HK1164288A - Novel substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives as gamma secretase modulators - Google Patents

Description

Novel substituted benzo  oxazole, benzimidazole,  oxazolopyridine and imidazopyridine derivatives as gamma secretase modulators

Technical Field

The present invention relates to novel substituted benzols useful as gamma secretase modulatorsAzole, benzimidazole, imidazole, or imidazole,Azolopyridine and imidazopyridine derivatives. 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 marked by loss of memory, cognition and behavioral stability. AD afflicts 6-10% of the population over the age of 65 and up to 50% over the age of 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. At present, AD is not effectively treated. The total net cost associated with AD in the united states is over 1000 billion dollars per year.

AD has a complex 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 levels of education. Specific neuropathological lesions of the limbic and cerebral cortex include intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and extracellular deposits of fibrillar aggregates of amyloid β peptide (amyloid plaques). The major components of amyloid plaques are amyloid beta (A-beta, Abeta or A beta) peptides of various lengths. It is believed that a variant of A.beta.1-42-peptide (A.beta.42), is the major causative agent of amyloid formation. Another variant is the A.beta.1-40-peptide (A.beta.40). Amyloid beta is a proteolytic product of the precursor protein, beta amyloid precursor protein (beta-APP or APP).

Early onset autosomal dominant forms of AD are associated with missense mutations in beta amyloid precursor protein (beta-APP or APP) and 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, more recently, the discovery of mutations in α 2-macroglobulin, which may be associated with at least 30% of the AD population. Despite this heterogeneity, all types of AD present similar pathological findings. Genetic analysis has provided the best clues to the rational treatment of AD. All mutations discovered to date affect the quantitative or qualitative production of the amyloidogenic peptide known as the a β -peptide (a β), specifically a β 42, and strongly support the "amyloid cascade hypothesis" for AD (Tanzi and Bertram, 2005, Cell 120, 545). The link between a β peptide production and AD pathology urgently requires a better understanding of the mechanisms of a β production and therapeutic approaches to modulate a β levels.

The release of a β peptides is regulated by proteolytic activity of at least two enzymes called β -secretase and γ -secretase, which cleave at the N-terminus (Met-Asp bond) and C-terminus (residues 37-42) of a β peptides, respectively. In the secretory pathway, there is evidence that β -secretase cleavage first results in secretion of s-APP β (s β) and retains the 11kDa membrane-bound carboxy-terminal fragment (CTF). The latter is believed to yield a β peptide after cleavage by γ -secretase. 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 familial alzheimer's disease. Thus, a β 42 is considered by many researchers to be the major cause of the pathogenesis of alzheimer's disease.

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

Gamma (γ) -secretase activity is present within a multiprotein complex that contains at least four components: presenilin (PS) heterodimer, apo-protein, aph-1, and pen-2. The PS heterodimer consists of an amino-and carboxy-terminal PS fragment generated by endoproteolysis of a precursor protein. The two compartments of the catalytic site are in the binding part of this heterodimer. Recently, it has been suggested that the bent protein acts as a gamma-secretase-substrate receptor. The function of the other members of the gamma-secretase is unknown, but they are all required for activity (Steiner, 2004.Curr. Alzheimer Research1 (3): 175-.

Thus, while the molecular mechanism of the second cleavage step has been difficult to understand until now, γ -secretase-complex has become one of the main targets for the search for compounds for the treatment of alzheimer's disease.

Various Strategies have been proposed for targeting gamma-secretase in alzheimer's disease, ranging from direct targeting to the catalytic site, the development of substrate-specific inhibitors and modulators of activity of gamma-secretase (Marjaux et al, 2004.Drug Discovery Today: Therapeutic variants, vol.1, 1-6). Thus, various compounds have been described using Secretases as targets (Larner, 2004.Secretases as therapeutics targets in Alzheimer's disease: patents 2000-2004. Ext Opin. Ther. patents 14, 1403-1420).

Indeed, this finding was recently supported by biochemical studies in which the effects of certain NSAIDs on gamma-secretase were shown (Weggen et al (2001) Nature 414, 6860, 212 and WO 01/78721 as well as US 2002/0128319; Morihara et al (2002) J.Neurochem.83, 1009; Eriksen (2003) J.Clin.invest.112, 440). Potential limitations of using NSAIDs for the prevention or treatment of AD are their COX enzyme inhibitory activity, which can lead to undesirable side effects, as well as their low CNS penetration capacity (Peretto et al, 2005, j.med.chem.48, 5705-.

US 2008/0280948a1 relates to aminophenyl derivatives for use as modulators of amyloid β.

WO-2009/005729 relates to heterocyclic compounds and their use as gamma-secretase modulators.

WO-2008/097538 includes 2- [ 4-imidazolyl) -phenyl ] vinyl-heterocyclic derivatives that selectively reduce A β (1-42) production and are useful for treating Alzheimer's disease.

WO-2004/017963 discloses benzimidazoles as inhibitors of factor Xa which are useful in the treatment of thromboembolic disorders.

WO-2005/115990 discloses cinnamamide compounds useful for the treatment of neurodegenerative diseases caused by amyloid beta protein such as alzheimer's disease, senile dementia, down's syndrome and amyloidosis.

WO-2007/044895 discloses diarylamines and their use in lubricating oil compositions and stabilizer-containing compositions.

WO-2008/156580 discloses triazole derivatives useful for the treatment of diseases associated with the deposition of A β in the brain, in particular Alzheimer's disease.

There is a great need for new compounds that modulate gamma-secretase activity to open up new avenues for the treatment of alzheimer's disease. It is an object of the present invention to overcome or reduce 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.

Summary of The Invention

The compounds of the present invention have been found to be useful as gamma secretase modulators. The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating or preventing alzheimer's disease.

The present invention relates to novel compounds of formula (I) below and the stereoisomeric forms thereof and the pharmaceutically acceptable addition salts and solvates thereof:

wherein:

R¹is hydrogen, cyano, CF₃Halogen or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from hydroxy and C_1-4An alkoxy group;

R²is hydrogen, C_1-4Alkyl or halo;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, morpholinyl, pyrrolidinyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinylTetrahydropyranyl group, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen, C_1-4Alkyl orC_1-4An alkylcarbonyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from halogen, cyano, phenyl and C_3-7Cycloalkyl and C_1-4An alkoxy group.

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

The compounds of the present invention have surprisingly been found to modulate gamma-secretase activity in vitro and in vivo and are therefore useful in the treatment or prevention of alzheimer's disease, traumatic brain injury, Mild Cognitive Impairment (MCI), senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, preferably alzheimer's disease and other diseases with beta-amyloid pathology (e.g. glaucoma).

In view of the above-mentioned pharmacological properties of the compounds of formula (I), it is concluded that they are suitable for use as medicaments.

More particularly the compounds are suitable for the treatment or prophylaxis of alzheimer's disease, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica or down syndrome.

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

Preferably the use of a compound of formula (I) to modulate gamma-secretase activity, resulting in a reduction in the relative amount of a β 42-peptide produced.

One advantage of the compounds of the invention or a portion of the compounds of the invention may be their enhanced CNS penetration.

The invention will now be further elucidated. In the following, 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 described as being preferred or advantageous may be combined with any other feature or features described 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.

Whenever the term "substituted" is used in the present invention, unless indicated otherwise or clear from context, it is intended to mean that in the expression "substituted" one or more hydrogen atoms, especially 1 to 4 hydrogen atoms, preferably 1 to 3 hydrogen atoms, more preferably 1 hydrogen atom, on the atom or group in question is replaced with a group selected from the group, 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 be separated from the reaction mixture to a useful purity and formulated as a therapeutic drug.

The terms "halo" (halo), "halo" or "halogen" as a group or part of a group typically refer to fluoro, chloro, bromo, iodo, unless otherwise indicated.

The term "C" as a group or part of a group_1-6Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein 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, and still 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 may contain. Thus, for example, C_1-6Alkyl includes all straight-chain or branched alkyl groups containing from 1 to 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 isomersIsomers, hexyl and its isomers, and the like.

The term "C" as a group or part of a group_2-6Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein n is a number from 2 to 6. C_2-6The alkyl group contains 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, more especially 2 to 3 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as described herein. Thus, for example, C_2-6Alkyl includes all straight or branched chain alkyl groups containing from 2 to 6 carbon atoms and thus includes, for example, 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 isomers, and the like.

The term "C" as a group or part of a group_1-4Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein 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. The term "C" as a group or part of a group_1-3Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein n is a number from 1 to 3. Alkyl groups may be straight or branched chain and may be substituted as described herein. Thus, for example, C_1-4Alkyl includes all straight or branched chain alkyl groups containing 1 to 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" as a group or part of a group_1-6Alkoxy "means having the formula-OR^bWherein R is^bIs C_1-6An alkyl group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "C" as a group or part of a group_1-4Alkoxy "means having the formula-OR^cWherein R is^cIs C_1-4An alkyl group. Non-limiting examples of suitable alkoxy groups includeMethoxy (also known as methoxy), ethoxy (also known as ethoxy), propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

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

The term "C" alone or in combination_3-7Cycloalkyl "refers to a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Suitable C_3-7Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "C" alone or in combination_3-7Cycloalkyloxy "means having the formula-OR^dWherein R is^dIs C_3-7A cycloalkyl group. Suitable C_3-7Non-limiting examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.

The term "thienyl" corresponds to "thienyl".

The chemical names of the compounds of the present invention were generated according to the nomenclature agreed upon by the chemical abstracts Service (U.S.A.).

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

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

It will be appreciated that some compounds of formula (I) and 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 hereinabove defines all possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound means the mixture of all possible stereochemically isomeric forms. More specifically, stereogenic (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 (regioisomeric) 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 the other isomers.

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

Pharmaceutically acceptable acid and base addition salts as mentioned hereinbefore or hereinafter are meant to include therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are capable of forming. Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, 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, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Instead the salt form can be converted to the free base form by treatment with a suitable base.

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, ammonium salts, alkali metal and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic 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 salts, and salts with amino acids such as arginine, lysine, and the like. Instead, the salt form can 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, and salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.

The compounds of formula (I) as prepared by the methods described below can be synthesized as 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 specific stereoisomer is desired, said compound should be synthesized by stereospecific methods of preparation. These processes advantageously employ enantiomerically pure starting materials.

Within the framework of this application, the compounds of the invention are inherently chiralIncluding all isotopic combinations of the chemical elements thereof. Within the framework of this application, chemical elements include all isotopes and isotopic mixtures of such elements, especially when referred to in relation to compounds of formula (I). For example, when referring to hydrogen, it is understood to mean¹H、²H、³H and mixtures thereof.

The compounds of the invention thus 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 have been replaced by one of its radioactive isotopes. The term "radiolabeled compound" refers to any compound of formula (I) or a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom. For example, the compounds may be labeled with positrons or with gamma-emitting radioisotopes. In the case of the radioligand binding technique,³h atom or¹²⁵The I atom is the atom of choice substituted. For imaging, the most commonly used Positron Emission (PET) radioisotopes are¹¹C、¹⁸F、¹⁵O and¹³n, all of which are produced by the accelerator and have half-lives of 20, 100, 2 and 10 minutes, respectively. Because the half-life of these radioisotopes is so short, they are only suitable for use by facilities having accelerators at the site for their production, thus limiting their use. The most widely used of them is¹⁸F、^99mTc、²⁰¹Tl and¹²³I. the handling of these radioisotopes, their production, isolation and incorporation into molecules is known to the skilled person.

In particular, the radioactive atoms are selected from 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. By way of example, "a compound" means one compound or more than one compound.

The terms described above, as well as other terms used in the specification, are well understood by those skilled in the art.

Preferred features of the compounds of the invention will now be elucidated.

The present invention relates to novel compounds of formula (I) below and the stereoisomeric forms thereof and the pharmaceutically acceptable addition salts and solvates thereof:

wherein:

R¹is hydrogen, cyano, CF₃Halogen or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from hydroxy and C_1-4An alkoxy group;

R²is hydrogen, C_1-4Alkyl or halo;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, morpholinyl, pyrrolidinyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and with aC substituted by one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from halogen, cyano, phenyl and C_3-7Cycloalkyl and C_1-4An alkoxy group.

In one embodiment, the present invention relates to compounds of formula (I) and the stereoisomeric forms and the pharmaceutically acceptable addition salts and solvates thereof, wherein

R¹Is hydrogen, cyano, CF₃Halogen or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from hydroxy and C_1-4An alkoxy group;

R²is hydrogen, C_1-4Alkyl or halo;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, morpholinyl, pyrrolidinyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolidinyl, piperidinyl,O-Ar、NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

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

(a)R¹is hydrogen, cyano, halo or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from hydroxy and C_1-4An alkoxy group;

(b)R⁵is hydrogen;

(c)Y¹is CH or N; y is²Is CR⁴Or N; y is³Is CH; provided that Y is¹And Y²Only one of which may represent N;

(d)R⁴is hydrogen, halo, C_1-4Alkoxy radical, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

(e)R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, tetrahydropyranyl, O-Ar, C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl and morpholinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸、C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group; or a 5-or 6-membered heteroaryl selected from pyridyl and thienyl; wherein the 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo and C substituted with one or more halo substituents_1-4An alkyl group;

(f) each R⁸Independently selected from C_1-4Alkyl or C_1-4An alkylcarbonyl group.

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

(a)R¹is hydrogen, cyano, Br or methyl optionally substituted with one or more substituents each independently selected from hydroxy and methoxy;

(b)R²is hydrogen, methyl or I;

(c) x is CH or N;

(d)R⁶is hydrogen, F or methoxy;

(d)Y¹is CH or N; y is²Is CR⁴Or N; y is³Is CH; provided that Y is¹And Y²Only one of which may represent N;

(e)R⁴is hydrogen, F, methoxyAlkyl, cyclopropyl, 1-propen-2-yl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from F and methoxy;

(f)R³is n-propyl substituted with one or more F substituents; c optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from piperidinyl, Ar, methoxy, tetrahydropyranyl and cyclopropyl; cyclopropyl substituted with one or more phenyl substituents optionally substituted with one or more Cl substituents; cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, tetrahydropyranyl, O-Ar, C_1-4Alkoxy radical, C_1-4Alkylthio, Ar, CH₂-O-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl and morpholinyl can each be substituted with one or more substituents each independently selected from methyl, methylcarbonyl, F and tert-butoxycarbonyl;

wherein each Ar is independently selected from one or more of halo, methoxy, ethoxy, isopropoxy, cyano, NR⁷R⁸Methyl, isopropyl, methoxy substituted with one or more F substituents and C substituted with one or more F substituents_1-4Phenyl optionally substituted with alkyl substituents; or a 5-or 6-membered heteroaryl selected from pyridyl and thienyl; wherein said 5-or 6-membered heteroaryl is substituted with one or more substituents each independently selected from F and C substituted with one or more substituents F_1-4The substituents of the alkyl group are optionally substituted;

(g) each R⁷Independently selected from hydrogen or methyl;

(h) each R⁸Independently selected from methyl or methylcarbonyl;

(i)R⁹is hydrogen or C optionally substituted with one or more substituents each independently selected from F, phenyl and methoxy_1-4An alkyl group.

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

(a)R¹is C_1-4Alkyl, especially methyl;

(b)R²is hydrogen;

(c) x is CH or N;

(d)A¹is CR⁶；

(e)R⁶Is hydrogen, methoxy or halo; especially hydrogen, methoxy or F;

(f)A²is CH or N;

(g)A³and A⁴Is CH;

(h)Y¹is CH or N; y is²Is CR⁴；Y³Is CH;

(i)R⁴is hydrogen, halo or C_1-4An alkyl group; especially hydrogen, F, methyl or isopropyl;

(j)R³is phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, NR⁷R⁸And C substituted with one or more halo substituents_1-4An alkyl group; especially one or more compounds selected from F, Cl, methoxy, NR⁷R⁸And CF₃Phenyl substituted with the substituent of (1);

(k)R⁷is hydrogen;

(l)R⁸is C_1-4An alkylcarbonyl group; especially methyl carbonyl;

(m) Z is NR⁹；

(n)R⁹Is C_1-6An alkyl group; especially is C_1-4An alkyl group; more particularly methylOr an isopropyl group.

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

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl radicals, said substitutionEach radical is independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4Alkyl is optionally substituted;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen or C_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

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

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N; wherein R is⁵Is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N; with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R³is C substituted with one or more substituents selected from halo_2-6An alkyl group; with one or more radicals selected from piperidinyl, Ar, C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7C with cycloalkyl optionally substituted_1-6An alkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein each of piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more groups selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4The substituent of alkoxycarbonyl is optionally substituted;

wherein each Ar is independently selected from the group consisting of halo, C, and_1-4alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more substituents selected from halo_1-4Phenyl optionally substituted with alkyl substituents; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,A 5-or 6-membered heteroaryl group which is oxadiazolyl, pyridazinyl or pyrazinyl; wherein said 5-or 6-membered heteroaryl is independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more substituents selected from halo_1-4The substituents of the alkyl group are optionally substituted;

wherein each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

wherein each R⁸Independently selected from hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or with one or more radicals selected from halo or C_1-4C with substituents of alkoxy being optionally substituted_1-4An alkyl group;

z is O or NR⁹(ii) a Wherein R is⁹Is hydrogen, with one or more radicals selected from halo, phenyl and C_1-4C with substituents of alkoxy being optionally substituted_1-6An alkyl group.

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

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen or C_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

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

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N; wherein R is⁵Is H or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N; with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N; y is²Is CR⁴；Y³Is CH;

R³is C substituted with one or more substituents selected from halo_2-6An alkyl group; with one or more radicals selected from piperidinyl, Ar, C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7C with cycloalkyl optionally substituted_1-6An alkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical,C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein each of piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more groups selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4The substituent of alkoxycarbonyl is optionally substituted;

wherein each Ar is independently selected from the group consisting of halo, C, and_1-4alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more substituents selected from halo_1-4Phenyl optionally substituted with alkyl substituents; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,A 5-or 6-membered heteroaryl group which is oxadiazolyl, pyridazinyl or pyrazinyl; wherein said 5-or 6-membered heteroaryl is independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more substituents selected from halo_1-4The substituents of the alkyl group are optionally substituted;

wherein R is⁷Is hydrogen or C_1-4An alkyl group;

wherein R is⁸Is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano or C optionally substituted with one or more substituents selected from halo_1-4An alkyl group;

z is O or NR⁹(ii) a Wherein R is⁹For hydrogen, useOne or more selected from halo, phenyl and C_1-4C with substituents of alkoxy being optionally substituted_1-6An alkyl group.

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

R¹is hydrogen, C_1-4Alkyl, cyano or halo;

R²is hydrogen or C_1-4An alkyl group;

x is CH or N;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH or N;

provided that Y is¹And Y³Only one of which may represent N;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, O-Ar, C_1-6Alkoxy radical, C_1-6Alkylthio, Ar or NH-Ar;

wherein each of the piperidinyl and morpholinyl groups may be taken by one or more substituentsSubstituted by substituents each independently selected from C_1-4Alkyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently selected from the group consisting of halo, C, and_1-4alkoxy and C_1-4Phenyl optionally substituted with alkyl substituents; or a pyridyl group;

R⁴is hydrogen, halo, cyano or C optionally substituted with one or more halo substituents_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

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

R¹is hydrogen, C_1-4Alkyl, cyano or halo;

R²is hydrogen or C_1-4An alkyl group;

x is CH or N;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, O-Ar, C_1-6Alkoxy radical, C_1-6Alkylthio, Ar or NH-Ar;

wherein piperidinyl and morpholinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently selected from the group consisting of halo, C, and_1-4alkoxy and C_1-4Phenyl optionally substituted with alkyl substituents; or a pyridyl group;

R⁴is hydrogen, halo, cyano or C optionally substituted with one or more halo substituents_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

In another embodiment, the present invention relates to compounds of formula (I) and the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts and solvates thereof, wherein:

R¹is hydrogen, methyl, cyano or bromine;

R²is hydrogen or methyl;

x is CH or N;

A¹is CR⁶Or N;

R⁶is hydrogen, F or methoxy;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH;

R³is 3, 3, 3-trifluoropropyl; c optionally substituted with one or more substituents each independently selected from piperidinyl, Ar, methoxy, tetrahydropyranyl and cyclopropyl_1-6An alkyl group; hexyl, pentyl, piperidinyl, morpholinyl, O-Ar, isopropoxy, isobutylthio, Ar or NH-Ar;

wherein piperidinyl and morpholinyl may each be substituted with one or more substituents each independently selected from methyl, methylcarbonyl, F and tert-butoxycarbonyl;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from Cl, F, methoxy, ethoxy, methyl, and isobutyl; or a pyridyl group;

R⁴is hydrogen, F, methyl, cyano or CF₃；

Z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents each independently selected from F, phenyl and methoxy_1-4An alkyl group.

