HK1178163A - Novel substituted bicyclic triazole derivatives as gamma secretase modulators - Google Patents

Description

Novel substituted bicyclic triazole derivatives as gamma secretase modulators

Technical Field

The present invention relates to novel substituted indazole and aza-indazole derivatives useful as gamma secretase modulators. The invention also relates to processes for the preparation of such novel compounds, pharmaceutical compositions comprising said compounds as active ingredient and the use of said compounds as medicaments.

Background

Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by loss of memory, recognition and behavioral stability. AD afflicts 6-10% of people over 65 years of age and up to 50% of people over 85 years of age. This is the major cause of dementia and the third leading cause of death after cardiovascular disease and cancer only. There is currently no effective treatment for AD. The total net cost of AD in the united states is over one billion dollars per year.

AD does not have a simple etiology, however, it is associated with certain risk factors including (1) age, (2) family history, and (3) head trauma; other factors include environmental toxins and low education. Specific neuropathological lesions in the limbus and cerebral cortex include intracellular neurofibrillary tangles composed of phosphorylated tau protein and extracellular deposits of amyloid beta peptide fibrils aggregates (amyloid plaques). The major components of amyloid plaques are amyloid beta (a- β, Abeta or a β) peptides of varying lengths. One such variant is the A β 1-42-peptide (Abeta-42), which is believed to be the major causative agent of amyloid formation. Another variant is the A.beta.1-40-peptide (Abeta-40). A β is the proteolytic product of the precursor protein, β amyloid precursor protein (β -APP or APP).

The family of AD, the early-onset autosomal dominant forms of inheritance, are associated with missense mutations in the beta-amyloid precursor protein (beta-APP or APP) and in the presenilin proteins 1 and 2. In some patients, late-onset forms of AD are associated with specific alleles of the apolipoprotein e (apoe) gene, and with recent findings of mutations in α 2-macroglobulin, which may be associated with at least 30% of the AD population. Despite this heterogeneity, all forms of AD show similar pathological consequences. Genetic analysis provides the best clues for a logical approach to the treatment of AD. All mutations found to date affect the quantity or quality of production of amyloid peptides called Abeta-peptides (a β), particularly α β 42 (amyloidogenic peptides), and provide strong support for the "amyloid cascade hypothesis" of AD (Tanzi and Bertram, 2005, Cell 120, 545). The possible link between a β peptide production and AD pathology emphasizes the need for a better understanding of the mechanisms of a β production and strongly warrants a therapeutic approach in regulating a β levels.

The release of A beta peptides is regulated by at least two proteolytic activities, respectively referred to as in A beta peptidesN-Cleavage by beta-and gamma-secretase at the terminal (Met-Asp linkage) and at the C-terminus (residues 37-42). In the secretory pathway, there is evidence that β -secretase cleavage first results in secretion of s-APP β (s β) and retention of the 11 kDa membrane-bound carboxy-terminal fragment (CFT). The latter is believed to produce a β peptide upon gamma-secretase cleavage. The amount of the longer isoform, a β 42, is selectively increased in patients with certain mutations in a particular protein (presenilin), and these mutations are associated with early-onset family AD. Thus, a β 42 is believed by many researchers to be the major cause of the pathogenesis of AD.

It is now clear that gamma-secretase activity cannot be attributed to a single protein, and is in fact associated with the assembly of different proteins.

Gamma (γ) -secretase activity is located in a multiple protein complex containing at least four components: presenilin (PS) heterodimer, apo-1, and pen-2. PS heterodimers are amino-and carboxy-terminal PS fragments generated from precursor proteins via endoproteolysis. The two aspartates of the catalyst site are located at the interface of this heterodimer. Dumb proteins have recently been proposed to act as gamma-secretase-matrix receptors. The functions of the other members of the gamma-secretase are not known, but all are required for activity (Steiner, 2004. Curr. Alzheimer Research 1(3): 175-.

Accordingly, while the molecular mechanism of the second cleavage step has remained elusive to date, the γ -secretase-complex has become one of the primary objectives in finding compounds for the treatment of AD.

Various Strategies have been proposed for the gamma-secretase enzyme of AD, including the development of inhibitors of substrate specificity and modulators of gamma-secretase activity directed against the catalytic site (Marjaux et al, 2004. Current Drug development: Therapeutic Strategies (Drug Discovery: Therapeutic Strategies), Vol.1, 1-6). Thus, a number of secretase-targeted compounds (Larner, 2004. secretase as a therapeutic target in Alzheimer's patients) 2000-2004. Expert Opin. the. patent 14, 1403-1420 are described.

In fact, this finding was confirmed by biochemical studies in which the effect of certain nonsteroidal anti-inflammatory drugs (NSAIDs) on gamma-secretase was demonstrated (US 2002/0128319; Eriksen (2003) J. Clin. invest. 112, 440). Potential limitations of using NSAIDs for the prevention or treatment of AD are their Cyclooxygenase (COX) inhibitory activity, which can lead to unwanted side effects, and their low CNS penetration (Peretto et al, 2005, j. med. chem. 48, 5705-. Recently, the NSAID R-flurbiprofen (flurbiprofen), an enantiomer lacking Cox-inhibiting activity and associated gastric toxicity, failed in a large third phase trial because the drug did not significantly improve the patient's ability to think and perform daily activities compared to patients receiving placebo.

WO-2009/103652 relates to 1H-1,2, 4-triazol-3-amine derivatives as modulators of A β;

WO-2009/032277 relates to heterocyclic compounds useful as modulators of gamma secretase;

WO-2009/050227 relates to pyridazine derivatives useful for inhibiting the reduction of beta amyloid peptide;

WO-2004/110350 relates to thiazolyl derivatives and their use in a β modulation;

WO-2010/010188 relates to [1,2,4]]Triazolo- [1,5-a]Pyridine compounds including 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl useful for the treatment of degenerative joint diseases and inflammatory diseases]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, 5- (4-methoxyphenyl) -N- [4- (3-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines and 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine;

WO-2010/098495 relates to imidazolyl pyrazine derivatives as AD therapeutic agents;

and WO-2010/083141 relates to bicyclic compounds for use in reducing beta amyloid production.

There is a strong need for new compounds that can modulate gamma-secretase activity, thus opening new routes for the treatment of AD. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. It is therefore an object of the present invention to provide such novel compounds.

Brief description of the invention

The compounds of the present invention have been found to be useful as gamma secretase modulators. The compounds according to the invention, and their pharmaceutically acceptable compositions, can be used for the treatment or prevention of AD.

The present invention relates to novel compounds of formula (I):

and stereoisomeric forms thereof, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a-4),

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²--

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　(b-4)；

--CH=N-CH=CH--　　　　　　　　(b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing one unsaturated bond may be substituted on one or more carbon atoms with one or (when possible) two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted (when possible) with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

wherein each aryl group¹Independently represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

and pharmaceutically acceptable thereofTo the addition salts and solvates of such compounds; provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, 5- (4-methoxyphenyl) -N- [4- (3-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines or 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine.

The invention also relates to processes for the preparation of compounds of formula (I) and pharmaceutical compositions containing them.

It has been found that the compounds of the present invention modulate γ -secretase activity in vitro and in vivo, and are therefore useful in the treatment or prevention of Alzheimer's Disease (AD), Traumatic Brain Injury (TBI), Mild Cognitive Impairment (MCI), aging, dementia associated with lewy bodies, amyloid cerebrovascular disease, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, preferably AD and other diseases associated with beta-amyloid pathologies (e.g. glaucoma).

In view of the above-mentioned pharmacological properties of the compounds of formula (I), they have been shown to be suitable for use as medicaments.

More specifically, the compounds are suitable for the treatment or prophylaxis of AD, amyloid cerebrovascular disease, multi-infarct dementia, dementia pugilistica or Down syndrome

The invention also relates to the use of a compound of general formula (I), its stereoisomeric forms and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for the preparation of a medicament for modulating the activity of gamma-secretase.

The use of compounds of formula (I) for modulating gamma-secretase activity such that the relative amount of a β 42 peptide produced is reduced is preferred. An advantage of the compounds of the invention or a portion of the compounds of the invention may be their increased CNS-permeability.

The invention will now be further illustrated. In the following paragraphs, the different aspects of the invention are defined in more detail. Aspects so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature that is recited as being preferred or advantageous may be combined with any feature or features that are recited as being preferred or advantageous.

Detailed Description

When describing the compounds of the present invention, the terms used are to be construed in accordance with the following definitions, unless the context indicates otherwise.

When the term "substituted" is used in the present invention, unless otherwise indicated or clear from context, it is intended that one or more hydrogens, particularly from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or group to which the expression "substituted" is applied is replaced with a group selected from the group indicated, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently stable to survive isolation from the reaction mixture to a useful purity and formulation into a therapeutic agent.

Unless otherwise indicated or clear from the context, the term "halo" as a group or part of a group generally refers to fluoro, chloro, bromo, iodo.

The term "C_1-6When alkyl "is a group or part of a group, it refers to formula C_nH_2n+1Wherein n is a number from 1 to 6. C_1-6The alkyl group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, even more preferably 1 to 2 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as described herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the group referred to may contain. Thus, for example, C_1-6Alkyl includes all straight-chain or branched alkyl groups containing between 1 and 6 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomersAnd the like.

The term "C_1-4When alkyl "is a group or part of a group, it refers to formula C_nH_2n+1Wherein n is a number from 1 to 4. C_1-4The alkyl group contains 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C_1-4Alkyl includes all straight or branched chain alkyl groups containing between 1 and 4 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl), and the like.

The term "C_2-6When alkyl "is a group or part of a group, it refers to formula C_nH_2n+1Wherein n is a number ranging from 2 to 6. C_2-6The alkyl group includes 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms, more particularly 2 to 3 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as indicated herein. When a subscript used herein follows a carbon atom, the subscript refers to the number of carbon atoms that the group referred to may contain. Thus, for example, C_2-6Alkyl includes all straight or branched chain alkyl groups having between 2 and 6 carbon atoms and thus includes, for example, ethyl, propyl, isopropyl,Is justPropyl group,Different from each otherPropyl, 2-methyl-ethyl, butyl and isomers thereof (e.g. methyl-ethyl)Is justButyl, isobutyl, or isobutyl,Different from each otherButyl and t-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term "C_1-6When an alkyloxy group "is a group OR part of a group, it is intended to have the formula OR^bWherein R is^bIs C_1-6An alkyl group. Non-limiting examples of suitable alkyloxy groups include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, tert-butyloxy, tert,Middle schoolButyl oxy group,Tert-butyl radicalOxy, pentyloxy, and hexyloxy.

The term "C_1-4When an alkoxy group is a group OR part of a group, it is intended to have the formula-OR^cWherein R is^cIs C_1-4An alkyl group. Suitable C_1-4Of alkoxy groupsNon-limiting examples include methyloxy (i.e., methoxy), ethyloxy (i.e., ethoxy), propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

In the framework of the present application, C_2-6Alkenyl is a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms containing one double bond, such as ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl and the like.

The term "C_3-7Cycloalkyl "alone or in combination, refers to a cyclic saturated hydrocarbon group containing 3 to 7 carbon atoms. Suitable C_3-7Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "C_1-3Alkyldiyl "when used as a group or part of a group is defined as a divalent straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms, such as methylene or methylidinyl, ethan-1, 2-diyl, propan-1, 3-diyl, propan-1, 2-diyl, and the like.

The term "C_2-6Alkanediyl "as a group or part of a group is defined as a divalent straight or branched chain saturated hydrocarbon radical having 2 to 6 carbon atoms, such as ethyl-1, 2-diyl, propyl-1, 3-diyl, propyl-1, 2-diyl, butyl-1, 4-diyl, pentyl-1, 5-diyl, hexyl-1, 6-diyl, 2-methylbutyl-1, 4-diyl, 3-methylpentyl-1, 5-diyl, and the like.

In a particular embodiment, C_1-3Alkanediyl and C_2-6Alkanediyl is defined as a divalent straight-chain saturated hydrocarbon group.

The term "C_2-6As a group or part of a group, an alkenediyl group is defined as a divalent straight-chain or branched hydrocarbon group containing one double bond and having 2 to 6 carbon atoms, such as 1, 2-ethenediyl (ethenediyl), 2-propenediyl (propelediyl), 3-butenediyl (butelediyl), 2-pentenediyl (penteniyl), 3-pentenediyl, 3-methyl-2-butenediyl, and the like.

In a particular embodiment, C_2-6Alkenediyl is defined as a divalent straight-chain hydrocarbon radical.

The term "thienyl" is equivalent to "thienyl".

When L is¹By definition, for example, NH- (C = O), this means nitrogen and contains A¹、A²、A³And A⁴The 6-membered ring structure of (a) and the carbonyl group is attached to the triazole moiety.

When L is¹Defined as, for example, (C = O) -NH, this refers to a carbonyl group and a group containing A¹、A²、A³And A⁴The 6-membered ring structure of (a) and the nitrogen is attached to the triazole moiety.

The symbol "- -" refers to the point of attachment to the rest of the molecule.

The Chemical Name of the compound of the present invention was generated using the naming software (ACD/Name product version 10.01; Build 15494, 2006, 12, 1) of Advanced Chemical Development, inc.

In tautomeric forms, it should be clear that other tautomeric forms not described are also included within the scope of the invention.

When any variable occurs more than one time in any constituent, each definition is independent.

It will be appreciated that certain compounds of formula (I) and the pharmaceutically acceptable addition salts and stereoisomeric forms thereof may contain one or more chiral centers and exist as stereoisomeric forms.

The term "stereoisomeric forms" as used above defines all possible isomeric forms which the compounds of formula (I) have. Unless otherwise mentioned or indicated, the chemical designation of compounds represents a mixture of all possible stereochemically isomeric forms. More specifically, stereogenic centers may have either the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. Compounds containing a double bond may have E-or Z-stereochemistry at the double bond. Stereoisomeric forms of the compounds of formula (I) are included within the scope of the present invention.

When a particular stereoisomeric form is indicated, this means that said form is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2%, and most preferably less than 1% of other isomers

When a particular regioisomeric form (regioisomeric form) is indicated, this means that said form is essentially free, i.e. binds less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably less than 1% of other isomers.

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

The pharmaceutically acceptable acid or base addition salts mentioned above or below are meant to be the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) may form. Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic (i.e., oxalic), malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanoic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, the salt form may be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, the ammonium salts, alkali metal and alkaline earth metal salts, such as the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, such as aliphatic and aromatic primary, secondary and tertiary amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, hydrabamine salt, and salts with amino acids such as arginine, lysine, and the like. Conversely, the salt form may be converted to the free acid form by treatment with an acid.

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

The compounds of formula (I) prepared in the processes described below can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. A method of separating the enantiomeric forms of the compounds of formula (I) comprises liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These methods would facilitate the use of enantiomerically pure starting materials.

The compounds of formula (I) or parts of the compounds of the invention may have improved solubility compared to the compounds disclosed in the prior art.

In the framework of this application, the compounds according to the invention are all isotopic combinations inherently intended to include their chemical elements. The architecture of the present applicationA chemical element, in particular when mentioned in the compounds according to formula (I), includes all isotopes and isotopic mixtures of this element. For example, when reference is made to hydrogen, this is to be understood as meaning¹H，²H，³H and mixtures thereof.

Thus, compounds according to the present invention inherently include compounds containing one or more isotopes of one or more elements, and mixtures thereof, including radioactive compounds, also known as radiolabeled compounds, in which one or more non-radioactive atoms are replaced by one of its radioactive isotopes. The term "radiolabeled compound" means any compound according to formula (I) or a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom. For example, the compounds may be labeled with a positron or gamma emitting radioisotope. For use in radioligand binding techniques,³h-atom or¹²⁵The I-atom is a selection of atoms that are substituted. For imaging, the most commonly used Positron Emitting (PET) radioisotope is¹¹C，¹⁸F，¹⁵O and¹³n, which are all accelerator production and have half-lives of 20, 100, 2 and 10 minutes, respectively. Because of the short half-life of these radioisotopes, it is only feasible that a facility with an accelerator can use them on site for their production, thus limiting their use. The most widely used of these isotopes is¹⁸F，^99mTc，²⁰¹Tl and¹²³I. the skilled worker is familiar with the handling of these radioisotopes, their production, isolation and incorporation into molecules.

Specifically, the radioactive atoms are selected from the group consisting of hydrogen, carbon, nitrogen, sulfur, oxygen, and halogens. In particular, the radioisotope is selected from³H，¹¹C，¹⁸F，¹²²I，¹²³I，¹²⁵I，¹³¹I，⁷⁵Br，⁷⁶Br，⁷⁷Br and⁸²Br。

as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one compound or more than one compound.

The terms described above and others used in the specification are well known to those skilled in the art.

Preferred features of the compounds of the invention are now set out.

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

and stereoisomeric forms thereof, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a-4),

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group- - - -R- -of the formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7)¹-R²-L²---

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　　(b-4)；

--CH=N-CH=CH--　　　　　　　　　(b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

and pharmaceutically acceptable addition salts and solvates thereof; provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines or 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine.

In one embodiment, the present invention relates to compounds of formula (I) and stereoisomeric forms thereof, wherein:

Het¹is a heterocyclic ring having the formula (a-1), (a-2), (a-3a) or (a-4),

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²--

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　　(b-4)；

--CH=N-CH=CH--　　　　　　　　　(b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group; or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

and pharmaceutically acceptable addition salts and solvates thereof; provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines or 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine.

