HK1182101B

HK1182101B - Triazole derivatives as ligands for gaba receptors

Info

Publication number: HK1182101B
Application number: HK13109399.3A
Authority: HK
Inventors: 斯蒂芬．迪姆斯．加布里埃尔; 安德鲁．托马斯
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2010-11-09
Filing date: 2011-11-02
Publication date: 2015-11-27

Description

Triazole derivatives as ligands for GABA receptors

The present invention relates to triazole compounds having affinity and selectivity for the GABAA α 5 receptor, their manufacture, pharmaceutical compositions containing them and their use as medicaments.

The invention relates to compounds of formula (I)

Wherein A, X, Y, u, v, R¹、R²And R³As described below and in the claims, and pharmaceutically acceptable salts thereof.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), fall into two major classes: (1) GABA a receptors, which are members of the ligand-gated ion channel superfamily, and (2) GABA B receptors, which are members of the G-protein linked receptor family. GABA a receptor complexes are membrane-bound heteropentameric protein polymers consisting mainly of α, β and γ subunits. A total of 21 subunits of GABAA receptor have been cloned and sequenced. Three types of subunits (α, β and γ) are required for the construction of recombinant GABA a receptors that most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA a receptors obtained from mammalian brain cells. There is strong evidence to suggest that benzodiazepinesThe binding site is located between the alpha and gamma subunits. In recombinant GABA A receptors, alpha 1 beta 2 gamma 2 mimics typical type I benzodiazepinesMany of the effects of receptor (BzR) subtypes, whereas the α 2 β 2 γ 2, α 3 β 2 γ 2 and α 5 β 2 γ 2 ion channels are referred to as type II BzR (R.M. McKernan, P.J. Whiting, in combinant Cell Surface Receptors: Focal Point for therapeutic interaction, M.J. Brown (eds.) (1997) Chapter 8: 155. 173, R.G. Landes Co., Austin, TX).

It has been shown by McNamara and Skelton (Psychotiology, 1993, 21: 101-: benzodiazepineThe receptor inverse agonist β -CCM enhances spatial learning in the Morris water maze (watermaze). However, beta-CCM andother conventional benzodiazepinesReceptor inverse agonists are proconvulsive or convulsive agents, which prevent their use as cognitive enhancers in humans. Furthermore, these compounds are non-selective within the GABA a receptor subunit, whereas partially or fully inverse agonists of the GABA a α 15 receptor that are relatively inactive at the GABA a α 1 and/or α 2 and/or α 03 receptor binding site may be used to provide medicaments that may be used to enhance cognition with reduced or no proconvulsive activity. GABAA α 25 inverse agonists may also be used which are not inactive at the GABAA α 1 and/or α 2 and/or α 3 receptor binding site, but which are functionally selective for the α 5-containing subunit. However, inverse agonists that are selective for the GABAA α 5 subunit and relatively inactive at the GABAA α 1, α 2 and α 3 receptor binding sites are preferred.

Literature has been published to establish links between the GABA A α 5 subunit and the treatment of various diseases of the central nervous system (Neuroscience letters (2005) 381: 108-13, neurosychrobiology (2001)43 (3): 141-44, Amer.J.Med.genetics (2004) 131B: 51-9, Autosmim (2007)11 (2): 135-47, investigration Clinica (2007) 48: 529-41, Nature Neuroscience (2007) 10: 411-13, Neuroscience letters (2008) 433: 22-7, Cell (2008) 135: 549-60).

Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the treatment or prevention of diseases in which GABA A α 5 is involved. The compounds of the invention are preferably inverse agonists of GABAA α 5.

The compounds of the invention and their pharmaceutically acceptable salts have high affinity and selectivity for GABA A alpha 5 receptors and can be used as cognition enhancers or for the treatment or prevention of acute and/or chronic neurological disorders (acute and/or chronic neurological disorders), cognitive disorders (cognitive disorders), Alzheimer's disease (Alzheimer's), memory deficits (memorial disorders), schizophrenia (schizophrenia), positive, negative and/or cognitive symptoms associated with schizophrenia (positive, negative and/or cognitive disorders), bipolar disorders (bipolar disorders), autism (autism), Down syndrome (Down syndrome), neurofibrillary disorder I (inflammatory disorder), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS (dementias cautioned by AIDS), psychiatric disorders (substance-induced psychiatric disorders), anxiety disorders (anxiety disorders), generalized anxiety disorder (generalized anxiety disorder), panic disorder (systemic disorder), delusional disorder (delusional disorder), obsessive/complex disorder (obsessive/complex disorder), acute stress disorder (acute stress disorder), drug addiction (drug addictions), movement disorder (movement disorders), Parkinson's disease (Parkinson's disease), restless leg syndrome (depression), cognitive deficiency (cognitive deficiency disorder), mental disorder (mental-mental disorder), depression (depression-mental disorder), mental disorder (mental-mental disorder), stroke (stroke) and attentive disorders (attentional disorders).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, suitable methods and materials are described below.

Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

Unless otherwise mentioned, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the formulae herein indicates the presence of hydrogen.

The definitions described herein apply regardless of whether the terms discussed appear alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically relevant combinations, such as "heterocycloalkyl-aryl," haloalkyl-heteroaryl, "" aryl-alkyl-heterocycloalkyl, "or" alkoxy-alkyl. The last member of the combination is a radical substituted in reverse order by the other members of the combination.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

The term "substituent" refers to an atom or group of atoms replacing a hydrogen atom on a parent molecule.

The term "substituted" means that the specified group bears one or more substituents. In the case where any group may carry multiple substituents, and multiple possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When referring to the number of substituents, the term "one or more" means from one substituent to the highest possible number of substituents, i.e., substitution of one hydrogen by a substituent to substitution of all hydrogens by substituents.

The terms "compound(s) of the invention" and "compound(s) of the invention" refer to compounds of formula (I) and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

The term "pharmaceutically acceptable salt" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

The term "pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from: aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid (malonicacid), succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

The term "pharmaceutically acceptable base addition salts" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include the following: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tricarboxymethylaminomethane (trimethamine), dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

The term "solvate" refers to a crystalline form of a solvent incorporated in a crystalline lattice, with either stoichiometric or non-stoichiometric amounts. If the solvent incorporated is water, the solvate formed is a hydrate. When the solvent incorporated is an alcohol, the solvate formed is an alcoholate.

The term "stereoisomer" refers to a compound that possesses the same molecular connectivity and bond multiplicity, but differs in the arrangement of its atoms in space.

The terms "halo", "halogen" and "halide" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine. A particular halogen of the present invention is fluorine. Particular examples of halogen include fluorine.

The term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms, especially 1 to 7 carbon atoms, more especially 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Specific examples of alkyl groups include methyl and isopropyl.

The term "alkoxy" refers to a group of the formula-O-R ', wherein R' is alkyl. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

The term "haloalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atom, especially a fluorine atom. Examples of haloalkyl include monofluoro-, difluoro-or trifluoromethyl, -ethyl or-propyl, such as 3, 3, 3-trifluoropropyl, 2-fluoroethyl, 2, 2, 2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced with the same or different halogen atoms.