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

(a)R¹is C_1-4An alkyl group; especially methyl;

(b)R²is hydrogen;

(c) x is CH;

(d)A¹is CR⁶；

(e)R⁶Is F or methoxy; especially methoxy;

(f)A²is N or CH; in particular N;

(g)A³and A⁴Is CH;

(h)Y¹is CH or N;

(i)Y²is CR⁴；

(j)Y³Is CH;

(k)R⁴is hydrogen or methyl;

(l)R³is phenyl optionally substituted with one or more substituents each independently selected from halo and methoxy; especially R³Is phenyl substituted with one or more substituents each independently selected from halo and methoxy; more specifically R³Is phenyl substituted with one or two substituents each independently selected from halo and methoxy; even more particularly R³Is phenyl substituted with one or two substituents each independently selected from F and methoxy;

(m) Z is NR⁹；

(n)R⁹Is C_1-6An alkyl group; in particular is C_1-4An alkyl group; more particularly methyl.

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

(a)R¹is C_1-4An alkyl group; especially methyl;

(b)R²is hydrogen;

(c) x is CH;

(d)A¹is COCH₃；A²Is N; a. the³Is CH; a. the⁴Is CH;

(e)Y¹、Y²and Y³Is CH;

(f)R³is phenyl optionally substituted with one or more halo substituents; especially phenyl substituted with one or more halo substituents; more particularly phenyl substituted with one halo substituent; even more particularly phenyl substituted with one F substituent;

(g) z is NR⁹；

(h)R⁹Is C_1-6An alkyl group; especially is C_1-4An alkyl group; more particularly methyl.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R¹Is methyl and wherein R²Is hydrogen.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R¹Is hydrogen and wherein R²Is methyl.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R¹Is hydrogen, wherein R²Is methyl and wherein X is N.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R¹Is hydrogen, C_1-4Alkyl, cyano or halo.

In another embodiment, the invention relates to compounds of any other embodiment wherein X is CR⁵。

In another embodiment, the present invention relates to compounds of any other embodiment wherein X is N.

In another embodiment, the invention relates to a compound of any other embodiment wherein X is N or CH.

In another embodiment, the invention relates to a compound of any other embodiment wherein X is CH.

In another embodiment, the invention relates to a compound of any other embodiment, wherein Y is¹Is CH or N; y is²Is CR⁴(ii) a And Y³Is CH or N; provided that Y is¹And Y³Only one of which may represent N.

In another embodiment, the invention relates to a compound of any other embodiment, wherein Y is¹Is CH; y is²Is CR⁴(ii) a And Y³Is CH.

In another embodiment, the invention relates to a compound of any other embodiment, wherein Y is¹Is N; y is²Is CR⁴(ii) a And Y³Is CH.

In another embodiment, the invention relates to a compound of any other embodiment, wherein Y is¹Is CH; y is²Is N; and Y³Is CH.

In another embodiment, the invention relates to a compound of any other embodiment, wherein Y is¹Is CH; y is²Is CR⁴(ii) a And Y³Is N.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R³Is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl.

In another embodiment, the invention relates to compounds of any other embodiment, wherein

R³Is C substituted with one or more halo substituents_2-6An alkyl group; with one or more radicals each independently selected from Ar, C_1-6Alkoxy radical, C_3-7Cycloalkyloxy and C_3-7C with cycloalkyl optionally substituted_1-6An alkyl group; ar or CH₂-O-Ar; wherein each Ar is independently selected from the group consisting of halo, C, and_1-4alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4Alkyl substituents are optionally substituted phenyl.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R³Is isobutyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl, C substituted by methoxy_2-4Alkyl radical, CH₂-O-Ar or Ar.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R³Is Ar.

In another embodiment, the present invention relates to compounds of any other embodiment wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and substituted by one or more halo radicalsSubstituted C_1-4An alkyl group; or is selected from pyridyl,Azolyl, thienyl, thiazolyl anda 5-or 6-membered heteroaryl group which is oxadiazolyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group.

In another embodiment, the present invention relates to compounds of any other embodiment wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or pyridyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group.

In another embodiment, the present invention relates to compounds of any other embodiment wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Azolyl, thiazolylIsothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁴Is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or with one or more radicals each independently selected from halo and C_1-4C with substituents of alkoxy being optionally substituted_1-4An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁴Is hydrogen, halo, C_1-4Alkoxy, cyano, or C optionally substituted with one or more halo substituents_1-4An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁴Is hydrogen, halo or C optionally substituted with one or more halo substituents_1-4An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁴Is hydrogen, halo, methyl, cyano or CF₃。

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁴Is hydrogen, F or CF₃。

In another embodiment, the invention relates to compounds of any other embodiment wherein Z is O.

In another embodiment, the present invention relates to anyOther embodiments are compounds wherein Z is NR⁹。

In another embodiment, the invention relates to compounds of any other embodiment, wherein Z is NR⁹And wherein R⁹Is formed by one or more compounds each independently selected from C_1-4Alkoxy and CF₃C optionally substituted by a substituent of (3)_1-6An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein R⁹Is C_1-3An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment or any combination of other embodiments, wherein each R is independently selected from the group consisting of⁸Independently selected from hydrogen or C_1-4An alkyl group.

In another embodiment, the invention relates to compounds of any other embodiment, wherein a¹Is N, CH, CF or COCH₃。

In another embodiment, the invention relates to compounds of any other embodiment, wherein a²Is CH.

In another embodiment, the invention relates to compounds of any other embodiment, wherein a³Is CH or N.

In another embodiment, the invention relates to compounds of any other embodiment, wherein a⁴Is CH.

In another embodiment, the invention relates to compounds of any other embodiment, wherein a²、A³And A⁴Each independently is CH or N; with the proviso that A¹、A²、A³And A⁴No more than two of which are N.

In another embodiment, the invention relates to compounds of any other embodiment, wherein a³And A⁴Is CH.

In another embodiment, the present invention relates to compounds of any other embodiment, wherein:

A²is CH, CF or N; and

A³and A⁴Each independently is CH or N; with the proviso that A¹、A²、A³And A⁴No more than two of which are N.

In another embodiment, the present invention relates to compounds of any other embodiment, wherein:

A¹is N, CH, CF or COCH₃；

A²Is CH;

A³is CH or N; and

A⁴is CH.

In another embodiment, the invention relates to a compound of any other embodiment, wherein C_1-6Alkyl radicals restricted to C_1-4An alkyl group.

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

1)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

2) 2-cyclohexyl-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

3)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

4) 2-cyclopentyl-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

5) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-2- (2-methylpropyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

6) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-2- (3-pyridinyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

7)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

8)4- [4- [ [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]Amino group]-2-benzoAzolyl radical]1-piperidinecarboxylic acid, 1, 1-dimethylethyl ester,

9)2- (2-chlorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

10)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1- (phenylmethyl) -1H-benzimidazol-4-amine,

11) 2-cyclohexyl-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

12)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

13) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-methoxyphenyl) -1-methyl-1H-benzimidazol-4-amine,

14)2- (2, 4-difluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

15)2- (2, 6-dimethyl-4-morpholinyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -phenyl ] -1-methyl-1H-benzimidazol-4-amine,

16)2- (2-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

17) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-2- (2-methoxyphenyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

18) 1-acetyl-4- [4- [ [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]Amino group]-2-benzoAzolyl radical]-a piperidine compound,

19)2- [ (4-fluorophenyl) methyl group]-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

20) n- [4- (4-bromo-1H-imidazol-1-yl) -3-methoxyphenyl ] -2- (4-fluorophenyl) -1-methyl-1H-benzimidazol-4-amine,

21) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-2- (1-methyl-4-piperidinyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

22) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- (2-methyl-propyl) -1H-benzimidazol-4-amine,

23)2- (4-fluorophenyl) -N- [ 5-methoxy-6- (4-methyl-1H-imidazol-1-yl) -3-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

24)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

25)1- [4- [ [2- (4-fluorophenyl) -1-methyl-1H-benzimidazol-4-yl ] amino ] -2-methoxy-phenyl ] -1H-imidazole-4-carbonitrile,

26)2- (4-fluorophenyl) -N- [4- (1H-imidazol-1-yl) -3-methoxyphenyl ] -1-methyl-1H-benzimidazol-4-amine,

27) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (2-methylphenyl) -1- (phenylmethyl) -1H-benzimidazol-4-amine,

28)2- (1, 1-Dimethylethyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

29)2- (4-fluorophenyl) -1-methyl-N- [5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1H-benzimidazol-4-amine,

30)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

31) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- [ (tetrahydro-2H-pyran-4-yl) methyl ] -1H-benzimidazol-4-amine,

32)2- [ (4-fluorophenyl) methyl ] -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

33)2- (4-fluorophenyl) -N- [ 4-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

34)2- (4-fluorophenyl) -1-methyl-N- [4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

35)2- (4-fluorophenyl) -1-methyl-N- [2- (4-methyl-1H-imidazol-1-yl) -5-pyrimidinyl ] -1H-benzimidazol-4-amine,

36) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (2-methylphenyl) -1H-benzimidazol-4-amine,

37)2- (4, 4-difluoro-1-piperidinyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

38) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2-phenoxy-1H-benzimidazol-4-amine,

39) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- (1-piperidinyl) -1H-benzimidazol-4-amine,

40)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1H-imidazo [4, 5-c ] pyridin-4-amine,

41)1- (2-methoxyethyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1H-benzimidazol-4-amine,

42)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

43) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1-methyl-1H-benzimidazol-4-amine,

44)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

45)2- (4-fluorophenyl) -N- [ 3-fluoro-4- (1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

46) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- (1-methyl-ethoxy) -1H-benzoimidazol-4-amine,

47) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- [ (2-methyl-propyl) thio ] -1H-benzimidazol-4-amine,

48) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- (3, 3, 3-trifluoropropyl) -1H-benzimidazol-4-amine,

49) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- (4-piperidinyl-methyl) -1H-benzimidazol-4-amine,

50) 1-acetyl-4- [ [4- [ [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] amino ] -1-methyl-1H-benzimidazol-2-yl ] methyl ] -piperidine,

51) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-2- [ (1-methyl-4-piperidinyl) methyl ] -1H-benzimidazol-4-amine,

52)2- (4-fluorophenyl) -1-methyl-N- [6- (4-methyl-1H-imidazol-1-yl) -3-pyridyl ] -1H-benzimidazol-4-amine,

53)2- (4-fluorophenyl) -1-methyl-N- [6- (3-methyl-1H-1, 2, 4-triazol-1-yl) -3-pyridyl ] -1H-benzimidazol-4-amine,

54) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1-methyl-1H-benzimidazol-4-amine,

55) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]-2- (2-methylpropyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

56)2- [ 4-ethoxy-2-methyl-5- (1-methylethyl) phenyl ] -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

57)2- [ 4-ethoxy-2-methyl-5- (1-methylethyl) phenyl]-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

58) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2-methyl-1- (phenylmethyl) -1H-benzimidazol-4-amine,

59)2- (cyclopropylmethyl) -1-ethyl-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

60)2- (4-fluoro-3-methoxyphenyl) -N- [ 3-fluoro-4- (1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

61)2- (4-fluorophenyl) -1- (1-methylethyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

62)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

63)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine, 2HCl,

64)1- (1, 1-dimethylethyl) -2- (4-fluorophenyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

65)1- (1, 1-dimethylethyl) -2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

66)N²- [ 4-ethoxy-2-methyl-5- (1-methylethyl) phenyl group]-N⁴- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl]-1-methyl-1H-benzimidazole-2, 4-diamine,

67) 2-methyl-N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (phenylmethyl) -1H-benzimidazol-4-amine,

68)1, 2-bis (2-methylpropyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

69)1- (2-methoxyethyl) -2- (2-methylpropyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

70)2- (2-methylpropyl) -N- [5- (3-methyl-1H-1, 2, 4-triazol-1-yl) -2-pyridinyl]-4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

71)2- (4-fluorophenyl) -1- (1-methylethyl) -N- [6- (3-methyl-1H-1, 2, 4-triazol-1-yl) -3-pyridyl-1H-benzimidazol-4-amine,

72) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2-methyl-1- (1-methyl-ethyl) -1H-benzimidazol-4-amine,

73)2- (4-fluorophenyl) -1-methyl-N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -6- (trifluoromethyl) -1H-benzimidazol-4-amine,

74) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (3-methoxypropyl) -1-methyl-1H-benzimidazol-4-amine,

75) 1-ethyl-N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (3, 3, 3-trifluoro-propyl) -1H-benzimidazol-4-amine,

76) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1-methyl-1H-benzimidazol-4-amine,

77)2- (3-methoxyphenyl) -1-methyl-N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

78)2- (4-fluorophenyl) -1- (1-methylethyl) -N- [5- (3-methyl-1H-1, 2, 4-triazol-1-yl) -2-pyridyl ] -1H-benzimidazol-4-amine,

79) 2-methyl-1- (1-methylethyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

80)2- (4-fluorophenyl) -1- (1-methylethyl) -N- [4- (5-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

81) n- [ 3-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1- (1-methylethyl) -1H-benzimidazol-4-amine,

82) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1- (1-methylethyl) -1H-benzimidazol-4-amine,

83)2- (1, 1-dimethylethyl) -N- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

84)2- (3-chlorophenyl) -N- [ 3-methoxy-4- (5 methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

85)2- (2-chloro-3-methoxyphenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1-methyl-1H-benzimidazol-4-amine,

86)2- (3-methoxyphenyl) -1- (1-methylethyl) -N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

87)2- (4-chloro-3-methoxyphenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

88) 2-butyl-N- [ 3-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

89)2- (4-fluorophenyl) -1-methyl-N- [6- (4-methyl-1H-imidazol-1-yl) -3-pyridazinyl ] -1H-benzimidazol-4-amine,

90)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

91) 6-fluoro-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxy-phenyl) -1-methyl-1H-benzimidazol-4-amine,

92) 6-fluoro-N- [ 3-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxy-phenyl) -1-methyl-1H-benzimidazol-4-amine,

93) 6-fluoro-2- (3-methoxyphenyl) -1-methyl-N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) -phenyl ] -1H-benzimidazol-4-amine,

94)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

95)2- (4-fluorophenyl) -1-methyl-N- [6- (3-methyl-1H-1, 2, 4-triazol-1-yl) -3-pyridyl ] -6- (trifluoromethyl) -1H-benzimidazol-4-amine,

96) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 2-dimethyl-1H-benzimidazol-4-amine,

97) n- [ 3-fluoro-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

98) n- [ 3-fluoro-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

99)2- (2, 4-difluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

100) n- [ 3-methoxy-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-2- (phenoxy-methyl) -1H-benzimidazol-4-amine,

101) n- [ 3-fluoro-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

102)2- (cyclopropylmethyl) -N- [ 3-methoxy-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

103) n- [3, 5-difluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1-methyl-1H-benzimidazol-4-amine,

104)2- (4-fluorophenyl) -1-methyl-N- [4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

105)2- (2, 4-difluorophenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

106) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (2-methylpropyl) -1- (2, 2, 2-trifluoroethyl) -1H-benzimidazol-4-amine,

107) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

108)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3-methyl-5- (1-methylethyl) -3H-imidazo [4, 5-b ] pyridin-7-amine,

109)2- (4-chloro-3-methoxyphenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

110)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -3-methyl-5- (1-methylethyl) -3H-imidazo [4, 5-b ] pyridin-7-amine,

111)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-6- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

112) 6-fluoro-2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

113) 6-fluoro-2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

114)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

115) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -3, 5-dimethyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

116)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3, 5-dimethyl-3H imidazo [4, 5-b ] pyridin-7-amine,

117)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3-methyl-5- (1-methylvinyl) -3H-imidazo [4, 5-b ] pyridin-7-amine,

118)1- [4- [ [2- (4-fluorophenyl) -1-methyl-1H-benzimidazol-4-yl ] amino ] -2-methoxyphenyl ] -1H-imidazole-4-methanol,

119)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

120)2- (2, 4-difluorophenyl) -N- [ 2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

121) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

122) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-4-amine,

123) n- [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1- (1-methylethyl) -2- [6- (trifluoromethyl) -3-pyridinyl ] -1H-benzimidazol-4-amine,

124) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

125) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-2- [2- (trifluoromethyl) phenyl ] -1H-imidazo [4, 5-c ] pyridin-4-amine,

126)2- (2, 5-difluorophenyl) -1-ethyl-6-fluoro-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1H-benzimidazol-4-amine,

127) n- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -2- (3-methoxyphenyl) -1- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

128)2- (2-chlorophenyl) -6-fluoro-N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

129)2- (2-chlorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

130)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -5- (3-methoxypropyl) -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

131)2- (2-chlorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

132)2- (4-fluorophenyl) -N- [ 3-methoxy-4- [4- (methoxymethyl) -1H-imidazol-1-yl ] phenyl ] -1-methyl-1H-benzimidazol-4-amine,

133)2- (5-chloro-2-thienyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

134)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3-methyl-3H-imidazo [4, 5-c ] pyridin-7-amine,

135)2- (3-chlorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

136)2- [1- (4-chlorophenyl) ethyl ] -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

137)2- [1- (4-chlorophenyl) cyclopropyl ] -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

138)2- (2-chlorophenyl) -6-fluoro-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

139)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

140)2- (2-chlorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

141)2- (2-chlorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

142)2- (2-chlorophenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

143) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

144) 5-cyclopropyl-N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

145) 6-chloro-2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

146)4- [ [4- [ [ 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl ] amino ] -1-methyl-1H-benzimidazol-2-yl ] methyl ] -1-piperidinecarboxylic acid 1, 1-dimethylethyl ester,

147) 5-cyclopropyl-2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

148) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -3-methyl-5- (1-methylethyl) -3H-imidazo [4, 5-b ] pyridin-7-amine,

149) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1-methyl-6- (1-methylethyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

150) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

151)2- (4-fluorophenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

152) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -5-methoxy-3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

153)2- (4-fluorophenyl) -5-methoxy-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

154) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl]-2- (3-methoxyphenyl) -4-benzoThe presence of an azole amine in the presence of a salt of the azole amine,

155)2- (3-bromo-4-fluorophenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

156) n- [ 3-fluoro-4- (2-iodo-4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

157)2- (3-ethoxyphenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

158)5- [4- [ [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] amino ] -1-methyl-1H-benzimidazol-2-yl-1-methyl-2 (1H) -pyridinone,

159)5- [4- [ [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] amino ] -1-methyl-1H-benzimidazol-2-yl ] -1-methyl-2 (1H) -pyridinone,

160) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (2-methoxyphenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

161)2- (2-fluoro-4-methoxyphenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

162) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-2- (3-pyridyl) -1H-imidazo [4, 5-c ] pyridin-4-amine,