In one embodiment, the present invention relates to novel compounds of formula (I) and stereoisomeric forms thereof, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a-4),

　(a-1)　　　　　　　(a-2) 　　　　　　　(a-3a)　　　　　(a-4)；

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²--

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　　(b-4)；

--CH=N-CH=CH-　　　　　　　　　 (b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹Aryl radical¹-carbonyl, aryl¹-O, aryl¹-NR^13d、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹Aryl radical¹-carbonyl, aryl¹-O, aryl¹-NR^13f、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹Aryl radical¹-carbonyl, aryl¹-O, aryl¹-NR^13e、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹Aryl radical¹-carbonyl group, C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group; or a 5-or 6-membered heteroaryl selected from: pyridyl, pyrimidinyl, oxazolyl, furanyl, thienyl, pyrazolyl, morpholinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

and pharmaceutically acceptable addition salts and solvates thereof; provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine.

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof. Or any subgroup thereof mentioned in any other embodiment, wherein one or more of the following restrictions apply:

(i) Het¹is a heterocyclic ring having formula (a-1), (a-2) or (a-3);

(ii) R³is C_1-4An alkyl group;

(iii) R⁴、R⁵and R⁶Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

(iv) R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, or C optionally substituted with one or more halo substituents_1-4An alkyl group;

(v) R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²- -; in particular (b-1), (b-2), (b-3), (b-4) or (b-5); more particularly (b-1), (b-2) or (b-3);

wherein (b-1) or (b-2) is substituted on a carbon atom by an aryl group¹(ii) is substituted with groups, and optionally, (b-1) or (b-2) is further substituted on one or more other carbon atoms with a total of one or two substituents each independently selected from: c_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

in particular, wherein (b-1) or (b-2) is substituted on a carbon atom by an aryl group¹Is substituted by radicals, and optionally (b-1) or (b-2) is optionally substituted on one other carbon atom by a C_1-4Alkyl substituents are further substituted;

wherein (b-3), (b-4) or (b-5) is substituted with an aryl group¹Substituent group substitution;

(vi) y represents a direct bond, NR¹⁴Or O; in particular NR¹⁴Or O;

wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

(vii) m represents 3 or 4;

(viii) n represents 1;

(ix) aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

(x) Each R^11eIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

(xi) Each R^12eIndependently is hydrogen or C_1-4An alkyl group.

In one embodiment, the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein:

Het¹is a heterocyclic ring having formula (a-1), (a-2) or (a-3);

R³is C_1-4An alkyl group; in particular methyl;

R⁴is hydrogen;

R⁵is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R⁶is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R^7ais hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R^7bis hydrogen, C_1-4Alkyloxy or C optionally substituted with one or more halo substituents_1-4An alkyl group; especially hydrogen, methyl, trifluoromethyl or methoxy;

R^7cis hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

X^ais CH or N;

X^bis O;

A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo, or C_1-4An alkyloxy group; in particular, wherein R⁹Is hydrogen, fluorine or methoxy;

A²is CH or N;

A³and A⁴Is CH;

L¹is carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group; in particular wherein R¹⁰Is hydrogen or methyl;

R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) —, -₂)₂-CH (aryl)¹)-CH₂--；

Wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

y represents NR¹⁴Or O; wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl, or C_1-4An alkyl group; in particular, R¹⁴Represents hydrogen, methylcarbonyl or methyl;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from:halo, C_1-4Alkyloxy, NR^11eR^12eAnd C optionally substituted by one or more halo substituents_1-4An alkyl group; in particular, aryl radicals¹Represents phenyl, optionally substituted with one, two or three substituents each independently selected from: fluorine, chlorine, methoxy, N (CH)₃)₂And methyl optionally substituted with one or more fluoro substituents;

R^11eis hydrogen or C_1-4An alkyl group; especially hydrogen, isopropyl or methyl;

each R^12eIndependently is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl; and pharmaceutically acceptable addition salts and solvates thereof, with the proviso that said compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine.

In one embodiment, the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein

Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3);

R³is C_1-4An alkyl group; in particular methyl;

R⁴is hydrogen;

R⁵is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R⁶is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R^7ais hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

R^7bis hydrogen, C_1-4Alkyloxy or C optionally substituted with one or more halo substituents_1-4Alkyl, in particular hydrogen, methyl, trifluoromethyl or methoxy;

R^7cis hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl;

X^ais CH or N;

X^bis O;

A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group; in particular wherein R⁹Is hydrogen, fluorine or methoxy;

A²is CH or N;

A³and A⁴Is CH;

L¹is carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group; in particular wherein R¹⁰Is hydrogen or methyl;

R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂--；

Wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group; in particular R¹⁴Represents hydrogen, methylcarbonyl, or methyl;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halogenGeneration, C_1-4Alkyloxy, NR^11eR^12eAnd C optionally substituted by one or more halo substituents_1-4An alkyl group; in particular aryl radicals¹Represents phenyl, optionally substituted with one, two or three substituents each independently selected from: fluorine, chlorine, methoxy, N (CH)₃)₂And methyl optionally substituted with one or more fluoro substituents;

R^11eis hydrogen or C_1-4An alkyl group; especially hydrogen, isopropyl or methyl;

each R^12eIndependently is hydrogen or C_1-4An alkyl group; in particular hydrogen or methyl; and pharmaceutically acceptable addition salts and solvates thereof, with the proviso that said compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine.

In one embodiment, the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2) or (a-3a)

R³Is C_1-4An alkyl group;

R⁴、R⁵and R⁶Each independently is hydrogen or C_1-4An alkyl group;

R^7ais hydrogen, or C_1-4An alkyl group;

R^7band R^7cEach independently is hydrogen or C_1-4An alkyl group;

X^ais CH or N;

X^bis O;

A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A¹、A²、A³And A⁴At most two of them are N;

L¹is NR¹⁰Carbonyl or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3) or (b-4) -R¹-R²-L²---

--(CH₂)_m-n-Y-(CH₂)_n-- (b-1)；

--(CH₂)_n-Y-(CH₂)_m-n-- (b-2)；

--CH=CH-CH=CH-- (b-3)；

--CH=CH-N=CH-- (b-4)；

Wherein (b-1) or (b-2) is substituted on a carbon atom by an aryl group¹Substituent group substitution;

wherein (b-3) or (b-4) may be substituted with an aryl group when possible¹Substituent group substitution;

y represents a direct bond, O or NR¹⁴(ii) a Wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof, with the proviso that said compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) benzeneBase of]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine.

In one embodiment, the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein

Het¹Is a heterocycle having formula (a-1), (a-2), (a-3) or (a-4);

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo, or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group- -R- -of the formula (b-1), (b-2), (b-3), (b-4) or (b-5)¹-R²-L²--，

--(CH₂)_m-n-Y-(CH₂)_n-- (b-1)；

--(CH₂)_n-Y-(CH₂)_m-n-- (b-2)；

--CH=CH-CH=CH-- (b-3)；

--CH=CH-N=CH-- (b-4)；

--CH=N-CH=CH-- (b-5)；

Wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing one unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups; and is

Wherein Y represents NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4; in particular m represents 3;

n represents 1;

wherein each aryl group¹Independently represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13dAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

and pharmaceutically acceptable addition salts and solvates thereof; provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, 5- (4-methoxyphenyl) -N- [4- (3-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines or 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine.

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein one or more of the following limitations apply:

(a) Het¹is a heterocyclic ring having formula (a-1), (a-2) or (a-3); in particular Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3 a);

(b) R³is C_1-4An alkyl group;

(c) R⁴、R⁵and R⁶Each independently is hydrogen or C_1-4An alkyl group;

(d) R^7ais hydrogen or C_1-4An alkyl group;

(e) R^7band R^7cEach independently is hydrogen or C_1-4An alkyl group;

(f) X^bis O;

(g) A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

(h) A²is CH or N; and A is³And A⁴Is CH;

(i) L¹is NR¹⁰Carbonyl or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

(j) R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3) or (b-4) -R¹-R²-L²- -; in particular (b-1) or (b-2);

(k) (b-1) or (b-2) may be substituted on a carbon atom by an aryl group¹Substituted by groups;

(l) (b-3) or (b-4) may be substituted with an aryl group when possible¹Substituent group substitution;

(m) Y represents a direct bond, O or NR¹⁴；

(n) R¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group;

(o) aryl group¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy and C optionally substituted with one or more halo substituents_1-4An alkyl group.

Another embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein one or more of the following limitations apply:

(a) Het¹is a heterocyclic ring having formula (a-1), (a-2) or (a-3 a);

(b) R³is methyl;

(c) R⁴、R⁵and R⁶Each independently hydrogen or methyl;

(d) R^7ais hydrogen or methyl;

(e) R^7band R^7cEach independently hydrogen or methyl;

(f) X^bis O;

(g) A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, fluorine, or methoxy;

(h) A²is CH or N; and A is³And A⁴Is CH;

(i) L¹is NR¹⁰Carbonyl or (C = O) -NH; wherein R is¹⁰Is hydrogen or methyl;

(j) R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3) or (b-4) -R¹-R²-L²--；

(k) (b-1) or (b-2) may be substituted on a carbon atom by an aryl group¹Radical (I)Substitution;

(l) (b-3) or (b-4) may be substituted with an aryl group when possible¹Substituent group substitution;

(m) Y represents a direct bond, O or NR¹⁴；

(n) R¹⁴Is hydrogen, methylcarbonyl or methyl;

(o) aryl group¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: fluorine, methoxy and methyl optionally substituted with one or more fluorine substituents.

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein one or more of the following limitations apply:

(i) Het¹is a heterocyclic ring having formula (a-1) or (a-3 a); in particular (a-1)

(ii) R³Is C_1-4An alkyl group; in particular methyl;

(iii) R⁴is hydrogen;

(iv) R^7aand R^7bIs hydrogen; r^7cIs C_1-4An alkyl group; in particular, R^7cIs methyl;

(v)X^ais N;

(vi) A¹is CR⁹Wherein R is⁹Is C_1-4An alkyloxy group; in particular R⁹Is methoxy;

A²、A³and A⁴Is CH;

(vii) L¹is NH.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group- -R- -of the formula (b-1), (b-2), (b-3), (b-4) or (b-5)¹-R²-L²- -; in particular (b-1), (b-2), (b-3) or (b-4); more particularly (b-1) or (b-2); wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing one unsaturated bond may be substituted with the substituents listed in any of the other embodiments;

wherein (b-3), (b-4) or (b-5) may be substituted with any of the substituents listed in the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group- -R- -of the formula (b-1), (b-2), (b-3), (b-4) or (b-5)¹-R²-L²- -; in particular (b-1), (b-2), (b-3) or (b-4); more particularly (b-1) or (b-2); wherein (b-1), (b-2), (b-3), (b-4) or (b-5) may be substituted with substituents as set forth in any of the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group of formula (b-3), (b-4) or (b-5) -R¹-R²-L²- -; in particular (b-4) or (b-5);

wherein (b-3), (b-4) or (b-5) may be substituted with any of the substituents listed in the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical of formula (b-1) or (b-2) — R¹-R²-L²-, wherein (b-1) and (b-2) may be optionally substitutedAnd substituents listed in other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group selected from: - - -R¹-R²-L²--：--(CH₂)₄--、--(CH₂)₂-NH-CH₂--、--(CH₂)₂-N(CH₃)-CH₂--、--(CH₂)₂-N(COCH₃)-CH₂--、--(CH₂)₂-O-CH₂-, - -CH = CH-and-CH = CH-N = CH- -; wherein each of these radicals may be substituted by one aryl radical¹And (4) substituent substitution.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group selected from: - - -R¹-R²-L²--：--(CH₂)₃-CH (aryl)¹)--、--(CH₂)₂-NH-CH (aryl)¹)--、--(CH₂)₂-N(CH₃) -CH (aryl)¹)--、--(CH₂)₂-N(COCH₃) -CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-CH = C (aryl)¹) - - - - - - - - - - - - - (CH- -N = C) (aryl group)¹)--。

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) —, -₂)₂-CH (aryl)¹)-CH₂--；

Wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂--；

Wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

wherein Y represents NR¹⁴Or O.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂- -; wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R together form a divalent group-R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, - - (CH)₂)₂-CH (aryl)¹)-CH₂and-CH (aryl)¹)-(CH₂)₃- -; wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radicalRadical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂-, wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂-, wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH-and-CH = CH-CH = C (1-piperidinyl) - -, wherein 1-piperidinyl may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - - - (CH)₂)₂-NR¹⁴-CH (aryl)¹) - - (CH)₂)₂-O-CH (aryl)¹)--。

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - - - - (CH)₂)₂-CH-C(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-CH (aryl)¹)-CH₂-, especially- - (CH)₂)₂-CH (aryl)¹)-CH₂--。

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, (b-3) is limited to-CH = CH-CH = C (aryl group)¹) -, wherein (b-4) is limited to- -CH = CH- -N = C (aryl group)¹) -, and wherein (b-5) is limited to- -CH = N- -CH = C (aryl group)¹)--。

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - (CH)₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹)--、--(CH₂)₂-CH (aryl)¹)-CH₂-, (b-3), (b-4) and (b-5), wherein (b-3), (b-4) or (b-5) may be further substituted according to any of the other embodiments;

in particular, - -R¹-R²-L²- - -is selected from: - - (CH)₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹)--、--(CH₂)₂-CH (aryl)¹)-CH₂-, (b-3), (b-4) and (b-5), wherein (b-3), (b-4) or (b-5) may be further substituted according to any of the other embodiments; even more particularly, - -R¹-R²-L²- - -is selected from: - - (CH)₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, (b-3), (b-4) and (b-5), wherein (b-3), (b-4) or (b-5) may be further substituted according to any of the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a compound of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7) or- - (CH)₂)₂-CH (aryl)¹)-CH₂A divalent radical of- -R¹-R²-L²- -; in particular (b-1), (b-2), (b-3), (b-4), (b-5) or--(CH₂)₂-CH (aryl)¹)-CH₂-, wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group; wherein said 1-piperidinyl, 1-pyrrolidinyl, or 4-morpholinyl may be substituted with one or more trifluoromethyl groups;

wherein (b-6) or (b-7) may be in one or more CH₂Substituted on the group by one or, where possible, by two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4Alkyl radical。

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂- -; more particularly- - - -R¹-R²-L²- - - - (CH)₂)₂-CH₂-CH (aryl)¹)--。

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂- -; more particularly- - - -R¹-R²-L²- - - - - (CH)₂)₂-CH₂-CH (aryl)¹) - -; wherein Y represents NR¹⁴Or O.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂- -; wherein R is¹⁴Represents hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹) -, - -CH = CH-C (aryl)¹) and-CH = CH-CH = C (1-piperidinyl) - -, wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups.

Another embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein (b-1) or (b-2) contain only saturated bonds, and wherein (b-1) or (b-2) may be substituted on one or more carbon atoms by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹、(C=O)-Aryl radicals¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group of formula (b-1), (b-3) or (b-4) -R¹-R²-L²- -; more particularly R¹and-L²-R²Together form a divalent group of formula (b-3), (b-4) or (b-1) -R¹-R²-L²- -, wherein (b-1) is- - (CH)₂)₄--、--(CH₂)₂-NH-CH₂--、--(CH₂)₂-N(CH₃)-CH₂--、--(CH₂)₂-N(COCH₃)-CH₂- - (CH)₂)₂-O-CH₂--，

Wherein the divalent radical may be substituted with any of the substituents listed in the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical of formula (b-1) or (b-2) — R¹-R²-L²- -; in particular (b-1); more particularly- - (CH)₂)₄--、--(CH₂)₂-NH-CH₂--、--(CH₂)₂-N(CH₃)-CH₂-- 、--(CH₂)₂-N(COCH₃)-CH₂- - (CH)₂)₂-O-CH₂- -; even more particularly- - (CH)₂)₄--；

Wherein the divalent group may be substituted with substituents as listed in any of the other embodiments.

Another embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein (b-3), (b-4) or (b-5) may be substituted, where possible, by one or more substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein, the other divalent radical- -R¹-R²-L²May be substituted as listed for substituents in any of the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical of formula (b-1) or (b-2) — R¹-R²-L²-, wherein (b-1) or (b-2) may be substituted with substituents as set forth in any of the other embodiments;

and wherein Het¹Is a heterocyclic ring having formula (a-3); in particular Het¹Is a heterocyclic ring having formula (a-3 a).

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is a heterocyclic ring having formula (a-1) or (a-3); in particular (a-1) or (a-3 a).

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is a heterocyclic ring having the formula (a-3), in particular (a-3 a).

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is of the formula (a-2)) The heterocycle of (a-3); in particular (a-2) or (a-3 a).

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3).

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3).

Another embodiment of the invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein Y represents NR¹⁴Or O.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein R⁹Is hydrogen or C_1-4An alkyloxy group; in particular C_1-4An alkyloxy group.

Another embodiment of the invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein Y represents a direct bond.

One embodiment of the present invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein A¹、A²、A³And A⁴At least one of which is not CH.

One embodiment of the present invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein at least one A is¹、A²、A³And A⁴Is N; preferably, wherein A is determined¹、A²、A³And A⁴Is N.

One embodiment of the present invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein A³And A⁴Is CH.