The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl or 2- (hydroxymethyl) -3-hydroxypropyl.

The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, especially a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having two carbon atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two carbon atoms. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutaneyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicycloalkyl are bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl or adamantyl.

The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings having two ring atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepinyl, homopiperazinyl, or oxepanyl. An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl, or 3-thia-9-aza-bicyclo [3.3.1]Nonyl radical. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. Specific examples of the heterocycloalkyl group include an oxetanyl group, an oxetanyl group substituted with one methyl group, a tetrahydropyranyl group and a morpholinyl group.

The term "aromaticity" refers to the conventional concept of aromaticity as defined in the literature, especially in IUPAC-Complex of chemical technology, 2nd, A.D.McNaught & A.Wilkinson (eds.) Blackwell Scientific Publications, Oxford (1997).

The term "aryl" refers to a monovalent aromatic carbocyclic mono-or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Specific examples of the aryl group include a phenyl group and a phenyl group substituted with one fluorine.

The term "aryloxy" refers to a group of the formula-O-R ', wherein R' is aryl. An example of aryloxy is phenoxy.

The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical, diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinolylA quinoline group, a carbazole group or an acridine group. One particular example of heteroaryl includes pyridyl.

The term "alkylene" refers to a straight chain saturated divalent hydrocarbon radical of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon radical of 3 to 7 carbon atoms. Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.

The term "active pharmaceutical ingredient" (or "API") refers to a compound in a pharmaceutical composition that has a particular biological activity.

The term "pharmaceutically acceptable" refers to materials that can be used to prepare pharmaceutical compositions, which are generally safe, non-toxic, and not biologically or otherwise undesirable and acceptable for veterinary as well as human pharmaceutical applications.

The term "pharmaceutically acceptable excipient" refers to any ingredient used in formulating pharmaceutical products that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, osmotic agents (osmotic agents), stabilizers, antioxidants, surfactants, or lubricants.

The term "pharmaceutical composition" (or "composition") refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient for administration to a mammal, such as a human, in need thereof.

The term "inhibition constant" (Ki) refers to the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor would occupy 50% of the cases of the receptor if no competing ligand (e.g., radioligand) were present. Ki values can be logarithmically converted to pKi values (-log Ki), where a larger value indicates exponentially greater potency.

Detailed Description

In particular, the present invention relates to compounds of formula (I),

wherein

A is-CH₂-O-, or-CH ═ CH-;

x is S or CH;

y is O, NR⁹Or CR⁹Provided that if X is S, then Y is CR⁹And if X is CH, Y is O or NR⁹；

u, v each represent a single bond or a double bond, with the proviso that u and v are not both double bonds and not both single bonds;

R¹，R²is alkyl, aryl optionally substituted with 1 or 2 halogens or heteroaryl optionally substituted with 1 or 2 halogens, wherein R is¹And R²One of which is alkyl;

R³is halogen, cyano, alkyl, haloalkyl, nitro, -C (O) R⁴or-C (O) NR⁵R⁶；

R⁴Is H, alkyl, aryl, hydroxy, alkoxy or aryloxy;

R⁵is H, alkyl, haloalkyl, hydroxyalkyl, - (CH)₂)_n-cycloalkyl, - (CH)₂)_n-heterocycloalkyl, - (CH)₂)_n-aryl, - (CH)₂)_n-heteroaryl, - (CH)₂)_m-NR⁷R⁸Or is- (CH)₂)_m-OR⁷Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with halogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxy.

R⁶Is H, alkyl, or with R⁹Together are an alkylene group;

or R⁵And R⁶Together with the nitrogen to which they are attached form a heterocycloalkyl group;

R⁷，R⁸independently is H, alkyl, or aryl;

R⁹is H, alkyl, or R⁹And R⁶Together are an alkylene group;

n is an integer of 0 to 6;

m is an integer from 2 to 6;

and pharmaceutically acceptable salts thereof.

Particular embodiments of the present invention are compounds of formula (I) and pharmaceutically acceptable salts thereof.

Furthermore, it will be understood that reference to specific residues a, X, Y, u, v, R as disclosed herein is made¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸Or R⁹May be related to another residue a, X, Y, u, v, R as disclosed herein¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸Or R⁹Any other embodiment of (a) or (b) in combination.

A particular embodiment of the present invention relates to compounds of the formula (I), in which

A is-CH₂-O-, or-CH ═ CH-;

x is S or CH;

R¹，R²is alkyl, aryl or heteroaryl optionally substituted with one halogen, wherein R is¹And R²One of which is alkyl;

R³is-C (O) NR⁵R⁶；

R⁵Is alkyl, or heterocycloalkyl optionally substituted with alkyl;

R⁶is H;

R⁹is H, or alkyl;

and pharmaceutically acceptable salts thereof.

In a particular embodiment of the invention, a is attached to the triazole ring via a carbon atom.

In a particular embodiment of the invention, A is-CH₂-O-。

In a particular embodiment of the invention, a is-CH ═ CH-.

In a particular embodiment of the invention, X is S and Y is CR⁹(ii) a Or X is CH and Y is O; or X is CH and Y is NR⁹。

In a particular embodiment of the invention, X is S and Y is CR⁹U is a single bond and v is a double bond; or X is CH, Y is O, u is a double bond, and v is a single bond; or X is CH and Y is NR⁹U is a double bond and v is a single bond.

In a particular embodiment of the invention, X and Y together with the carbon and nitrogen atoms to which they are attached form a 5-membered heteroaryl group having two heteroatoms, in particularWhich is X and Y together with the carbon and nitrogen atoms to which they are attached form a group selected from thiazol-2-yl, iso-butyl5-membered heteroaryl in oxazol-3-yl and pyrazol-3-yl.

A particular embodiment of the present invention relates to compounds of the formula (Ia)

Wherein A, R¹，R²，R³And R⁹As defined herein.

A particular embodiment of the present invention relates to compounds of the formula (Ib)

Wherein A, R¹，R²And R³As defined herein.

A particular embodiment of the present invention relates to compounds of the formula (Ic)

Wherein A, R¹，R²，R³And R⁹As defined herein.

A particular embodiment of the present invention relates to compounds of the formula (I

Wherein X, Y, u, v, R¹，R²And R³As herein describedAs defined.

A particular embodiment of the present invention relates to compounds of formula (I ″)

Wherein X, Y, u, v, R¹，R²And R³As defined herein.

In a particular embodiment of the invention, R¹And R²One is alkyl and the other is aryl optionally substituted with one halogen or heteroaryl optionally substituted with one halogen.

In a particular embodiment of the invention, R¹And R²One is methyl, ethyl or butyl and the other is phenyl optionally substituted with one halogen, or pyridinyl optionally substituted with one halogen.

In a particular embodiment of the invention, R¹And R²One of which is methyl and the other is phenyl substituted with one fluoro, or pyridyl.

In a particular embodiment of the invention, R¹Is an alkyl group; and R²Is aryl, or aryl substituted with one halogen.

In a particular embodiment of the invention, R¹Is methyl, and R²Is phenyl substituted by one fluoro.