163)2- [3- (dimethylamino) phenyl ] -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

164) n- [3- [4- [ [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] amino ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-2-yl ] phenyl ] -acetamide,

165)2- (4-chloro-3-methoxyphenyl) -6-fluoro-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

166)2- (4-chloro-3-methoxyphenyl) -N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

167)2- (4-chloro-3-methoxyphenyl) -N- [ 3-methoxy-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

168)2- (4-chloro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

169)2- (4-chloro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

170) 6-fluoro-N- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1- (1-methylethyl) -1H-benzimidazol-4-amine,

171)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -3-methyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

172)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (3-methyl-1H-1, 2, 4-triazol-1-yl) -2-pyridyl ] -1- (1-methylethyl) -1H-benzimidazol-4-amine,

173)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (3-methyl-1H-1, 2, 4-triazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

174)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -3, 5-dimethyl-3H-imidazo [4, 5-b ] pyridin-7-amine,

175)2- (4-fluorophenyl) -6-methoxy-N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

176)2- (3-bromo-4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

177)2- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

178)2- (3, 5-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

179) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [3- (trifluoromethyl) phenyl ] -1H-benzimidazol-4-amine,

180) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [4- (trifluoromethyl) phenyl ] -1H-benzimidazol-4-amine,

181)2- (4-fluoro-3-iodophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

182) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [2- (trifluoromethoxy) phenyl ] -1H-benzimidazol-4-amine,

183)2- (3-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

184) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [2- (trifluoromethyl) phenyl ] -1H-benzimidazol-4-amine,

185)2- [3- (dimethylamino) phenyl ] -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

186) n- [3- [4- [ [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] amino ] -1-methyl-1H-benzimidazol-2-yl ] phenyl ] -acetamide,

187)2- (3, 4-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

188)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

189) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -2- (3-methoxyphenyl) -1-methyl-1H-benzimidazol-4-amine,

190) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -2- (4-methoxyphenyl) -1-methyl-1H-benzimidazol-4-amine,

191)2- (3-ethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

192)2- (2-fluoro-5-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate,

193)2- (2-fluoro-5-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

194) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [3- (1-methylethoxy) phenyl ] -1H-benzimidazol-4-amine,

195)2- (2-fluoro-4-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

196) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -2- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1-methyl-1H-benzimidazol-4-amine,

197)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

198)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate,

199)2- (4-fluoro-2-methylphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

200)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

201)2- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

202)2- (3-fluoro-5-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

203) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [3- (trifluoromethoxy) phenyl ] -1H-benzimidazol-4-amine,

204)2- (2, 4-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

205) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [4- (trifluoromethoxy) phenyl ] -1H-benzimidazol-4-amine,

206)2- [ 4-fluoro-3- (trifluoromethyl) phenyl ] -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

207)2- (2-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

208) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -2- (4-methoxy-2-methylphenyl) -1-methyl-1H-benzimidazol-4-amine,

209) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2- [ 2-methyl-5- (trifluoromethyl) phenyl ] -1H-benzimidazol-4-amine,

210) n- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-2-phenyl-1H-benzimidazol-4-amine,

211)2- [4- (dimethylamino) phenyl ] -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine, and

212)3- [4- [ [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] amino ] -1-methyl-1H-benzimidazol-2-yl ] -benzonitrile,

including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

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

1) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

2) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine, bis-methanesulfonate,

3) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine dihydrochloride,

4)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

5)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride,

6)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine dihydrochloride monohydrate,

7)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

8)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate,

9)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

10)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine dihydrochloride monohydrate, and

11)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

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

1) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

2)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

3)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate,

4)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine dihydrochloride monohydrate, and

5)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate.

In one embodiment, the compound of formula (I) is 2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine, including pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the compound of formula (I) is 2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine.

In one embodiment, the compound of formula (I) is 2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate.

In one embodiment, the compound of formula (I) is 2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine, including the pharmaceutically acceptable addition salts and solvates thereof.

All possible combinations of the above presented target embodiments are considered to be included within the scope of the present invention.

The invention also includes processes for the preparation of compounds of formula (I) and subgroups thereof. In the described reactions, it may be necessary to protect reactive functional groups, such as hydroxyl, amino or carboxyl groups, when these are desired in the final product, to avoid their unwanted participation in the reaction. Conventional protecting Groups may be employed in accordance with standard practice, see, for example, t.w.greene and p.g.m.wuts, "protecting Groups in Organic Chemistry", john wiley and Sons, 1999.

The compounds of formula (I) and subgroups thereof may be prepared by a series of steps as described hereinafter. They are generally prepared from starting materials that are commercially available or prepared by standard methods apparent 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 procedure preparation of some representative examples is shown below:

experimental method 1

In general, compounds of formula (I) can be prepared as presented in scheme 1 below, wherein all variables are as defined below:

the compound of formula (I) may be prepared via a coupling reaction between an intermediate of formula (II-a) and an intermediate of formula (III-a), or via a coupling reaction between an intermediate of formula (II-b) and an intermediate of formula (III-b). In scheme 1, halo is defined as Cl, Br or I. The reaction may be carried out in the presence of a suitable base such as Cs₂CO₃Or in the presence of sodium tert-butoxide. The reaction can be carried out in a reaction-inert solvent such as toluene, N-Dimethylformamide (DMF), 1, 2-Dimethoxyethane (DME), tert-butanol or di-butanolIn an alkane. The reaction is usually carried out in the presence of a suitable catalyst such as tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) Palladium (II) acetate (Pd (OAc)₂) And ligands such as (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis [ diphenylphosphine](Xantphos), [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](BINAP), bis (2-diphenylphosphinophenyl) ether (DPEphos) or dicyclohexyl [2 ', 4', 6 '-tris (1-methylethyl) [1, 1' -biphenyl ]]-2-yl]-a phosphine (X-phos) in the presence of a catalyst system. Preferably the reaction is carried out under an inert atmosphere, such as a nitrogen or argon atmosphere. Reaction rate and yield can be enhanced by microwave-assisted heating.

The traces of palladium present after the work-up of the reaction can optionally be removed by treating a solution of the compound of formula (I) with N-acetyl-L-cysteine or thiol-functionalized silica in a suitable solvent or solvent mixture, such as DCM and MeOH.

In an alternative process, the process is only carried out when Y is in the definition of (III-a)¹Or Y³Is N, Y can be prepared by aromatic nucleophilic substitution between intermediates of formula (II-a) and (III-a)¹Or Y³A compound of formula (I) which is N. The reaction can be carried out under basic or acidic conditions, for example in the presence of HCl or methanesulfonic acid, in a reaction-inert solvent such as 2-propanol. Reaction rate and yield can be enhanced by microwave-assisted heating.

R containing suitable functional groups³Groups such as halo, (protected) amines, alcohols or ketones may be used to incorporate further substitution patterns in the compounds of formula (I).

Experimental method 2

As shown in scheme 2 below, intermediates of formula (II-a) can be prepared by reduction of intermediates of formula (IV), wherein all variables are as defined previously. By conventional methods, e.g. reductive hydrogenation or with metals or metal salts and acids [ e.g. metals such as iron or metal salts such as SnCl ]₂With acids, e.g. mineral acids (HCl, H)₂SO₄Etc.) or organic acids (acetic acid, etc.)]Reduction, or use of niterOther well known methods for converting a group to the corresponding amine may be carried out to reduce (IV) to (II-a).

Experimental method 3

Intermediates of formula (II-a) wherein halo is defined as Br or I and wherein all other variables are as defined above, can also be prepared by copper catalyzed reaction of an intermediate of formula (V) with an (un) substituted imidazole or triazole of formula (VI) according to scheme 3. The reaction may be carried out under a protective atmosphere such as N₂The reaction is carried out under an atmosphere. Stirring, elevated temperature (e.g., between 70-200 ℃) and/or pressure may enhance the reaction rate. The reaction is usually carried out in an organic solvent such as dimethyl sulfoxide (DMSO) or Dimethylformamide (DMF). Optionally, the reaction is carried out in a base such as K₂CO₃、Cs₂CO₃Or triethylamine (Et)₃N) and/or ligands such as N, N' -dimethylethylenediamine or 1, 10-phenanthroline. Copper catalysts, for example copper salts such as copper (I) oxide, copper (I) iodide or copper (I) bromide, can be used in catalytic or stoichiometric amounts. The amino group in intermediate (V) may be protected prior to the reaction by use of a suitable amino protecting group according to standard practice and may be deprotected after the reaction, see for example t.w.greene and p.g.m.wuts, "Protective Groups in organic Chemistry", John Wiley and Sons, 1999.

Experimental method 4

Intermediates of formula (II-a) can also be prepared according to scheme 4 by converting the halo substituent in intermediate (II-b) to an amino group or a masked amino functionality, which can then be converted to an amino group. In scheme 4, typical reaction conditions known to those skilled in the art can be employed. In scheme 4, halo is defined as Cl, Br, or I, and all other variables are defined as mentioned above.

Experimental method 5

Intermediates of formula (IV) can be prepared according to scheme 5 by aromatic nucleophilic substitution of intermediates of formula (VII) with (un) substituted imidazoles or triazoles of formula (VI), wherein halo is defined as F, Cl or Br and wherein all other variables are defined as mentioned above. The reaction may be carried out under a protective atmosphere such as N₂The reaction is carried out under an atmosphere. Stirring, elevated temperature (e.g., between 70-170 ℃) and/or pressure may enhance the reaction rate. The reaction is usually carried out in an organic solvent such as DMSO, DMF or N-methylpyrrolidone (NMP) in a base such as K₂CO₃、Cs₂CO₃Or Et₃In the presence of N.

Experimental method 6

Intermediates of formula (II-b) can be prepared from intermediates of formula (II-a) by conversion of (II-a) to the corresponding diazonium salt via a Sandmeyer reaction, followed by treatment with a reagent such as KI, CuBr or CuCl, according to scheme 6. Typical reaction conditions known to those skilled in the art can be employed in scheme 6. All variables in flow 6 are defined as before.

Experimental method 7

According to scheme 7, A is substituted with an (un) substituted imidazole or triazole of formula (VI)¹And/or A³An intermediate (VIII) of N, in which LG is defined as F, Cl, Br or NO₂Wherein halo is defined as Br or I, and wherein all other variables are as defined above, may be prepared wherein A is¹And/or A³Is N, and is thus referred to as an intermediate of formula (II-b 1). The reaction can be carried out under similar conditions as described for experimental method 5.

Experimental method 8

According to scheme 8, the reaction is carried out in a reaction inert solvent such as THF and optionally in a suitable base such as Et₃Acylation of Intermediate (IX) in the presence of N gives intermediate (X), and intermediates of formula (II-b) wherein X represents CH, thus termed intermediates of formula (II-b2), may also be prepared. Followed by reaction in an inert solvent such as DMF and a suitable base such as Cs₂CO₃Or K₂CO₃Intermediates of formula (XII) may be prepared by alkylating an intermediate of formula (X) with an intermediate of formula (XI) in the presence of a catalytic amount of an iodide salt such as KI or NaI. Intermediate (XII) with an ammonia source such as ammonium acetate (NH)₄OAc) followed by condensation to give the compound of formula (II-b 2). In scheme 8, halo is defined as Cl, Br or I, halo 2 is defined as Cl or Br, and all other variables are defined as mentioned above.

To construct the imidazole ring in the intermediate of formula (II-b2), R was introduced²And R¹The order of (a) may be reversed. Reactions of this type are described in US2006/0004013 for 1- (4-bromo-2-methoxy)Phenyl) -4-methyl-1H-imidazole is described.

Experimental method 9

According to scheme 9, wherein R is prepared by acylation of intermediate (XIII) with an intermediate of formula (XIV), followed by condensation³To a heterocyclic carbon, and wherein Z is N-R⁹And are thus referred to as intermediates of formula (III-a 1). The acylation reaction may be carried out in a solvent such as pyridine or a reaction inert solvent such as DMF. The reaction can be carried out in a base such as Et₃In the presence of N. The subsequent condensation reaction may be carried out by heating the crude acylation product in a solvent such as acetic acid. In scheme 9, halo is defined as Cl, Br, or I, and all other variables are as defined before.

By a similar condensation process, by using the formula R³The carboxylic acid of-COOH directly condensed intermediate (XIII) to intermediate (III-a 1). The reaction can be carried out under dehydrating conditions, for example, by heating in a solvent such as polyphosphoric acid.

Experimental method 10

Intermediates of formula (III-a1) can also be prepared by treating an intermediate of formula (XIII) with an aldehyde of formula (XV). The reaction can generally be carried out in the presence of a reducing agent such as sodium metabisulphite. According to scheme 10, the reaction can be generally carried out in a reaction-inert solvent such as N, N-Dimethylacetamide (DMA). In scheme 10, halo is defined as Cl or Br and all other variables are defined as previously mentioned.

Experimental method 11

Intermediates of formula (III-a1) can also be prepared by treating an intermediate of formula (XVI) with an aldehyde of formula (XV). The reaction may be carried out in the presence of a reducing agent such as sodium dithionite. The reaction can generally be carried out in a reaction-inert solvent such as ethanol. In scheme 11, halo is defined as Cl or Br and all other variables are defined as mentioned above.

Experimental method 12

Or, from wherein R⁹Intermediate of formula (IIIa1) which is H, resulting in the preparation of an intermediate designated formula (III-a3) wherein R⁹Is an intermediate of formula (III-a1) other than H, and is thus referred to as an intermediate of formula (III-a 2). As depicted in scheme 12, the group R^9aCan be introduced via N-alkylation, leading to the formation of predominantly intermediates of the formula (III-a2), wherein R^9aAre substituents other than hydrogen as defined before.

Experimental method 13

As shown in scheme 13, the reduction of an intermediate of formula (XVI) can produce an intermediate of formula (XIII), wherein halo is defined as Br or Cl and wherein all other variables are as previously defined. By conventional methods, e.g. reductive hydrogenation or with metals or metal salts and acids [ e.g. metals such as iron or metal salts such as SnCl ]₂With acids such as inorganic acids (hydrochloric acid, sulfuric acid, etc.) or organic acids (acetic acid, etc.)]Reduction of (XVI) to (XIII) may be carried out by reduction, or other well known methods for converting the nitro group to the corresponding amine.

Experimental method 14

As shown in scheme 14 below, via formula R⁹-NH₂The intermediates of formula (XVI) can be prepared by subjecting an intermediate of formula (XVII) to a substitution reaction, wherein halo is defined as Br, I, or Cl, wherein halo 2 is defined as F, Cl or Br, and wherein all other variables are as previously defined.

Experimental method 15

Can be prepared as shown in scheme 15, wherein R³To a heterocyclic carbon and Z is N-R⁹And are thus referred to as intermediates of formula (III-b 1). In the first step, intermediate (XVIII) is acylated with an activated carboxylic acid derivative, such as an acid chloride, to give intermediate (XIX), which can be condensed to an intermediate of formula (XX). Alternatively, the intermediate of formula (XVIII) is reacted with the compound of formula R by heating under dehydrating conditions, e.g. in a solvent such as polyphosphoric acid⁹The carboxylic acid condensation of-COOH, also allows the one-step preparation of the intermediate (XX).

Deprotonation of the intermediate of formula (XX) with a base such as lithium hexamethyldisilazide in a reaction inert solvent such as toluene or (methyl) tetrahydrofuran, followed by an alkylating agent such as CH₃I treatment leads to the formation of intermediates of formula (XXI).

Reduction of the intermediate of formula (XXI) by reductive hydrogenation or treatment with a reducing agent such as iron in acetic acid (XXI) or other well known methods for converting nitro groups to the corresponding amine gives the desired intermediate of formula (III-b 1).

In the flow 15, all variables are defined as mentioned before.

Experimental method 16

Alternatively, intermediates of formula (III-b1) can be prepared as set forth in scheme 16 below. The intermediate of formula (XXII) is deprotonated with a base such as lithium hexamethyldisilazide, usually in a reaction inert solvent such as toluene or (methyl) tetrahydrofuran, followed by an alkylating agent such as CH₃Treatment of I results in the formation of an intermediate of formula (XXIII). With halogenating agents, e.g. phosphorus oxychloride (POCl)₃) Treating the intermediate of formula (XXIII) to obtain an intermediate of formula (XXIV). This intermediate can be converted into an intermediate of the formula (XXV) by reaction with amines, alcohols, thiols or by Suzuki reaction with aryl-or alkyl-borates. The desired intermediate of formula (III-b1) is obtained by reductive hydrogenation or reduction of an intermediate of formula (XXV) with a reducing agent such as iron in acetic acid or other known methods for converting the nitro group to the corresponding amine, as shown in scheme 15. In the flow 16, all variables are defined as mentioned before.

Experimental method 17

Intermediates of formula (III-a1) can also be prepared as set forth in scheme 17. Condensation of the intermediate of formula (XIII) with urea, carbonyldiimidazole, phosgene or a phosgene equivalent, e.g. diphosgene or triphosgene, gives an intermediate of formula (XXVI). With halogenating agents, e.g. POCl₃Treating an intermediate of formula (XXVI) to give an intermediate of formula (XXVII). Intermediates of formula (XXVII) can be converted into intermediates of formula (III-a1) by reaction with amines, alcohols, thiols or by Suzuki reaction with aryl-or alkyl-borates. In scheme 17, halo is defined as Br, I, or Cl, and all other variables are defined as previously mentioned.All reaction steps in scheme 17 can be carried out by employing typical reaction conditions known to those skilled in the art.

Experimental method 18

Wherein R can be prepared as set forth in scheme 18 below³Is limited to C_1-6Alkylthio and wherein Z is N-R⁹To intermediates of formula (III-a3) and are thus referred to as intermediates of formula (III-a 3). The intermediate of formula (XIII) is condensed with thiourea or 1, 1' -thiocarbonyldiimidazole by heating in a reaction-inert solvent such as THF to give the intermediate of formula (XXVIII). Then, in a base such as K₂CO₃In the presence of, e.g. C_1-6The alkyl iodide may alkylate the intermediate of formula (XXVIII). This reaction step can generally be carried out in a reaction-inert solvent such as acetone to give the intermediate of formula (III-a 3). In scheme 18, halo is defined as Br, I or Cl, R^3aIs defined as C_1-6Alkylthio, and all other variables are as defined above.

Experimental method 19

Wherein R can be prepared as set forth in scheme 19 below³An intermediate of formula (III-a) attached to a heterocyclic carbon and wherein Z is O, thereby designated an intermediate of formula (III-a 4). With activated carboxylic acid derivatives, e.g. of formula R³Acylation of the intermediate of formula (XXIX) with an acid chloride of COCl to give an intermediate of formula (XXX). Subsequently, intermediates of formula (XXX) may be O-arylated to a benzo of formula (III-a4)Azole intermediateAnd (3) a body. In scheme 19, halo is defined as Br, I or Cl, halo 2 is defined as Cl, Br or I, and all other variables are defined as before.

Experimental method 20

Intermediates of formula (III-b) can also be prepared according to scheme 20 by converting the halo substituent in an intermediate of formula (III-a) wherein halo is defined as Cl, Br, or I, and wherein all other variables are as defined above, to an amino group or a masked amino functional group, which can then be converted to an amino group. Typical well-known reaction conditions known to those skilled in the art can be employed in scheme 20.

Experimental method 21

Starting from the coupling reaction between an intermediate of formula (XXVII) and an intermediate of formula (II-a) according to the conditions described under Experimental method 1, an intermediate of formula (XXXI) is obtained, which is subsequently converted into a compound of formula (I-a) via reaction with an amine, an alcohol, a thiol or via a Suzuki reaction with an aryl-or alkyl-borate, it is possible to prepare compounds in which Z is N-R⁹Thereby being referred to as a compound of formula (I-a). This final reaction in scheme 21 can be carried out by employing typical reaction conditions known to those skilled in the art.

