III-Fluoro-5-(3-fluorophenylethynyl)pyridin-2-yl|-(4-hydroxy-2,2-dimethylpiperidin-1-ylumethanone) (c) av d

E de E iv)

The title compound was obtained as a yellow oil, Me: m/e - 371.4 (M-NU), using a method similar to that described in Example 1, stage 2, with (H85)-(5-bromo- 3-fluoropyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanone (Example 67, stage 1) and 3-fluorophenylacetylene.

Example 68 (85)-(5-(2,5-Difluorophenylethynyl)-3-fluoropyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)umethanones) 5

E - where E's)

IS

The title compound was obtained as a yellow precipitate, M: m/e - 389.4 (M-NU), using a method similar to that described in Example 1, stage 2, from (A5)-(5-bromo- 3-fluoropyridin-2-yl)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone (Example 67, stage 1) and 2,5-difluorophenylacetylene.

Coo)

Claims (16)

FORMULA OF THE INVENTION 1. The compound of the formula (c) V in mass and r, 2 ku I where M denotes M or C-83; WZ denotes hydrogen, methyl, halogen or nitrile; B denotes phenyl or pyridinyl, which may be substituted by halogen, C:-4-alkyl or C:-4-alkyl; B2/A? independently of each other denote hydrogen, C:-4-alkyl or C--alkyl substituted by halogen, or B: and B", together with the M atom to which they are attached, can form a morpholine ring, a piperidine ring or an azetidine ring, which are unsubstituted or substituted by one or more substituents selected from C:-4-alkyl, halogen, hydroxy or methyl; BBA? independently of each other denote hydrogen or C-4-alkyl, or B" and B" together form C3- 5-cycloalkyl, tetrahydrofuran or oxetane ring; or a pharmaceutically acceptable acid addition salt, racemic mixture or corresponding enantiomer and/or optical isomer, and/or stereoisomer thereof. 2. The compound of formula A according to claim 1 (c) и» X and DU 2 M LA where M denotes M or C-83; WZ denotes hydrogen, methyl, halogen or nitrile; B' denotes phenyl or pyridinyl, which may be substituted by halogen, C:-4-alkyl or C:-4-alkoxy; or its pharmaceutically acceptable acid addition salt, racemic mixture or corresponding enantiomer and/or optical isomer, and/or stereoisomer. 3. The compound of formula IA according to any of claim 1 or claim 2, which is selected from the group including: B-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; Zo 5-(2,5-difluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; B-pyridin-3-ylethynylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-fluoropyridin-3-ylethynyl)/pyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; C-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; C-fluoro-5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide; C-chloro-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide; C-cyano-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide. 4. The compound of formula I according to claim 1, where B' denotes phenyl, possibly substituted by halogen. 5. The compound of formula I according to any of claims 1 or 4, which is selected from the group including: B-phenylethynylpyridine-2-carboxylic acid tert-butylamide; B-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide; 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide; 5-(4-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; B-m-tolylethynylpyrimidine-2-carboxylic acid tert-butylamide; 5-(3Z-chlorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylamide; 5-(2,5-difluorophenylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(4-fluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; C-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; C-fluoro-5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(2,5-difluorophenylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid cyclobutylmethylamide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid oxetane-3-ylamide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide; 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide; 5-(2,5-difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide; 5-(3,4-difluorophenylethynyl)pyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl)amide; 5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide; 5-(4-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)amide; Zo 5-(33-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)-amide; B-m-tolyethynylpyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide; (2,2-dimethylmorpholin-4-yl)-15-(3-fluorophenylethynyl)pyridin-2-yl|methanone; 15-(2,5-difluorophenylethynyl)pyridin-2-yl1-(2,2-dimethylmorpholin-4-yl)umethanone; I5-(3-fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-4-methylpiperidin-1-yl)umethanone; (85)-(4-hydroxy-2,2-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-yl)umethanone; (85)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyridin-2-yl)umethanone; (85)-I(5-(4-fluorophenylethynyl)pyridin-2-ylI-(4-hydroxy-3,3-dimethylpiperidin-1-yl)methanone; (85)-I5-(3-fluorophenylethynyl)pyridin-2 -yl1-(4-hydroxy-3,3-dimethylpiperidin-1-yl)methanone; 3-fluoro-5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid methyl-(1-methylcyclopropyl)-amide; 3-chloro -5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(3-fluorophenylethynyl)pyrimidine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)-amide; (3,3-difluoroazetidin-1-yl)-(5 -phenylethynylpyrimidin-2-yl)umethanone; (3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone; (85)-(4-hydroxy-2,2-dimethylpiperidin-1-yl) )-(5-phenylethynylpyrimidin-2-yl)umethanone; (85)-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-(5-phenylethynylpyrimidin-2-yl)umethanone; (85)-I5- (3-fluorophenylethynyl)pyrimidin-2-yl|-(4-hydroxy-3,3-dimethylpiperidin-1-ylumethanone; 3-fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(3-methyloxetan-3-yl) amide; (85)-3-fluoro-5-phenylethynylpyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)-amide; 3-cyano no-5-phenylethynylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(33-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)-amide; (85)-5-(3-chlorophenylethynyl)pyridine-2-carboxylic acid /(2,2,2-trifluoro-1-methylethyl)amide; (85)-5-(3-chlorophenylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methylethyl)amide. 6. Compound of formula I according to claim 1, where B! denotes pyridinyl, possibly substituted by halogen. 7. The compound of formula I according to any of claims 1 or 6, which is selected from the group including: B-pyridin-3-ylethynylpyridine-2-carboxylic acid tert-butylmethylamide; bo 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-fluoropyridin-3-ylethynyl)/pyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)pyrimidine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)-3-methylpyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)-3-fluoropyridine-2-carboxylic acid tert-butylmethylamide; 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid methyl-(1-trifluoromethylcyclopropyl)amide; 5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)-amide; 5-(5-chloropyridin-3-ylethynyl)pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethylethyl)amide; (85)-5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide; 5-(2-chloropyridin-4-ylethynyl)pyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethylethyl)amide; (Y) or (5)-5-(2-chloropyridin-4-ylethynyl)/pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide; (55 or (5)-5-(2-chloropyridin-4-ylethynyl)pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methylethyl)amide. 8. The method of obtaining the compound of the formula | according to claim 1, according to which: the interaction of the compound of formula (c) is carried out; kv ma sa y ry М АХ b with a suitable compound of the formula - Nai 7 with the formation of a compound of the formula (c) In m ra sa and DU i, dp ku I where the substituents are defined in claim 1, and, if necessary, convert the obtained the compound of formula I to a pharmaceutically acceptable acid addition salt. Zo 9. The method of obtaining the compound of formula I according to claim 1, according to which: the compound of formula (c) is reacted with a suitable compound of formula p 4 B 4 Z5 with the formation of a compound of formula 5O0 (c) kv m a a M v2 r, U v where the substituents are defined in claim 1, and, if necessary, convert the obtained compound of formula I into a pharmaceutically acceptable acid addition salt. 10. The method of obtaining the compound of the formula I according to claim 1, according to which: the interaction of the compound of the formula (c) M y: on U ku ku 9 with a suitable compound of the formula Hera Shchiik r v 2 is carried out with the formation of the compound of the formula (c) B v m a t M p2 DDAI in ku I where the substituents are defined in claim 1, and, if necessary, convert the obtained compound of formula I into a pharmaceutically acceptable acid addition salt. 11. A compound according to any of claims 1-7 for use as a therapeutically active substance. 12. A pharmaceutical composition containing a compound according to any one of claims 1-7 and a therapeutically active carrier. 13. Use of the compound according to any one of claims 1-7 for the treatment of schizophrenia or cognitive disorders. 14. Use of the compound according to any of claims 1-7 in the manufacture of a medicinal product for the treatment of schizophrenia or cognitive disorders. 15. A compound according to any one of claims 1-7 for the treatment of schizophrenia or cognitive disorders. 16. A method of treating schizophrenia or cognitive disorders, in which the subject is administered an effective amount of the compound according to any one of claims 1-7.