In a particular embodiment of the invention, R²Is an alkyl group; and R¹Is aryl, aryl substituted with one halogen, heteroaryl, or heteroaryl substituted with one halogen.

In a particular embodiment of the invention, R²Is methyl, and R¹Is phenyl substituted by one fluoro, or pyridyl.

In a particular embodiment of the invention, R³is-C (O) NR⁵R⁶。

In a particular embodiment of the invention, R⁵Is alkyl, or heterocycloalkyl optionally substituted with alkyl.

In a particular embodiment of the invention, R⁵Is isopropyl, oxetanyl substituted by methyl, tetrahydro-pyranyl, or morpholinyl.

In a particular embodiment of the invention, R⁶Is H.

In a particular embodiment of the invention, R⁹Is H, or alkyl.

In a particular embodiment of the invention, R⁹Is H, or methyl.

A particular embodiment of the present invention relates to compounds of formula (I) as described in the examples as individual compounds and pharmaceutically acceptable salts thereof. Furthermore, substituents as found in the specific examples described below independently constitute separate specific embodiments of the invention.

Particular compounds of formula (I) of the present invention are those selected from the group consisting of:

3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-isoOxazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

5- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid morpholin-4-ylamide;

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (3-methyl-oxetan-3-yl) -amide;

2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid isopropylamide;

2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid isopropylamide;

4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3] triazol-4-yl) -vinyl ] -thiazole-5-carboxylic acid isopropylamide;

4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3] triazol-4-yl) -vinyl ] -thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide; and

a pharmaceutically acceptable salt thereof.

The present invention also relates to a process for the preparation of a compound of formula (I) as defined above, said process comprising:

a) reaction of a compound of formula (II) with a compound of formula (III) to give a compound of formula (I'), wherein A is-CH₂-O-

Or

b) Reaction of a compound of formula (IV) with a compound of formula (V) to give a compound of formula (VI), followed by subsequent reaction with a compound of formula (VI) to give a compound of formula (I'), wherein A is-CH ═ CH-

Wherein X, Y, u, v, R¹，R²And R³As defined herein.

The invention also relates to a compound of formula (I) as defined above, obtainable by a process as described above.

Unless otherwise mentioned, compounds of formula (I) can be prepared according to standard procedures described below, wherein A, X, Y, u, v, R¹，R²And R³As described above and in the claims.

In which A is-CH₂-O-and R²Compounds of formula (I') and their pharmaceutically acceptable salts, which are alkyl, may be prepared according to schemes 1 and 2:

scheme 1

According to scheme 1, compounds of formula (1), wherein R is alkyl, may be reacted with triphenylphosphine oxide and Tf₂The reaction of O in the presence of a base such as triethylamine in a suitable solvent such as 1, 2-dichloroethane gives compounds of formula (2). Alternatively, the compound of formula (1) may be treated with a strong base such as BuLi in the presence of ethyl chloroformate in a suitable solvent to give the compound of formula (2). The compound of formula (2) may be reacted with a compound of formula (3) wherein i is an integer from 1 to 7, especially 1, 2 or 4, most especially 1, in a suitable solvent such as benzene with heating to give a compound of formula (4). The compound of formula (4) may be reacted with a reducing agent such as lithium aluminum hydrideTreatment in a suitable solvent such as THF to give a compound of formula (5), the compound of formula (5) may be treated with TBAF in a suitable solvent such as THF in water to give a compound of formula (6).

Scheme 2

According to scheme 2, a compound of formula (6) can be reacted with a compound of formula (7) in the presence of triphenylphosphine and diethyl azodicarboxylate in a suitable solvent such as THF to give a compound of formula (I'), wherein A is-CH₂-O-and R²Is an alkyl group.

In which A is-CH₂-O-and R¹Compounds of formula (I') and their pharmaceutically acceptable salts, which are alkyl, may be prepared according to schemes 3 and 2:

scheme 3

The compound of formula (8) may be treated with a compound of formula (9) to give a compound of formula (10), which is treated with a base such as potassium hydroxide in a suitable solvent such as methanol to give a compound of formula (11). The compound of formula (11) may then be treated with a strong base such as BuLi in a suitable solvent such as THF and then reacted with DMF to give the compound of formula (12). The compound of formula (12) may be treated with a reducing agent such as sodium borohydride in a suitable solvent such as methanol to give the compound of formula (13). The compounds of formula (13) are equivalent in their subsequent reactivity to the compounds of formula (6) and can therefore be operated as described above. In which A is-CH₂-O-and R¹Compounds of formula (I') and their pharmaceutically acceptable salts, which are alkyl, can be prepared from compounds of formula (13) according to scheme 3.

In the inventionA is-CH ═ CH-and R²Compounds of formula (I ") which are alkyl groups and their pharmaceutically acceptable salts may be prepared according to schemes 4 and 5:

scheme 4

According to scheme 4, a compound of formula (14) is reacted with a compound of formula (3), wherein I is an integer from 1 to 7, particularly 1, 2 or 4, most particularly 1, in the presence of cu (I) I in a suitable solvent such as DMF in the presence of a base such as DIPEA to give a compound of formula (15), which can then be treated with TBAF in a suitable solvent such as THF in water to give a compound of formula (16). Alternatively, the compound of formula (14) may be reacted with Cu (I) I and sodium azide and with a compound of formula IR²Is treated in the presence of ascorbic acid under activating conditions such as sonication to give a compound of formula (16). The compound of formula (16) may then be treated with a strong base such as BuLi in a suitable solvent such as THF, and then reacted with DMF to give the compound of formula (17).

Scheme 5

According to scheme 5, a compound of formula (17) can be reacted with a compound of formula (18) in the presence of a strong base such as BuLi in a suitable solvent such as THF to give a compound of formula (19). The compound of formula (19) may be treated with sulfuric acid to give the compound of formula (I ").

Wherein a is-CH ═ CH-and R¹Compounds of formula (I ") that are alkyl groups and their pharmaceutically acceptable salts can be prepared according to schemes 3 and 5. The compounds of formula (16) are equivalent in their subsequent reactivity to the compounds of formula (17) and can therefore be operated as indicated above.

According to scheme 6, whichIn R³＝-C(O)NR⁵R⁶The compounds of formula (I) can be prepared according to standard procedures from the compounds of formula (I) wherein R³＝-C(O)R⁴A compound of formula (I) of (I).

Scheme 6

To the extent that their preparation is not described in the examples, the compounds of formula (I) as well as all intermediate products may be prepared according to similar methods or according to the methods given above. The starting materials are commercially available, known to those skilled in the art or can be prepared by methods known in the art or similar thereto.

The invention also relates to compounds of formula (I) as defined above, prepared by a process as described above.

BuLi ═ n-butyl lithium

1, 1 f-carbonyldiimidazole

DCM ═ dichloromethane

DIPEA ═ N, N-diisopropylethylamine (Hunigs base)

DMF ═ dimethylformamide

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

HOBt ═ hydroxybenzotriazole

high vacuum of hv

on-overnight

r.t. room temperature

TBD ═ 1, 5, 7-triazabicyclo [4.4.0] dec-5-ene

TBTU ═ O- (benzotriazol-1-yl) -N, N' -tetramethylureaTetrafluoroborate salt

Tf₂O ═ trifluoromethanesulfonic anhydride

THF ═ tetrahydrofuran

Another embodiment provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.