Experimental method 22

According to the experimental method 1The intermediates of formula (XXXII) can be prepared starting from the coupling reaction between an intermediate of formula (XVI) and an intermediate of formula (II-a) under the conditions described, in which R³To a heterocyclic carbon, and wherein Z is N-R⁹Thereby being referred to as a compound of formula (I-b). Intermediates of formula (XXXII) may be converted directly to compounds of formula (I-b) according to the conditions described under Experimental method 11, or (XXXII) may be first reduced to intermediates of formula (XXXIII) according to the conditions described under Experimental method 13, followed by conversion of (XXXIII) to compounds of formula (I-b) according to the conditions described under Experimental method 10.

Intermediates of formula (V), (VI), (VII), (VIII), (IX), (XI), (XIV), (XV), (XVII), (XXII) and formula (XXIX) are commercially available or can be readily prepared by the skilled person.

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

intermediates of formula (III-a) or (III-b) and compounds of formula (I), any subgroup, addition salts, solvates and stereochemically isomeric forms thereof may be converted into further intermediates and compounds of the invention by methods known in the art.

To obtain the HCl salt form of the compound, several methods known to those skilled in the art can be employed. In a typical procedure, for example, the free base can be dissolved in DIPE or Et₂O and may be subsequently added dropwise to a 6N HCl solution in 2-propanol or in Et₂1N HCl solution in O. The mixture is usually stirred for 10 minutes, after which the product can be filtered off. The HCl salt is typically dried in vacuo.

It will be appreciated by those skilled in the art that in the above described process, 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 may be deprotected after the reaction step.

Pharmacology of

The compounds of the present invention have been found to modulate gamma-secretase activity. The compounds of the present invention and pharmaceutically acceptable compositions thereof are therefore useful in the treatment or prevention of Alzheimer's Disease (AD), traumatic brain injury, Mild Cognitive Impairment (MCI), senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, preferably alzheimer's disease.

The term "modulating gamma secretase activity" as used herein refers to the effect on APP processing by the gamma secretase-complex. Preferably, it refers to an effect wherein the overall rate of APP processing is substantially maintained without administration of said compound, but wherein the relative amount of processed product is altered, more preferably in such a way that the amount of A β 42-peptide produced is reduced. For example, different Abeta-like substances may be produced (e.g.Abeta-38 or other Abeta peptide substances of shorter amino acid sequence than Abeta-42) or the relative amounts of the products may be different (e.g.the ratio of Abeta-40 to Abeta-42 is altered, preferably increased).

It has previously been shown that the gamma secretase complex is also involved in Notch protein processing. Notch is a signaling protein that plays a key role in developmental processes (reviewed, for example, in Schweisguth F (2004) curr. biol.14, R129). For the use of gamma secretase modulators in therapy, it would seem particularly advantageous not to interfere with the Notch processing activity of gamma secretase activity in order to avoid the expected adverse side effects. While gamma secretase inhibitors exhibit side effects due to the concomitant inhibition of Notch processing, gamma secretase modulators may have the advantage of selectively reducing the production of the highly aggregated and neurotoxic form of a β, a β 42, without reducing the less aggregated form of a β, a β 38, and without concomitant inhibition of Notch processing. Therefore, compounds that do not affect the Notch processing activity of the γ secretase complex are preferred.

The term "treatment" as used herein refers to all methods in which there may be delay, hindrance, inhibition or termination of disease progression but not necessarily all symptoms are shown to be eliminated.

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

The invention also relates to compounds of general formula (I), their stereoisomeric forms and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of a disease or disorder selected from alzheimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia or down syndrome.

The invention also relates to compounds of general formula (I), their stereoisomeric forms and their pharmaceutically acceptable acid or base addition salts and solvates thereof for use in the treatment or prevention of a disease selected from AD, MCI, senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia or down syndrome.

In one embodiment, the disease or disorder is preferably alzheimer's disease.

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

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

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

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

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

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

In the present invention, IC's inhibiting A β 42-peptide production as measured by suitable assays, e.g., the assay used in the examples below, are particularly preferred₅₀A compound of formula (I) or any subgroup thereof with a value of less than 1000nM, preferably less than 100nM, more preferably less than 50nM, even more preferably less than 20 nM.

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

In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from, or preventing, any of the diseases described hereinbefore.

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

The skilled person in the treatment of such diseases may determine the daily effective therapeutic amount from the test results given below. A daily effective therapeutic amount is from about 0.005mg/kg to 50mg/kg, especially from 0.01mg/kg to 50mg/kg body weight, more especially from 0.01mg/kg to 25mg/kg body weight, preferably from about 0.01mg/kg to about 15mg/kg, more preferably from about 0.01mg/kg to about 10mg/kg, even more preferably from about 0.01mg/kg to about 1mg/kg, most preferably from about 0.05mg/kg to about 1mg/kg body weight. The amount of the compounds of the present invention, also referred to herein as active ingredients, required to achieve a therapeutic effect will naturally vary depending on the particular circumstances, e.g., the particular compound employed, the route of administration, the age and condition of the recipient, and the particular condition or disease being treated.

The method of treatment may further comprise administering the active ingredient on a regimen of 1-4 intakes per day. In these methods of treatment, it is preferred to formulate the compounds of the invention prior to administration. Suitable pharmaceutical formulations are prepared by known methods using well known and readily available ingredients, as described hereinafter.

The compounds of the present invention suitable for the treatment or prevention of 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, and administration of the compound of formula (I) and each of the other therapeutic agents via its own separate pharmaceutical dosage formulation. 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 provided in 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 of formula (I).

A 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 subject compounds may be formulated in a variety of pharmaceutical forms for administration purposes. The compounds of the present invention, in particular the compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all compositions generally used for systemic administration can be cited.

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 combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are in unit dosage forms suitable for administration, especially orally, rectally, subcutaneously, parenterally, by injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like are used. Because of their ease of administration, tablets and capsules represent the best oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually contain, at least in large part, sterile water, although other ingredients such as solubilizing agents may also be included. For example, injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solution. For example, injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solution. Injectable solutions containing the compounds of formula (I) may be formulated in oil to provide a 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 and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for subcutaneous administration, the carrier optionally contains a penetration enhancer and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minor proportions, which additives do not introduce significant damaging effects on the skin. The additives may facilitate administration of the drug to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, such as transdermal patches, spot-on, ointments. Acid or base addition salts of the compounds of formula (I) are more suitable for the preparation of aqueous compositions because of their increased water solubility than the corresponding base or acid form.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to 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, powders, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

Because the compounds of the present invention are active orally administrable compounds, pharmaceutical compositions containing such compounds for oral administration are particularly advantageous.

To improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions, it may be advantageous to use α -, β -or γ -cyclodextrins or their derivatives, especially hydroxyalkyl-substituted cyclodextrins such as 2-hydroxypropyl- β -cyclodextrin or sulfobutyl- β -cyclodextrin. Co-solvents such as alcohols may also improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

Depending on the mode of administration, the pharmaceutical composition preferably comprises 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 "DCM" denotes dichloromethane, "MeOH" denotes methanol, "LCMS" denotes liquid chromatography/mass spectrometry, "HPLC" denotes high performance liquid chromatography, "sol." denotes solution, "sat." denotes saturated, "aq." denotes aqueous solution, "r.t." denotes room temperature, "AcOH" denotes acetic acid, "m.p." denotes melting point, "RP" denotes reverse phase, "BDS" denotes base deactivated silica, "min" denotes minutes, "h" denotes hours, "i.d." denotes internal diameter, "EtOAc" denotes ethyl acetate, "Et" denotes ethyl acetate₃N "represents triethylamine and" BINAP "represents [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](racemic), "EtOH" means ethanol, "eq" means equivalent, "r.m." means reaction mixture, "DIPE" means diisopropyl ether; "q.s." means an appropriate amount, "DMA" means N, N-dimethylacetamide, "NMP" means N-methyl-2-pyrrolidone, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "DMSO" means dimethyl sulfoxide, "mCPBA" means 3-chloroperoxybenzoic acid, "DMF" means N, N-dimethylformamide, "LiHMDS" means lithium hexamethyldisilazide, "X-Phos" means dicyclohexyl [2 ', 4', 6 '-tris (1-methylethyl) [1, 1' -biphenyl ] amide]-2-yl]Phosphine, "DCE" represents 1, 2-dichloroethane, and "HBTU" represents 1- [ bis (dimethylamino) methylene ] hexafluorophosphate]-1H-benzotriazole-1-3-oxide, "Pd (PPh)₃)₄"represents tetrakis (triphenylphosphine) palladium," Pd (OAc)₂"denotes palladium diacetate (2 +)" PdCl₂(PPh₃)₂"represents bis (triphenylphosphine) palladium dichloride; and "Pd₂(dba)₃"denotes tris [ mu- [ (1, 2-. eta.: 4, 5-. eta.) - (1E, 4E) -1, 5-diphenyl-1, 4-pentadien-3-one]]Dipalladium.

A. Preparation of intermediates

Example A1

a) Preparation of intermediate 1

1-chloro-2-methoxy-4-nitrobenzene (50g, 0.26mol), 4-methyl-1H-imidazole (43.77g, 0.53mol) and K₂CO₃(36.84g, 0.26mol) mixture in DMSO (500ml) in an autoclave in N₂The reaction was carried out at 150 ℃ for 6 hours under an atmosphere. The reaction was repeated twice with 50g of 1-chloro-2-methoxy-4-nitrobenzene each time. Subsequently, 3 batches of the reaction mixture (a total of 150g of 1-chloro-2-methoxy-4-nitrobenzene) were worked up together. The mixture was poured out into 61 ice water. The solid is filtered off and taken up in H₂And O washing. Dissolve the solid in DCM and dissolve with H₂O washing the solution. Drying (MgSO)₄) The organic layer was separated, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM/MeOH from 100/0-97/3). The product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried in an oven. Yield: 48.54g of intermediate 1 (26%).

b) Preparation of intermediate 2a and intermediate 2

Intermediate 1(13.2g, 56.6mmol) was dissolved in MeOH (250 ml). To the solution was added Pd/C (0.5g) and washed with H₂The resulting suspension was stirred at 50 ℃ overnight (under normal pressure). In absorption of H₂After (1 eq.) the catalyst was filtered off. The organic layer was evaporated to give intermediate 2a (free base). Intermediate 2a was dissolved in HCl/EtOH solution and stirred for 30 minutes. The solvent was removed in vacuo. The residue was crystallized from EtOH containing a small amount of petroleum ether to give the desired product. Yield: 4.7g of intermediate 2 (41%).

Example A2

a) Preparation of intermediate 3 and intermediate 4 (regioisomers)

1-fluoro-2-methoxy-4-nitrobenzene (821mg, 4.8mmol), 5-methyl-1H-1, 2, 4-triazole (800mg, 9.63mmol), K₂CO₃A mixture of (4.8mmol) and DMSO (8ml) was stirred at 120 ℃ for 1 hour. After cooling, the reaction mixture was poured into ice water. The solid is filtered off, washed with water and dried in vacuo at 50 ℃. Yield: 0.554g of intermediate 3 (49%). The aqueous layer was saturated with NaCl, extracted with DCM and dried (MgSO)₄) The organic layer was filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.147g of intermediate 4 (13%).

b) Preparation of intermediate 5

In N₂MeOH (50ml) was added to Pd/C10% (150mg) under atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (1ml) and intermediate 3(550mg, 2.348mmol) were added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 3 equivalents of H had been absorbed₂. The catalyst was filtered off over celite. The filtrate was evaporated and the residue was suspended in DIPE, filtered off and dried in vacuo. Yield: 0.350g of intermediate 5 (73%).

Example A3

a) Preparation of intermediate 6 and intermediate 7 (regioisomers)

3, 4-difluoro-nitrobenzene (15.7g, 96.7mmol), 5-methyl-1H-1, 2, 4-triazole (9.94g, 116mmol), K₂CO₃A mixture of (20g, 145mmol) and DMF (150ml) was stirred at 75 ℃ for 2 h. After cooling, the reaction mixture was poured into ice water. The precipitate was filtered off and washed with water. The resulting solid is reacted with hydrogen₂Recrystallization from O/MeOH gave intermediate 6 as a monohydrate solid (yield: 9.2g, 43%) and the mother liquor. The mother liquor was concentrated in vacuo to give 3.1g of a residue containing 44% intermediate 6 and 55% intermediate 7.

b) Preparation of intermediate 8

In N₂MeOH (150ml) was added to Pd/C10% (2g) under an atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (1ml) and intermediate 6(9.1g, 37.9mmol) were added. At H₂The reaction mixture was stirred at 50 ℃ under an atmosphere until 3 equivalents of H had been taken up₂. The catalyst was filtered off over celite and the filtrate was evaporated. In DCM and H₂The residue was partitioned between O. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Yield: 7.23g of intermediate 8 (99%).

c) Preparation of intermediate 9

In N₂MeOH (150ml) was added to Pd/C10% (1g) under an atmosphere. Next, a 0.4% thiophene solution in DIPE (0.5ml) and a mixture of intermediate 6 and intermediate 7 present in a ratio of 4/5 (3.1g, 12.9mmol) were added. At H₂The reaction mixture was stirred at 50 ℃ under an atmosphere until 3 equivalents of H had been taken up₂. The catalyst was filtered off over celite and the filtrate was evaporated. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH]The residue was purified. The product fractions were collected and worked up. Yield: 1.2g of intermediate 9 (48%).

Example A4

a) Preparation of intermediate 10

An 8M methylamine solution in EtOH (100ml, 0.8mol) was added to 1-bromo-3-fluoro-2-nitro-benzene (19.8g, 90mmol) and cooled on a water bath. The reaction mixture was stirred at room temperature overnight. The solvent was then evaporated and the residue partitioned between water and DCM. Drying (MgSO)₄) Combined organic layers. Filtered and concentrated in vacuo. Yield: 20g of intermediate 10 (96%), which was used as such in the next reaction step.

b) Preparation of intermediate 11

Intermediate 10(20g, 86.6mmol) and iron powder (15g, 269mmol) were added to AcOH (150ml) and the resulting suspension was stirred and heated at 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 14g of intermediate 11 (80%), which was used as such in the next reaction step.

c) Preparation of intermediate 12

Adding Et₃N (8.1g, 80mmol) was added to a solution of intermediate 11(10g, 39.8mmol) in DCM (250 ml). 4-fluoro-benzoyl chloride (5.5g, 34.7mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and dried (MgSO₄) The organic layer was filtered and concentrated in vacuo. The residue was dissolved in AcOH (100ml) and concentrated aqueous HCl (3ml) was added. The reaction mixture was stirred at 100 ℃ for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM and saturated NaHCO₃Aqueous solution and water wash. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 12g of intermediate 12, which is used as such in the next reaction step.

Example A5

a) Preparation of intermediate 13

A mixture of intermediate 11(3g, 14.9mmol) and urea (1g, 17.9mmol) in THF (30ml) was stirred at 60 deg.C for 3 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH from 99.5/0.5-99/1). The desired fractions were collected and the solvent was evaporated. Yield: 3.4g of intermediate 13 (100%).

b) Preparation of intermediate 14

Adding POCl₃(27.9ml, 299mmol) was added slowly to intermediate 13(3.4g, 14.9mmol) while cooling on ice and stirring. The reaction mixture was then heated at 100 ℃ for 3 hours. The reaction mixture was concentrated in vacuo. Yield: 3.1g of crude intermediate 14, which was thus used in the next reaction step.

c) Preparation of intermediate 15

A mixture of intermediate 14(800mg), NaOH (391mg, 9.78mmol) and 4, 4-difluoropiperidine hydrochloride (616mg, 3.91mmol) in THF (10ml) was heated under microwave radiation at 150 ℃ for 4 h. The reaction mixture was cooled to room temperature and saturated NH was added₄Aqueous Cl solution. The mixture was extracted with DCM. Drying (Na)₂SO₄) The organic layer was filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (eluent: EtOAc/heptane from 10/90-50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.2g of intermediate 15.

Example A6

Preparation of intermediate 16

A mixture of intermediate 14(1g), NaOH (489mg, 12.2mmol) and phenol (460mg, 4.89mmol) in THF (10ml) was heated under microwave radiation at 110 ℃ for 4 h. The reaction mixture was cooled to room temperature and saturated NH was added₄Aqueous Cl solution. The mixture was extracted with DCM. Drying (Na)₂SO₄) The organic layer was filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (eluent: EtOAc/heptane from 10/90.5-50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.2g of intermediate 16.

Example A7

Preparation of intermediate 17

A mixture of intermediate 11(1g, 4.97mmol) and 1, 1' -thiocarbonyldiimidazole (1.15g, 6.47mmol) in THF (20ml) was heated under microwave irradiation at 125 ℃ for 1.5 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in acetone (30ml) and 1-iodo-2-methyl-propane (1.83g, 9.95mmol) and K were added₂CO₃(1.37g, 9.95 mmol). The reaction mixture was heated at 100 ℃ for 0.5 h under microwave irradiation. The reaction mixture was cooled and partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.6g of intermediate 17 (33%).

Example A8

a) Preparation of intermediate 18

Isopropylamine (12.9g, 218mmol) was added to a solution of 1-bromo-3-fluoro-2-nitro-benzene (8.0g, 36mmol) in EtOH (40 ml). The reaction mixture was stirred at room temperature overnight. The solvent was then evaporated and the residue partitioned between water and DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Yield: 8.3g of intermediate 18 (88%), which was used as such in the next reaction step.

b) Preparation of intermediate 19

Intermediate 18(8.3g, 32mmol) and iron powder (8.95g, 160mmol) were added to AcOH (50ml) and the resulting suspension was stirred and heated at 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 7.5g of intermediate 19 (100%), which was used as such in the next reaction step.

c) Preparation of intermediate 20

4-fluoro-benzaldehyde (2.28g, 18.3mmol) and Na₂S₂O₅(3.73g, 19.6mmol) was added to a solution of intermediate 19(3g, 13.1mmol) in DMA (50 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water, which resulted in the formation of a solid precipitate. The solid was filtered off, washed with water and suspended in DIPE. The resulting solid was filtered off, washed with DIPE and dried. Yield: 2.3g of intermediate 20 (53%).

Example A9

a) Preparation of intermediate 21

Adding Et₃N (2.02g, 20mmol) and 4-fluoro-benzoyl chloride (1.58g, 10mmol) were added to 3-nitro-benzene-1, 2-diamine (1.53g, 10mmol) in DCM (50ml) and CH₃CN (25ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was suspended in DIPE and the resulting solid was filtered off and dried in vacuo. Yield: 2.3g of intermediate 21 (84%).

b) Preparation of intermediate 22

Intermediate 21(1.35g, 4.9mmol) and concentrated aqueous HCl (0.5ml) were added to AcOH (15ml) and the resulting mixture was stirred and heated under microwave irradiation at 150 ℃ for 0.5 h. The reaction mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The precipitate was filtered off, washed with AcOH and DIPE, then dried in vacuo. Yield: 1g of intermediate 22 (69%).

c) Preparation of intermediate 23

In N₂To a solution of intermediate 22(290mg, 0.99mmol) in THF (10ml) was added dropwise a 1M solution of LiHMDS in THF (2.96ml, 2.96mmol) at 0 ℃ under an atmosphere. The reaction mixture was stirred at 0 ℃ for 30 minutes and then CH was added₃I (210mg, 1.48 mmol). The reaction mixture was stirred at 55 ℃ overnight. The mixture was allowed to cool, then washed with brine and the organic phase separated and dried (MgSO₄) Filtered and the solvent evaporated in vacuo. The residue was suspended in DIPE. The resulting solid was filtered off, washed with DIPE and dried. Yield: 160mg of intermediate 23 (60%).

d) Preparation of intermediate 24

Intermediate 23(150mg, 0.55mmol) and iron powder (162mg,2.9mmol) was added to AcOH (10ml) and the resulting suspension was stirred and heated at 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 120mg of intermediate 24 (90%), which was used as such in the next reaction step.

e) Preparation of intermediate 52

Intermediate 46 was prepared following the procedure as described in example a9, starting from 3-nitro-benzene-1, 2-diamine and 2, 4-difluoro-benzoyl chloride.