One embodiment of the present invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein at most one A is present¹、A²、A³And A⁴Is N.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R⁴、R⁵、R⁶And R⁸Each independently is hydrogen or C_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any of the other embodiments, wherein each aryl group¹Independently represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group; in particular each aryl group¹Independently represents phenyl substituted in the ortho position by trifluoromethyl or halo; more particularly, each aryl group¹Independently represents phenyl substituted in the ortho position by trifluoromethyl or chlorine.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein

R¹and-L²-R²Together form a compound of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or(b-7) divalent group- -R¹-R²-L²- -; in particular (b-1), (b-2), (b-3), (b-4) or (b-5);

wherein (b-1) or (b-2) may contain an unsaturated bond; in particular, wherein (b-1) or (b-2) contains only saturated bonds;

wherein (b-1), (b-2) or, where appropriate, a group containing an unsaturated bond is substituted on one or more carbon atoms by an aryl group¹Substituent group substitution; and wherein optionally (b-1), (b-2) or, where appropriate, a radical containing an unsaturated bond is further substituted on the other carbon atoms by a C_1-4Alkyl substitution;

wherein (b-3), (b-4) or (b-5) is substituted with one substituent selected from the group consisting of: aryl radicals¹And 1-piperidinyl; and wherein optionally (b-3), (b-4) or (b-5) is further substituted by a C_1-4Alkyl substitution;

wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

in particular, wherein (b-3), (b-4) or (b-5) is substituted by an aryl group¹Is substituted by a substituent, and wherein optionally (b-3), (b-4) or (b-5) is further substituted by a C_1-4Alkyl moieties are substituted.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein

R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹)=CH--、--(CH₂)₂-CH (aryl)¹)-CH₂-and-CH = CH-CH = C (1-piperidinyl) - -; wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

in particular, wherein- -R¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂--。

One embodiment of the present invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹)=CH--、--(CH₂)₂-CH (aryl)¹)-CH₂-and-CH = CH-CH = C (1-piperidinyl) - -; wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein Y represents NR¹⁴Or O;

in particular, wherein- -R¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-Y-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂- -; wherein Y represents NR¹⁴Or O.

One embodiment of the present invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹)=CH--、--(CH₂)₂-CH (aryl)¹)-CH₂-and-CH = CH-CH = C (1-piperidinyl) - -; wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups; wherein R is¹⁴Representative H, C_1-4Alkylcarbonyl or C_1-4An alkyl group;

in particular, wherein- -R¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) = CH-and- - (CH)₂)₂-CH (aryl)¹)-CH₂- -; wherein R is¹⁴Representative H, C_1-4Alkylcarbonyl or C_1-4An alkyl group.

An embodiment of the present invention relates to said compound of formula (I) or any subgroup thereof mentioned in any other embodiment, wherein Het¹Is a heterocyclic ring having formula (a-1).

An embodiment of the present invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group- -R- -of the formula (b-1), (b-2), (b-3), (b-4) or (b-5)¹-R²-L²--：

--(CH₂)_m-n-Y-(CH₂)_n-- (b-1)；

--(CH₂)_n-Y-(CH₂)_m-n-- (b-2)；

--CH=CH-CH=CH-- (b-3)；

--CH=CH-N=CH-- (b-4)；

--CH=N-CH=CH-- (b-5)；

Wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups; and

wherein Y represents NR¹⁴Or O.

One embodiment of the present invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof mentioned in any other embodiment, wherein R¹and-L²-R²Together form a divalent group of formula (b-3), (b-4) or (b-5) -R¹-R²-L²--，

--CH=CH-CH=CH-- (b-3)；

--CH=CH-N=CH-- (b-4)；

--CH=N-CH=CH-- (b-5)；

Wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups.

Another embodiment of the present invention relates to said compounds of formula (I) or any subgroup thereof mentioned in any other embodiment, wherein one or more of the following limitations apply

(i) m represents 3 or 4; in particular 3; or in particular m represents 4;

(ii) q represents 3,4, 5 or 6; in particular 3,4 or 5; more particularly 3 or 4; even more particularly 3;

(iii) r represents 0, 1,2 or 3; in particular 0, 1 or 2; more particularly 0 or 1; even more particularly 0; or even more particularly r represents 1.

Another embodiment of the present invention relates to said compounds of formula (I) or any subgroup thereof mentioned in any other embodiment, wherein R⁴、R⁵、R⁶And R⁸Each independently is hydrogen or C_1-4An alkyl group.

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein L¹Is NH.

Another embodiment of the invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, or any subgroup thereof as mentioned in any other embodiment, wherein aryl¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group.

Another embodiment of the invention relates to those compounds of formula (I), or any subgroup thereof mentioned in any other embodiment, wherein the structure of the heterocycle (a-3) is limited to (a-3a)

。

It is understood that any divalent radical, especially a divalent radical- -R¹-R²-L²In any of the above embodiments, may be substituted with the substituents listed in any of the other embodiments.

Another embodiment of the invention relates to those compounds of formula (I) or any subgroup thereof mentioned in any other embodiment, wherein the expression "in one or more CH₂"limited to" one or two CH's in a group₂On a radical ".

In one embodiment, the compound of formula (I) is selected from:

N- [8- (4-fluorophenyl) -5,6,7, 8-tetrahydro [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -benzamide,

8- (2-chlorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- [ 4-fluoro-2- (trifluoromethyl) phenyl]-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]Pyrazine esters-a (2-amine) of a (meth) acrylic acid,

8- [ 4-fluoro-2- (trifluoromethyl) phenyl]-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-7-methyl-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

8- (4-fluoro-2-methylphenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

7-acetyl-5, 6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

8- (4-fluoro-2-methylphenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (4-methyl-5-oxazolyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [4- (4-methyl-5-oxazolyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8-[3- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [3- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-5-oxazolyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-N-methyl-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, HCl,

5,6,7, 8-tetrahydro-N- [4- (2-methyl-5-oxazolyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [4- (4-methyl-5-oxazolyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy group-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -N- [ 3-fluoro-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -N- [4- (2, 6-dimethyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [3- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

(8R) -8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

(8S) -8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-amine,

8- [ 2-fluoro-5- (trifluoromethyl) phenyl]-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- (3-methoxyphenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-2-amine 2HCl₂O，

N- [4- (2, 5-dimethyl-4-pyridyl) phenyl group]-5,6,7, 8-tetrahydro-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluorophenyl) -5,6,7, 8-tetrahydro-N- (2-methoxy-2 '-methyl [3,4' -bipyridine)]-6-yl) - [1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -N- [ 6-methoxy-5- (4-methyl-1)H-imidazol-1-yl) -2-pyridinyl]-[1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

8- (4-fluoro-2-methylphenyl) -N- (2-methoxy-2' -methyl [3 ]4' -bipyridine]-6-yl) - [1,2,4]Triazolo [1,5-a]The reaction product of a pyrazine-2-amine,

8- (3-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- (3-methoxyphenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-amine 1.8 HCl.0.9H₂O，

8- (3-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-7- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-7- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, HCl,

8- (2-chlorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a]The pyridine-2-carboxamide is a compound of formula (I),

5, 6-dihydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl]-[1,2,4]Triazolo [1,5-a]Pyrazine-2-amine, HCl,

8- (4-fluoro-2-methylphenyl) -N- (2-methoxy-2 '-methyl [3,4' -bipyridine)]-6-yl) - [1,2,4]Triazolo [1,5-a]Pyrazine-2-amine, HCl,

8- [ 2-fluoro-5- (trifluoromethyl) phenyl]-5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- [4- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- [3- (dimethylamino) phenyl group]-5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2, 4-difluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2, 4-difluorophenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-fluoro-5-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine, 1.7HCl,

8- [ 2-fluoro-5- (trifluoromethyl) phenyl]-5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-fluoro-5-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (3-fluoro-5-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (3-fluoro-5-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [4- (4-pyridyl) benzeneBase of]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

(8S) -8- (4-fluoro-2-methylphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

(8R) -8- (4-fluoro-2-methylphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-8- (3-methoxyphenyl) -N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluorophenyl) -N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-7-methyl- [1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (3-fluoro-4-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine 1.6HCl.2.4H₂O，

8- (3-fluoro-4-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-ylamine, 1.3HCl.2.3H₂O，

8- (2-fluoro-5-methoxyphenyl) -N- [ 3-fluoro-4- (2-methyl-4-pyridyl) phenyl group]-5,6,7, 8-tetrahydro- [1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-fluoro-4- (2-methyl-4-pyridyl) phenyl group]-5,6,7, 8-tetrahydro-8- (3-methoxyphenyl) - [1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-3-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-3-methoxyphenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- [3- (trifluoromethyl) -1-piperidinyl]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine 1.5HCl 1.7H₂O，

5, 6-dihydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

N- [ 3-fluoro-4- (2-methyl-4-pyridyl) phenyl group]-5, 6-dihydro-8- [2- (trifluoromethyl) phenyl]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (2-chlorophenyl) -5, 6-dihydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (2-chlorophenyl) -5, 6-dihydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (2-chlorophenyl) -N- [ 3-fluoro-4- (2-methyl-4-pyridyl) phenyl group]-5, 6-dihydro-8H- [1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (4-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-7-methyl- [1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chloro-6-fluorophenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chloro-6-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridine)Radical) phenyl]-8- [ 2-methyl-5- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8- [ 2-methyl-5- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (4-fluoro-2-methylphenyl) -5, 6-dihydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- (2, 4-difluorophenyl) -5, 6-dihydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

5,6,7, 8-tetrahydro-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [4- (3-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5, 6-dihydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [2- (trifluoromethyl) phenyl]-8H-[1,2,4]Triazolo [5,1-c][1,4]An oxazin-2-amine, having a reactive group,

8- [ 2-fluoro-5- (trifluoromethyl) phenyl]-5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-fluorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-8- [4- (trifluoromethyl) phenyl][1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-7- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-5- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine 1.8HCl 3H₂O，

In its stereoisomeric form, the compound of formula (I),

and pharmaceutically acceptable addition salts, free bases and solvates thereof.

In one embodiment, the compound of formula (I) is selected from:

5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

in its stereoisomeric form, the compound of formula (I),

and pharmaceutically acceptable addition salts, free bases and solvates thereof.

All possible combinations of the above-mentioned important embodiments are to be considered as being comprised within the scope of the present invention.

Preparation of the Compounds

The invention also encompasses methods of making the compounds of formula (I) and subgroups thereof. In such reactions, it may be desirable to protect reactive functional groups, such as hydroxyl, amino or carboxyl groups, which are desirable in the final product, from participating in unwanted reactions. Conventional protecting Groups can be used in accordance with standard practice, see, for example, T.W. Greene and P.G.M. Wuts for "protecting Groups in Organic Chemistry", John Wiley and Sons, 1999.

The compounds of formula (I) and subgroups thereof may be prepared by the sequential steps described hereinafter. It is generally prepared from starting materials that are either commercially available or prepared by standard methods that are obvious to those skilled in the art. The compounds of the invention can also be prepared using standard synthetic methods commonly used by those skilled in the art of organic chemistry.

General preparation of some exemplary embodiments is shown below. All variables are defined as described above unless otherwise indicated.

Experimental procedures 1

In general, where L¹Compounds of formula (I) representing NH, referred to herein as compounds of formula (I-a), may be prepared as described in scheme 1 below, wherein halo is defined as Cl, Br or I, and wherein all other variables are defined as described above:

the compounds of formula (I-a) may be prepared by coupling reactions between intermediates of formula (II) and (III), or alternatively by coupling reactions between intermediates of formula (IV) and (V) (scheme 1). The reaction may be carried out in the presence of a suitable base, such as Cs₂CO₃Or sodium tert-butoxide. The reaction can be carried out in a reaction-inert solvent, such as toluene, DMF, tert-butanol (Ct-BuOH) or dioxane. The reaction is typically carried out in the presence of a suitable catalyst, such as palladium (II) acetate (Pd (OAc)₂) Or tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) And ligands such as (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis [ diphenylphosphine](Xantphos), [1,1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine ]](BINAP) or dicyclohexyl[ 2', 4', 6 '-Tris (1-methylethyl) [1,1' -biphenyl ]]-2-yl]-a phosphine (X-phos) in the presence of a catalytic system. Preferably, the reaction is carried out under an inert atmosphere, such as nitrogen or argon. The reaction rate and yield can be enhanced by microwave-assisted heating.

Experimental procedures 2

Wherein L is¹Compounds of formula (I) representing (C = O) -NH, referred to herein as compounds of formula (I-b), may be prepared from standard amide bond formation reactions using intermediates of formula (V) as the amine source and intermediates of formula (VI) as the carboxylic acid source. Alternatively, the compounds of formula (I-b) may be prepared by Pd-catalysed CO-insertion between an intermediate of formula (IV) and an intermediate of formula (V). Two synthetic schemes are illustrated in scheme 2, wherein halo is defined as Cl, Br or I, and wherein all other variables are defined as described above. Stirring at elevated temperature (e.g., 150 ℃) and/or pressure can increase the reaction rate. The reaction may be carried out with the addition of CO gas and typically may be carried out in an organic solvent such as THF. The reaction can be carried out from Pd, such as tetrakis (triphenylphosphine) palladium(Pd(PPh₃)₄)、Pd(OAc)₂Or Pd₂(dba)₃In combination with a suitable ligand.

Experimental procedures 3

Wherein L is¹Compounds of formula (I) representing NH- (C = O), herein referred to as compounds of formula (I-C), may be prepared according to scheme 3 from a Pd-catalyzed CO-insertion reaction between an intermediate of formula (III) and an intermediate of formula (II), wherein halo is defined as Cl, Br or I, and wherein all other variables are as defined above. Stirring at elevated temperature (e.g., 150 ℃) and/or pressure can increase the reaction rate. The reaction may be carried out with the addition of CO gas and typically may be carried out in an organic solvent such as THF. The reaction may be of Pd origin, e.g. Pd (O)Ac)₂、Pd₂(dba)₃Or Pd (PPh)₃)₄To catalyze. Suitable ligands may be added to the reaction.

Alternatively, the compounds of formula (I-c) may also be prepared from standard amide bond formation reactions using amine sources of formula (II) and the corresponding carboxylic acid derivatives of intermediates of formula (III). This reaction can be carried out under typical reaction conditions, similar to those described in experimental procedure 2.

Experimental procedures 4

Intermediates of formula (IV), wherein all variables are as defined above, can be prepared by converting the amino-moiety of intermediates of formula (II) into halo-group by the reaction known as Sandmeyer (scheme 4). In scheme 4, halo is defined as Cl, Br, or I, and all other variables are defined as described above. Intermediate (II) is first treated with a nitrite source, e.g. NaNO₂Treated under acidic conditions to convert to the corresponding diazonium salt, and then treated with a halide source such as KI, CuBr or CuCl. Typical reaction conditions known to those skilled in the art may be used.

Experimental procedures 5

Intermediates of formula (II), wherein all variables are as defined above, can be prepared according to scheme 5 by reduction of intermediates of formula (VII). Reduction of the intermediate of formula (VII) to the intermediate of formula (II) may be carried out by conventional methods, for example reductive hydrogenation with a metal or metal salt and acid [ e.g. a metal such as Fe, or a metal salt such as SnCl₂And acids such as mineral acids (HCl、H₂SO₄Or the like) or an organic acid (acetic acid or the like)]To proceed with. Alternatively, other well-known methods of converting nitro groups to the corresponding amines may be used.

Experimental procedures 6

Intermediates of formula (VII) or (II) wherein Het¹Is defined as a heterocyclic ring having the formula (a-1) wherein R^aIs defined as NO₂Or NH₂And wherein the other variables are defined as hereinbefore, referred to herein as intermediates of formula (X), may be prepared according to scheme 6 by nucleophilic aromatic substitution of an intermediate of formula (IX) with an intermediate of formula (VIII), wherein LG is defined as a leaving group, e.g. F, Cl, Br, I, tosylate, mesylate or triflate, especially F, Cl, Br or I, more especially Cl, Br or I; and wherein all other variables are as defined above. The reaction may be carried out under an inert atmosphere, e.g. N₂The process is carried out as follows. Stirring at elevated temperature (e.g., between 70-170 ℃) and/or pressure can increase the reaction rate. The reaction is typically carried out in an organic solvent such as DMSO, DMF or NMP: (N-methylpyrrolidone), in a base such as K₂CO₃、Cs₂CO₃Or Et₃In the presence of N.

The reaction may be carried out in the presence of a copper catalyst. Catalytic or stoichiometric copper salts such as Cu may be used₂O, CuI or CuBr.

Experimental procedures 7

Intermediates of formula (VII) wherein Het¹Is defined as being via R⁶Substituted oxazolyl, referred to herein as an intermediate of formula (XIII), can be prepared by condensation of an intermediate of formula (XI) with an intermediate of formula (XII), as shown in scheme 7. Intermediate (XI) is commercially available or can be prepared according to conventional reaction procedures generally known in the art. The condensation reaction is carried out in a suitable base, e.g. K₂CO₃Or sodium ethoxide (NaOEt). The reaction can be carried out in a polar solvent, such as methanol (MeOH) or ethanol (EtOH). Agitation and/or elevated temperature (e.g., between 70-110 ℃) may increase the reaction rate. In scheme 7, all variables are defined as described above.

Experimental procedures 8

Intermediates of formula (VII) wherein Het¹Defined as passing through R in the 2-position⁵Substituted and by CH in the 4-position₃Substituted oxazoles, referred to herein as intermediates of formula (XIV), can be prepared according to scheme 8 by condensation of an intermediate of formula (XI) with an intermediate of formula (XV), wherein all variables are as defined above. Both intermediates are commercially available or can be prepared according to conventional reaction procedures generally known in the art. This condensation reaction is typically carried out in a solvent such as pyridine. Agitation and/or elevated temperature (e.g., between 70-110 ℃) may increase the reaction rate.

Experimental procedures 9

Intermediates of formula (VII) or (II) wherein Het¹The heterocyclic ring defined as (a-2), (a-3) or (a-4), referred to herein as an intermediate of formula (XVII), can be prepared according to scheme 9 from an intermediate of formula (XVI) (wherein Het¹A heterocyclic ring defined by formula (a-2), (a-3) or (a-4) and an intermediate of formula (IX) wherein R is^aCan be NO₂Or NH₂) By the Suzuki-Miyaura cross-coupling reaction. In formula (IX), LG^aDefined as a leaving group, such as Cl, Br, I, tosylate, mesylate or triflate, especially Cl, Br or I; and in formula (XVI), B (OR)₂Boric acid B (OH)₂Or a corresponding boronic ester thereof, such as pinacol (pinacol) ester. The reaction is carried out with a Pd catalyst, such as Pd (PPh)₃)₄Or [1,1' -bis (diphenylphosphino-. kappa.P) ferrocene]Palladium dichloride (PdCl)₂(dppf)). The reaction is carried out in a suitable base such as K₂CO₃Or K₃PO₄In the presence of a reaction inert solvent such as toluene, DMF, MeCN (and may include H)₂O). Stirring at elevated temperature (e.g., between 50-120 ℃) and/or pressure can increase the reaction rate, which can be done using microwave irradiation or by conventional heating.