The compositions are formulated, dosed (dosed), and administered in a manner consistent with good medical practice. Factors to be considered herein include the particular disease being treated, the particular mammal being treated, the clinical status of the individual patient, the predisposition to the disease, the site of agent delivery, the method of administration, the timing of administration, and other factors known to practitioners.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and extrameningeal and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient form of administration such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. These compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH modifying agents, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants, and other active agents. They may also contain other therapeutically valuable substances.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are known to those skilled in the art and are described in detail, for example, in Ansel H.C. et al, Ansel's Pharmaceutical Delivery Forms and Drug Delivery systems (2004) Lippincott, Williams & Wilkins, Philadelphia; gennaro a.r. et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a elegant appearance of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., medicament).

The doses at which the compounds of the invention can be administered may vary within wide limits and will, of course, be fitted to the needs of the individual in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 to 1000mg of a compound of formula (I) per person will be appropriate, although the above upper limit may also be exceeded when desired.

An example of a suitable oral pharmaceutical dosage form is a tablet comprising: about 100mg to 500mg of a compound of the invention, formulated with about 90 to 30mg of anhydrous lactose, about 5 to 40mg of croscarmellose sodium, about 5 to 30mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

An example of an aerosol formulation may be prepared by: the compound of the invention, for example 10 to 100mg, is dissolved in a suitable buffer solution, for example phosphate buffer, and if desired an osmotic agent, for example a salt such as sodium chloride, is added. The solution may be filtered, for example using a 0.2 μm filter, to remove impurities and contaminants.

As mentioned above, the novel compounds of the present invention and their pharmaceutically acceptable salts possess valuable pharmacological properties and are found to be ligands for the GABAA α 5 receptor. The compounds of the invention may therefore be used, alone or in combination with other drugs, for the treatment or prevention of diseases which are modulated by ligands for the GABAA receptor containing the α 5 subunit. These diseases include, but are not limited to: acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, down syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychiatric disorders, substance-induced psychiatric disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorder, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke, attention-deficit disorder, and a need for cognitive enhancement.

The invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable excipient.

The invention likewise comprises compounds as described above for use as therapeutically active substances.

The invention also comprises compounds as described above for use as therapeutically active substances for the treatment or prevention of diseases which are related to the gaba a α 5 receptor.

The invention likewise comprises compounds as described above for use as therapeutically active substances for the treatment or prophylaxis of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive impairment disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders, or as cognitive enhancers.

The invention likewise comprises compounds as described above for the treatment or prophylaxis of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychiatric disorders, substance-induced psychiatric disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorders, drug addictions, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders, or as cognitive enhancers.

In another embodiment, the invention relates to a method for the treatment or prevention of diseases related to the gaba a α 5 receptor.

In another embodiment, the invention relates to a method for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychiatric disorders, substance-induced psychiatric disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders or for cognitive enhancement, said method comprising administering a compound as defined above to a human or animal.

The invention also includes the use of a compound as defined above for the treatment or prevention of diseases related to the GABA a α 5 receptor.

The invention also comprises the use of a compound as defined above for the treatment or prophylaxis of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychiatric disorders, substance-induced psychiatric disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders or for cognitive enhancement.

The invention also relates to the use of a compound as described above for the preparation of a medicament for the treatment or prevention of diseases related to the GABAA α 5 receptor, in particular for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythm, Amyotrophic Lateral Sclerosis (ALS), dementia caused by aids, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorder, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders, or for the preparation of cognitive enhancers. These medicaments comprise compounds as described above.

More particularly, the present invention relates to the use of a compound as described above for the treatment, prevention and/or delay of progression of CNS symptoms caused by a neurodevelopmental defect leading to excessive GABAergic (GABAergic) inhibition in the cortex and hippocampus, wherein the CNS symptoms are selected from cognitive disorders in down syndrome, in autism, in neurofibromatosis type I or after stroke.

The treatment or prevention of cognitive disorders, alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, down's syndrome, and neurofibromatosis type I are particular embodiments of the present invention.

A particular embodiment of the invention encompasses the treatment or prevention of alzheimer's disease.

A particular embodiment of the invention encompasses the treatment or prevention of down syndrome.

A particular embodiment of the invention encompasses the treatment or prevention of type I neurofibromatosis.

The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

Example 1

3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-isoAzole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide

a) (4-fluoro-phenyl) -propionic acid ethyl ester

Synthesis Communications (1989) 3: 217-218 were prepared similarly. To a solution of triphenylphosphine oxide (3.77g, 14mmol) in 1, 2-dichloroethane (42mL) was added triflic anhydride (2.25mL, 14mmol) dropwise at 0 deg.C, and the grey suspension was stirred at 0 deg.C for 15 min. A solution of 3- (4-fluoro-phenyl) -3-oxo-propionic acid ethyl ester (2.85g, 14mmol) in 1, 2-dichloroethane (14mL) was then added, followed by triethylamine (3.78mL, 28mmol) dropwise at 0 ℃. The brown solution was refluxed for 2.5 h. After cooling, the mixture was poured onto ice-water and the organic layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) gave the title compound (1.53g, 59%) as a yellow solid. MS: m/e 193.2[ M + H ]]⁺。

b)5- (4-fluoro-phenyl) -3-trimethylsilylmethyl-3H- [1，2，3]Triazole-4-carboxylic acid ethyl ester

To a solution of (4-fluoro-phenyl) -propionic acid ethyl ester (1.45g, 7.55mmol) in benzene (25mL) was added azidomethyl-trimethyl-silane (1.17g, 9.05mmol) and the reaction mixture was refluxed under nitrogen for 72 h. A subsequent batch of azidomethyl-trimethyl-silane (0.29g, 2.26mmol) was added and reflux continued for 5 h. The mixture was then evaporated and purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (1.0g, 41%) as a yellow oil. MS: m/e is 322.2[M+H]⁺。

c) [5- (4-fluoro-phenyl) -3-trimethylsilylmethyl-3H- [1, 2, 3]Triazol-4-yl]-methanol

To 5- (4-fluoro-phenyl) -3-trimethylsilylmethyl-3H- [1, 2, 3]A solution of triazole-4-carboxylic acid ethyl ester (880mg, 2.74mmol) in dry THF (8.2mL) was added lithium aluminium hydride (119mg, 3.15mmol) portionwise at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 1 h. Then water (119 μ L) and NaOH (15%, 119 μ L) were added followed by water (357 μ L). The precipitate was then filtered off and the filtrate was evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (649mg, 85%) as a white solid. MS: 280.1[ M + H ] M/e]⁺。

d) [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-methanol

To [5- (4-fluoro-phenyl) -3-trimethylsilylmethyl-3H- [1, 2, 3]Triazol-4-yl]A solution of methanol (616mg, 2.20mmol) in THF (37mL) was added water (79 μ L, 4.41mmol) and then tetrabutylammonium fluoride (1M in THF, 2.65mL, 2.65mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 15 minutes. The resulting mixture was poured into water and then THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (410mg, 90%) as an off-white solid. MS: m/e is 208.0[ M + H ]]⁺。

e)3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-iso Azole-5-carboxylic acid methyl ester Acid methyl ester