Example A10

Preparation of intermediate 24

A stainless steel autoclave was charged with intermediate 12(370mg, 1.21mmol), copper (I) oxide (10mg) and NH₃In two0.5M solution (30ml, 15mmol) in alkane. The autoclave was closed and the reaction mixture was heated at 150 ℃ for 18 hours. The reaction mixture was then cooled and saturated NH was added₄Aqueous OH (5ml) and the reaction mixture was heated at 150 ℃ for a further 18 h. The reaction mixture was cooled and concentrated in vacuo. In DCM with saturated NH₄The residue was partitioned between aqueous Cl. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 240mg of intermediate 24 (82%), which was used as such in the next reaction step.

Example A11

a) Preparation of intermediate 25

In N₂A1M solution of LiHMDS in THF (4.94ml, 4.94mmol) was added dropwise to a solution of intermediate 22(290mg, 0.99mmol) in THF (15ml) at 0 deg.C under an atmosphere. The reaction mixture was stirred at 0 ℃ for 30 minutes and then 2-iodopropane (1.68g, 9.9mmol) was added. The reaction mixture was stirred at 55 ℃ overnight. The reaction mixture was transferred to a microwave vial and additional amounts of a 1M solution of LiHMDS in THF (2ml, 2mmol) and 2-iodopropane (0.84g, 5mmol) were added. The reaction mixture was stirred and heated at 150 ℃ for 4 hours under microwave irradiation. The mixture was cooled, then washed with brine and the organic phase separated and dried (MgSO₄) Filtered and the solvent evaporated in vacuo. Preparative HPLC on reversed phase [ RP ShandonHyperprepC18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 50mg of intermediate 25 (17%).

b) Preparation of intermediate 26

Intermediate 25(50mg, 0.167mmol) and iron powder (49mg, 0.88mmol) were added to AcOH (4ml) and the resulting suspension was stirred and heated at 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 40mg of intermediate 26 (89%), which was used as such in the next reaction step.

Example A12

a) Preparation of intermediate 27

4-bromo-2-chloropyrimidine (5g, 25.8mmol), 4-methyl-1H-imidazole (4.25g, 51.7mmol) and K in NMP (100ml)₂CO₃(10.72g, 77.5mmol) was heated at 85 ℃ overnight. The mixture was separated between DCM and water. Drying (MgSO)₄) The organic layer was filtered and the solvent was evaporated. Water was added to the residue and the resulting precipitate was collected by filtration and dried in vacuo. Yield: 4.7g of intermediate 27 (76%).

b) Preparation of intermediate 28

2-methyl-2-propanol sodium salt (1.69g, 17.6mmol), BINAP (195mg, 0.314mmol), Pd in toluene (40 ml; previously deoxygenated)₂(dba)₃(287mg, 0.31mmol), intermediate 27(3g, 12.5mmol) and benzophenone imine (2.27g, 12.5mmol) were stirred and heated at 120 ℃ for 4 hours. The mixture was separated between DCM and water. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Yield: 3.4g of crude intermediate 28.

c) Preparation of intermediate 29

1N aqueous HCl (11ml, 11mmol) was added to a solution of intermediate 28(3.4g, 4.1mmol) in THF (10 ml). Stirring at room temperatureThe mixture should be allowed to stand for 2 hours. The solvent was evaporated in vacuo and the residue was separated between DCM and water, washed with NH₄The aqueous OH solution was basified until pH 10. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The product was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 98/2-95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.36g of intermediate 29 (16% yield over 2 steps).

Example A13

a) Preparation of intermediate 30

In N₂Under flow, CuI (8.25g, 43mmol) was added to 5-bromo-pyridin-2-ylamine (5g, 28.9mmol), 4-methyl-1H-imidazole (5.9g, 72mmol), and Cs₂CO₃(9.4g, 28.9mmol) in DMSO (100 ml). The reaction mixture was heated at 130 ℃ for 2 night and then cooled. Adding CH₃CN, formed a blue precipitate, which was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was separated between DCM and water. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 98/2-95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.628g of intermediate 30. The aqueous layer was concentrated under reduced pressure until some additional product precipitated, filtered off and dried in vacuo to yield 0.16g of intermediate 30.

Example A14

a) Preparation of intermediate 31 and intermediate 32 (regioisomers)

In N₂Under flow, CuI (2.64g, 13.9mmol) was added to 2-bromo-pyridin-5-ylamine (6 g)34.7mmol), 5-methyl-1H-1, 2, 4-triazole (4.03g, 48.5mmol) and Cs₂CO₃(22.6g, 69.4mmol) in DMF (50 ml). The reaction mixture was heated at 120 ℃ for 2 night and then cooled and concentrated in vacuo. The residue was separated between DCM and water. The aqueous phase was saturated with NaCl and further extracted with DCM and MeOH. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 1150mg of intermediate 32 (19%) and 1500mg of intermediate 31 (25%).

Example A15

a) Preparation of intermediate 33

In N₂MeOH (100ml) was added to Pt/C5% (1g) under an atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (2ml) and 4-amino-2-bromo-3-nitro-pyridine (3.5g, 16mmol) were added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 3 equivalents of H had been absorbed₂. The catalyst was filtered off over celite and the filtrate was concentrated in vacuo. Yield: 1.8g of intermediate 33 (63%), which was used as such in the next reaction step.

b) Preparation of intermediate 34

Intermediate 33(1.8g, 9.57mmol) and 4-fluoro-benzoic acid (1.34g,9.57mmol) in polyphosphoric acid (25g) and heated at 180 ℃ for 1 hour. The reaction mixture was cooled to room temperature and water was added. By K₂CO₃The resulting solution was neutralized and the precipitate formed was filtered off and washed with water. Yield: 1g of crude intermediate 34, which was used as such in the next reaction step.

c) Preparation of intermediate 35

Intermediate 34(825mg, 2.8mmol), CH₃I (400mg, 2.8mmol) and K₂CO₃(830mg, 6mmol) was added to DMF (25 ml). The resulting mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was separated between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH]The residue was purified. The product fractions were collected and worked up. Yield: 180mg of intermediate 35 (21%).

Example A16

a) Preparation of intermediate 36

Adding Et₃N (0.78mL, 5.7mmol) was added to a solution of 2, 4-dichloro-3-nitropyridine (cas 5975-12-2) (1g, 5.2mmol) in DMF (10mL) at 0 ℃. Isopropylamine (0.444ml, 5.2mmol) was then added and the reaction mixture stirred for 5 minutes. The reaction mixture was diluted with EtOAc and washed with water and saltThe resulting mixture was washed with water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-99/1). The product fractions were collected and the solvent was evaporated. Yield: 1.1g of intermediate 36 (98%).

b) Preparation of intermediate 37

4-fluorobenzaldehyde (589mg, 4.74mmol) and Na were added₂S₂O₄(3.0g, 17.2mmol) was added to a solution of intermediate 36(930mg, 4.31mmol) in EtOH (15 ml). The reaction mixture was heated at 160 ℃ for 45 minutes under microwave conditions. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-96/4). The product fractions were collected and the solvent was evaporated. Yield: 450mg of intermediate 37 (36%).

Example A17

a) Preparation of intermediate 38

Mixing Na₂S₂O₅(1.64g, 8.62mmol) and 4-fluoro-benzaldehyde (891mg, 7.18mmol) were added to a solution of 3-bromo-5-trifluoromethyl-1, 2-diaminobenzene (1.65g, 6.47mmol) in DMA (40 ml). The reaction mixture was stirred at 70 ℃ overnight. The reaction mixture was then allowed to cool to room temperature and poured into water. The solid was filtered off, washed with water and suspended in DIPE and a few drops of 2-propanol. The resulting solid was filtered off, washed with DIPE and dried. Yield: 1.95g of intermediate 38 (84%).

b) Preparation of intermediate 39

In N₂A1M solution of LiHMDS in THF (9.2ml, 9.2mmol) was added dropwise to a solution of intermediate 38(1.65g, 4.6mmol) in THF (50ml) at room temperature under an atmosphere. The reaction mixture was stirred at room temperature for 30 minutes and then CH was added₃I (3.26g, 23 mmol). The reaction mixture was stirred at room temperature for 1 hour and then saturated NaHCO₃Aqueous solution and brine. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 720mg of intermediate 39 (42%).

Example A18

Preparation of intermediate 40

4- (2-oxo-ethyl) -piperidine-1-carboxylic acid tert-butyl ester (682mg, 3mmol) and Na₂S₂O₅(741mg, 3.9mmol) was added to a solution of intermediate 11(603mg, 3mmol) in DMA (15 ml). The reaction mixture was stirred at room temperature overnight. Water was then added and the mixture was extracted with EtOAc. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-98/2). The product fractions were collected and the solvent was evaporated. Yield: 840mg of intermediate 40, which is used as such in the next reaction step.

Example A19

a) Preparation of intermediate 42

A mixture of formic acid (12.8ml, 340mmol) and acetic anhydride (8.54ml, (91mmol) was stirred at room temperature for 40 minutes, then a solution of 3-amino-6-bromo-2-methoxy-pyridine (5g, 24.6mmol) in THF (30ml) was added dropwise and the resulting reaction mixture stirred at 60 ℃ overnight, the reaction mixture was cooled and poured into ice water, resulting in the formation of a solid precipitate, the solid was filtered off, washed with water and dried, yield 5.2g of intermediate 42 (76%).

b) Preparation of intermediate 43

1-chloro-propan-2-one (4.34g, 46.9mmol) was added dropwise to intermediate 42(5.2g, 18.8mmol), potassium iodide (0.343g, 2.06mmol), Cs₂CO₃(21.4g, 65.9mmol) in DMF (50 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with EtOAc. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. The residue was suspended in DIPE and the resulting solid was filtered off, washed with DIPE and dried. Yield: 4.43g of intermediate 43 (82%).

c) Preparation of intermediate 44

Intermediate 43(4.4g, 15.3mmol) was added to ammonium acetate (5.41g, 70.2mmol)In a mixture in AcOH (10 ml). The reaction mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into a mixture of ice water and EtOAc. The mixture was basified to pH 9 with 50% w/v (weight/volume percent solution) NaOH in water. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. The resulting solid product was used as such in the next reaction step. Yield: 3.78g of crude intermediate 44.

d) Preparation of intermediate 45

Sodium salt of 2-methyl-2-propanol (0.717g, 7.46mmol), BINAP (464mg, 0.75mmol), Pd in toluene (20 ml; previously deoxygenated)₂(dba)₃(342mg, 0.37mmol), intermediate 44(1.0g, 3.73mmol) and benzophenone imine (0.845g, 4.66mmol) were stirred and heated under microwave conditions at 100 ℃ for 2 hours. The mixture was cooled and the solvent was removed in vacuo. To the residue were added THF (50ml) and 1N aqueous HCl (50ml) and the mixture was stirred at room temperature for 1 hour. With 10% Na₂CO₃The reaction mixture was basified with aqueous solution and extracted with EtOAc. Drying (MgSO)₄) The organic layer was filtered and the solvent was evaporated in vacuo. The product was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.6g of intermediate 45 (52% yield over 2 reaction steps).

In another alternative, Cu is added₂O (320mg, 2.24mmol) and 7N NH in MeOH₃A solution (48ml, 336mmol) was added to a solution of intermediate 44(6g, 22.4mmol) in ethylene glycol (50 ml). The reaction mixture was heated at 100 ℃ for 12 hours in a closed pressure vessel. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. Drying (MgSO)₄) The organic layer was filtered and the solvent was evaporated in vacuo. The residue was triturated with DIPE. Yield: 4g of intermediate 45 (87%).

Example A20

a) Preparation of intermediate 46

2-chlorobenzoyl chloride (1.46g, 8.37mmol) was added to a solution of 2, 6-dibromoaniline (2.0g, 7.97mmol) in THF (24ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (30mL) and saturated NaHCO₃The organic phase was washed with aqueous solution and dried (MgSO)₄) The solvent was filtered and evaporated. The residue was triturated with DIPE, filtered off, washed extensively with DIPE and dried in vacuo. Yield: 1.08g of intermediate 46 (35%).

b) Preparation of intermediate 47

Mixing intermediate 46(0.5g, 1.28mmol), CuI (0.025g, 0.13mmol), Cs₂CO₃A mixture of (0.63g, 1.93mmol), 1, 10-phenanthroline (0.046g, 0.257mmol) in DME (10ml) was stirred in a sealed tube at 90 ℃ for 3 days. By H₂The mixture was diluted with O (10ml) and DCM (50 ml). Drying (MgSO)₄) The organic phase was separated, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: heptane/DCM isocratic 1/2). The product fractions were collected and evaporated off. Yield: 0.18g of intermediate 47 (46%).

Example A21

a) Preparation of intermediate 48

Cyclohexanecarbonyl chloride (0.61g, 4.18mmol) was added to a solution of 2, 6-dibromoaniline (1.0g, 3.98mmol) in THF (12ml) at room temperature. The reaction mixture was stirred at room temperature for 4 days. The mixture was diluted with EtOAc (30mL) and saturated NaHCO₃The organic phase was washed with aqueous solution and dried (MgSO)₄) The solvent was filtered and evaporated. The residue was triturated with DIPE, filtered off, washed extensively with DIPE and dried in vacuo. Yield: 0.62g of intermediate 48 (43%).

b) Preparation of intermediate 49

Intermediate 48(0.15g, 0.41mmol), CuI (0.008g, 0.04mmol), Cs₂CO₃A mixture of (0.203g, 0.62mmol) and 1, 10-phenanthroline (0.015g, 0.08mmol) in DME (2ml) was stirred in a sealed tube at 90 deg.C overnight. By H₂The mixture was diluted with O (2ml) and DCM (2 ml). Passing the separated organic phase through ExtreltAnd the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: heptane/DCM 30/70). The product fractions were collected and the solvent was evaporated. Yield: 0.095g of intermediate 49 (77%).

Example A22

a) Preparation of intermediate 50

Adding SOCl₂(1.38ml, 19.0mmol) was added to a solution of isovaleric acid (1.87g, 18.2mmol) and pyridine (1.48ml, 18.3mmol) in DCM (15ml) and the reaction mixture was stirred at room temperature for 2 h. 2, 6-dibromoaniline (0.92) is addedg, 3.5mmol) in DCM (5ml) and the reaction mixture was stirred at room temperature for 2 days. Up to 5 additional equivalents of acid chloride were prepared and added to the reaction mixture, which was further stirred overnight. The mixture was diluted with DCM (20ml) and then with 1M HCl solution and saturated NaHCO₃The organic phase was washed with aqueous solution and dried (MgSO)₄) The solvent was filtered and evaporated. The crude product was isolated from DIPE/CH₃And (5) recrystallizing CN. Yield: 0.21g of intermediate 50 (17%).

b) Preparation of intermediate 51

Mixing intermediate 50(0.21g, 0.63mmol), CuI (0.012g, 0.063mmol), Cs₂CO₃A mixture of (0.306g, 0.94mmol) and 1, 10-phenanthroline (0.023g, 0.125mmol) in DME (3ml) was stirred in a sealed tube at 90 deg.C overnight. By H₂The mixture was diluted with O (20ml) and DCM (20 ml). Passing the separated organic phase through ExtreltAnd the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: heptane/DCM 30/70). The product fractions were collected and evaporated off. Yield: 0.110g of intermediate 51 (69%).

Example A23

a) Preparation of intermediate 53

Benzylamine (17g, 159mmol) was added to a solution of 1-bromo-3-fluoro-2-nitro-benzene (10g, 45.5mmol) in THF (100 ml). The reaction mixture was stirred at room temperature overnight. The precipitate formed was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCMAnd then with aqueous AcOH, saturated NaHCO₃The aqueous solution and water wash the resulting solution. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The crude residue was dissolved in AcOH (100mL) and iron powder (7.62g, 136mmol) was added. The resulting suspension was stirred and heated at 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 6.5g of intermediate 53 (80% purity according to LC-MS analysis) was used as such in the next reaction step.

b) Preparation of intermediate 54

Adding Et₃N (1.21g, 12mmol) and 2-methyl-benzoyl chloride (923mg, 5.97mmol) were added to a solution of intermediate 53(2.07g, 5.97mmol) in DCM (50ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was dissolved in AcOH (25ml) and concentrated aqueous HCl (0.5ml) was added. The resulting mixture was stirred and heated at 100 ℃ for 18 hours. The reaction mixture was cooled and concentrated in vacuo. In DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. The organic layer was washed with water and dried (MgSO)₄) Filtered and concentrated in vacuo. Yield: 2.2g of intermediate 54 (98%), which was used as such in the next reaction step.

Example A24

a) Preparation of intermediate 55

Mixing Na₂S₂O₅(5.56g，29.2mmol) and 4-fluoro-benzaldehyde (2.91g, 23.4mmol) were added to a solution of 3-bromo-5-fluoro-1, 2-diaminobenzene (4.0g, 19.5mmol) in DMA (80 ml). The reaction mixture was stirred at 70 ℃ overnight. The reaction mixture was then cooled to room temperature and poured into water. The solid was filtered off, washed with water and dried. Yield: 6g of intermediate 55.

b) Preparation of intermediate 56

A suspension of NaH (60% in mineral oil; 233mg, 5.82mmol) in N was added₂Add to a cooled (5 ℃) solution of intermediate 55(900mg, 2.91mmol) in THF (5ml) under an atmosphere. The reaction mixture was stirred at 5 ℃ for 30 minutes and then isopropyl iodide (1.98g, 11.6mmol) was added. The reaction mixture was stirred at 130 ℃ for 2 hours under microwave irradiation. The reaction mixture was cooled, additional THF (appropriate) was added and the mixture was washed with brine. The organic phase was separated and dried (MgSO)₄) The solvent was filtered and evaporated. The residue was purified by flash column chromatography on silica gel (eluent: heptane/DCM 50/50-0/100). The product fractions were collected and the solvent was evaporated. Yield: 350mg of intermediate 56 (34%).