Experimental procedures 10

Intermediates of formula (IV) wherein at least one A¹Or A³Represents N, and wherein Het¹Defined as formula (a-1) and wherein all other variables are as previously defined, referred to herein as intermediates of formula (XIX), can be obtained according to scheme 10 via intermediates of formula (XVIII) wherein at least one A is¹Or A³Represents N, with an optionally substituted imidazole or triazole of formula (VIII), wherein LG is as defined hereinbefore, wherein halo is defined as Cl, Br or I, and wherein all other substituents are as defined hereinbefore. The reaction can be carried out under reaction conditions similar to those described in experimental procedure 4.

Experimental procedures 11

Intermediates of formula (IV) wherein Het¹Represents a group of the formula (a-1), wherein X^aLimited to CH, wherein all other variables are as defined above, are referred to herein as intermediates of formula (XXIV), according to scheme 11, by acylation of intermediate (XX) in a reaction inert solvent such as THF, and optionally in a suitable base such as Et₃In the presence of N. The intermediate of formula (XXIII) may then be prepared by alkylation of the intermediate of formula (XXI) with an intermediate of formula (XXII) in a reaction-inert solvent such as DMF and a suitable base such as Cs₂CO₃Or K₂CO₃And optionally in the presence of catalytic amounts of iodide salts such as KI or NaI. Finally, intermediate (XXIII) is reacted with an ammonia source such as ammonium acetate (NH)₄OAc) to give a compound of formula (XXIV). In scheme 11, halo is defined as Cl, Br or I, halo^aAre defined as Cl or Br and all other variables are as defined above.

Experimental procedures 12

Intermediates of formula (III), wherein all variables are as defined above, can be prepared by converting the amino-moiety of intermediates of formula (V) into halo-group by Sandmeyer reaction (scheme 12). In scheme 12, halo is defined as I, Br or Cl and all other variables are as defined above. Intermediate (V) is first treated with a nitrite source, e.g. NaNO₂Under acidic conditions or isoamyl nitrite or tert-butyl nitrite in an organic solvent such as CH₃Treated in CN to the corresponding diazonium salt and then treated with a halide source such as KI, CuBr or CuCl.Typical reaction conditions known to those skilled in the art may be used.

Experimental procedures 13

An intermediate of formula (V) wherein R¹and-L²-R²Taken together to form a divalent radical as shown in scheme 13, wherein t is 0 or 1, and wherein all other variables are as defined in the compounds of formula (I), herein referred to as intermediates of formula (V-b1), can be prepared by condensation reactions between intermediates of formula (XXXI) and aminoguanidines of formula (XXXII), as shown in scheme 13. Stirring at elevated temperature (e.g., 40-160 ℃) and/or pressure can increase the reaction rate, which can be done using microwave irradiation or by conventional heating. Typically an alcoholic solvent such as 2-propanol may be used.

Experimental procedures 14

Alternatively, intermediates of formula (V-b1), intermediates of formula (XXXII-a) which can be produced by substitution with hydrazine (step a), followed by reaction with an intermediate bearing LG^bCondensation of amidines of leaving groups, for example benzotriazole (step b). The substitution reaction is carried out in the presence of a suitable base, such as NaH, and in a reaction-inert solvent, such as DMF. This reaction is typically carried out at low or room temperature (r.t), however elevated temperatures (e.g., between 40-160 ℃) and/or pressures can increase the reaction rate, which can be carried out using microwave irradiation or conventional heating. Reactions of this type can typically be carried out in alcoholic solvents such as 2-propanol.

Experimental procedures 15

An intermediate of formula (V) wherein R¹and-L²-R²Together form a divalent group of formula-CH = CH-or-CH = CH-N = CH-referred to herein as intermediate (Z-b 2) of formula (V-b2)^aRepresents N, CH or C-C_1-4Alkyl (e.g. C-CH)₃) Prepared according to scheme 15 starting from a condensation reaction between an intermediate of formula (XXXV) and an isothiocyanate of formula (XXXVI) in a reaction inert solvent such as dioxane at r.t.. This reaction is typically carried out at low or room temperature (r.t), however elevated temperatures (e.g., between 40-160 ℃) and/or pressures can increase the reaction rate, which can be carried out using microwave irradiation or conventional heating. The condensation reaction between an intermediate of formula (XXXVII) and an amine source, such as hydroxylamine, to give intermediate (V-b2), typically can be carried out in an alcoholic solvent such as EtOH or MeOH at r.t., however, microwave elevated temperatures (e.g., between 40 and 160 ℃) and/or pressures can increase the reaction rate.

Intermediates of formula (V-b2) wherein R is a divalent radical of formula-CH = CH-or-CH = CH-N = CH-can be prepared according to a similar reaction procedure¹-R²-L²-further substituted by a substituent as defined for the compound of formula (I). In such cases, the Pd mediated coupling of the intermediate of formula (XXXIV) with the corresponding amine, phenol, boronic acid or ester is typically carried out to give an intermediate of formula (XXXV-a), which can be further reacted in scheme 15. Halo is defined as Br, Cl or I; z^aAs defined above. This reaction is illustrated in scheme 15a below.

Alternatively, an intermediate of formula (V-b2), wherein R is a divalent group of formula-CH = CH-or-CH = CH-N = CH-¹-R²-L²Further substituted with substituents as defined for compounds of formula (I), herein referred to as intermediates of formula (V-b4), can be prepared by converting intermediates, e.g., intermediates of formula (XXXIV), to intermediates of formula (V-b3) according to the reaction scheme described in scheme 15. Subsequently, intermediates of formula (V-b3) can be converted to intermediates of formula (V-b4) in a Pd mediated coupling, for example with a corresponding amine, phenol or boronic acid or ester. This reaction is illustrated in scheme 15b below. All variables are defined as mentioned in scheme 15 a.

If the substituent in formula (XXXV-a) or (V-b4) is aryl¹Then intermediates of formula (XXXIV) or (V-b3), respectively, can be reacted with boronic acids (aryl groups)¹-B(OH)₂) Or ester derivatives (aryl)¹-B(OR)₂) And (4) reacting. The coupling reaction can be carried out in a suitable solvent such as dioxane over a Pd catalyst such as Pd (PPh)₃)₄And bases such as NaHCO₃In the presence of H₂In the presence of O. The reaction may be carried out using microwave irradiation or conventional heating (e.g. 150 ℃).

If the substituent in formula (XXXV-a) or (V-b4) is NR^13f-aryl radical¹Typically, then the intermediate of formula (XXXIV) or (V-b3), respectively, may be reacted with an aryl group¹Amine derivative of (H)₂N-aryl radical¹) And (4) reacting. The coupling reaction may be carried out in a suitable solvent such astIn BuOH over a Pd catalyst such as Pd₂(dba)₃And bases such as Cs₂CO₃In the presence of (a). This reaction can be carried out in the presence of a ligand such as X-Phos. Typically, the reaction can be carried out using conventional heating (e.g., 100 ℃).

If the substituent in formula (XXXV-a) or (V-b4) is O-aryl¹Typically, then the intermediate of formula (XXXIV) or (V-b3), respectively, may be reacted with an aryl group¹Phenol derivatives of (HO-aryl)¹) And (4) reacting. The coupling reaction may be carried out in a suitable solvent such asN,N-Dimethylacetamide (DMA), in the presence of a copper catalyst. Using copper salts, e.g. Cu₂O, CuI, or CuBr. Usually by adding a base such as K to the reaction mixture₂CO₃. Typically, the reaction can be carried out using conventional heating (e.g., 150-.

If the substituent in formula (XXXV-a) or (V-b4) is (C = O) -aryl¹Or C_1-4Alkyl-carbonyl, typically an intermediate of formula (XXXIV) or (V-b3) may be substituted with aryl¹Corresponding aldehyde (aryl) of¹- (C = O) H) or C_1-4Alkyl radical (C)_1-4Alkyl- (C = O) H). This coupling reaction can typically be carried out in the presence of an organometallic compound, particularly an organolithium reagent such as n-butyllithium. The reaction can generally be carried out in a suitable solvent such as THF. In the final step, the hydroxyl group can be oxidized to the corresponding ketone using reaction conditions known to those skilled in the art.

If the substituent in formula (XXXV-a) or (V-b4) is C_1-4Alkyl, then typically intermediates of formula (XXXIV) or (V-b3), respectively, can be reacted with the corresponding aldehyde. This coupling reaction can typically be carried out in the presence of an organometallic compound, particularly an organolithium reagent such as n-butyllithium. The reaction can generally be carried out in a suitable solvent such as THF. Subsequently, the hydroxyl group can be reacted with tosyl chloride in a base such as Et₃In the presence of N, in a suitable solvent, such as typically DCM, to form the tosylate. In the final step, the tosylate group may be reduced with a reducing agent such as NaBH₄Removed in the presence of an alcoholic solvent such as MeOH. The reaction can be carried out at r.t. or at elevated temperature.

Experimental procedures 16

Aromatic intermediates of formula (V-b2), (V-b3) and (V-b4)The bodies may be hydrogenated in a conventional manner, for example reductively or in the presence of a metal or metal salt and an acid [ e.g. a metal such as Fe, or a metal salt such as SnCl ]₂And acids such as mineral acids (HCl, H)₂SO₄Or the like) or an organic acid (acetic acid or the like)]Reducing to the corresponding reduced form. Alternatively, other well known methods of converting aromatics to their corresponding reduced forms can be used.

Analogous reaction procedures can be used to synthesize compounds of formula I wherein R¹and-L²-R²Compounds of formula (I) which together form a divalent group of formula-CH = CH-or-CH = CH-N = CH-are converted to their corresponding reduced form.

The starting materials in the above schemes are commercially available or can be prepared by one skilled in the art.

Any one or more of the following additional steps may be performed in any order, as necessary or desired:

the compounds of formula (I), any subgroup, addition salts, solvates and stereochemically isomeric forms thereof may be converted into further compounds according to the invention using methods known in the art.

It will be appreciated by those skilled in the art that in the above methods, the functional groups of the intermediate compounds may need to be blocked with protecting groups. If the functional groups of the intermediate compounds are blocked with protecting groups, they can be deprotected after the reaction step.

Pharmacology of

The compounds of the invention have been found to modulate gamma-secretase activity. Thus, the compounds according to the present invention and pharmaceutically acceptable compositions thereof may be used for the treatment or prevention of AD, TBI, MCI, aging, dementia associated with lewy bodies, cerebrovascular amyloid diseases, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, preferably AD.

The compounds according to the invention and their pharmaceutically acceptable compositions may be used for the treatment or prevention of a disease or condition selected from: AD. TBI, MCI, senility, dementia with Lewy bodies, amyloid cerebrovascular disease, multi-infarct dementia, dementia pugilistica, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

As used herein, the term "modulating γ -secretase activity" refers to the effect on the treatment of APP by the γ -secretase-complex. Preferably it refers to a method wherein the overall rate of treatment of APP remains substantially the effect of no administration of the compound, but wherein the relative amount of product treated is altered, more preferably the production of a β 42-peptide is reduced. For example, different A.beta.species may be produced (e.g., A.beta.38 of shorter amino acid sequence or other A.beta.peptide species in place of A.beta.42) or the relative amounts of the products may be different (e.g., the ratio of A.beta.40 to A.beta.42 is altered, preferably increased).

It was previously demonstrated that the γ -secretase complex is also involved in handling Notch (Notch) -proteins. Notch is a signaling protein that plays a critical role in developmental processes (as reviewed, for example, in Schweisguth F (2004) curr. biol. 14, R129). Regarding the use of gamma-secretase modulators in medicine, it appears to be particularly advantageous for notch-processing activities that do not interfere with gamma-secretase activity, in order to avoid the presumed unwanted side effects. Although gamma-secretase inhibitors exhibit side effects as a result of treatment accompanied by inhibition of notch, gamma-secretase modulators may have the following advantages: the selective reduction in production of a β in a highly aggregated and neurotoxic form, i.e., a β 42, is not accompanied by inhibition of notch processing, while the reduction in production of a β in a less aggregated form, i.e., a β 38, is not accompanied by inhibition of notch processing. Thus, preferred compounds are those that do not affect the notch-processing activity of the γ -secretase-complex.

As used herein, the term "treatment" means the entire process in which the progression of the disease can be slowed, interrupted, arrested or stopped, but need not indicate complete elimination of all symptoms.

The present invention relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use as a medicament.

The invention also relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, which are useful for modulating gamma-secretase activity.

The invention also relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of a disease or disorder selected from the group consisting of AD, TBI, MCI, senility, dementia associated with lewy bodies, amyloid cerebrovascular disease, multi-infarct dementia, down syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid.

In one embodiment, the disease or disorder is preferably AD.

The invention also relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, which are useful for the treatment of said diseases.

The invention also relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of said diseases.

The invention also relates to compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prophylaxis, in particular in the treatment of γ -secretase mediated diseases or disorders.

The invention also relates to the use of a compound according to general formula (I), its stereoisomeric forms and the pharmaceutically acceptable acid or base addition salts and solvates thereof for the preparation of a medicament.

The invention also relates to the use of a compound according to general formula (I), its stereoisomeric forms and the pharmaceutically acceptable acid or base addition salts and solvates thereof for the preparation of a medicament for modulating the activity of gamma-secretase.

The invention also relates to the use of a compound according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof for the preparation of a medicament for the treatment or prevention of any one of the above mentioned disease conditions.

The invention also relates to the use of compounds according to general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for the preparation of a medicament for the treatment of any of the above mentioned disease states.

In the present invention, it is particularly preferred to administer a compound of formula (I) or any subgroup thereof which inhibits the IC production of the A β 42-peptide₅₀Values are less than 1000 nM, preferably less than 100 nM, more preferably less than 50 nM, and even more preferably less than 20 nM, when determined according to a suitable assay, such as the assay used in the examples below.

The compounds of the present invention may be administered to a mammal, preferably a human, for the treatment or prevention of any of the above-mentioned diseases.

In view of the use of the compounds of formula (I), there is provided a method of treating or preventing the development of any one of the above-mentioned diseases in warm-blooded animals, including humans.

Said method comprising the administration, that is to say systemic or topical administration, preferably oral administration, of an effective amount of a compound of formula (I), its stereoisomeric forms and pharmaceutically acceptable addition salts and solvates thereof, to warm-blooded animals including humans.

From the results presented below, a skilled artisan treating the disease can determine the daily amount of effective treatment. A therapeutically effective daily amount will be from about 0.005 mg/kg to 50 mg/kg, especially 0.01 mg/kg to 50 mg/kg body weight, more especially 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect will, of course, vary from case to case as a function of the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

The method of treatment may also include administering the active ingredient on a schedule between one and four intakes per day. In these methods of treatment, the compounds according to the invention are preferably formulated prior to administration. Suitable pharmaceutical formulations are prepared by known methods using well known and readily available ingredients, in accordance with the description herein below.

Compounds of the present invention suitable for treating or preventing Alzheimer's disease or symptoms thereof may be administered alone or in combination with one or more other therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation containing a compound of formula (I) and one or more other therapeutic agents, as well as administration of a compound of formula (I) and each of the additional therapeutic agents under their respective separate pharmaceutical dosage formulations. For example, the compound of formula (I) and the therapeutic agent may be administered to the patient together in a single oral dosage composition, such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

Although the active ingredient may be administered alone, it is preferably present as a pharmaceutical composition.

Accordingly, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to formula (I).

The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

For ease of administration, the compounds of the present invention may be formulated in different pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds according to formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, or any subgroup or combination thereof, may be formulated into different pharmaceutical forms for administration purposes. Suitable compositions may refer to all compositions typically used for systemic administration of drugs.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is intimately admixed with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation to be administered. These pharmaceutical compositions need to be in unit dosage form, suitable in particular for oral, rectal, subcutaneous, parenteral injection or inhalation administration. For example, in preparing the compositions in orally administrable form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like may be employed. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may be included, for example to aid solubility. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing the compounds of formula (I) may be formulated in oils for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures of these with other oils. Suspensions which can be injected can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be used. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier optionally contains penetration enhancers and/or suitable wetting agents, optionally in combination with small amounts of suitable additives of any nature that do not cause significant deleterious effects on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, for example as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of the compounds of formula (I) are more suitable for the preparation of aqueous compositions because of their increased aqueous solubility over the corresponding base or acid form.

It is particularly advantageous to formulate the above-described pharmaceutical compositions in unit dosage form to provide ease of administration and uniformity of dosage. Unit dosage form as used herein means physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

Since the compounds according to the invention are effective orally administrable compounds, orally administrable pharmaceutical compositions containing said compounds are particularly advantageous.

In order to increase the solubility and/or stability of the compounds of formula (I) in the pharmaceutical composition, it may be advantageous to use α -, β -or γ -cyclodextrins or derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl- β -cyclodextrin or sulfobutyl- β -cyclodextrin. Auxiliary solvents such as alcohols may also improve the solubility and/or stability of the compounds according to the invention in the pharmaceutical composition.

Depending on the mode of administration, the pharmaceutical composition will preferably contain from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of a compound of formula (I), and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The following examples illustrate the invention.