To [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-solution of methanol (290mg, 1.4mmol) in THF (30mL) at ambient temperature under argon atmosphereAdding 3-hydroxy 5-isoMethyl oxazolecarboxylate (200mg, 1.4mmol) and triphenylphosphine (477mg, 1.82 mmol). Diethyl azodicarboxylate (641 μ L, 3.5mmol) was then added and the reaction mixture was stirred at room temperature for 72 h. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) gave the title compound (464mg, 100%) as a white solid. MS: 333.2[ M + H ] M/e]⁺。

f)3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-iso Azole-5-carboxylic acid

A solution of sodium hydroxide (2N, 10mL) was added dropwise to 3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-isoOxazole-5-carboxylic acid methyl ester (460mg, 1.38mmol) in bisA suspension in an alkane (20mL) and then the reaction mixture was heated at 90 ℃ for 1.5 h. The reaction mixture was then evaporated and acidified with HCl (2N) and the resulting precipitate was filtered off to give the title product (320mg, 73%) as a white solid and used directly in the next step.

g)3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-iso Azole-5-carboxylic acid methyl ester Acid (tetrahydro-pyran-4-yl) -amides

To 3- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-isoA solution of oxazole-5-carboxylic acid (40mg, 0.13mmol) and TBTU (64.6mg, 0.20mmol) in DMF (2.0mL) was added DIPEA (106.9. mu.L, 0.63 mmol). 4-Aminotetrahydropyran (14mg, 0.14mmol) was then added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purified by chromatography (silica, 50 to 100% ethyl acetate in heptane) to give the title compound (35mg, 70%) as a white solid. MS: m/e is 402.2[ M + H ]]⁺。

Example 2

5- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide

a)5- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid methyl ester

To [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]A solution of methanol (290mg, 1.4mmol) in THF (30mL) at ambient temperature under an argon atmosphere was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (218mg, 1.4mmol) and triphenylphosphine (477mg, 1.82 mmol). Diethyl azodicarboxylate (641 μ L, 3.5mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) gave the title compound (483mg, 100%) as a white solid. MS: 346.2[ M + H ] M/e]⁺。

b)5- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid

A solution of sodium hydroxide (2N, 10mL) was added dropwise to a solution of the above-obtained compound (NAME) (480mg, 1.39mmol) in dichloromethaneA suspension in an alkane (20mL), and then the reaction mixture was heated at 90 ℃ for 1.5 h. The reaction mixture was then evaporated and acidified with HCl (2N) and the resulting precipitate filtered off to give the title product (340mg, 74%) as a white solid and used directly in the next step. MS: 330.2[ M + H ] M/e]⁺。

c)5- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide

To a solution of the compound (name) obtained above (40mg, 0.13mmol) and TBTU (64.6mg, 0.20mmol) in DMF (2.0mL) was added DIPEA (106.9. mu.L, 0.63 mmol). 4-Aminotetrahydropyran (13mg, 0.13mmol) was then added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purified by chromatography (silica, 50 to 100% ethyl acetate in heptane) to give the title compound (42mg, 85%) as a white solid. MS: 415.2[ M + H ] M/e]⁺。

Example 3

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide

a) 1-azido-4-fluoro-benzene

And j.org.chem. (1989) 54: 5938-. To a solution of sulfuric acid (40mL) and trifluoroacetic acid (200mL) was added 4-fluoroaniline (22.1mL, 0.23mol) dropwise. An ice-cooled solution of sodium nitrite (20.6g, 0.3mol) in water (200mL) was then added over 30 minutes at 15-18 ℃. The solution was then stirred for 30 minutes while remaining in the ice bath. A solution of sodium azide (25.42g, 0.39mol) in water (150mL) was added dropwise over 30 minutes. The mixture was foamed and the temperature was raised to 10 ℃ while cooling with an ice bath. The reaction mixture was stirred without cooling for 1h, before extraction with diethyl ether. The combined organic layers were washed twice with water. The combined organic layers were then diluted with saturated aqueous sodium carbonate (500mL) until the mixture became basic. The organic phase was separated and washed with brine and extracted again with diethyl ether. The organic layer was dried over sodium sulphate and evaporated at 40 ℃ at a minimum of 50 mbar (product distilled) to give the title product (30.42g, 96%) as a brown liquid.

b)1- [3- (4-fluoro-phenyl) -5-methyl-4, 5-dihydro-3H- [1, 2, 3]Triazol-4-yl]-piperidine (III)

Prepared analogously to EP0433842a 2. A mixture of 1-azido-4-fluoro-benzene (2.80g, 20mmol) and 1- (1-propenyl) -piperidine (18%, 14.2g, 20mmol) was stirred under ice cooling (initially slowly exothermally) and at room temperature for 144h without light. Hexane was then added to the brown solution and a solid formed, which was filtered off, washed with hexane and dried in hv to give the title product (1.1g) as a pale pink solid. The filtrate was then evaporated and purified by chromatography (silica, 10 to 50% ethyl acetate in heptane) to give the title compound (4.34g) as a light yellow solid. Total yield (5.44g, 98%). MS: 263.1[ M + H ] M/e]⁺。

c)1- (4-fluoro-phenyl) -4-methyl-1H- [1, 2, 3]Triazole compounds

Prepared analogously to EP0433842a 2. 1- [3- (4-fluoro-phenyl) -5-methyl-4, 5-dihydro-3H- [1, 2, 3]Triazol-4-yl]A mixture of piperidine (1.15g, 0.004mol) and potassium hydroxide in MeOH (2N, 29.2mL, 58mmol) was heated at reflux for 6h, before cooling to room temperature. The mixture was then poured into water and extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title product (555mg) as a white solid. The filtrate was evaporated and purified by chromatography (silica, 10 to 60% ethyl acetate in heptane) to give the titleThe title compound (41mg, 79%) was an off-white solid. Total yield (596mg, 77%). MS: m/e 178.1[ M + H ]]⁺。

d)3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazole-4-carbaldehyde

To 1- (4-fluoro-phenyl) -4-methyl-1H- [1, 2, 3]A solution of triazole (3.67g, 21mmol) in THF (110mL) was added n-BuLi (1.6M in hexanes, 15.53mL, 25mmol) dropwise at-75 deg.C under argon. The resulting solution was stirred at-75 ℃ for 1h, after which DMF (2.1mL, 27mmol) was added dropwise at-75 ℃ and the reaction mixture was allowed to warm to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (3.85g, 91%) as a white solid. MS: 206.2[ M ] M/e]⁺。

e) [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]-methanol

To 3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]A solution of triazole-4-carboxaldehyde (2.28g, 11mmol) in MeOH (180mL) was added sodium borohydride (210mg, 6.0mmol) at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 30 minutes, after which the mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (2.05g, 89%) as a white solid. MS: m/e is 208.2[ M%]⁺。