Example A25

a) Preparation of intermediate 57

N-Iodosuccinimide (26.7g, 119mmol) and TFA (2.5ml, 32.4mmol) were added to 2, 4-dichloro-pyridin-3-ylamine (17.6g, 108mmol) in CH₃Suspension in CN (150 ml). The reaction mixture was stirred at room temperature for 16 hours and then heated to 40 ℃ for 6 hours. The reaction mixture was diluted with EtOAc and saturated Na₂S₂O₃And (4) washing with an aqueous solution. By usingThe aqueous phase was extracted with EtOAc and dried (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated. Yield: 22g of intermediate 57 (71%).

b) Preparation of intermediate 58 and intermediate 59 (regioisomer)

A solution of methylamine in THF (2M, 25ml, 50mmol) was added to a solution of intermediate 57(4.8g, 16.6mmol) in EtOH (20 ml). The reaction mixture was stirred at 160 ℃ for 8 hours under microwave irradiation. Then, the solvent is evaporated and the residue is washed with NaHCO₃The residue was partitioned between aqueous and DCM. Drying (Na)₂SO₄) The combined organic layers were filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: heptane/DCM 100/0-0/100). The product fractions were collected and the solvent was evaporated. Yield: 950mg of intermediate 58 (20%) and 2900mg of intermediate 59 (62%).

c) Preparation of intermediate 60

Adding Et₃N (3.61ml, 26.5mmol) and 4-fluoro-benzoyl chloride (1.68g, 10.6mmol) were added to a solution of intermediate 59(2.5g, 8.8mmol) in DCM (100ml) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo. Yield: 2.7g of crude intermediate 60 (75%), which was used as such in the next reaction step.

d) Preparation of intermediate 61

Adding POCl₃(907mg, 5.9mmol) was added to a solution of intermediate 60(2.0g, 4.93mmol) in DCE (15ml) and the resulting mixture was stirred and heated under microwave radiation at 150 ℃ for 15 min. The reaction mixture is concentrated in vacuo and flash column chromatographed on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 1.56g of intermediate 61 (81%).

e) Preparation of intermediate 62

Isopropenylboronic acid pinacol ester (867mg, 5.16mmol) and Pd (PPh)₃)₄(298mg, 0.258mmol) was added to intermediate 61(2.0g, 5.16mmol) in bisAlkane (8ml) and NaHCO₃In solution in aqueous solution (4 ml). The reaction mixture was stirred and heated at 160 ℃ for 10 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and filtered through celite with EtOAc. The filtrate was evaporated. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 1.25g of intermediate 62 (80%).

f) Preparation of intermediate 63

In N₂MeOH (40ml) was added to Pt/C5% (100mg) under an atmosphere. Then, intermediate 62(1.25g, 4.14mmol) was added. At H₂Stirring and reacting under the atmosphere at 25 DEG CThe compound is allowed to absorb 1 equivalent of H₂. The catalyst was filtered off over celite and the filtrate was evaporated. Yield: 0.9g of crude intermediate 63 (71%), which was used as such in the next reaction step.

g) Preparation of intermediate 64

Methylboronic acid (93mg, 1.55mmol) and Pd (PPh)₃)₄(71mg, 0.062mmol) was added to intermediate 61(600mg, 0.31mmol) in twoAlkane (10ml) and NaHCO₃In solution in aqueous solution (5 ml). The resulting mixture was stirred and heated at 150 ℃ for 20 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and partitioned between water and DCM. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Yield: 180mg of crude intermediate 64, which was thus used in the next reaction step.

h) Preparation of intermediate 74

Reduction of Zn (CN)₂(36mg, 0.31mmol) and Pd (PPh)₃)₄(30mg, 0.026mmol) was added to a solution of intermediate 61(200mg, 0.52mmol) in DMF (5 ml). The resulting mixture was stirred and heated at 160 ℃ for 10 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate is concentrated in vacuo and flash column chromatographed on silica gel (eluent: DCM/MeOH (NH)₃)100/0-97/3) purifying the residue. The product fractions were collected and the solvent was evaporated. Yield: 0.14g of intermediate 74 (95%).

i) Preparation of intermediate 75

Mixing intermediate 61(200mg, 0.52mmol), 4, 7-dimethoxy- [1, 10%]Phenanthroline (25mg, 0.1mmol) and Cs₂CO₃A mixture of (336mg, 1mmol) in MeOH (1ml) was degassed and stirred under microwave irradiation at 110 ℃ for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and DCM. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The residue was triturated with DIPE. Yield: 100mg of intermediate 75 (66%).

j) Preparation of intermediate 76

In N₂THF (40ml) was added to Pd/C10% (0.1g) under an atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (1ml) and intermediate 61(800mg, 2.06mmol) were added. At H₂The reaction mixture was stirred at room temperature under an atmosphere until 1 equivalent of H was absorbed₂. The catalyst was filtered off over celite. The filtrate was evaporated and the residue was used as such in the next reaction step. Yield: 0.45g of intermediate 76 (83%).

Example A26

a) Preparation of intermediate 65

4-fluorobenzaldehyde (1.11g, 8.93mmol) and Na₂S₂O₄(3.89g, 22.3mmol) was added to 2-chloro-N-6-dimethyl-3-nitro-pyridin-4-amine (1.5)g, 7.44mmol) in EtOH (15 ml). The reaction mixture was heated at 160 ℃ for 1 hour under microwave conditions. The reaction mixture was cooled to room temperature and filtered through celite with EtOAc. This was repeated three times. The combined filtrates were evaporated and subjected to preparative reverse phase HPLC [ RP Vydec Denali C18(10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 1.95g of intermediate 65 (32%).

Example A27

a) Preparation of intermediate 66

Adding Et₃N (1.87ml, 13.8mmol) and 4-fluoro-benzoyl chloride (873mg, 5.5mmol) were added to a solution of intermediate 58(1.3g, 4.6mmol) in DCM (80ml) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. Yield: 1.5g of crude intermediate 66 (81%), which was used as such in the next reaction step.

b) Preparation of intermediate 67

Adding POCl₃(121mg, 0.79mmol) was added to a solution of intermediate 66(267mg, 0.66mmol) in DCE (2ml) and the resulting mixture was stirred and heated under microwave irradiation at 150 ℃ for 15 min. The reaction mixture is concentrated in vacuo and flash column chromatographed on silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 215mg of intermediate 67 (84%).

c) Preparation of intermediate 68

Isopropenylboronic acid pinacol ester (434mg, 2.58mmol) and Pd (PPh)₃)₄(149mg, 0.129mmol) was added to intermediate 67(1.0g, 2.58mmol) in bisAlkane (8ml) and NaHCO₃To a solution in aqueous solution (4ml) and the resulting mixture was stirred and heated under microwave irradiation at 160 ℃ for 10 minutes. The reaction mixture was cooled to room temperature and filtered through celite with EtOAc, and the filtrate was evaporated. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.72g of intermediate 68 (92%).

d) Preparation of intermediate 69

In N₂MeOH (40ml) was added to Pt/C5% (100mg) under an atmosphere. Then, intermediate 68(0.75g, 2.49mmol) was added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 1 equivalent of H had been absorbed₂. The catalyst was filtered off over celite and the filtrate was evaporated. Yield: 0.55g of crude intermediate 69 (73%), which was used as such in the next reaction step.

e) Preparation of intermediate 77

Cyclopropylboronic acid (86mg, 1.0mmol) and Pd (PPh)₃)₄(78mg, 0.067mmol) was added to intermediate 67(260mg, 0.67mmol) in dichloromethaneAlkane (6ml) and NaHCO₃To a solution in aqueous solution (3ml) and the resulting mixture was stirred and heated under microwave irradiation at 160 ℃ for 10 minutes. The reaction mixture was cooled to room temperature and filtered through celite with EtOAc, and the filtrate was evaporated. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.15g of intermediate 77 (74%).

Example A28

a) Preparation of intermediate 70

4-methyl-1H-imidazole (37.2g, 0.452mol) and K₂CO₃(62.5g, 0.452mol) was added to a solution of 3, 4-difluoro-nitrobenzene (60g, 0.377mol) in DMF (800 ml). The reaction mixture was heated at 125 ℃ for 4 hours. The mixture was cooled and poured into ice water. The solid is filtered off and washed (H)₂O) and drying. Yield: 60.2g of intermediate 70 (72%).

b) Preparation of intermediate 71

In N₂MeOH (250ml) was added to Pd/C10% (5g) under an atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (1ml) and intermediate 71(60.2g, 272mmol) were added. At H₂The reaction mixture was stirred at 50 ℃ under an atmosphere until 3 equivalents of H had been taken up₂. The catalyst was filtered off over celite. The filtrate was evaporated and subjected to flash column chromatography on silica gel (elution)Liquid: DCM/MeOH (NH)₃) From 100/0-95/5). The product fractions were collected and the solvent was evaporated. Yield: 36.5g of intermediate 71 (70%).

Example A29

a) Preparation of intermediate 72

Adding Et₃N (2.65ml, 19mmol) and 3-amino-4-methylamino-2-chloropyridine (1500mg, 9.52mmol) were added to a solution of HBTU (4.51g, 11.9mmol) and 4-chloro-3-methoxy-benzoic acid (1776mg, 9.52mmol) in DMF (30 ml). The reaction mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was diluted with DCM and saturated Na₂CO₃The aqueous solution and water wash the mixture. Yield: 1.8g of crude intermediate 72 (58%), which was used as such in the next reaction step.

b) Preparation of intermediate 73

Adding POCl₃(1.05ml, 11.5mmol) was added to a solution of intermediate 72(1.7g, 5.2mmol) in DCE (16 ml). The reaction mixture was stirred and heated at 150 ℃ for 35 minutes under microwave irradiation. The reaction mixture was diluted with DCM and saturated NaHCO₃And (4) washing with an aqueous solution. Drying (MgSO)₄) The organic phase was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH 100/0-90/10). The product fractions were collected and the solvent was evaporated. Trituration of the residue with DIPE, then dissolution in DCM and application of Cs₂CO₃And (4) washing the solution. Drying (MgSO)₄) The organic phase was filtered and concentrated in vacuo. Yield: 400mg of intermediate 73 (25%).

Example A30

a) Preparation of intermediate 78

In N₂MeOH (150ml) was added to Pt/C5% (1g) under an atmosphere. Next, a 0.4% thiophene solution in DIPE (2ml) and 2-bromo-4-methoxy-6-nitroaniline (5g, 20.2mmol) were added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 3 equivalents of H had been absorbed₂. The catalyst was filtered off over celite and the filtrate was concentrated in vacuo. Yield: 4.33g of intermediate 78 (99%) are used as such in the next reaction step.

b) Preparation of intermediate 79

4-fluoro-benzaldehyde (1.17ml, 11.1mmol) and Na₂S₂O₅(2.63g, 13.8mmol) was added to a solution of intermediate 78(2g, 9.2mmol) in DMA (40 ml). The reaction mixture was stirred at 90 ℃ overnight. The reaction mixture was then poured into water, resulting in the formation of a solid precipitate. The solid was filtered off, washed with water and suspended in DIPE. The resulting solid was filtered off, washed with DIPE and dried. Yield: 2.9g of intermediate 79 (98%).

c) Preparation of intermediate 80

In N₂A suspension of 60% NaH in mineral oil (486mg, 12.1mmol) was added to a solution of intermediate 79(2.6g, 8.1mmol) in DMF (15ml) at 5 ℃ under an atmosphere. Stirring at 5 deg.CThe reaction mixture was allowed to react for 30 minutes, and then CH was added₃I (1.26ml, 20.2 mmol). The reaction mixture was stirred at room temperature for 3 hours and partitioned between EtOAc and water. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH 100/0-99/1). The product fractions were collected and the solvent was evaporated. Yield: 1.25g of intermediate 80 (46%).

Example A31

a) Preparation of intermediate 81

Concentrated HNO₃(12.5ml) was added to 3, 5-dibromo-pyridine N-oxide (4.5g, 17.8mmol) in concentrated H₂SO₄(16ml) in water. The reaction mixture was refluxed for 4 hours, then cooled and poured into ice water. The precipitate was collected by filtration and dried. Yield: 3.1g of intermediate 81 (58%), which was used as such in the next reaction step.

b) Preparation of intermediate 82

A 2M solution of methylamine in THF (7.15ml, 14.3mmol) was added to a mixture of intermediate 81(2.66g, 8.9mmol) in THF (100 ml). The reaction mixture was stirred at 60 ℃ for 2 days and then concentrated in vacuo. In DCM and NaHCO₃The residue was partitioned between aqueous solutions. The organic phase was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. Flash column chromatography over silica gel (eluent: heptane/DCM/MeOH (NH)₃) 100/0/0-0/100/0-0/70/30). The product fractions were collected and the solvent was evaporated. Yield: 1.2g of intermediate 82 (54%; N-oxide).

c) Preparation of intermediate 83

4-fluorobenzaldehyde (252mg, 2.0mmol) and Na were added₂S₂O₄(1.18g, 6.8mmol) was added to a solution of intermediate 82(420mg, 1.7mmol) in EtOH (6 ml). The reaction mixture was heated at 160 ℃ for 45 minutes under microwave conditions. The reaction mixture was cooled to rt and diluted with EtOAc. With NaHCO₃The mixture was washed with aqueous solution and brine. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃)100/0-97/3) purifying the residue. The product fractions were collected and the solvent was evaporated. Yield: 0.35g of intermediate 83 (68%).

Example A32

a) Preparation of intermediate 84

CuI (1.71g, 8.9mmol) and N, N' -dimethylethylenediamine (1.91ml, 17.92mmol) were added to 2-amino-5-iodopyridine (5.03g, 22.4mmol), 3-methyl-1H-1, 2, 4-triazole (2.42g, 29.1mmol) and Cs₂CO₃(14.60g, 44.81mmol) in DMF (40 ml). The reaction mixture was heated at 110 ℃ for 7 h, allowed to cool, EtOAc was added and the mixture was washed with water. The aqueous layer was extracted 5 times with EtOAc. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated in vacuo. By reverse phase preparative HPLC [ RPShandon Hyperprep ]C18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and the solvent was evaporated. Yield: 1.5g of intermediate 84 (38%).

b) Preparation of intermediate 85

Intermediate 84(3.3g, 18.8mmol) was dissolved in THF (20mL) and Et was added₃N (13.1ml, 94.2mmol) and acetic anhydride (17.8ml, 188.4 mmol). The reaction mixture was stirred at 65 ℃ for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in DIPE. The resulting solid was filtered off, washed with DIPE and dried. Yield: 3.25g of intermediate 85 (79%).

c) Preparation of intermediate 86

Intermediate 85(10g, 46.0mmol) was dissolved in DCM (500ml) and mCPBA (14.75g, 59.84mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. DCM and NaHCO were added₃10% solution in water. The organic phase is separated and washed with NaHCO₃The 10% solution in water was washed twice. The combined aqueous layers were extracted 10x with DCM. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated in vacuo. Yield: 10.1g of intermediate 86 (94%; N-oxide).

d) Preparation of intermediate 87

Intermediate 86(10.1g, 43.3mmol) was dissolved in acetic anhydride (307ml, 3.25 mol). The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in DIPE. The resulting solid was filtered off. Yield: 10.5g of crude intermediate 87, which was used as such in the next reaction step.

e) Preparation of intermediate 88

Intermediate 87(2.5g, 9.1mmol) and K₂CO₃(1.26g, 9.1mmol) was added to MeOH (30 ml). The reaction mixture was stirred at room temperature for 1 hour. The residue was purified directly by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-90/10) (without evaporation of the solvent). The product fractions were collected and the solvent was evaporated in vacuo. The residue was suspended in DIPE. The solid was filtered off, washed with DIPE and dried. Yield: 1g of intermediate 88 (47%).

f) Preparation of intermediate 89

Intermediate 88(1g, 4.28mmol), CH₃I (0.4ml, 6.43mmol) and Ag₂CO₃(1.18g, 4.29mmol) was added to DMF (50 ml). The resulting mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was cooled to room temperature, filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/EtOAc from 100/0-0/100). The product fractions were collected and the solvent was evaporated. Yield: 450mg of intermediate 89 (42%).

g) Preparation of intermediate 90

Intermediate 89(1.1g, 4.45mmol) was dissolved in MeOH (120ml) and NaOH 10% (30ml) in water was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 870mg of intermediate 90 (95%).

Example A33

Preparation of intermediate 91

Intermediate 14(14g, 40.75mmol) in DCM with NH₄The aqueous OH solution was partitioned. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was dissolved in 2-methyl-2-propanol (750ml) and intermediate 45(8.32g, 40.75mmol), Pd were added₂(dba)₃(3.73g, 4.08mmol), X-Phos (5.83g, 12.2mmol) and Cs₂CO₃(40g, 122 mmol). With N₂The reaction mixture was purged and then heated under reflux for 16 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo. The residue was suspended in DCM and the resulting mixture was filtered through celite. With dilute NaHCO successively₃The aqueous solution and water wash the filtrate. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. The residue was triturated with a mixture of DIPE and 2-propanol. Yield: 4.5g of intermediate 91 (30%).

Example A34

a) Preparation of intermediate 92

In N₂Under the atmosphere, intermediate 45(2.02g, 9.9mmol) and Pd₂(dba)₃(635mg, 0.7mmol), X-Phos (992mg, 2.08mmol) and Cs₂CO₃(9.7g, 29.7mmol) was added to a solution of intermediate 10(2.29g, 9.9mmol) in 2-methyl-2-propanol (100 ml). With N₂The reaction mixture was purged and then heated at reflux for 16 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo. In DCM followed by dilute NaHCO₃The residue was partitioned between aqueous and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 1.3g of intermediate 92 (37%).

b) Preparation of intermediate 93

A mixture of intermediate 92(354mg, 1mmol) and iron powder (223mg, 4mmol) in AcOH was stirred at 60 ℃ for 1 hour. The mixture was cooled and filtered, and the filtrate was concentrated in vacuo. In DCM and K₂CO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 324mg of crude intermediate 93, which was thus used in the next reaction step.

Example A35

Preparation of intermediate 94

A mixture of 2-chloro-N-6-dimethyl-3-nitro-pyridin-4-amine (600mg, 2.98mmol) and intermediate 71(1.14g, 5.95mmol) in DMA (12ml) was heated under microwave conditions at 140 ℃ for 5h and subsequently at 160 ℃ for 90 min. The reaction mixture was cooled to room temperature and poured into water. The precipitate formed is filtered off, washed with water and dried. Yield: 528mg of intermediate 94 (50%).

Example A36

a) Preparation of intermediate 95

A mixture of 2-chloro-N-4, 6-dimethyl-3, 4-pyridinediamine (2.99g, 17.4mmol) and urea (1.31g, 21.8mmol) in xylene (40ml) was stirred at reflux overnight. The reaction mixture was allowed to cool and the resulting solid was collected by filtration and washed with water. The solid was triturated with DIPE. Yield: 3.15g of intermediate 95, which is used as such in the next reaction step.

b) Preparation of intermediate 96

In N₂Under the atmosphere, intermediate 71(592mg, 3.1mmol) and Pd₂(dba)₃(334mg, 0.36mmol), X-Phos (347mg, 0.73mmol) and Cs₂CO₃(3.56g, 10.9mmol) was added to a solution of intermediate 95(1g, 1.7mmol) in 2-methyl-2-propanol (35 ml). The reaction mixture was heated at 100 ℃ overnight. Adding additional Pd₂(dba)₃(334mg, 0.36mmol), X-Phos (347mg, 0.73mmol) and stirring the reaction mixture again at 100 ℃ overnight. In addition, additional Pd was added₂(dba)₃(174mg, 0.18mmol), X-Phos (167mg, 0.37mmol) and stirring the reaction mixture again at 100 ℃ overnight. The mixture was cooled and partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. Yield: 300mg of intermediate 96 (50%).

c) Preparation of intermediate 97

Adding POCl₃(10ml) was added to intermediate 96(1.03g, 2.8mmol) and the reaction mixture was heated at 115 ℃ for 24 h. The reaction mixture was concentrated in vacuo. With saturated NaHCO₃The residue was neutralized with aqueous solution and extracted with EtOAc. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Yield: 635mg of crude intermediate 97, which was thus used in the next reaction step.

Example A37

a) Preparation of intermediate 98

1-fluoro-2-methoxy-4-nitrobenzene (2.45g, 14.3mmol), 4-hydroxymethyl-1H-imidazole (1.54g, 15.7mmol) and K₂CO₃A mixture of (3.95g, 28.6mmol) in DMF (20ml) was stirred at 100 ℃ for 16 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The undissolved material was collected by filtration and dissolved in THF and CH₃CN in a mixture. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated. The residue was triturated with DIPE/2-propanol, filtered off and dried. Yield: 1.2g of intermediate 98, which was used as such in the next reaction step.

b) Preparation of intermediate 99

In N₂MeOH (100ml) was added to Pd/C10% (0.5g) under an atmosphere. Subsequently, a 0.4% thiophene solution in DIPE (2ml) and intermediate 98(1.2g, 3.4mmol) were added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 3 equivalents of H had been absorbed₂. The catalyst was filtered off over celite. The filtrate was evaporated. Yield: 0.56g of intermediate 99, which is used as such in the next reaction step.