Examples

Hereinafter the term "THF" refers to tetrahydrofuran; the term "DCM" refers to dichloromethane; "MeOH" refers to methanol; "EtOH" refers to ethanol; "HPLC" refers to high performance liquid chromatography; "sat." means saturated; "sol." refers to a solution; "aq." refers to an aqueous solution; "EtOAc" refers to ethyl acetate; "r.t." means room temperature; "r.m." means the reaction mixture; "HOAc" refers to acetic acid; "Et₃N "refers to triethylamine; "RP" refers to inverse phase; "o.l." means an organic layer; "min" means minutes; "conc." means concentration; "h" means hours; "q.s." means appropriate amounts; "i.d." means inside diameter; "Et₂O "means diethyl ether; "SFC" refers to supercritical liquid chromatography; "DCE" refers to 1, 2-dichloroethane; "DIPEA" refers to diisopropylethylamine; "eq." means equivalent; "DIPE" refers to diisopropyl ether; "DME" refers to 1, 2-dimethoxyethane; "DMF" refers toN,N-dimethylformamide; "Pd (PPh)₃)₄"refers to tetrakis (triphenylphosphine) palladium; "Pd (OAc)₂"refers to palladium (II) acetate; "Grubbs second generation catalyst" refers to (1, 3-bistrimethylphenylimidazolidin-2-ylidene) (tricyclohexylphosphine) benzylidene ruthenium dichloride; ' Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium; "X-Phos" refers to dicyclohexyl [ 2', 4', 6 '-tris (1-methylethyl) [1,1' -biphenyl ]]-2-yl]-a phosphine; "Xantphos" means (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis [ diphenylphosphine](ii) a "Tebbes reagent" meansμ-chloro-bis (η5-2, 4-cyclopentadien-1-yl) (dimethylaluminum) -μ-methylene-titanium; "Dess-Martin periodinane" means 1,1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-phenyliodoxy-3 (1H) -one (benziodoxol-3(1H) -one); "rac" refers to a racemic mixture; and "iPrOH" refers to 2-propanol.

The absolute stereochemical configuration of certain compounds was determined using Vibronic Circular Dichroism (VCD). Description of the determination of absolute configuration using VCD can be found in dyetkin a.b. et al,Chirality, 14: 215, 219 (2002).

A. Preparation of intermediates

Example A1

a) Preparation of intermediate 1

4-Fluorophenylboronic acid (1.21 g, 8.7 mmol) and Pd (PPh)₃)₄(0.42 g, 0.36 mmol) was added to 2-amino-3-bromopyridine (1.25 g, 7.20 mmol) in DMF (10 ml), water (4 ml) and K₂CO₃(3.00 g, 21.70 mmol). The resulting mixture was heated at 160 ℃ for 30 minutes under microwave irradiation. R.m. was cooled to r.t. and partitioned between water and DCM. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 1.20 g ofIntermediates 1(88%)。

b) Preparation of intermediate 2

Ethoxycarbonyl isothiocyanate (1.92 g, 15 mmol) was added dropwise to a mixture of intermediate 1 (2.4 g, 13 mmol) in dioxane (125 ml) at r.t. The mixture was stirred at r.m. for 6 h. The solvent was then evaporated under reduced pressure. The resulting solid was triturated in DIPE, filtered and dried under vacuum to give 2.9 g ofIntermediates 2 (71%)。

c) Preparation of intermediate 3

DIPEA (3.4 g, 26 mmol) was added dropwise to a stirring mixture of hydroxylamine hydrochloride (3.05 g, 44 mmol) in MeOH (100 ml) and EtOH (10 ml) at r.t. The mixture is stirred at r.m. and r.t. for 30 min. Intermediate 2(2.80 g, 8.8 mmol) was then added portionwise and the r.m. stirred at reflux for 16 h. The r.m. was cooled to r.t. and evaporated under reduced pressure. The residue was dissolved in DCM and the solution was washed with brine. The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 1.4 g ofIntermediates 3(70%)。

d) Preparation of intermediate 4

In N₂MeOH (100 ml) was added to Pt/C5% (200 mg) under atmosphere. A mixture of intermediate 3(1.20 g, 5.26 mmol) in HCl/iPrOH (6N; q.s.) was added. R.m. at 25 ℃ and H₂Stirred under atmosphere until 2 eq.H₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The residue was suspended in DIPE, filtered and dried to give 1.1 g ofIntermediates 4(78%)。

e) Preparation of intermediate 5

A solution of intermediate 4(830 mg, 3.57 mmol) in HOAc (7.2 ml) was added to NaNO at 10 deg.C₂(277 mg, 4.13 mmol) in conc. H₂SO₄(5.5 ml). The mixture is stirred at r.m. and r.t. for 30 min. Subsequently, a solution of CuBr (1.05 g, 7.34 mmol) in 48% HBr (7.2 ml) was added dropwise. The mixture was stirred at r.t. for 1h and then carefully added to the stirred sat aq. NaHCO₃Solution and DCM. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 570 mg ofIntermediates 5(54%)。

Example A2

a) Preparation of intermediates 6,7 and 8

Intermediates 6,7 and 8 were prepared by analogous reaction procedures as described in examples a1.a, a.1.b and a1. c.

b) Preparation of intermediate 9

A solution of intermediate 8(1 g, 4.09 mmol) in HOAc (8 ml) was added to NaNO at 10 deg.C₂(315 mg, 5.57 mmol) in conc H₂SO₄(6.7 ml). R.m. was stirred at r.t. for 30 min and then added dropwise to a solution of CuBr (1.17 g, 8.18 mmol) in 48% HBr (8 ml). R.m. was stirred at r.t. for 1h, then added carefully to the stirred saturated NaHCO₃Aqueous solution and DCM. The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 10)0/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 0.6 g ofIntermediates 9(48%)。

Example A3

a) Preparation of intermediate 10

Intermediates 10Prepared according to the 3-step preparation described in examples a1.a, a1.b and a1.c, starting from 2- (trifluoromethyl) phenylboronic acid and 2-amino-3-bromopyridine.

b) Preparation of intermediate 11

Isopentyl nitrite (379 mg, 3.24 mmol) and CuI (616 mg, 3.24 mmol) were added to intermediate 10(450 mg, 1.62 mmol) in CH at r.t₃CN (10 ml). The r.m. was stirred under reflux for 1 h. The r.m. was cooled to r.t. and filtered through celite. The filtrate was evaporated and the residue was dissolved in DCM. At 37% NH₄The solution was washed with OH solution. The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 0.36 g ofIntermediates 11(57%)。

Example A4

a) Preparation of intermediate 12

Intermediates 12Prepared according to the 3-step preparation described in examples a1.a, a1.b and a1.c starting from 2- (trifluoromethyl) phenylboronic acid and 2-amino-3-chloropyrazine.

Example A5

a) Preparation of intermediate 13

Intermediates 13Prepared according to the 3-step preparation described in examples a1.a, a1.b and a1.c, starting from 4-fluoro-2- (trifluoromethyl) phenylboronic acid and 2-amino-3-bromo-pyridine.

b) Preparation of intermediate 14

A solution of intermediate 13(498 mg, 1.68 mmol) in HOAc (3.3 ml) was added to NaNO at 10 deg.C₂(130 mg, 1.88 mmol) in conc. H₂SO₄(2.8 ml). R.m. was stirred at r.t. for 30 min and then added dropwise to a solution of CuBr (500 mg, 3.49 mmol) in 48% HBr (3.3 ml). R.m. was stirred at r.t. for 1h, then added carefully to the stirred saturated NaHCO₃Aqueous solution and DCM. The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 50 mg ofIntermediates 14(8%)。

Example A6

a) Preparation of intermediate 15

Intermediates 15Starting from 2-amino-3-bromopyridine, the preparation is carried out according to the synthesis described in examples A1.b and A1. c.

b) Preparation of intermediate 16

Intermediates 16Prepared according to the synthesis described in example a1.a starting from intermediate 15 and 2-fluoro-5- (trifluoromethyl) phenylboronic acid.

c) Preparation of intermediate 17

Intermediates 17Prepared according to the synthesis described in example a1.a starting from intermediate 15 and 3-methoxyphenylboronic acid.

d) Preparation of intermediate 18

Intermediates 18Prepared according to the synthetic method described in example a1.a starting from intermediate 15 and 3-fluoro-phenylboronic acid。

e) Preparation of intermediate 19

Intermediates 19Prepared according to the synthetic method described in example a1.a starting from intermediate 15 and 3- (trifluoromethyl) phenylboronic acid.

f) Preparation of intermediate 20

Intermediates 20Prepared according to the synthesis described in example a1.a starting from intermediate 15 and 4-fluoro-2-methylphenylboronic acid.

g) Preparation of intermediate 21

Intermediates 21Prepared according to the 2-step preparation described in examples a6.a and a6.b starting from 2-amino-4-bromopyridine and 2- (trifluoromethyl) phenylboronic acid.

Example A7

a) Preparation of intermediate 22

NaH (60% in mineral oil)The dispersion of (1); 2.0 g, 49 mmol) was added at 0 ℃ to a solution of methyl-2-chlorophenylacetate (8.3 g, 45 mmol) in DMF (120 ml). R.m. was stirred at 0 ℃ for 10 min and r.t. for 30 min, then r.m. was cooled to 0 ℃ and 1-chloro-3-iodopropane (5.1 ml, 48.1 mmol) was added dropwise with stirring. The mixture is stirred at r.m. and r.t. for 20 h. Then carefully add H₂O, followed by Et₂O, and carrying out layering. The organic layer is treated with H₂O and brine, dried (MgSO)₄) Then evaporating under reduced pressure to obtainIntermediates 22(8.75 g, 75%) which was used as such in the next reaction step.

b) Preparation of intermediate 23

Aminoguanidine dicarbonate (15.4 g, 113 mmol) was added to a solution of intermediate 22(7.4 g, 28.3 mmol) in 2-propanol (130 ml). The r.m. was placed in a sealed container and heated at 145 ℃ for 48 h. Then r.m. is cooled to r.t., the solids are filtered off and the filtrate is concentrated under reduced pressure. The residue was dissolved in DCM and NaHCO₃Aqueous solution and brine rinse. The organic layer was dried (MgSO₄) And concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 1.5 g ofIntermediates 23(21%)。

Example A8

a) Preparation of intermediate 24

Sodium methoxide (176.2 g, 3.26 mol) was added portionwise to a solution of 3-amino-2, 6-dibromopyridine (100 g, 939 mmol) in 1, 4-dioxane (1 l) and r.m. stirred at reflux for 3 h. Cooling downThen, r.m. is poured into sat. aq. NH₄Cl aq. sol (1 l). Additional NH was added₄Cl (150 g) and H₂O (1 l) and stirring r.m. at r.t. for 30 min. Et was added₂O (2 l) and r.m. stirred for 30 min. Layering with H₂The aqueous layer was diluted with O (1.5 l) and further Et₂O (6X 0.5 l). The combined o.l. was treated with brine (2 × 0.5 l) and dried (MgSO)₄) And concentrated under reduced pressure to give a black residue. The residue was purified by flash chromatography on silica gel (glass filter, eluent DCM). The product stream was combined and concentrated under reduced pressure to give an orange-brown solid residue. Yield: 67.2 g ofIntermediates 24(78.3%).

b) Preparation of intermediate 25

Acetic anhydride (110 ml, 1.16mol) was added dropwise to formic acid (170 ml) at r.t. and the sol was stirred at r.t. for 30 min. A solution of intermediate 24(67.2 g, 308 mmol) in THF (300 ml) was then added dropwise and r.m. stirred at 60 ℃ for 16 h. After cooling, r.m. was poured into ice/H₂O (1.5 l) and the resulting suspension was stirred for 30 min and then filtered. The filtrate was crystallized to give additional product. Yield: 65 g ofIntermediates 25(91.3%)。

c) Preparation of intermediate 26

Chloropropione (55.9 ml, 701 mmol) was added dropwise to the machine-stirred intermediate 25(65 g, 281 mmol), K₂CO₃(135.6 g, 981 mmol) and KI (4.65 g, 28 mmol) in DMF (542 ml). Stirring r.m. at r.t. for 16H, then pouring ice/H₂The off-white solid formed was collected by filtration in O (2 l) and dried under vacuum at 60 ℃. Yield: 776 g ofIntermediates 26(96.1%).

d) Preparation of intermediate 27

Intermediate 26(77.6 g, 270 mmol) was added dropwise to the machine-stirred NH₄OAc (105 g, 1.362mol) in HOAc (500 ml). Reflux r.m. for 1H, cool and pour into ice/H₂O (1 l) and then diluted with toluene (1 l). This mixture was neutralized by the addition of 50% NaOH aq. sol (590 ml). The layers were separated and the aqueous layer was further extracted with toluene (4X 0.3 l) and EtOAc (2X 0.5 l). The combined o.l. was dried, filtered and concentrated under reduced pressure. The residue was chromatographed over a silica gel column (eluent: DCM/MeOH 99/1). The product fractions were collected and the solvent was removed under reduced pressure. The resulting white-brown residue was triturated in DIPE to give an off-white solid, which was filtered off, washed with DIPE and dried in vacuo at 60 ℃. Yield: 40 g ofIntermediates 27(55.2%)。

Example A9

Preparation of intermediate 28

In N₂MeOH (100 ml) was added to Pd/C10% (0.5 g) under atmosphere. Intermediate 21(0.65 g, 2.34 mmol) and HCl/iPrOH solution (6N; 0.78 ml) were added. R.m. at 50 ℃ and H₂Stirred under atmosphere until 2 eq.H₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The residue was partitioned between DCM and aq. NH₄And OH solution. The combined organic layers were washed with brine and dried (MgSO)₄) And concentrated under reduced pressure to give 0.5 g ofIntermediates 28(76%)。

Example A10

a) Preparation of intermediate 29

Intermediates 29Starting from 2-amino-6-bromopyridine, the preparation is carried out according to the synthesis described in examples A1.b and A1. c.

b) Preparation of intermediate 30

Intermediates 30Prepared according to the synthetic method described in example a1.a starting from intermediate 29 and 2- (trifluoromethyl) -phenylboronic acid.

c) Preparation of intermediate 31

In N₂MeOH (100 ml) was added to Pd/C10% (1 g) under atmosphere. Intermediate 30(2.11 g, 7.58 mmol) and HCl/iPrOH solution (6N; 1.27 ml) were added. R.m. at 50 ℃ and H₂Stirred under atmosphere until 2 eq.H₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The residue was crystallized from DIPE and the resulting product was dried in vacuo to give 2.05 g ofIntermediates 31(96%)。

Example A11

a) Preparation of intermediates 37 and 38

1-fluoro-2-methoxy-4-nitrobenzene (821 mg, 4.80 mmol), 5-methyl-1H-1,2, 4-triazole (800 mg, 9.63 mmol), K₂CO₃A mixture of (4.80 mmol) and DMSO (8 ml) was stirred at 120 ℃ for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with water and dried in vacuo at 50 ℃. Yield: 0.55 g ofIntermediates 37(49%). The aqueous layer was saturated with NaCl, extracted with DCM and the organic layer dried (MgSO)₄) The solvent was filtered and evaporated. The residue was subjected to silica gel column chromatography (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.15 g ofIntermediates 38(13%).

b) Preparation of intermediate 39

In N₂MeOH (50 ml) was added to Pd/C10% (150 mg) under atmosphere. Then 0.4% thiophene in DIPE (1 ml) and intermediate 37(550 mg, 2.35 mmol) were added. R.m. at 25 ℃ and H₂Stirring under atmosphere until 3 eq₂Is absorbed. The catalyst was filtered off over celite. The filtrate was evaporated and the residue was suspended in DIPE, filtered and dried in vacuo. Yield: 0.35 g ofIntermediates 39(73%)。

Example A12

a) Preparation of intermediate 40

In N₂2-fluoro-5-nitrobenzyl ether (50 g, 0.29mol) was added to 4-methyl-1 in a stainless steel autoclave under atmosphereHImidazole (36.0 g, 0.44mol) and K₂CO₃(40.38 g, 0.29mol) in DMSO (150 ml). The vessel was sealed and heated r.m. at 125 ℃ for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H is to be₂O (q.s.) was added to the residue and the precipitated product was collected by filtration. The solid was then triturated with DIPE and collected by filtration to give a light brown solid. Yield: 53.8 g ofIntermediates 40(79%)。

b) Preparation of intermediate 41

Intermediate 40(215 g, 0.92mol) was added to a stirred mixture of 10% Pd/C (10 g) in 4% thiophene in MeOH (700 ml). R.m. at 50 ℃ and H₂Stirring under atmosphere until 3 eq₂Is absorbed. The catalyst was removed by filtration through celite. The filtrate was evaporated under reduced pressure and the crude product was chromatographed over a silica gel column (eluent: MeOH/DCM 10/90). The product stream was combined and evaporated to give a light brown solid. Yield: 180 g ofIntermediates 41(96%)。

c) Preparation of intermediate 42

Mixing the stirred NaNO₂(7.47 g, 108 mmol) in onc. H₂SO₄The solution in (160 ml) was cooled to 10 ℃. A solution of intermediate 41(20.0 g, 98.4 mmol) in HOAc (200 ml) was added at a rate such that the r.m. temperature was maintained below 10 ℃. After the addition was complete, the mixture was stirred at r.t. for 30 min. This solution was added dropwise at r.t. to a stirred solution of CuBr (28.2 g, 197 mmol) in 48% HBr (200 ml)In solution. The mixture was stirred for 1h and then diluted with ice water (1 l). The resulting white precipitate was collected by filtration and purified by H₂And O washing to obtain a solid (a) and a mother liquor (b).

The solid (a) was suspended in DCM and saturated Na₂CO₃In a mixture of aqueous solutions. The resulting slurry was filtered through celite. With dilute NH₄The organic layer of the filtrate was washed with OH solution until the blue color disappeared. The organic layer was dried (MgSO₄) Filtered and evaporated to give a brown solid.