f)5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid methyl ester

To [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]A solution of methanol (500mg, 2mmol) in THF (30mL) at ambient temperature under an argon atmosphere was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (377mg, 2mmol) and triphenylphosphine (823mg, 3 mmol). Then adding azodicarboxylic acid diethyl esterEster (40% in toluene, 1.44mL, 3mmol) and the reaction mixture was stirred at room temperature for 24 h. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane, and then 2% methanol in dichloromethane) gave the title compound (671mg, 81%) as a white solid. MS: 346.1[ M + H ] M/e]⁺。

g)5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid

A solution of lithium hydroxide monohydrate (146mg, 3.48mmol) in water (6mL) was added dropwise to 5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-suspension of methyl 2-methyl-2H-pyrazole-3-carboxylate (600mg, 1.74mmol) in THF (6 mL). The reaction mixture was then stirred at room temperature for 2h and then evaporated, and the residue was dissolved in water, acidified with HCl (1N), and the resulting precipitate was filtered off to give the title product (544mg, 95%) as a white solid. MS: 330.2[ M-H ] with M/e]^-。

h)5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyridine Azole-3-carboxylic acid (tetrahydro-pyran-4-yl) -amide

To 5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-ylmethoxy]A solution of-2-methyl-2H-pyrazole-3-carboxylic acid (85mg, 0.26mmol) and TBTU (91mg, 0.28mmol) in DMF (3.0mL) was added DIPEA (220. mu.L, 1.28 mmol). 4-Aminotetrahydropyran (29mg, 0.28mmol) was then added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purified by chromatography (silica, 50 to 100% ethyl acetate in heptane) to give the title compound (72mg, 68%) as a white solid. MS: 415.4[ M + H ] M/e]⁺。

Example 4

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid morpholin-4-ylamide

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3 as described for example 3, using 4-aminomorpholine instead of 4-aminotetrahydropyran]Triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85mg, 0.26mmol) was converted to the title compound (86mg, 81%) which was obtained as a white solid. MS: 416.3[ M + H ] M/e]⁺。

Example 5

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-ylmethoxy ] -2-methyl-2H-pyrazole-3-carboxylic acid (3-methyl-oxetan-3-yl) -amide

5- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3, using 3-methyl-3-oxetanylamine instead of 4-aminotetrahydropyran as described for example 3]Triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85mg, 0.26mmol) was converted to the title compound (98mg, 95%) which was obtained as a white solid. MS: m/e 401.3[ M + H ]]⁺。

Example 6

2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid isopropylamide

a)4- (4-fluoro-phenyl) -1-trimethylsilylmethyl-1H- [1，2，3]Triazole compounds

To a suspension of copper (I) iodide (1.14g, 20 mol%) in DMF (300mL) at room temperature were added DIPEA (5.14mL, 6.0mmol) and 4-fluorophenylacetylene (3.60g, 30mmol), and then trimethyl (azidomethyl) silane (3.88g, 30.0 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water: brine (1: 1) and then extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (5.96g, 80%) as an off-white solid. MS: 250.1[ M + H ] M/e]⁺。

b)4- (4-fluoro-phenyl) -1-methyl-1H- [1, 2, 3]Triazole compounds

To 4- (4-fluoro-phenyl) -1-trimethylsilylmethyl-1H- [1, 2, 3]A solution of triazole (5.80g, 23mmol) in THF (85mL) was added water (840. mu.L, 47mmol) and then tetrabutylammonium fluoride (1M in THF, 27.9mL, 28mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h. The resulting mixture was poured into water, and then THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) gave the title compound (4.0g, 98%) as an off-white solid. MS: m/e 178.1[ M + H ]]⁺。

c)5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazole-4-carbaldehyde

To 4- (4-fluoro-phenyl) -1-methyl-1H- [1, 2, 3]A solution of triazole (709mg, 4.0mmol) in THF (20mL) was added n-BuLi (1.6M in hexane, 3.0mL, 4.8mmol) dropwise at-75 deg.C under argon. The resulting solution was stirred at-75 ℃ for 1h, after which DMF (401 μ L, 5.2mmol) was added dropwise at-75 ℃ and the reaction mixture was allowed to warm to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the combined organic extracts were washed with brine,dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (773mg, 94%) as a white solid. MS: 206.2[ M ] M/e]⁺。

d)2- {2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-2-hydroxy-ethyl } -4- Methyl-thiazole-5-carboxylic acid methyl ester

To a suspension of 2, 4-dimethylthiazole-5-carboxylic acid (236mg, 1.5mmol) in THF (12mL) under Ar at-75 deg.C was added n-BuLi (1.6M in hexane, 1.88mL, 3.0mmol) dropwise. The brown suspension was stirred at-75 ℃ for 2H and then 5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] was added at-75 ℃]A solution of triazole-4-carbaldehyde (308mg, 1.50mmol) in THF (4.5mL) and the brown suspension was stirred at-75 ℃ for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 15mL) and allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0% to 30% methanol in dichloromethane) gave 2- {2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-2-hydroxy-ethyl } -4-methyl-thiazole-5-carboxylic acid (417mg, 77%) as yellow foam. The acid was then dissolved in methanol (4mL) and diethyl ether (2mL) and trimethylsilyldiazomethane (2M in diethyl ether, 5X0.38mL, 3.75mmol) was added dropwise. The reaction was quenched with a few drops of AcOH and evaporated. To the brown oil was added sodium hydroxide (1N, 20mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0% to 30% methanol in dichloromethane) gave the title compound (214mg, 38%) as a light brown foam. MS: 377.3[ M + H ] M/e]⁺。

e)2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl } -4-methyl Yl-thiazole-5-carboxylic acid

2- {2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-2A suspension of-hydroxy-ethyl } -4-methyl-thiazole-5-carboxylic acid methyl ester (204mg, 0.54mmol) in sulfuric acid (concentrated, 3.19mL) was heated at 160 ℃ under Ar for 2 h. After cooling to room temperature, the mixture was poured into ice and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (165mg, 88%) as an off-white solid. MS: m/e 343.0[ M-H ]]^-。

f)2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl } -4-methyl Yl-thiazole-5-carboxylic acid isopropylamide

To 2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl } -4-methyl-thiazole-5-carboxylic acid (75mg, 0.22mmol) and TBTU (77mg, 0.24mmol) in DMF (0.4mL) was added DIPEA (186. mu.L, 1.09 mmol). Isopropylamine (21 μ L, 0.24mmol) was then added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purified by chromatography (silica, 1% to 5% methanol in dichloromethane) to give the title compound (28mg, 33%) as an off-white solid after recrystallization from ethyl acetate and heptane. MS: 386.4[ M + H ] M/e]⁺。

Example 7

2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide

2- { (E) -2- [5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3, using 4-aminotetrahydropyran instead of isopropylamine, as described for example 6f]Triazol-4-yl]-vinyl } -4-methyl-thiazole-5-carboxylic acid (75mg, 0.22mmol) was converted to the title compound (63mg, 68%) which was obtained as a light yellow solid. MS: 428.3[ M + H ] M/e]⁺。