Example A38

a) Preparation of intermediate 100

In N₂Under the atmosphere, intermediate 61(500mg, 1.29mmol), 3-methoxy-propyne (99mg, 1.4mmol), PdCl₂(PPh₃)₂(36mg, 0.05mmol) and CuI (9mg, 0.049mmol) in Et₃The mixture in N (6ml) was stirred at 50 ℃ for 20 h. The mixture was concentrated in vacuo and the residue partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 440mg of intermediate 100 (quantitative).

b) Preparation of intermediate 41

In N₂Under the atmosphere, intermediate 5(62mg, 0.3mmol), Pd₂(dba)₃(28mg, 0.03mmol), X-phos (28mg, 0.06mmol) and Cs₂CO₃(300mg, 0.91mmol) was added to a solution of intermediate 100(100mg, 0.3mmol) in 2-methyl-2-propanol (15 ml). At 100 DEG CThe reaction mixture was heated for 20 hours. The reaction mixture was then cooled, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated. Flash chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 140mg of intermediate 41 (93%).

B. Preparation of the Compounds

Example B1

Preparation of Compound 1

2-methyl-2-propanol sodium salt (0.299g, 3.1mmol), BINAP (97mg, 0.16mmol), Pd (OAc)₂(23mg, 0.1mmol) and intermediate 24(332mg, 1.24mmol) were added to a solution of 1- (4-bromo-2-methoxyphenyl) -4-methyl-1H-imidazole (250mg, 1.04mmol) in toluene (10ml) and treated with N₂The mixture was purged for 5 minutes. In N₂The reaction mixture was stirred under atmosphere and heated at 100 ℃ overnight. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. The residue was triturated with DIPE. The solid was collected and dried in vacuo. Yield: 0.28g of Compound 1 (63%).

Example B2

Preparation of Compound 2

Pd is added₂(dba)₃(14mg，0.015mmol)And X-Phos (34mg, 0.06mmol) was added to 1- (4-bromo-2-methoxyphenyl) -4-methyl-1H-imidazole (51mg, 0.19mmol), intermediate 26(40mg, 0.15mmol), and Cs₂CO₃N in toluene (5ml) (97mg, 0.3mmol)₂In the purged mixture. In N₂The reaction mixture was heated at 100 ℃ under an atmosphere overnight. The solvent was then evaporated and the residue partitioned between water and DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Preparative HPLC on reversed phase [ RP ShandonHyperprepC18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 30mg of Compound 2 (44%).

Example B3

Preparation of Compound 3

2-methyl-2-propanol sodium salt (207mg, 2.15mmol), BINAP (25mg, 0.04mmol), Pd (OAc)₂(6mg, 0.027mmol) and 1- (4-bromo-2-methoxyphenyl) -4-methyl-1H-imidazole (215mg, 0.81mmol) were added to a solution of intermediate 52(139mg, 0.54mmol) in toluene (10ml) and the solution was washed with N₂The mixture is purged. The reaction mixture was stirred and heated at 150 ℃ for 1 hour under microwave irradiation. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, i.d.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/H/CH₃CN]The residue was purified. The product fractions were collected and worked up. Yield: 67mg of Compound 3 (28%).

Example B4

Preparation of Compound 4

In N₂Under the atmosphere, intermediate 5(340mg, 1.66mmol) and Pd₂(dba)₃(152mg, 0.166mmol), X-Phos (173mg, 0.366mmol) and Cs₂CO₃(1.63g, 5mmol) was added to a solution of intermediate 12(508mg, 1.66mmol) in 2-methyl-2-propanol (25 ml). The reaction mixture was heated at 110 ℃ for 2 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and worked up. The residue was triturated with DIPE. The solid was collected and dried in vacuo. Yield: 0.31g of Compound 4 (44%).

Example B5

Preparation of Compound 5

In N₂Under the atmosphere, intermediate 30(155mg, 0.89mmol), Pd₂(dba)₃(71mg, 0.077mmol), X-Phos (81mg, 0.17mmol) and Cs₂CO₃(757mg，2.32mmol) was added to a solution of intermediate 12(236mg, 0.77mmol) in 2-methyl-2-propanol (5 ml). The reaction mixture was heated at 110 ℃ for 20 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-98/2). The product fractions were collected and the solvent was evaporated. At NH₄The residue was partitioned between aqueous OH and DCM. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated. Yield: 0.05g of Compound 5 (16%).

Example B6

Preparation of Compound 6

In N₂Under the atmosphere, intermediate 29(70mg, 0.4mmol) and Pd₂(dba)₃(50mg, 0.055mmol), X-Phos (58mg, 0.12mmol) and Cs₂CO₃(537mg, 1.65mmol) was added to a solution of intermediate 12(168mg, 0.55mmol) in 2-methyl-2-propanol (5 ml). The reaction mixture was heated at 110 ℃ for 20 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-98/2). Yield: 0.075g of Compound 6 (34%).

Example B7

Preparation of Compound 7

In N₂Under the atmosphere, 1-, (4-aminophenyl) -4-methyl-1H-imidazole (130mg, 0.75mmol), Pd₂(dba)₃(60mg, 0.065mmol), X-Phos (69mg, 0.144mmol) and Cs₂CO₃(641mg, 1.97mmol) was added to a solution of intermediate 12(200mg, 0.65mmol) in 2-methyl-2-propanol (5 ml). The reaction mixture was heated at 110 ℃ for 20 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-98/2). The product fractions were collected and concentrated in vacuo. The residue was further purified by reverse phase preparative SFC [ RP Shandon HyperprepC18BDS (8 μm, 250g, I.D.5 cm); mobile phase: 35% MeOH (containing 0.2% isopropylamine), 65% CO₂. The product fractions were collected and worked up. Yield: 0.052g of Compound 7 (20%).

Example B8

Preparation of Compound 8

In N₂Under the atmosphere, intermediate 2a (93mg, 0.457mmol) and Pd₂(dba)₃(42mg, 0.046mmol), X-Phos (58mg, 0.1mmol) and Cs₂CO₃(456mg, 1.4mmol) was added to a solution of intermediate 35(140mg, 0.457mmol) in 2-methyl-2-propanol (5 ml). The reaction mixture was heated at 110 ℃ for 20 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-99/1). With DIPE and 1 drop of CH₃CN treated the residue to give a solid. Yield: 0.063g of Compound 8 (32%).

Example B9

a1) Preparation of Compound 212

In N₂Under the atmosphere, intermediate 2a (2.01g, 6.17mmol) and Pd₂(dba)₃(188mg, 0.206mmol), dicyclohexyl [2 ', 4', 6 '-tris (1-methylethyl) [1, 1' -biphenyl]-2-yl]Phosphine (216mg, 0.453mmol) and Cs₂CO₃(1.63g, 5mmol) was added to a solution of intermediate 40(840mg, 1.83mmol) in 2-methyl-2-propanol (40 ml). The reaction mixture was heated at 110 ℃ for 20 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and the solvent was evaporated. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-96/4). The product fractions were collected and the solvent was evaporated. Yield: 0.685g of compound 212 (70%).

a2) Preparation of Compound 9

Compound 212(660mg, 1.24mmol) was added to a mixture of DCM (5ml) and TFA (5 ml). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and taken up in DCM with saturated NaHCO₃The residue was partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. 430mg of compound 9 (80%) was obtained, which was used as such in the following step. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (10 μm, 250g, I.D.5 cm); mobile phase: gradient is (in water)0.25% NH₄HCO₃solution)/MeOH/CH₃CN]Further purify 80 mg. Collecting the product fraction and carrying out post-treatment to obtain: 47mg of pure compound 9.

b) Preparation of Compound 10

To a solution of compound 9(65mg, 0.15mmol) in DCM (5ml) was added acetic anhydride (16mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with water (1ml) and then passed through IsoluteFiltering and drying by using an HM-N filter. The organic layer was evaporated. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. Collecting the product fraction and carrying out post-treatment to obtain: 41mg of Compound 10 (58%).

c) Preparation of Compound 11

A mixture of compound 9(70mg, 0.163mmol), aqueous formaldehyde (37% by weight, 0.054ml, 0.65mmol) in DCE (1.5ml) and MeOH (1.5ml) was cooled to 0 ℃. To the mixture was added sodium triacetoxyborohydride (69mg, 0.325mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Preparative HPLC on reversed phase [ RP ShandonHyperprepC18BDS (10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH]The residue was purified. The product fractions were collected and worked up to yield 8mg of compound 11 (10%).

Example B10

Preparation of Compound 12

In N₂Under an atmosphere, intermediate 2a (123mg, 0.61mmol) and Pd were added₂(dba)₃(56mg, 0.061mmol), X-Phos (63mg, 0.13mmol) and Cs₂CO₃(592mg, 1.82mmol) was added to a solution of intermediate 15(200mg, 0.61mmol) in 2-methyl-2-propanol (15 ml). The reaction mixture was heated at 110 ℃ for 6 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with EtOAc. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH/CH₃CN]The residue was purified. The product fractions were collected and worked up to yield 90mg of compound 12 (33%).

Example B11

Preparation of Compound 13

In N₂Under the atmosphere, adding Cs₂CO₃(472mg, 1.45mmol), X-Phos (46mg, 0.097mmol) and Pd₂(dba)₃(44mg, 0.048mmol) was added to a solution of intermediate 37(140mg, 0.483mmol) and intermediate 9(93mg, 0.483mmol) in 2-methyl-2-propanol (5 ml). The reaction mixture was heated at 100 ℃ for 16 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Preparative HPLC on reverse phase [ RP Vydac DenaliC18(10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/MeOH]The residue was purified. The product fractions were collected and worked up to yield 51mg of compound 13 (24%).

Example B12

Preparation of Compound 14

In N₂Under the atmosphere, intermediate 31(113mg, 0.643mmol), Cs₂CO₃(629mg, 1.93mmol), X-Phos (61mg, 0.129mmol) and Pd₂(dba)₃(59mg, 0.064mmol) was added to a solution of intermediate 39(240mg, 0.643mmol) in 2-methyl-2-propanol (10 ml). The reaction mixture was heated at 110 ℃ for 16 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MeOH from 100/0-98/2). The residue was treated with DIPE to give a solid. Yield: 0.2g of Compound 14 (66%).

Example B13

Preparation of Compound 15

In N₂Under the atmosphere, intermediate 45(232mg, 0.819mmol), Cs₂CO₃(801mg, 2.46mmol), X-Phos (86mg, 0.18mmol) and Pd₂(dba)₃(75mg, 0.082mmol) was added to a solution of intermediate 12(250mg, 0.819mmol) in 2-methyl-2-propanol (15 ml). The reaction mixture was heated at 110 ℃ for 6 hours. Then, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. By reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH in water)₄HCO₃solution)/CH₃CN]The residue was purified. The product fractions were collected and worked up to yield 45mg of compound 15 (13%).

Example B14

Preparation of Compound 16

Intermediate 2a (0.178g, 0.875mmol), Pd₂(dba)₃(0.053g, 0.058mmol), X-Phos (0.061g, 0.128mmol) and Cs₂CO₃(0.570g, 1.75mmol) was added to a solution of intermediate 47(0.18g, 0.583mmol) in 2-methyl-2-propanol (5ml) and the reaction mixture was heated at 110 ℃ overnight. Then H is added₂O and the product extracted with DCM. Drying (MgSO)₄) The organic phase is evaporated off. By preparative HPLC [ RP ShandonHyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: (0.5% NH)₄Ac aqueous solution + 10% CH₃CN，MeOH]The residue was purified. The product fractions were collected and worked up, yield: 0.072g of Compound 16 (28.6%).

Example B15

Preparation of Compound 17

Intermediate 2a (0.123g, 0.607mmol), Pd₂(dba)₃(0.028g, 0.030mmol), X-Phos (0.032g, 0.067mmol) and Cs₂CO₃(0.296g, 0.91mmol) was added to a solution of intermediate 49(0.085g, 0.303mmol) in 2-methyl-2-propanol (5ml) and the reaction mixture was heated at 110 ℃ for 20 h. Then H is added₂O and the product extracted with DCM. Drying (MgSO)₄) The organic phase is evaporated off. By preparative HPLC [ RP ShandonHyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: (0.25% NH)₄CO₃Aqueous, MeOH) the residue. The product fractions were collected and worked up, yield: 0.015g of Compound 17 (12%).

Example B16

Preparation of Compound 18

Intermediate 2a (0.160g, 0.787mmol), Pd₂(dba)₃(0.036g, 0.039mmol), X-Phos (0.041g, 0.086mmol) and CsCO₃(0.384g, 1.18mmol) was added to a solution of intermediate 51(0.1g, 0.394mmol) in 2-methyl-2-propanol (5ml) and the reaction mixture was heated at 110 ℃ for 20 h. Then H is added₂O and the product extracted with DCM. Drying (MgSO)₄) The organic phase is evaporated off. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-98/2). The product fractions were collected and concentrated in vacuo. Yield: 0.110g of Compound 18 (71%).

Example B17

a) Preparation of Compound 46

Intermediate 2a (0.244g, 1.2mmol), Pd₂(dba)₃(0.092g, 0.1mmol), BINAP (0.093g, 0.15mmol) and Cs₂CO₃(0.977g, 3mmol) was added to a solution of intermediate 54(0.377g, 1mmol) in DMF (15ml) and the reaction mixture was heated under microwave irradiation at 150 ℃ for 5 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water. Drying (MgSO)₄) The organic phase was concentrated in vacuo. By preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: (0.25% NH)₄CO₃Aqueous solution of MeOH/CH₃CN) purification of the residue. The product fractions were collected and worked up. Yield: 0.155g of compound 46 (31%).

b) Preparation of Compound 45

In N₂MeOH (50ml) was added to Pd/C10% (20mg) under atmosphere. Next, compound 46(143mg, 0.286mmol) was added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 1 equivalent of H had been absorbed₂. Filtering off the catalyst with diatomaceous earth and evaporating the filtrateAnd (4) liquid. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-95/5). The product fractions were collected and evaporated. The residue was treated with DIPE/2-propanol to give a solid. Subjecting to reverse phase preparative HPLC [ RP Shandon Hyperprep ]C18BDS (8 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH)₄HCO₃Aqueous solution)/MeOH/CH₃CN]And (5) further purifying. The product fractions were collected and worked up. Yield: 41mg of Compound 45 (35%).

Example B18

Preparation of Compound 106

In N₂Under the atmosphere, intermediate 45(81mg, 0.40mmol), Cs₂CO₃(390mg, 1.2mmol), X-Phos (46mg, 0.096mmol) and Pd₂(dba)₃(30mg, 0.032mmol) was added to a solution of intermediate 56(140mg, 0.40mmol) in 2-methyl-2-propanol (10 ml). The reaction mixture was heated at 100 ℃ for 3 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-96/4). The product fractions were collected and concentrated in vacuo. The residue was suspended in DIPE. The solid was filtered off, washed with DIPE and dried. Yield 120mg of compound 106 (63%).

Example B19

Preparation of Compound 107

In N₂Under the atmosphere, intermediate 5(118mg, 0.58mmol), Cs₂CO₃(709mg, 2.18mmol), X-Phos (69mg, 0.145mmol) and Pd₂(dba)₃(66mg, 0.073mmol) was added to a solution of intermediate 56(200mg, 0.66mmol) in 2-methyl-2-propanol (8 ml). The reaction mixture was heated at 100 ℃ for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and concentrated in vacuo. Yield 186mg of compound 107 (60%).

Example B20

a) Preparation of Compound 108

In N₂Under the atmosphere, intermediate 71(1.2g, 6.3mmol), Cs₂CO₃(7.22g, 22.2mmol), X-Phos (704mg, 1.48mmol) and Pd₂(dba)₃(677mg, 0.74mmol) was added to a solution of intermediate 65(2.32g, 7.39mmol) in 2-methyl-2-propanol (50 ml). The reaction mixture was heated at 100 ℃ for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and concentrated in vacuo. Yield 1.96g of compound 108 (62%).

b) Alternative method for preparing Compound 108

Intermediate 71(6.24g, 32.6mmol) and methanesulfonic acid (10.5g, 109mmol) were added to a solution of intermediate 65(10g, 36.3mmol) in 2-propanol (88 ml). At 90 deg.C addingThe reaction mixture was heated for 36 hours. The reaction mixture was then slowly cooled to room temperature and the resulting precipitate was collected by filtration. In DCM with saturated NaHCO₃The solids were partitioned between aqueous solutions. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. 11.2g of compound 108 (85%) are obtained.

Example B21

a) Preparation of Compound 109

In N₂Under the atmosphere, intermediate 5(195mg, 0.96mmol), Cs₂CO₃(1.1g, 3.38mmol), X-Phos (107mg, 0.23mmol) and Pd₂(dba)₃(103mg, 0.11mmol) was added to a solution of intermediate 62(340mg, 1.13mmol) in 2-methyl-2-propanol (15 ml). The reaction mixture was heated at 100 ℃ for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and concentrated in vacuo. Yield 310mg of compound 109 (59%).

b) Preparation of Compound 110

In N₂MeOH (40ml) was added to Pt/C5% (100mg) under an atmosphere. Next, compound 109(310mg, 0.66mmol) was added. At H₂The reaction mixture was stirred at 25 ℃ under an atmosphere until 1 equivalent of H had been absorbed₂. The catalyst was filtered off over celite and the filtrate was concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). Collecting the product streamPartitioned and concentrated in vacuo. The residue was triturated with ether. Yield: 250mg of compound 110.

Example B22

Preparation of Compound 111

In N₂Under the atmosphere, intermediate 45(118mg, 0.58mmol), Cs₂CO₃(709mg, 2.18mmol), X-Phos (69mg, 0.145mmol) and Pd₂(dba)₃(66mg, 0.073mmol) was added to a solution of intermediate 63(200mg, 0.66mmol) in 2-methyl-2-propanol (8 ml). The reaction mixture was heated at 100 ℃ for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and concentrated in vacuo. Yield 166mg of compound 111 (53%).

Example B23

Preparation of Compound 112

In N₂Under the atmosphere, intermediate 71(187mg, 0.98mmol), Cs₂CO₃(957mg, 2.94mmol), X-Phos (93mg, 0.196mmol) and Pd₂(dba)₃(89mg, 0.098mmol) was added to a solution of intermediate 64(270mg, 0.98mmol) in 2-methyl-2-propanol (10 ml). The reaction mixture was heated at 100 ℃ for 20 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/M)eOH(NH₃) From 100/0-99/1). The product fractions were collected and concentrated in vacuo. Using DIPE/CH₃CN grinds the residue. Yield 37mg of compound 112 (9%).

Example B24

Preparation of Compound 113

In N₂Under the atmosphere, intermediate 5(55mg, 0.27mmol), Cs₂CO₃(284mg, 0.87mmol), X-Phos (28mg, 0.058mmol) and Pd₂(dba)₃(26mg, 0.029mmol) was added to a solution of intermediate 64(80mg, 0.29mmol) in 2-methyl-2-propanol (10 ml). The reaction mixture was heated at 100 ℃ for 20 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and evaporated. Preparative HPLC [ RP Vydac Denali C18(10 μm, 250g, I.D.5 cm); mobile phase: (0.25% NH)₄CO₃Aqueous solution of MeOH/CH₃CN) purification of the residue. The product fractions were collected and worked up. The residue was triturated with DIPE. Yield: 27mg of Compound 113 (21%).