The mother liquor (b) is treated with solid Na₂CO₃Basified and then extracted with DCM. The combined organic extracts are diluted NH₄The OH solution washes until the blue color disappears. The organic layer was dried (MgSO₄) Filtration and evaporation gave a brown solid. The two brown solids were combined to give 24.0 g ofIntermediates 42(91%)。

d) Preparation of intermediate 65

In N₂Intermediate 42(24.0 g, 89.8 mmol) in a stainless steel autoclave in THF/H under an atmosphere₂Pd (OAc) was added to a solution in O (300 ml/3 ml)₂(403 mg, 1.80 mmol) and 1, 3-bis (diphenylphosphino) propane (1.48 g, 3.59 mmol). The vessel was sealed and pressurized to 20 bar CO (gas) and heated at 150 ℃ for 24 h. The cooled reaction mixture was evaporated under reduced pressure and then acidified with 30% aqueous HOAc. Et was added₂O and the resulting mixture is evaporated until crystals form. The light brown crystals were collected by filtration. Yield: 18.1 g ofIntermediates 65(87%)。

e) Preparation of intermediate 43

A mixture of intermediate 65(3.24 g, 13.95 mmol), oxalyl chloride (1.68 g, 13 mmol) and DMF (5 ml) in DCM (300 ml) was stirred and heated at reflux for 1 h. Then r.m. was concentrated and co-evaporated with toluene. This residue was used as such in the next step. Yield: 3.5 g (quantitative)Intermediates 43。

Example A13

a) Preparation of intermediate 44

Will K₂CO₃(9.6 g, 69.5 mmol) and 1-methyl-1-tolylmethyl isocyanate (8 g, 38.2 mmol) were added to a solution of 2-formyl-5-nitrobenzyl ether (6.29 g, 34.7 mmol) in MeOH (150 ml) and r.m. refluxed for 4 h. R.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic layer was washed with H₂O cleaning and drying (MgSO)₄) Filtration and evaporation of the solvent under vacuum. The residue was purified by flash chromatography on silica gel (eluent: n-heptane/EtOAc from 100/0 to 50/50). The product fractions were collected and the solvent was evaporated. Yield: 6.24 g ofIntermediates 44(77%)。

b) Preparation of intermediate 45

In N₂MeOH (150 ml) was added to Pd/C10% (1 g) under atmosphere. Then 0.4% thiophene in DIPE (1 ml) and intermediate 44(6.24 g, 26.6 mmol) were added. R.m. at 25 ℃ and H₂Stirring under atmosphere until 3 eq₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. Yield: 5.4 g ofIntermediates 45(99%)。

Example A14

a) Preparation of intermediate 46

In N₂Iodophenyldiacetate (5.49 g, 18.44 mmol) and trifluoromethanesulfonic acid (6.08 ml, 69.17 mmol) in CH under an atmosphere₃CN (100 ml) was stirred at r.t. for 1 h. 2 '-methoxy-4' -nitro-acetophenone (3.0 g, 15.37 mmol) was added all at once to the solution at r.t., then r.m. refluxed for 2h, then cooled to r.t. and carefully added to stirred Na₂CO₃Saturated aqueous solution (500 ml). The product was extracted with DCM and the organic layer was dried (MgSO)₄) Filtration and evaporation of the solvent under reduced pressure. The resulting dark brown oil was purified by flash column chromatography on silica gel (eluent: DCM/MeOH 95/5). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 3.0 g ofIntermediates 46(75%)。

b) Preparation of intermediate 47

In N₂MeOH (50 ml) was added to Pd/C10% (0.250 g) under atmosphere. Then 0.4% thiophene in DIPE (2 ml) and intermediate 46 were added(0.946 g, 4.04 mmol). R.m. at 25 ℃ and H₂Stirring under atmosphere until 3 eq₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The product was triturated with DIPE, filtered and dried in vacuo. Yield: 0.66 g ofIntermediates 47(80%)。

Example A15

a) Preparation of intermediate 48

2-methylpyridine-4-boronic acid pinacol ester (3.18 g, 14.5 mmol) and Pd (PPh)₃)₄(1.22 g, 1.06 mmol) was added to 2-bromo-5-nitrobenzyl ether (3.06 g, 13.2 mmol) and Cs₂CO₃(1.33 g, 40.9 mmol) in DME (40 mL) and H₂O (16 ml). R.m. was stirred and heated at reflux for 16 h. R.m. is cooled to r.t. and distributed to H₂O and DCM. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent. The combined organic layers were dried (MgSO)₄) Filtered and concentrated under vacuum. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 2.04 g ofIntermediates 48(63%)。

b) Preparation of intermediate 49

Intermediate 48(2.04 g, 9.50 mmol) was added to a stirred mixture of 10% Pd/C (500 mg) and 0.4% thiophene in MeOH (1 ml). R.m. at 50 ℃ and H₂Heating under an atmosphere. H to 3 eq₂After absorption, the catalyst was removed by filtration through celite. The filtrate was evaporated under reduced pressure and the crude product was chromatographed over a silica gel column (eluent: MeOH/DCM 10/90). The product fractions were combined and evaporated to give a light brown solid. Yield: 1.70 g ofIntermediates 49(95%)。

Example A16

a) Preparation of intermediate 50

2-methylpyridine-4-boronic acid pinacol ester (5.54 g, 25 mmol) and Pd (PPh)₃)₄(1.95 g, 1.68 mmol) was added to 4-bromo-3-fluoroaniline (4.0 g, 21 mmol) and Cs₂CO₃(21.3 g, 65.3 mmol) in DME (40 mL) and H₂O (25 ml). The resulting mixture was stirred and heated at 95 ℃ for 16 h. R.m. was cooled to r.t. and partitioned between water and DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 4.1 g ofIntermediates 50(96%)。

Example A17

b) Preparation of intermediate 51

2, 6-dimethylpyridine-4-boronic acid pinacol ester (5.96 g, 26 mmol) and Pd (PPh)₃)₄(2150 mg, 1.86 mmol) was added to 4-bromoaniline (4 g, 23 mmol) and Cs₂CO₃(21.3 g, 65.3 mmol) in DME (40 mL) and H₂O (25 ml). The resulting mixture was stirred and heated at 95 ℃ for 16 h. R.m. is cooled to r.t. and distributed to H₂O and DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 2.50 g ofIntermediates 51(54%)。

Example A18

a) Preparation of intermediate 52

2-methylpyridine-4-boronic acid pinacol (pinacol) ester (5 g, 22.8 mmol) and Pd (PPh)₃)₄(1.92 g, 1.66 mmol) was added to 1-iodo-4-nitrobenzene (5.17 g, 20.7 mmol) and Cs₂CO₃(21 g, 64.3 mmol) in DME (40 ml) and water (25 ml). The resulting mixture was stirred and heated at reflux for 16 h. R.m. was cooled to r.t. and partitioned between water and DCM. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent in vacuo. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 3.1 g ofIntermediates 52(70%)。

b) Preparation of intermediate 53

Intermediate 52(2.0 g, 9.34 mmol) was added to a stirred mixture of 10% Pd/C (1 g) and 0.4% thiophene in MeOH (2 ml). R.m. at 25 ℃ and H₂Heating under an atmosphere. H to 3 eq₂After absorption, the catalyst was removed by filtration through celite. The filtrate was evaporated under reduced pressure and the crude product was used as such in the next step. Yield: 1.5 g ofIntermediates 53(87%)。

Example A19

a) Preparation of intermediate 54

Mixing the stirred NaNO₂A solution of (5.63 g, 81.7 mmol) in conc. HCl (6.2 ml) was cooled to 10 ℃. A solution of 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at a rate to maintain the r.m. temperature below 10 ℃. After the addition was complete, the mixture was stirred at r.t. for 30 min. This solution was added dropwise at r.t. to a stirred solution of KI (37 g, 223 mmol) in 48% HBr (200 ml). The mixture was stirred for 1h and then diluted with ice water (1000 ml). The precipitate formed is collected by filtration and washed with H₂And O washing to obtain a solid (a) and a mother liquor (b).

The solid (a) was suspended in DCM and saturated Na₂CO₃In a mixture of aqueous solutions. The resulting slurry was filtered through celite. With dilute NH₄The organic layer of the filtrate was washed with OH solution until the blue color disappeared. The organic layer was dried (MgSO₄) Filtered and evaporated to give a brown solid.

By adding solid Na₂CO₃The mother liquor (b) was basified and then extracted with DCM. The combined organic extracts are diluted NH₄The OH solution washes until the blue color disappears. The organic layer was dried (MgSO₄) Filtration and evaporation gave a brown solid. The two brown solids were combined to give 24.0 g ofIntermediates 54(91%)。

b) Preparation of intermediate 55

2-methylpyridine-4-boronic acid pinacol ester (5.49 g, 25.1 mmol) and Pd (PPh)₃)₄(3.62 g, 3.1 mmol) was added to intermediate 54(9.8 g, 31.3 mmol) in dioxane (200 ml), H₂O (50 ml) and K₂CO₃(13 g, 94 mmol). The resulting mixture was stirred and heated at 100 ℃ for 18 h. R.m. is cooled to r.t. and distributed to H₂O and DCM. Drying the combined organic layersDried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/4). The product fractions were collected and concentrated in vacuo to give 4.5 g ofIntermediates 55(52%)。

Example A20

a) Preparation of intermediate 56

In 3, 5-dibromo-1H-1,2, 4-triazole (5.00 g, 22.04 mmol) in CH₃CN (50 ml) was added 2- (2-bromoethoxy) tetrahydro-2H-pyrane (5.07 g, 24.24 mmol) and DIPEA (4.00 ml, 24.24 mmol). The resulting solution was heated at 90 ℃ for 3 h. Subsequently, the mixture was cooled and diluted with EtOAc (100 ml). Then saturated NaHCO₃The resulting solution was washed with an aqueous solution and brine. The organic layer was dried (MgSO₄) And concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 6.00 g ofIntermediates 56(77%)。

b) Preparation of intermediate 57

To a solution of intermediate 56(4.30 g, 12.1 mmol) in THF (215 ml) at-78 deg.C was added n-butyllithium (4.85 ml, 12.1 mmol, 2.5M in hexane). The resulting solution was stirred at-78 ℃ for 20 min, after which a solution of 2- (trifluoromethyl) benzaldehyde (2.10 g, 12.1 mmol) in THF (43 ml) was added. The solution was then stirred at-78 ℃ for 20 min and sat₄Cl solution (5 ml) was quenched. The reaction was then allowed to warm to r.t., diluted with EtOAc (200 ml) and washed with EtOAcH₂O (2 × 100 ml) rinse. The organic layer was dried (MgSO₄) Filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 99/1). The product fractions were collected and concentrated in vacuo to give 5.00 g ofIntermediates 57(92%)。

c) Preparation of intermediate 58

To a solution of intermediate 57(3.00 g, 6.63 mmol) in methanol (300 ml) was added p-toluenesulfonic acid (230 mg, 1.33 mmol) at room temperature. The resulting solution was stirred for 2 h. Then r.m. was concentrated in vacuo and the residue was dissolved in DCM (100 ml) and saturated NaHCO₃Washing with aqueous solution, and drying (MgSO)₄) And concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 2.3 g ofIntermediates 58(94%)。

d) Preparation of intermediate 59

To a solution of intermediate 58(750 mg, 2.04 mmol) in toluene (100 ml) was added p-toluenesulfonic acid (389.00 mg, 2.04 mmol). The resulting solution was then refluxed for 25 h using a Dean Stark apparatus. The solution was then washed with 1M aqueous NaOH and brine, dried (MgSO)₄) And concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 90/10). The product fractions were collected and concentrated in vacuo to give 350 mg ofIntermediates 59(49%)。

Example A21

Alternative method for preparing intermediate 5

a) Preparation of intermediate 60

To 3, 5-dibromo-1H-1,2, 4-triazole (5.00 g, 22 mmol) in CH₃CN (50 ml) solution was added 4-bromo-1-butene (3.27 g, 24 mmol) and DIPEA (4.00 ml, 24 mmol), and the resulting solution was heated at 90 ℃ for 3 h. R.m. was then cooled and diluted with EtOAc (100 ml) and saturated NaHCO₃Washed with aqueous solution, then brine, and dried (MgSO)₄) And concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: heptane/DCM from 100/0 to 0/100). The product fractions were collected and concentrated in vacuo to give 5.55 g ofIntermediates 60(89%)。

b) Preparation of intermediate 61

To a solution of intermediate 60(4.50 g, 16 mmol) in THF (285 ml) at-78 deg.C was added n-butyllithium (6.41 ml, 16 mmol, 2.5M in hexane). R.m. was stirred at-78 ℃ for 20 min. A solution of 4-fluorobenzaldehyde (1.99 g, 16 mmol) in THF (56 ml) was then added and the solution was stirred at-78 deg.C for 20 min. Adding saturated NH₄Aqueous Cl (5 ml) to quench r.m. The reaction was allowed to warm to r.t., then diluted by addition of EtOAc (200 ml) and taken up with H₂O (2 × 100 ml) rinse. The organic layer was dried (MgSO₄) Filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 4.20 g ofIntermediates 61(80%)。

c) Preparation of intermediate 62

To a solution of intermediate 61(2.00 g, 6.13 mmol) in DCM (200 ml) was added pyridine (0.74 ml, 9.20 mmol) and Dess-Martin periodinane (2.73 g, 6.44 mmol) at 0 ℃. Stir r.m. at 0 ℃ for 1 h. Then, r.m. was diluted with DCM (200 ml) and saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (MgSO₄) And concentrating under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 1.65 g ofIntermediates 62(83%)。

d) Preparation of intermediate 63

To a solution of intermediate 62(1.00 g, 3.09 mmol) in THF (50 ml) was added Tebbes reagent (6.17 ml, 3.085 mmol) at r.t. Then r.m. was stirred for 18 h. By adding Et₂O (400 ml) diluted r.m. and quenched by addition of aqueous NaOH (30.8 ml, 0.5M). The mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 660 mg ofIntermediates 63(66%)。

e) Preparation of intermediate 64

To a solution of intermediate 63(550 mg, 1.71 mmol) in DCE (55 ml) was added Grubbs second generation catalyst (145 mg, 0.1 mmol)7 mmol). R.m. was then heated at 60 ℃ for 2h and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 350 mg ofIntermediates 64(69%)。

f) Preparation of intermediate 5

To a solution of intermediate 64(250 mg, 0.85 mmol) in MeOH (55 ml) was added sodium borohydride (322 mg, 8.50 mmol). The mixture was stirred at r.m. for 2 h. R.m. was concentrated under reduced pressure. The residue was dissolved in DCM and washed with aqueous HCl (0.5M) and dried (MgSO)₄) And concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo to give 220 mg ofIntermediates 5(87%)。

B. Preparation of the Compounds

Example B1

Preparation of Compound 1

In N₂Intermediate 49(176 mg, 0.825 mmol), Pd were added under an atmosphere₂(dba)₃(75 mg, 0.0825 mmol), X-Phos (86 mg, 0.182 mmol) and Cs₂CO₃(806 mg, 2.47 mmol) was added to a solution of intermediate 5(280 mg, 0.908 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue was purified by RP preparative HPLC [ R ]P Vydac Denali C18-10 μm, 250 g, I.D. 5 cm); mobile phase: gradient (0.25% NH)₄HCO₃Solution in water)/MeOH + CH₃CN]. The product fractions were collected and subjected to subsequent treatments. Yield: 115 mg ofCompound (I) 1(20%)。

Example B2

Preparation of Compound 2

In N₂Intermediate 49(200 mg, 0.933 mmol), Pd were added under atmosphere₂(dba)₃(85 mg, 0.0933 mmol), X-Phos (98 mg, 0.205 mmol) and Cs₂CO₃(912 mg, 2.8 mmol) was added to a solution of intermediate 9(300 mg, 0.933 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 0.160 g ofCompound (I) 2(39%)。

Example B3

Preparation of Compound 3

In N₂Intermediate 39(360 mg, 0.925 mmol), Pd were added under an atmosphere₂(dba)₃(85 mg, 0.0925 mmol), X-Phos (88 mg, 0.185 mmol) and Cs₂CO₃(904 mg, 2.78 mmol) was added to intermediate 11(189 mg, 0.925 mmol) of 2-methyl-2-propaneAlcohol (5 ml) solution. And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 98/2) to yield 0.175 g ofCompound (I) 3(41%)。

Example B4

Preparation of Compound 4

In N₂Intermediate 39(50 mg, 0.139 mmol), Pd were added under an atmosphere₂(dba)₃(24 mg, 0.18 mmol), X-Phos (7 mg, 0.014 mmol) and Cs₂CO₃(135 mg, 0.417 mmol) was added to a solution of intermediate 14(28 mg, 0.139 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue was purified by RP preparative HPLC [ RP Vydac Denali C18-10 μm, 250 g, I.D. 5 cm); mobile phase: gradient (0.25% NH)₄HCO₃In H₂Solution in O)/MeOH + CH₃CN]. The product fractions were collected and worked up. Yield: 10 mg ofCompound (I) 4(15%)。

Example B5

Preparation of Compound 5

In N₂The intermediate 42 (12) is reacted under an atmosphere0 mg, 0.52 mmol)、Pd₂(dba)₃(47 mg, 0.052 mmol), X-Phos (49 mg, 0.10 mmol) and Cs₂CO₃(673 mg, 2.07 mmol) was added to a solution of intermediate 4(157 mg, 0.52 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo. The residue was triturated in DIPE to give 0.038 g ofCompound (I) 5(18%)。