Example 8

2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide

a)2- {2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]-2-hydroxy-ethyl } -4- Methyl-thiazole-5-carboxylic acid methyl ester

As described for example 7d instead of 5- (4-fluoro-phenyl) -3-methyl-3H- [1, 2, 3]Triazole-4-carbaldehyde prepared by reacting 3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazole-4-carbaldehyde (630mg, 3.1mmol) was converted to the title compound (392mg, 34%) which was obtained as a light brown solid. MS: 377.3[ M + H ] M/e]⁺。

b)2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl } -4-methyl Yl-thiazole-5-carboxylic acid

2- {2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]A suspension of-2-hydroxy-ethyl } -4-methyl-thiazole-5-carboxylic acid methyl ester (355mg, 0.94mmol) in sulfuric acid (concentrated, 5.9mL) was heated at 160 ℃ under Ar for 30 min. After cooling to room temperature, the mixture was poured into ice and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (249mg, 77%) as a grey solid. MS: 345.1[ M + H ] M/e]⁺。

c)2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl } -4-methyl Yl-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide

To 2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3]Triazol-4-yl]-vinyl radicalA solution of 4-methyl-thiazole-5-carboxylic acid (72mg, 0.21mmol) and TBTU (74mg, 0.23mmol) in DMF (3mL) was added DIPEA (178. mu.L, 1.05 mmol). 4-Aminotetrahydropyran (23mg, 0.23mmol) was then added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purified by chromatography (silica, 30 to 80% ethyl acetate in heptane) to give the title compound (68mg, 76%) as a light yellow solid. MS: 428.3[ M + H ] M/e]⁺。

Example 9

2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3] triazol-4-yl ] -vinyl } -4-methyl-thiazole-5-carboxylic acid isopropylamide

2- { (E) -2- [3- (4-fluoro-phenyl) -5-methyl-3H- [1, 2, 3, using isopropylamine instead of 4-aminotetrahydropyran as described for example 8c]Triazol-4-yl]-vinyl } -4-methyl-thiazole-5-carboxylic acid (72mg, 0.21mmol) was converted to the title compound (57mg, 71%) which was obtained as an off-white solid. MS: 386.4[ M + H ] M/e]⁺。

Example 10

4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3] triazol-4-yl) -vinyl ] -thiazole-5-carboxylic acid isopropylamide

a) 2-ethynyl-pyridines

To a mixture of 2-pyridinecarboxaldehyde (0.96mL, 10mmol) in MeOH (43mL) at room temperature was added potassium carbonate (2.76g, 20mmol) followed by the addition of (1-diazo)A solution of 2-oxo-propyl) -phosphonic acid dimethyl ester (2.14g, 11mmol) in MeOH (14mL) and the resulting mixture was stirred for 1.5 h. The mixture was then poured into sodium carbonate solution (1M) and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, diethyl ether) gave the title compound (728mg, 71%) as a yellow liquid. MS: m/e 103.0[ M%]⁺。

b)2- (1-trimethylsilylmethyl-1H- [1, 2, 3]]Triazol-4-yl) -pyridines

To a suspension of copper (I) iodide (1.36g, 20 mol%) in DMF (360mL) at room temperature were added DIPEA (6.31mL, 36mmol) and 2-ethynyl-pyridine (110 μ l.1.00mmol), and then trimethyl (azidomethyl) silane (3.69g, 36 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water: brine (1: 1), and then extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) gave the title compound (6.05g, 73%) as a light yellow solid. MS: 233.1[ M + H ] M/e]⁺。

c)2- (1-methyl-1H- [1, 2, 3)]Triazol-4-yl) -pyridines

To 2- (1-trimethylsilylmethyl-1H- [1, 2, 3)]A solution of triazol-4-yl) -pyridine (6.05g, 26mmol) in THF (435mL) was added water (0.94mL, 52mmol) and then tetrabutylammonium fluoride (1M in THF, 31.2mL, 31mmol) was added dropwise at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 h. The resulting mixture was poured into water and then THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (3.53g, 85%) as a light brown solid. MS: 161.2[ M + H ] M/e]⁺。

d) 3-methyl-5-pyridin-2-yl-3H- [1, 2, 3]Triazole-4-carbaldehyde

To a solution of 2- (1-methyl-1H- [1, 2, 3] triazol-4-yl) -pyridine (3.52g, 22mmol) in THF (112mL) was added n-BuLi (1.6M in hexane, 16.5mL, 4.96mmol) dropwise at-75 ℃ and under Ar. The resulting light brown suspension was stirred at-75 ℃ for 1 h. Thereafter DMF (2.20mL, 29mmol) was added dropwise at-75 ℃ and the yellow solution was allowed to warm to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (3.75g, 91%) as a white solid. MS: 188.0[ M ] +, M/e.

e)2- [ 2-hydroxy-2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3]Triazol-4-yl) -ethyl]-4-A Yl-thiazole-5-carboxylic acid

To a suspension of 2, 4-dimethylthiazole-5-carboxylic acid (157mg, 1.0mmol) in THF (8mL) under Ar at-75 deg.C was added n-BuLi (1.6M in hexane, 1.25mL, 2.0mmol) dropwise. The brown suspension was stirred at-75 ℃ for 2H and then 3-methyl-5-pyridin-2-yl-3H- [1, 2, 3] was added at-75 ℃]A solution of triazole-4-carbaldehyde (188mg, 1.0mmol) in THF (3mL) was added and the brown suspension was stirred at-75 deg.C for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 10mL) and allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by recrystallization from ethyl acetate-heptane gave the title compound (288mg, 83%) as a light red solid. MS: m/e-344.0 [ M-H ═]^-。

f) 4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3]Triazol-4-yl) -ethenyl]- Thiazole-5-carboxylic acid

2- [ 2-hydroxy-2- (3-methyl-5-pyridine-2-yl-3H- [1, 2, 3)]Triazol-4-yl) -ethyl]-4-methyl groupA suspension of-thiazole-5-carboxylic acid (152mg, 0.44mmol) in sulfuric acid (concentrated, 2.59mL, 48.4mmol) was heated at 160 ℃ under Ar for 7 h. After cooling to room temperature, the mixture was poured into ice, adjusted to pH4 with NaOH (6N) and extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (114mg, 79%) as a yellow solid after trituration from methanol-water. MS: 326.2[ M-H ] M/e]^-。

g) 4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3]Triazol-4-yl) -ethenyl]- Thiazole-5-carboxylic acid isopropylamide

To 4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3]Triazol-4-yl) -ethenyl]A solution of thiazole-5-carboxylic acid (56mg, 0.17mmol) and TBTU (60mg, 0.19mmol) in DMF (0.9mL) was added DIPEA (146. mu.L, 0.86 mmol). Isopropylamine (16 μ L, 0.24mmol) was then added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purified by chromatography (silica, 1 to 10% methanol in dichloromethane) to give the title compound (36mg, 57%) as a light yellow solid after recrystallization from methanol-water. MS: 369.2[ M + H ] M/e]⁺。

Example 11

4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3] triazol-4-yl) -vinyl ] -thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl) -amide

4-methyl-2- [ (E) -2- (3-methyl-5-pyridin-2-yl-3H- [1, 2, 3) using 4-aminotetrahydropyran instead of isopropylamine as described for example 10g]Triazol-4-yl) -ethenyl]-thiazole-5-carboxylic acid (56mg, 0.17mmol) was converted to the title compound (46mg, 66%) which was obtained as a pale yellow solid. MS: 411.2[ M + H ] M/e]⁺。

Biochemical assay

The ability of the compounds of the invention to bind to GABA A receptor subtypes is determined by competition for [3H ] flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors constituting α 1 β 2/3 γ 2, α 2 β 3 γ 2, α 3 β 3 γ 2 and α 5 β 3 γ 2.

Membrane preparation

The cell pellets were suspended in Krebs-Tris buffer (4.8mM KCl, 1.2mM CaCl)₂，1.2mM MgCl₂120mM NaCl, 15mM Tris; pH7.5; binding assay buffer), homogenized by polytron on ice for about 20sec and centrifuged at 4 ℃ for 60min (50000 g; sorvall, rotor: SM24 ═ 20000 rpm). The cell particles were resuspended in Krebs-Tris buffer and homogenized by polytron on ice for about 15 sec. The protein was measured (Bradford method, Bio-Rad) and 1mL aliquots were prepared and stored at-80 ℃.

Radioligand binding assays

In a concentration of 1nM for the α 1, α 2 and α 3 subunits and 0.5nM for the α 5 subunit containing 100mL of a cell membrane³H]Flumazenil and a fluorine content in the range of 10-10^-3x10^-6Radioligand binding assays were performed in 200mL volumes (96-well plates) of test compounds in the M range. Nonspecific binding by 10^-5M diazepam defines and typically represents less than 5% of total binding. The analytes were incubated at 4 ℃ to equilibrium for 1 hour and harvested onto GF/C uni-filters (Packard) by filtration using a Packard harvester and washing with ice cold wash buffer (50mM Tris; pH 7.5). After drying, the radioactivity retained by the filter was detected by liquid scintillation counting.

Data computation

Ki values were calculated using Excel-Fit (Microsoft) and are the average of two determinations.

The compounds of the accompanying examples are as followsTested in the above assay, and found that a particular compound is useful for the substitution of α 5 subunit from the GABA A receptor of rat³H]Flumazenil has a Ki value below 100 nM. A particular embodiment includes compounds with Ki below 35 nM. In a particular embodiment, the compounds of the invention have binding selectivity for the α 5 subunit over the α 1, α 2 and α 3 subunits.

Representative assay results obtained by the above described assay measuring binding affinity to HEK293 cells expressing the human (h) receptor are given in table 1 below.

Table 1: binding affinity to HEK293 cells expressing human (h) receptors of representative examples

Examples	hK_i GABA Aα5[nM]
		1	28.8
2	45.3
		3	15.7
4	22.2
		5	43.2
6	11.3
		7	6.2
8	2.6
		9	6.8
10	20.7
		11	12.7

Claims

1. A compound of the formula (I),

wherein

A is-CH₂-O-, or-CH ═ CH-;

x is S or CH;

R¹，R²is C_1-7Alkyl, aryl optionally substituted with 1 or 2 halogens or heteroaryl optionally substituted with 1 or 2 halogens, wherein R is¹And R²Is one of C_1-7An alkyl group;

R³is-C (O) NR⁵R⁶；

R⁵Is C_1-7Alkyl, or optionally substituted by C_1-7An alkyl-substituted heterocycloalkyl group, a substituted heterocycloalkyl group,

R⁶is H or C_1-7An alkyl group;

R⁹is H or C_1-7An alkyl group;

wherein "aryl" refers to a monovalent aromatic carbocyclic mono-or bicyclic ring system containing 6 to 10 carbon ring atoms,

"heteroaryl" means a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon,

"heterocycloalkyl" means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon,

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein

A is-CH₂-O-, or-CH ═ CH-;

x is S or CH;

R¹，R²is C_1-7Alkyl, aryl optionally substituted with one halogen, or heteroaryl,wherein R is¹And R²Is one of C_1-7An alkyl group;

R³is-C (O) NR⁵R⁶；

R⁵Is C_1-7Alkyl, or optionally substituted by C_1-7Alkyl-substituted heterocycloalkyl;

R⁶is H;

R⁹is H, or C_1-7An alkyl group;

and pharmaceutically acceptable salts thereof.

3. The compound of any one of claims 1-2, wherein X is S and Y is CR⁹U is a single bond and v is a double bond; or X is CH, Y is O, u is a double bond and v is a single bond; or X is CH and Y is NR⁹U is a double bond and v is a single bond.

4. The compound of any one of claims 1-2, wherein R¹Is C_1-7An alkyl group; and R is²Is aryl, or aryl substituted with one halogen.

5. The compound of any one of claims 1-2, wherein R¹Is methyl; and R is²Is phenyl substituted by one fluoro.

6. The compound of any one of claims 1-2, wherein R²Is C_1-7An alkyl group; and R is¹Is aryl, aryl substituted with one halogen, heteroaryl, or heteroaryl substituted with one halogen.

7. The compound of any one of claims 1-2, wherein R²Is methyl; and R is¹Is phenyl substituted by one fluoro, or pyridyl.

8. According to claimThe compound of any one of claims 1-2, wherein R⁵Is isopropyl, oxetanyl substituted by methyl, tetrahydro-pyranyl, or morpholinyl.

9. The compound of claim 1, wherein R⁶Is H.

10. The compound of any one of claims 1-2, wherein R⁹Is H, or methyl.

11. The compound of any one of claims 1-2, selected from the group consisting of:

a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound according to any one of claims 1-11, the process comprising:

Wherein X, Y, u, v, R¹、R²And R³As defined in any one of claims 1 to 11.

13. A pharmaceutical composition comprising a compound according to any one of claims 1-11 and a pharmaceutically acceptable excipient.

14. The use of a compound according to any one of claims 1-11 for the preparation of a medicament for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, memory deficits, positive, negative and/or cognitive symptoms associated with schizophrenia, autism, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), panic disorders, delusional disorders, obsessive/compulsive disorders, acute stress disorders, drug addiction, movement disorders, restless leg syndrome, cognitive deficits, mood disorders, attention deficit/hyperactivity disorder, neuropathic pain, stroke and attention disorders, or for use as a cognitive enhancer.

15. The use of a compound according to any one of claims 1-11 for the preparation of a medicament useful for the treatment or prevention of alzheimer's disease, schizophrenia, down syndrome, dementia caused by aids, psychotic disorders, anxiety disorders, parkinson's disease, multi-infarct dementia, or depression.

16. The use of a compound according to any one of claims 1-11 for the preparation of a medicament useful for the treatment or prevention of bipolar disorder, substance-induced psychotic disorder, generalized anxiety disorder, or a neuropsychiatric disorder.