Example B6

Preparation of Compound 6

In N₂Intermediate 42(100 mg, 0.34 mmol), Pd were added under an atmosphere₂(dba)₃(31 mg, 0.034 mmol), X-Phos (32 mg, 0.068 mmol) and Cs₂CO₃(440 mg, 1.35 mmol) was added to a solution of intermediate 13(102 mg, 0.34 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo. The residue was triturated in DIPE to give 0.027 g ofCompound (I) 6(17%)。

Example B7

Preparation of Compound 7

In N₂Intermediate 42(176 mg, 0.72 mmol), Pd were added under an atmosphere₂(dba)₃(66 mg, 0.072 mmol), X-Phos (69 mg, 0.14 mmol) and Cs₂CO₃(937 mg, 2.88 mmol) was added to a solution of intermediate 8(218 mg, 0.72 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo. The residue was triturated in DIPE to give 0.140 g ofCompound (I) 7(45%)。

Example B8

a) Preparation of Compound 8

In N₂Intermediate 42(502 mg, 1.8 mmol), Pd were added under an atmosphere₂(dba)₃(165 mg, 0.18 mmol), X-Phos (172 mg, 0.36 mmol) and Cs₂CO₃(2.35 g, 7.2 mmol) was added to a solution of intermediate 12(546 mg, 1.8 mmol) in 2-methyl-2-propanol (20 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. is cooled to r.t., and H is added₂O and the mixture was extracted with DCM. The organic layer was dried (MgSO₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 403 mg ofCompound (I) 8(48%)。

b) Preparation of Compound 9

In N₂MeOH (40 ml) was added to Pt/C5% (50 mg) under atmosphere. Subsequently, a solution of compound 8(350 mg, 0.75 mmol) in a mixture of HCl/isopropanol (6N) (0.376 ml, 2.26 mmol) was added. R.m. at 25 ℃ and H₂Stirred under atmosphere until 2 eq.H₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The residue was suspended in DIPE, filtered and dried to give 200 mg ofCompound (I) 9(57%)。

c) Preparation of Compound 13

Compound 9(75 mg, 0.16 mmol) and formaldehyde (37% w/w aq. solution; 155 mg, 0.19 mmol) were dissolved in MeOH (2 ml). Stir r.m. at r.t. for 45 min. Subsequently, a drop of acetic acid was added to r.m., followed by addition of sodium cyanoborohydride (15 mg, 0.224 mmol). The r.m. was stirred at r.t. for 20 h. 1 drop of water was added and then r.m. was evaporated under reduced pressure. Partition the residue into DCM/H₂And O is between. The organic layer was separated and dried (MgSO)₄) Filtered and evaporated under reduced pressure. The residue was composed of DIPE and CH₃CN precipitated out of the mixture. The resulting solid was filtered and dried under vacuum to give 51 mg ofCompound (I) 13(66%)。

d) Preparation of Compound 14

Acetyl chloride (25 mg, 0.32 mmol) was added to compound 9(75 mg, 0.16 mmol) and Et at r.t₃N (0.066 ml, 0.48 mmol) in a mixture of DCM (3 ml). The r.m. was then stirred at r.t. for 20 h. Then 37% NH₄OH solution (1 ml) was added to r.m. Dividing into r.mPrepared in DCM and H₂And O is between. The organic layer was separated and dried (MgSO)₄) And evaporated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 99/1). The product fractions were collected and concentrated in vacuo to give 35 mg ofCompound (I) 14(43%)。

Example B9

Preparation of Compound 36

To a mixture of intermediate 4(60 mg, 0.26 mmol) in pyridine (0.06 ml, 0.78 mmol) and DCM (5 ml) was added intermediate 43(87 mg, 0.35 mmol) dropwise at 0 ℃. The r.m. was stirred at r.t. for 1 h. The r.m. was washed with aq. NaOH sol (1M). The organic layer was dried (MgSO₄) Filtered and evaporated under reduced pressure. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give 15 mg ofCompound (I) 36(13%)。

Example B10

Preparation of Compound 72

Intermediate 9(127 mg, 41 mmol), intermediate 41(99 mg, 0.41 mmol), (Pd (OAc))₂(2 mg, 0.01 mmol), XantPhos (5 mg, 0.01 mmol) and Et₃A mixture of N (125 mg, 1.20 mmol) in toluene (40 ml) was pressurized to 20 bar CO and the mixture was reacted at 110 ℃ for 18 h. The r.m. was cooled to r.t. and concentrated under reduced pressure. The residue was dissolved in DCM and washed with waterWashed and dried (MgSO)₄) Filtered and evaporated under reduced pressure. The residue was purified by RP preparative HPLC [ RP Vydac Denali C18-10 μm, 250 g, I.D. 5 cm); mobile phase: gradient (0.25% NH)₄HCO₃In H₂Solution in O)/MeOH]. The product fractions were collected and worked up. To give 9 mg ofCompound (I) 72(5%)。

Example B11

Preparation of Compound 65

In N₂Intermediate 59 (135 mg, 0.39 mmol), Pd were added under an atmosphere₂(dba)₃(36 mg, 0.039 mmol), X-Phos (37 mg, 0.078 mmol) and Cs₂CO₃(379 mg, 1.16 mmol) was added to a solution of intermediate 49(79 mg, 0.37 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. is cooled to r.t., and H is added₂O and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo. The residue was further purified by RP preparative HPLC [ RP Vydac Denali C18-10 μm, 250 g, I.D. 5 cm); mobile phase: gradient (0.25% NH)₄HCO₃In H₂Solution in O)/CH₃CN]. The product fractions were collected and subjected to subsequent treatments. Yield: 30 mg ofCompound (I) 65(16%)。

Example B12

Preparation of Compound 27

In N₂Intermediate 42(350 mg, 1.40 mmol), Pd were added under an atmosphere₂(dba)₃(128 mg, 0.14 mmol), X-Phos (134 mg, 0.28 mmol) and Cs₂CO₃(1.37 g, 4.22 mmol) was added to a solution of intermediate 23(478 mg, 1.41 mmol) in 2-methyl-2-propanol (5 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 97/3). The product fractions were collected and concentrated in vacuo. The residue was triturated in DIPE to give 0.400 g ofCompound (I) 27(62%)。

a) Preparation of Compounds 28 and 29

Compound 27(330 mg) was isolated as its enantiomer in preparative SFC (Chiralpak Diacel OJ 20 x 250 mm). Mobile phase (CO)₂MeOH containing 0.2% 2-propylamine) to yieldCompound (I) 28(80 mg, REnantiomer) andcompound (I) 29(70 mg, SIsomers).

Example B14

Preparation of Compound 34

In N₂MeOH (30 ml) was added to Pt/C5% (100 mg) under atmosphere. Subsequently, a solution of compound 20(165 mg, 0.36 mmol) in a mixture of HCl/isopropanol (6N) (0.178 ml, 1.1 mmol) was added. R.m. at 50 ℃ and H₂Atmosphere(s)Stirring until 2 eq.H₂Is absorbed. The catalyst was filtered off over celite and the filtrate was evaporated. The residue is then purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0 to 99/1). The product fractions were collected and concentrated in vacuo to give 21 mg ofCompound (I) 34(56%)。

Example B15

Preparation of Compound 33

To a solution of compound 31(110 mg, 0.24 mmol) in DMF (5 ml) was added NaH (60% solution in mineral oil; 9.4 mg, 0.24 mmol) at 0 ℃. Stir r.m. at 0 ℃ for 10 min. Methyl iodide (33.3 mg, 0.24 mmol) was then added to the r.m. and the r.m. was allowed to warm to r.t. Then r.m. diluted with water and extracted with EtOAc, Na₂SO₄Drying and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo. The residue was dissolved in diethyl ether (5 ml) and a solution of 6N HCl in 2-propanol (1 ml) was added dropwise to the stirring solution. The HCl salt was then collected by filtration and the product was dried under vacuum to give 75 mg ofCompound (I) 33(.HCl；66%)。

Example B17

Preparation of Compounds 66, 77 and 78

In N₂Intermediate 55(2.477 g, 7.9 mmol), Pd were added under an atmosphere₂(dba)₃(687 mg, 0.75 mmol)、X-Phos(715 mg, 1.5 mmol) and Cs₂CO₃(7.33 g, 22.5 mmol) was added to a solution of intermediate 23(2.06 g, 8.3 mmol) in 2-methyl-2-propanol (100 ml). And heating the r.m. at 110 ℃ for 20 h. Then r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtering and vacuum concentrating. The residue is purified by flash column chromatography on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0 to 97/3). The product fractions were collected and concentrated in vacuo. The residue was triturated in DIPE, filtered and dried to give 3.00 g ofCompound (I) 66(rac). By means of a preparative SFC (Chiralpak Diacel OJ 20X 250 mm; mobile phase: CO)₂MeOH containing 0.2% 2-propylamine) Compound 66 was isolated as its enantiomer to give 1.00 g ofCompound (I) 78 And1.01 g ofCompound (I) 77。

Tables 1a, 1b, 1c and 1d list compounds prepared analogously to one of the examples described above. 'Pr.' refers to the example number of the compound synthesized according to this scheme. 'Co. No.' refers to compound number.

If no specific stereochemistry of the stereocenter of the compound is indicated, this indicates that the resulting compound is a mixture of R and S forms (RS).

If no salt form is indicated, the resulting compound is the free base. Salt forms of the free base, such as the HCl salt form, can be readily prepared using typical procedures known to those skilled in the art. In a typical procedure for conversion to the HCl salt form, for example, the free base is dissolved in a solvent such as DIPE or Et₂O, and subsequent dropwise addition of HCl in a solvent such as 2-propanol or Et₂Solution in O. Stirring for a specified period of time, typically about 10 min, increases the reaction rate.

Watch (A) 1a

Watch (A) 1b (OR Finger optical rotation )

Watch (A) 1c

Watch (A) 1d

Analysis section

LCMS ( Liquid chromatography / Mass spectrometry )

General procedure A

LC measurements were performed using an acquisition UPLC (Ultra Performance Liquid Chromatography) (Waters) system including a binary pump, a sample organizer, a column heater (set at 55 ℃), a Diode Array Detector (DAD), and a column designated in the following methods. The flow from the column was split to the MS spectrometer. The MS detector is equipped with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizing gas. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data System.

General procedure B

HPLC measurements were performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump equipped with a degasser, an autosampler, a column oven (set at 40 ℃ C., unless otherwise specified), DAD and columns as specified in the methods below. The flow from the column was split to the MS spectrometer. The MS detector is equipped with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizing gas. Data acquisition was performed using a Waters-Micromass MassLynx-Openlynx data System.

General procedure C

The HPLC measurements were performed using an Agilent 1100 module comprising a pump, DAD (wavelength 220 nm), column heater and column as specified in the following methods. The liquid stream from the column was dispersed into the Agilent MSD series G1946C and G1956A MS. The MS detector was configured with API-ES (atmospheric pressure electrospray ionization). Mass spectra were obtained by scanning from 100 to 1000. The capillary needle voltage was 2500V in positive ionization mode and 3000V in negative ionization mode. The division voltage (fragmentation voltage) was 50V. The temperature of the drying gas was maintained at 350 ℃ and the flow rate was 10 l/min.

LCMS Method of producing a composite material 1

In addition to general procedure a: reverse phase UPLC was performed on a bridged ethylsiloxane/hybrid silica (BEH) C18 column (1.7 microns, 2.1 x 50 millimeters; Waters Acquity) using a flow rate of 0.8 ml/min (min). Two mobile phases (25 mmol ammonium acetate (NH)₄OAc) /CH₃In CN 95/5; mobile phase B: CH (CH)₃CN) was operated from 95% a and 5% B to 5% a and 95% B at 1.3 min and gradient conditions were maintained for 0.3 min. An injection volume of 0.5 microliters was used. The cone voltage for the positive ionization mode is 30V and the negative ionization mode is 30V.

LCMS Method of producing a composite material 2

In addition to general procedure B: the column heater was set at 40 ℃. On a Xterra MS C18 column (3.5)μm, 4.6 × 100 mm), reverse phase HPLC was performed at a flow rate of 1.6 ml/min. 3 mobile phases (mobile phase A: 95% 25 mM NH) were used₄OAc + 5% CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) to perform gradient conditions: from 100% A to 1% A, 49% B and 50% C in 6.5 min, to 1% A and 99% B in 1 min and holding these conditions for 1 min, and plateau at 100% AAnd (5) balancing for 1.5 min. Injection volumes of 10 microliters were used. The cone voltage for the positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method of producing a composite material 3

In addition to general procedure B: the column heater was set at 40 ℃. On a Xterra MS C18 column (3.5)μm, 4.6 × 100 mm), reverse phase HPLC was performed at a flow rate of 1.6 ml/min. 3 mobile phases (mobile phase A: 95% 25 mM NH) were used₄OAc + 5% CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) to perform gradient conditions: from 100% A to 1% A, 49% B and 50% C in 6.5 min to 1% A, 99% B in 0.5 min and maintaining these conditions for 1 min. Injection volumes of 10 microliters were used. The cone voltage for the positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method of producing a composite material 4

In addition to general procedure B: the column heater was set at 45 ℃. On an Atlantis C18 column (3.5)μm, 4.6 × 100 mm), reverse phase HPLC was performed at a flow rate of 1.6 ml/min. 2 mobile phases (mobile phase A: 70% MeOH + 30% H) were used₂O; mobile phase B: 0.1% formic acid in H₂O/MeOH 95/5) to perform gradient conditions: from 100% B to 5% B + 95% A within 9 min and these conditions were maintained for 3 min. Injection volumes of 10 microliters were used. The cone voltage for the positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method of producing a composite material 5

In addition to general procedure a: on a BEH C18 column (1.7)μm, 2.1 x 50 mm; waters Acquity), reverse phase UPLC was performed at a flow rate of 0.8 ml/min. 2 mobile phases (mobile phase A: 0.1% formic acid in H) were used₂O/MeOH 95/5; mobile phase B: MeOH) to perform gradient conditions: from 95% A and 5% B to 5% A and 95% B within 1.3 min and held for 0.2 min. An injection volume of 0.5 microliters was used. The cone voltage for the positive ionization mode is 10V and the negative ionization mode is 20V.

Melting Point

Unless otherwise stated, melting points (m.p.) were determined by DSC823e (Mettler-Toledo). Melting points are measured with a temperature gradient of 30 ℃/min. The maximum temperature was 400 ℃. The value is the high peak.

The results of the analytical measurements are shown in table 2 a.

Watch (A) 2a ：Residence time in minutes (R)_t)，[M+H]⁺Peak (protonated molecule), LCMS method and m.p. (melting point in ° c). (n.d. means no measurement).

For Co. number 66, [ M-H ] was detected]^-Peak: rt 1.10; [ M-H ]]^-444; LCMS method 1; melting point: 176.6 ℃.

Optical Rotation (OR)

Optical rotations were measured using a Perkin Elmer 341 polarimeter. [ alpha ] to]_D ²⁰Refers to the optical rotation measured at a temperature of 20 ℃ with light having a wavelength (lambda) of 365nm or 589 nm. The slot path length (cell pathlength) was 1 dm. Mentioned under the actual values are the wavelength (. lamda.) (in nm), the concentration (Conc.) and the solvent of the solution used for measuring the optical rotation.

Watch (A) 2b: optical rotation

SFC-MS

For SFC-MS, an analytical SFC system from Berger Instruments (Newark, DE, USA) was used, which system included a system for delivering CO₂A binary pump control module (FCM-1200) and a regulator, a thermal control module for column heating (TCM2100) with a temperature control range of 1-150 ℃ and a column selection valve (Valco, VICI, Houston, TX, USA) for selecting 6 different columns. Photodiode array detectors (Agilent 1100, Waldbronn, germany) were fitted with high pressure flow-through cells (up to 400 bar) and with CTC LC Mini PAL autosampler (Leap Technologies, carrborro, NC, USA). ZQ mass spectrometers (Waters, Milford, MA, USA) with an orthogonal Z-electrospray interface were connected to the SFC-system. Instrument control, data collection and processing were performed using an integrated platform consisting of SFC ProNTo software and Masslynx software.

Co, number 83-84: SFC-MS was performed on an OD-H column (500X 4.6 mm) (Daicel Chemical Industries Ltd) at a flow rate of 3 ml/min. Using two mobile phases (mobile phase A: CO)₂(ii) a Mobile phase B: containing 0.2% iPrNH₂MeOH) of (c). The first 25% B hold 18 min. A gradient was then applied from 25% B to 50% B over 2.5 min and held for 4.1 min. The column temperature was set at 50 ℃. Under these conditions, co. number 84 ('enantiomer a') has a shorter R on the column than co. number 83 ('enantiomer B')_t. This measurement can be compared to the racemic mixture.

Co, number 95-96: SFC-MS was performed on an OJ-H column (500X 4.6 mm) (Daicel Chemical Industries Ltd) at a flow rate of 3 ml/min. Using two mobile phases (mobile phase A: CO)₂(ii) a Mobile phase B: containing 0.2% iPrNH₂MeOH) of (c). The first 25% B was held for 18 min. Then a gradient was applied from 25% B to 50% B over 2.5 min and held for 4.1 min. The column temperature was set at 50 ℃. Under these conditions, co. number 96 ('enantiomer a') had on the columnR shorter than Co. number 95 ('enantiomer B')_t. This measurement can be compared to the racemic mixture.

Co, number 79-80: SFC-MS was performed on an OJ-H column (500X 4.6 mm) (Daicel Chemical Industries Ltd) at a flow rate of 3 ml/min. Using two mobile phases (mobile phase A: CO)₂(ii) a Mobile phase B: containing 0.2% iPrNH₂MeOH) of (c). The 35% B is held for 15 min. The column temperature was set at 50 ℃. Under these conditions, Co. number 80 (' enantiomer A ') had a shorter R on the column than Co. number 79 (' enantiomer B /)_t. This measurement can be compared to the racemic mixture.

NMR

For several compounds CHLOROFORM-d(deuterated chloroform, CDCl)₃) Or DMSO-d ₆(deuterated DMSO, dimethyl-d 6 sulfoxide) as solvent, recorded on a Bruker DPX-360, Bruker DPX-400 or Bruker Avance 600 spectrometer equipped with standard pulse sequences operating at 360 MHz, 400 MHz and 600 MHz respectively¹H NMR spectrum. Chemical shifts (δ) are reported in parts per million relative to Tetramethylsilane (TMS) used as an internal standard.

Pharmacology of

A) Screening of Compounds of the invention for Gamma-secretase-modulating Activity

Selection was performed using SKNBE2 cells carrying the APP 695-wild type grown in Dulbecco's Modified Eagle's Medium/Nutrient mixture F-12 (DMEM/NUT-mix F-12) (HAM) (Category No. 10371-029) supplied by Invitrogen containing 5% serum/Fe supplemented with 1% non-essential amino acids, 2 mM l-glutamine, 15 mM Hepes, 50U/ml penicillin (units/ml) and 50. mu.g/ml streptomycin. Cells were grown to near confluence.

Use is made of, for example, Citron et al (1997) in Nature Medicine 3: 67 for screening. Briefly, cells were plated at 10⁴Cells/well were seeded in Ultrafiltration (Lonza, BE12-725F) in 384-well plates supplemented with 1% glutamine (Invitrogen, 25030-024), 1% non-essential amino acids (NEAA), penicillin U/ml and streptavidin 50. mu.g/ml in the presence of different test concentrations of test compounds. The cell/compound mixture was incubated at 37 ℃ with 5% CO₂The culture was carried out overnight. The following day the media was analyzed for a β 42 and total a β by two sandwich immunoassays (sandwich immuno-assays).

Total Α β and Α β 42 concentrations were quantified in cell supernatants using the Aphalisa technique (Perkin Elmer). Alphalisa is a sandwich assay that uses biotinylated antibodies attached to streptavidin-coated donor beads and antibodies conjugated to acceptor beads. In the presence of antigen, the beads will be in close proximity. Excitation of the donor beads causes the release of singlet oxygen molecules, which trigger a cascade of energy transfers in the acceptor beads, resulting in light emission. To quantify the amount of A.beta.42 in the cell supernatants, monoclonal antibodies specific for the C-terminus of A.beta.42 (JRF/cA. beta. 42/26) were used in conjunction with acceptor beads and biotinylated antibodies specific for the N-terminus of A.beta. (JRF/A.beta.N/25) were used in conjunction with donor beads. To quantify the amount of total a β in the cell supernatants, monoclonal antibodies specific for the N-terminus of a β (JRF/a β N/25) were used in conjunction with the recipient strain and biotinylated antibodies specific for the middle region of a β (biotinylated 4G8) were used in conjunction with the donor strain.

To obtain the values reported in table 3, the data were calculated as a percentage of the maximum amount of amyloid β 42 measured in the absence of the test compound. Sigmoidal dose response curves were analyzed using non-linear regression analysis, plotting the percentage of control versus the log (log) concentration of compound. Determination of IC Using 4-parameter equation₅₀。

Watch (A) 3 ：

B) Demonstration of in vivo efficacy

The a β 42-lowering agents of the invention may be used to treat AD in mammals such as humans or demonstrate efficacy in animal models such as, but not limited to, mice, rats or guinea pigs. The mammal may not be diagnosed with AD, or may not have a genetic predisposition to AD, but may have a transgene that overproduces and eventually deposits a β in a similar manner as seen in humans suffering from AD.

The a β 42 lowering agent can be administered in any standard form using any standard method. For example, but not limited to, the a β 42 lowering agent may be in the form of a liquid, tablet or capsule that is administered orally or by injection. The a β 42 lowering agent can be administered at any dose sufficient to significantly reduce a β 42 level in blood, plasma, serum, cerebrospinal fluid (CSF) or brain.

To determine whether acute administration of an a β 42-lowering agent will lower a β 42 levels in vivo, non-transgenic rodents, such as mice or rats, are used. Animals treated with a β 42 lowering agents are examined and the soluble a β 42 and total a β levels in the brain are quantified by standard techniques, such as using ELISA, compared to those animals that are not treated or treated with vehicle. The duration of treatment varies from a few hours to several days and is adjusted according to the outcome of the a β 42 reduction (once the time course of onset is determined).

A typical protocol for measuring a β 42 decline in vivo is presented, but it is just one of many that can be used to optimize the changes in detectable a β levels. For example, the A β 42 reducing compound was formulated as 20% Captisol ® (sulfobutyl ether of β -cyclodextrin) or 20% hydroxypropyl β cyclodextrin in water. The a β 42-lowering agent is administered as a single oral dose or by any acceptable route of administration to an overnight fasted animal. After 4 hours, animals were sacrificed and analyzed for a β 42 levels.

Blood was collected into EDTA-treated collection tubes by decapitation and exsanguination. Blood was centrifuged at 1900 g for 10 minutes (min) at 4 ℃ and plasma was recovered and flash frozen for subsequent analysis. The brain was removed from the skull and hindbrain. The cerebellum is removed and the left and right hemispheres are separated. The left hemisphere was stored at-18 ℃ for quantitative analysis of the levels of test compounds. The right hemisphere was washed with Phosphate Buffered Saline (PBS) buffer and immediately frozen on dry ice and stored at-80 ℃ until homogenized for biochemical testing.

Mouse brains from non-transgenic animals are suspended in 8 volumes of 0.4% DEA (diethylamine)/50 mM NaCl containing protease inhibitors (Roche-11873580001 or 04693159001) per gram of tissue, for example 1.264 ml of 0.4% DEA for 0.158 g of brain is added. All samples were homogenized at 6 m/s for 20 seconds in the FastPrep-24 system (MP Biomedicals) using lysis matrix D (MPBio # 6913-100). The homogenate was centrifuged at 221.300 x g for 50 min. The resulting high-speed supernatant was then transferred to a new eppendorf tube. Nine supernatants were neutralized with 1 part quantity of 0.5M Tris-HCl pH 6.8 and used to quantify total A β and A β 42.

To quantify the amount of total a β and a β 42 in the soluble fraction of brain homogenate, an enzyme-linked immunosorbent assay was used. Briefly, standard solutions (dilutions of synthetic A.beta.1-40 and A.beta.1-42, Bachem) were prepared in 1.5 ml Eppendorf tubes at a final concentration ranging from 10000 to 0.3 pg/ml with Ultraculture. Samples and standards were co-incubated with an HRPO-labeled N-terminal antibody for A.beta.42 detection and a biotinylated middomain antibody 4G8 for total A.beta.detection. Then 50. mu.l of conjugate/sample or conjugate/standard mixture was added to the antibody-coated plate (capture antibody selectively recognizing the C-terminus of A.beta.42, antibody JRF/cA. beta. 42/26 for A.beta.42 detection; and the N-terminus of A.beta., antibody JRF/rA. beta./2 for total A.beta.detection). The plates were incubated at 4 ℃ overnight to allow antibody-amyloid complexes to form. After this incubation and subsequent washing step, Quanta Blu fluorescent peroxidase substrate was added to complete the a β 42 quantification of the ELISA according to the manufacturer's instructions (Pierce, Rockford, Il). The reading is taken after 10 to 15 min (excitation 320 nm/emission 420 nm).

For total a β detection, streptavidin-peroxidase-conjugate was added, another washing step was performed after 60 min and Quanta Blu fluorescent peroxidase matrix was added according to the manufacturer's instructions (Pierce, Rockford, Il). The reading is taken after 10 to 15 min (excitation 320 nm/emission 420 nm).

This model should be advantageous in that it reduces ap 42 by at least 20% compared to untreated animals.

The results are as followsWatch (A) 4Indicated (dose 30 mg/kg administered orally) (values for animals not treated as control group (Ctrl) were set to 100):

composition examples

The "active ingredient (a.i.)" used in these examples relates to a compound of formula (I), including any stereochemically isomeric form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; in particular any of the exemplified compounds.

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

1. tablet formulation

5 to 50 mg of active ingredient

Dicalcium phosphate 20 mg

Lactose 30 mg

Talcum powder 10 mg

Magnesium stearate 5 mg

Regulating potato starch to 200 mg

2. Suspension liquid

Aqueous suspensions for oral administration are prepared so that each ml contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and added water to adjust to 1 ml.

3. Injection solution

Parenteral compositions are prepared by stirring 1.5% (w/v) of the active ingredient in 0.9% NaCl solution or in 10% by volume propylene glycol in water.

4. Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanolin 5 g

White Vaseline 15 g

Adjusting water to 100 g

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

Reasonable variations are not to be regarded as a departure from the scope of the invention. The invention thus described may obviously be modified in many ways by a person skilled in the art.

Claims (15)

1.A compound of formula (I)

Or a stereoisomeric form thereof, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a-4),

R³is C_1-4An alkyl group;

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²--

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　　(b-4)；

--CH=N-CH=CH--　　　　　　　　　(b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

wherein each aryl group¹Independently represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituent substitution;

or a pharmaceutically acceptable addition salt or solvate thereof;

provided that the compound is not 5- (4-methoxyphenyl) -N- [4- (5-oxazolyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amine, 5- (4-methoxyphenyl) -N- [4- (3-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridine-2-amines or 5- (4-methoxyphenyl) -N- [6- (1H-pyrazol-4-yl) -3-pyridinyl]-[1,2,4]Triazolo [1,5-a]-pyridin-2-amine.

2. The compound of claim 1, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3a) or (a-4),

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group.

3. The compound of claim 1, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3a) or (a-4),

R⁴、R⁵、R⁶and R⁸Each independently hydrogen or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7ais hydrogen, halo or C_1-4An alkyl group;

R^7band R^7cEach independently of the others is hydrogen, halo, cyano, C_1-4Alkyloxy, ring C_3-7Alkyl, or C optionally substituted by one or more halo substituents_1-4An alkyl group;

X^ais CH or N;

X^bis O or S;

A¹is CR⁹Or N; wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N;

L¹is O, carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6) or (b-7) -R¹-R²-L²--

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　 (b-4)；

--CH=N-CH=CH--　　　　　　　　 (b-5)；

--(CH₂)_q-r-Y-(CH₂)_r-1, 2-benzenediyl- (b-6);

--(CH₂)_r-Y-(CH₂)_q-r-1, 2-benzenediyl- (b-7);

wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms by one or more groups containing one or more unsaturated bonds, where possibleTwo substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-6) or (b-7) is in one or more CH₂Which may be substituted on the radical by one or, where possible, by two substituents each independently selected from the group consisting of: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13e-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group; and wherein (b-6) or (b-7) may be substituted on the 1, 2-benzenediyl-moiety with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11dR^12dMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

y represents a direct bond, NR¹⁴Or O; wherein R is¹⁴Is hydrogen or aryl¹(C = O) -aryl¹、C_1-4Alkylcarbonyl or C optionally substituted by one or more halo substituents_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

q represents 3,4, 5 or 6;

r represents 0, 1,2 or 3;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, cyano, NR^11eR^12eMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group; or a 5-or 6-membered heteroaryl selected from: furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said 5-or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of: halo, C_1-4Alkyloxy, cyano, NR^11fR^12fMorpholinyl, and C optionally substituted with one or more halo substituents_1-4An alkyl group;

each R^11d、R^11eAnd R^11fIndependently of one another is hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

each R^12d、R^12eAnd R^12fIndependently is hydrogen or C_1-4An alkyl group;

each R^13d、R^13eAnd R^13fIndependently is hydrogen or C_1-4Alkyl radical, C_1-4Alkyl is optionally substituted by one or more substituents independently selected from halo and ring C_3-7Alkyl substituents.

4. The compound of claim 1, wherein

Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3);

R³is C_1-4An alkyl group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-4An alkyl group;

R⁶is hydrogen or C_1-4An alkyl group;

R^7ais hydrogen or C_1-4An alkyl group;

R^7bis hydrogen, C_1-4Alkyloxy or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R^7cis hydrogen or C_1-4An alkyl group;

X^ais CH or N;

X^bis O;

A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen or haloOr C_1-4An alkyloxy group;

A²is CH or N;

A³and A⁴Is CH;

L¹is carbonyl, NR¹⁰NH- (C = O) or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -¹-R²-L²- - -is selected from: - - -CH = CH- -CH = C (aryl group)¹) -, - -CH = CH-N = C (aryl)¹)--、--CH=CH-C(C_1-4Alkyl) = C (aryl group¹)--、--(CH₂)₂-CH₂-CH (aryl)¹)--、--(CH₂)₂-CH(C_1-4Alkyl) -CH (aryl)¹)--、--(CH₂)₂-NR¹⁴-CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-C (aryl)¹) -CH = C (1-piperidinyl) - -, and- (CH) — o₂)₂-CH (aryl)¹)-CH₂--；

Wherein the 1-piperidinyl group may be substituted by one or more trifluoromethyl groups;

wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkyloxy, NR^11eR^12eAnd C optionally substituted by one or more halo substituents_1-4An alkyl group;

R^11eis hydrogen or C_1-4An alkyl group;

each R^12eIndependently is hydrogen or C_1-4An alkyl group.

5. The compound of claim 1, wherein

Het¹Is a heterocyclic ring having formula (a-1), (a-2) or (a-3 a);

R³is C_1-4An alkyl group;

R⁴、R⁵and R⁶Each independently is hydrogen or C_1-4An alkyl group;

R^7ais hydrogen or C_1-4An alkyl group;

R^7band R^7cEach independently is hydrogen or C_1-4An alkyl group;

X^ais CH or N;

X^bis O;

A¹is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently is CH or N;

provided that A is¹、A²、A³And A⁴At most two of them are N; (ii) a

L¹Is NR¹⁰Carbonyl or (C = O) -NH; wherein R is¹⁰Is hydrogen or C_1-4An alkyl group;

R¹and-L²-R²Together form a divalent group of formula (b-1), (b-2), (b-3) or (b-4) -R¹-R²-L²--；

--(CH₂)_m-n-Y-(CH₂)_n--　　　　　　　(b-1)；

--(CH₂)_n-Y-(CH₂)_m-n--　　　　　　　(b-2)；

--CH=CH-CH=CH--　　　　　　　 (b-3)；

--CH=CH-N=CH--　　　　　　　　(b-4)；

Wherein (b-1) or (b-2) may be substituted on a carbon atom by an aryl group¹Substituent group substitution;

wherein (b-3) or (b-4) may be substituted with an aryl group when possible¹Substituent group substitution;

y represents a direct bond, O or NR¹⁴(ii) a Wherein R is¹⁴Is hydrogen, C_1-4Alkylcarbonyl or C_1-4An alkyl group;

m represents 3 or 4;

n represents 1;

aryl radicals¹Represents phenyl, optionally substituted with one or more substituents each independently selected from: halo, C_1-4Alkoxy and C optionally substituted by one or more halo substituents_1-4An alkyl group.

6. The compound of claim 1 or 2, wherein

R¹and-L²-R²Together form a divalent group- -R- -of the formula (b-1), (b-2), (b-3), (b-4) or (b-5)¹-R²-L²--；

Wherein (b-1) or (b-2) may contain an unsaturated bond;

wherein (b-1), (b-2) or a group containing an unsaturated bond may be substituted on one or more carbon atoms with one or, where possible, with two substituents each independently selected from: aryl radicals¹(C = O) -aryl¹O-aryl radical¹、NR^13d-aryl radical¹、C_1-4Alkylcarbonyl, halo, hydroxy and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein (b-3), (b-4) or (b-5) may be substituted, where possible, with one or more substituents each independently selected from the group consisting of: aryl radicals¹1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, (C = O) -aryl¹O-aryl radical¹、NR^13f-aryl radical¹、C_1-4Alkylcarbonyl and C optionally substituted with one or more halo substituents_1-4An alkyl group;

wherein said 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl may be substituted with one or more trifluoromethyl groups.

7. The compound of claim 1,2, 3,4 or 5 wherein

R¹and-L²-R²Together form a divalent radical- -R¹-R²-L²--：--(CH₂)₃-CH (aryl)¹)--、--(CH₂)₂-NH-CH (aryl)¹)--、--(CH₂)₂-N(CH₃) -CH (aryl)¹)--、--(CH₂)₂-N(COCH₃) -CH (aryl)¹)--、--(CH₂)₂-O-CH (aryl)¹) -, - -CH = CH-CH = C (aryl)¹) - - - - - - - - - - - - - (CH- -N = C) (aryl group)¹)--。

8. The compound of claim 1, wherein

Het¹Is a heterocyclic ring having the formula (a-1), (a-2), (a-3a) or (a-4),

。

9. the compound of claim 1,2, 3 or 5, wherein

A¹Is CR⁹(ii) a Wherein R is⁹Is hydrogen, halo or C_1-4An alkyloxy group; a. the²Is CH or N; and A is³And A⁴Is CH.

10. The compound of claim 1, wherein said compound is

5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-8- [2- (trifluoromethyl) phenyl]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a]Pyridin-2-amine, or

8- (2-chlorophenyl) -5,6,7, 8-tetrahydro-N- [ 3-methoxy-4- (2-methyl-4-pyridyl) phenyl group]-[1,2,4]Triazolo [1,5-a](ii) a pyridine-2-amine,

a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 10.

12. A compound as defined in any one of claims 1 to 10 for use as a medicament.

13. A compound as defined in any one of claims 1 to 10 for use in the treatment or prevention of a disease or condition selected from: alzheimer's disease, traumatic brain injury, mild cognitive impairment, aging, dementia with Lewy bodies, amyloid cerebrovascular disease, multi-infarct dementia, dementia pugilistica, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

14. The compound of claim 13, wherein the disease is alzheimer's disease.

15. Use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for modulating γ -secretase activity.