Example B25

Preparation of Compound 114

In N₂Under the atmosphere, intermediate 5(139mg, 0.68mmol), Cs₂CO₃(635mg, 1.95mmol), X-Phos (68mg, 0.143mmol) and Pd₂(dba)₃(59mg, 0.065mmol) was added to a solution of intermediate 73(200mg, 0.65mmol) in 2-methyl-2-propanol (10 ml). The reaction mixture was heated at 75 ℃ for 16 hours. However, the device is not suitable for use in a kitchenThe reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-99/1). The product fractions were collected and concentrated in vacuo. The residue was triturated with DIPE. Yield 70mg of compound 114 (22%).

Example B26

Preparation of Compound 174

3-Acetaminophenylboronic acid (134mg, 0.75mmol) and Pd (PPh)₃)₄(115mg, 0.1mmol) was added to intermediate 91(184mg, 0.5mmol) and K₂CO₃(207mg, 1.5mmol) in bisAlkane (10ml) and DMF (2.5 ml). The reaction mixture was stirred and heated at 140 ℃ for 20 hours in a closed vessel. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in a minimal amount of DCM and then filtered through celite. The organic layer was evaporated. Preparative HPLC on reverse phase [ RP Vydac Denali C18(10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH)₄HCO₃Aqueous solution)/MeOH]The residue was purified. The product fractions were collected and worked up. Yield 158mg of compound 174 (64%).

Example B27

Preparation of Compound 184

4-fluoro-3-methoxyphenylboronic acid (127mg, 0.75mmol) and Pd (PPh)₃)₄(115mg, 0.1mmol) was added to intermediate 91(184mg, 0.5mmol) and K₂CO₃(207mg, 1.5mmol) in bisAlkane (10ml) and DMF (2.5 ml). The reaction mixture was stirred and heated at 140 ℃ for 20 hours in a closed vessel. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in a minimal amount of DCM and then filtered through celite. The organic layer was evaporated. Preparative HPLC on reverse phase [ RP Vydac Denali C18(10 μm, 250g, I.D.5 cm); mobile phase: gradient was (0.25% NH)₄HCO₃Aqueous solution)/MeOH]The residue was purified. The product fractions were collected and worked up. The residue was dissolved in hot 2-propanol and treated with 6N HCl solution in 2-propanol. The resulting precipitate was collected by filtration and dried. Yield: 168mg of Compound 184 (61%) as HCl salt (.2HCl. H)₂O)。

Example B28

Preparation of Compound 133

Mixing Na₂S₂O₅(0.4g, 2.11mmol) and 3-bromo-4-fluoro-benzaldehyde (243mg, 1.2mmol) were added to a solution of intermediate 93(324mg, 1mmol) in DMA (10 ml). The reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was then allowed to cool to room temperature and poured into water. The mixture was extracted with DCM. Drying (MgSO)₄) The combined organic layers were filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-96/4). The product fractions were collected and concentrated in vacuo. The residue was triturated with DIPE. Yield: 110mg of Compound 133 (22%).

Example B29

Preparation of Compound 141

3-Acetaminophenylboronic acid (46mg, 0.26mmol), K₂CO₃(89mg, 0.64mmol) and Pd (PPh)₃)₄(37mg, 0.032mmol) was added to intermediate 97(80mg, 0.21mmol) in dichloromethaneAlkane (3.2ml) with DMF (0.8 ml). The reaction mixture was stirred and heated at 150 ℃ for 20 minutes under microwave irradiation. Additional 3-Acylaminophenylboronic acid (23mg), Pd (PPh) was added₃)₄(19mg) and DMF (0.5ml) and the reaction mixture was stirred and heated at 150 ℃ for 20 minutes under microwave irradiation. The mixture was cooled to room temperature and at H₂Partition between O and EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. Flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-95/5). The product fractions were collected and concentrated. Yield: 50mg of Compound 141 (50%).

Example B30

Preparation of Compound 154

A2M solution of lithium diisopropylamide in THF (1.6ml, 3.2mmol) was added to a solution of compound 108(460mg, 1.07mmol) in THF (35ml) at-40 deg.C. The reaction mixture was stirred at-40 ℃ for 1h and then I in THF (5ml) was added₂(271mg, 1.07 mmol). The reaction mixture was allowed to warm to room temperature and then partitioned between DCM and water. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. The reaction was repeated with 100mg of compound 108. Combining the crude products from the two batchesThe residue is subjected to flash column chromatography (eluent: DCM/MeOH (NH)₃) From 100/0-95/5). The product fractions were collected and concentrated in vacuo. Yield: 52mg of Compound 154 (7%).

Example B31

Preparation of Compound 119

Adding SOCl₂(62mg, 0.52mmol) was added to a solution of compound 118 (prepared from intermediate 99 and intermediate 12 as in example B4) (80mg, 0.17mmol) in DCM (5 ml). The reaction mixture was stirred at room temperature for 1 hour and then MeOH (10ml) was added. The reaction mixture was stirred at room temperature overnight and then DCM (100ml) was added. Successively using saturated NaHCO₃The aqueous solution and water wash the mixture. Drying (MgSO)₄) The organic layer was filtered and the solvent was evaporated. Preparative HPLC [ RP Vydac Denali C18(10 μm, 250g, I.D.5 cm); mobile phase: (0.25% NH)₄CO₃Aqueous, MeOH) the residue. The product fractions were collected and worked up. Yield: 26mg of Compound 119 (33%).

Example B32

Preparation of Compound 208

At H₂A mixture of intermediate 41(140mg, 0.28mmol) and Raney nickel (20mg) in THF (40ml) was stirred at room temperature (atmospheric pressure). In absorption of H₂After (2 equivalents), the catalyst was filtered off over celite. The solvent was evaporated and the residue was partitioned between DCM and water. Drying (MgSO)₄) The organic layer was filtered and concentrated in vacuo. Preparative HPLC [ RP Vydac DenaliC18(10 μm, 250g, I.D.5 cm); mobile phase: (0.25% N)H₄CO₃Aqueous solution, MeOH)]The residue was purified. The product fractions were collected, concentrated in vacuo and subjected to preparative HPLC [ RP VydacDenali C18(10 μm, 250g, I.D.5 cm); mobile phase: (0.25% NH)₄CO₃Aqueous solution, CH₃CN)]The residue was further purified. The product fractions were collected and concentrated under reduced pressure. Yield: 14mg of Compound 208 (10%).

Example B33

Preparation of Compound 187

2-fluoro-5-trifluoromethyl-benzaldehyde (189mg, 0.98mmol) and Na₂S₂O₄(427mg, 2.46mmol) was added to a solution of intermediate 92(290mg, 0.82mmol) in EtOH (15 ml). The reaction mixture was heated at 160 ℃ for 45 minutes under microwave conditions. The reaction mixture was cooled to room temperature and filtered through celite, eluting with EtOAc. The filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Flash column chromatography over silica gel (eluent: DCM/MeOH (NH)₃) From 100/0-97/3). The product fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and DIPE and treated with 6N HCl solution in 2-propanol. The resulting precipitate was collected by filtration and dried. Yield: 86mg of Compound 187 (18%) as HCl salt (.2HCl. H)₂O)。

Compounds 1-212 of tables 1a, 1b, 1c and 1d were prepared by a method analogous to one of the examples described above. If no salt form is indicated, the compound is obtained as the free base. No.' denotes the compound number. 'Pr.' refers to the example number from which the compound was synthesized according to its protocol. B1^*The compounds are shown synthesized according to the scheme as described in B1, but the intermediate of formula (II-a) is reacted with the intermediate of formula (III-a) instead of the intermediates of formula (II-B) and (III-B), as exemplified in B1As illustrated by way of example.

TABLE 1a

TABLE 1b

Compounds 165, 167, 168, 170-172, 176-187 and 190 as hydrochloride salt forms (.2HCl. H.)₂O) is obtained. Mixture 166 as the hydrochloride salt form (.1.5 HCl.1.4H)₂O) is obtained. Compounds 210 and 211 were obtained as the hydrochloride salt (.2 HCl). Compound 209 as the mesylate salt form (.2 CH)₃SO₃H) Thus obtaining the product. All other compounds in table 1b were obtained as free bases.

Table 1c (all compounds in Table 1c are obtained as free bases)

TABLE 1d

Analysis section

LCMS

General procedure A

LC measurements were performed using an acquisition UPLC (Waters) system with a binary pump, sample organizer, column heater (set at 55 ℃), Diode Array Detector (DAD) and columns as specified in the related methods below. The effluent from the column was split to an MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds (sec), with a dwell time of 0.02 seconds. The capillary needle (capillary needle) voltage was 3.5kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the nebulizer gas. Data were collected using a Waters-Micromass MassLynx-Openlynx data System.

General procedure B

HPLC measurements were performed using an Agilent 1100 series liquid chromatography system containing a deaerator equipped binary pump, an autosampler, a column oven, a UV detector, and a column as specified in the related methods below. The effluent from the column was split to an MS spectrometer. The MS detector was configured with an electrospray ionization source. The capillary voltage was 3kV, the quadrupole focuser temperature was maintained at 100 ℃ and the desolvation temperature was 300 ℃. Nitrogen was used as the nebulizer gas. Data were collected using an agilent chemstation data system.

General procedure C

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

LCMS method 1

In addition to general procedure a: reverse phase UPLC (ultra performance liquid chromatography) was performed on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1x50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. With two mobile phases (25mM NH)₄H of OAc₂O solution/CH₃CN 95/5; mobile phase B: CH (CH)₃CN) was performed under gradient conditions from 95% a and 5% B to 5% a and 95% B in 1.3 minutes for 0.3 minutes (min). The injection volume was 0.5. mu.l. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

LCMS method 2

In addition to general procedure a: reverse phase UPLC was performed on a BEH C18 column (1.7 μm, 2.1X50 mm; WatersACQUITY) at a flow rate of 0.8 ml/min. With two mobile phases (mobile phase A: 0.1% formic acid in H₂O solution/MeOH 95/5; mobile phase B: MeOH) was eluted with a gradient condition changing from 95% a and 5% B to 5% a and 95% B in 1.3 minutes for 0.2 minutes. The injection volume was 0.5. mu.l. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

LCMS method 3

In addition to general procedure B: reversed phase HPLC was performed on a YMC-Pack ODS-AQ C18 column (4.6X50mm) at a flow rate of 2.6 ml/min. Gradient elution was used, running conditions were 95% water and 5% CH in 4.80 min₃CN changed to 95% CH₃CN, held for 1.20 minutes. By scanning from 100 to1400 to obtain mass spectrum. The injection volume was 10. mu.l. The column temperature was 35 ℃.

LCMS method 4

In addition to general procedure C: the column heater was set to 60 ℃. Reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100mm) at a flow rate of 1.6 ml/min. With three mobile phases (mobile phase A: 95% 25mM NH)₄OAc+5％CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) was subjected to a gradient condition from 100% a to 50% B and 50% C in 6.5 minutes and to 100% B in 0.5 minutes, held for 1 minute under these conditions, and equilibrated with 100% a for another 1.5 minutes. The injection volume was 10. mu.l. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

LCMS method 5

In addition to general procedure C: the column heater was set to 45 ℃. Reverse phase HPLC was performed on an Atlantis C18 column (3.5 μm, 4.6X100mm) at a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70% MeOH + 30% H) were used₂O; mobile phase B: 0.1% formic acid in H₂O solution/MeOH 95/5) was subjected to a gradient of 100% B to 5% B + 95% a over 9 minutes, held for 3 minutes under these conditions. The injection volume was 10. mu.l. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

LCMS method 6

In addition to general procedure C: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100mm) at a flow rate of 1.6 ml/min. With three mobile phases (mobile phase A: 95% 25mM NH)₄OAc+5％CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) was subjected to gradient elution under conditions of 100% a to 1% a, 49% B and 50% C in 6.5 minutes and 1% a and 99% B in 1 minute, held for 1 minute under these conditions, and equilibrated with 100% a for another 1.5 minutes. The injection volume was 10. mu.l. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

LCMS method 7

In addition to general procedure a: reverse phase UPLC (ultra performance liquid chromatography) was performed on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1x50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. With two mobile phases (25mM NH)₄H of OAc₂O solution/CH₃CN 95/5; mobile phase B: CH (CH)₃CN) was subjected to gradient elution under conditions of changing from 95% a and 5% B to 5% a and 95% B in 1.3 minutes, and held for 0.3 minutes. The injection volume was 0.5. mu.l. The cone voltage is 30V for the positive ionization mode and 30V for the negative ionization mode.

LCMS method 8

In addition to general procedure C: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100mm) at a flow rate of 1.6 ml/min. Three mobile phases were used (mobile phase A: 95% 25mM NH)₄OAc+5％CH₃CN, mobile phase B: CH (CH)₃CN, mobile phase C: MeOH) was subjected to gradient conditions from 100% a to 1% a, 49% B, and 50% C in 6.5 minutes and to 1% a, 99% B in 0.5 minutes, and these conditions were maintained for 1 minute. A sample volume of 10. mu.l was used. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.

Melting Point

For many compounds, melting points (m.p.) were determined by DSC823e (Mettler-Toledo). Melting points were measured using a30 deg.C/min temperature gradient. The maximum temperature was 400 ℃. The value is the peak value.

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

Table 2: retention time (R)_t) Expressed in minutes, [ M + H]⁺Peak (protonated molecule), LCMS method and m.p. (melting point in ° c). (n.d. means not measured)

For Compound No. 137, [ M-H ] was detected]^-Peak: r_t 5.98；[M-H]^-415, LCMS method 5; melting point: 225.6 ℃.

¹H NMR

For many compounds, recordings were made on Bruker DPX-360, Bruker DPX-400 or Bruker Avance 600 spectrometers with standard pulse sequences running at 360MHz, 400MHz and 600MHz respectively¹H NMR spectrum using chloroform-d (deuterated chloroform, CDCl)₃) Or DMSO-d₆(deuterated DMSO, dimethyl-d)₆Sulfoxide) as solvent. Chemical shifts (δ) are reported in parts per million (ppm) relative to Tetramethylsilane (TMS), which is used as an internal standard.

Compound No. 1: (360MHz, DMSO-d₆)δppm 2.14(s，3H)，3.74(s，3H)，3.86(s，3H)，6.93(dd，J＝8.5，2.2Hz，1H)，7.01(s，1H)，7.12-7.23(m，5H)，7.43(t，6J＝8.8Hz，2H)，7.63(d，J＝1.3Hz，1H)，7.92(dd，J＝8.6，5.5Hz，2H)，8.46(s，1H).

Compound No. 2: (360MHz, DMSO-d₆)δppm 1.59(d，J＝6.9Hz，6H)，2.14(s，3H)，3.74(s，3H)，4.58-4.71(m，J＝6.9，6.9，6.9，6.9Hz，1H)，6.95(dd，J＝8.5，2.26Hz，1H)，7.01(s，1H)，7.12-7.20(m，4H)，7.29-7.37(m，1H)，7.43(t，J＝8.8Hz，2H)，7.63(d，J＝1.3Hz，1H)，7.73(dd，J＝8.5，5.5Hz，2H)，8.41(s，1H).

Compound No. 3: (360MHz, DMSO-d₆)δppm 2.14(s，3H)，3.70(s，3H)，3.73(s，3H)，6.93(dd，J＝8.5，2.3Hz，1H)，7.01(s，1H)，7.12(d，J＝2.3Hz，1H)，7.15-67.26(m，4H)，7.35(td，J＝8.5，2.6Hz，1H)，7.56(td，J＝9.9，2.5Hz，1H)，7.63(d，J＝1.3Hz，1H)，7.76-7.83(m，1H)，8.50(s，1H).

Compound No. 4: (360MHz, DMSO-d₆)δppm 2.32(s，3H)，3.78(s，3H)，3.86(s，3H)，6.95(dd，J＝8.7，2.2Hz，1H)，7.13(d，J＝2.2Hz，1H)，7.17-7.25(m，3H)，67.38(d，J＝8.6Hz，1H)，7.43(t，J＝8.8Hz，2H)，7.92(dd，J＝8.6，5.5Hz，2H)，8.55(s，1H)，8.61(s，1H).

Compound No. 5: (360MHz, CDCl)₃)δppm 2.31(s，3H)，3.86(s，3H)，6.93(s.1H)，6.99-7.06(m，2H)，7.26(t，2H)，7.34(t，J＝8.2Hz，1H)，7.53(dd，J＝8.8，2.7Hz，1H)，7.66(s，1H)，7.76(dd，J＝8.5，5.3Hz，2H)，7.92(s，1H)，8.24(d，J＝8.0Hz，1H)，8.36(d，J＝2.7Hz，1H).

Compound No. 6: (600MHz, CDCl)₃)δppm 2.30(d，J＝1.1Hz，3H)，3.86(s，3H)，6.93(br.s，1H)，7.03(dd，J＝8.1，0.8Hz，1H)，7.07(dd，J＝8.1，0.8Hz，1H)，7.24-7.28(m，3H)，7.53-7.56(m，J＝1.1，1.1，1.1，1.1Hz，1H)，7.75(dd，J＝8.7，5.3Hz，2H)，8.45(d，J＝1.3Hz，1H)，8.67(s，2H).

Compound No. 7: (600MHz, CDCl)₃)δppm 2.30(d，J＝1.1Hz，3H)，3.84(s，3H)，6.94(dd，J＝8.0，0.9Hz，1H)，6.95-6.96(m，J＝1.2，1.2，1.2，1.2Hz，1H)，7.10(br.s，1H)，7.19(dd，J＝8.0，0.9Hz，1H)，7.22-7.26(m，3H)，7.28(d，J＝8.7Hz，2H)，7.36(d，J＝8.7Hz，2H)，7.69(d，J＝1.4Hz，1H)，7.74(dd，J＝8.7，5.3Hz，2H).

Compound No. 8: (400MHz, DMSO-d)₆)δppm 2.15(d，J＝1.0Hz，3H)，3.81(s，3H)，3.86(s，3H)，7.04(s，1H)，7.17(d，J＝5.8Hz，1H)，7.23(d，J＝8.6Hz，1H)，67.45(t，J＝8.8Hz，2H)，7.66(s，1H)，7.91(dd，J＝8.6，2.2Hz，1H)，7.96(dd，J＝8.7，5.5Hz，2H)，8.00-8.02(m，2H)，9.23(s，1H).

Compound No. 15: (400MHz, CDCl)₃)ppm 2.29(d，J＝1.01Hz，3H)3.83(s，3H)4.06(s，3H)6.57(d，J＝8.31Hz，1H)6.86(t，J＝1.01Hz，1H)7.02(dd，J＝8.06，0.76Hz，1H)7.24(t，J＝8.81Hz，2H)7.31(t，J＝8.06Hz，1H)7.39(d，J＝8.06Hz，1H)7.62(d，J＝1.26Hz，1H)7.74(dd，J＝8.81，5.29Hz，2H)7.94(s，1H)8.16(d，J＝7.81Hz，1H).

Compound No. 16: (360MHz, CDCl)₃)δppm 2.31(s，3H)，3.83(s，3H)，6.89(s，1H)，6.91(s，1H)，6.93-6.98(m，2H)，7.16(dd，J＝7.3，1.5Hz，1H)，7.20(d，J＝9.1Hz，1H)，7.24-7.33(m，2H)，7.41-7.50(m，2H)，7.59(dd，J＝7.4，1.9Hz，1H)，7.64(s，1H)，8.14(dd，J＝7.2，2.3Hz，1H).

Compound No. 17: (360MHz, CDCl)₃)δppm 1.27-1.50(m，3H)，1.65-1.77(m，3H)，1.84-1.93(m，2H)，2.11-2.20(m，2H)，2.30(s，3H)，2.96(tt，J＝11.4，3.6Hz，1H)，3.81(s，3H)，6.72(s，1H)，6.85-6.91(m，3H)，7.02-7.08(m，1H)，7.14-7.22(m，3H)，7.63(s，1H).

Compound No. 18: (360MHz, CDCl)₃)δppm 1.05(d，J＝6.7Hz，6H)，2.23-2.36(m，1H)，2.30(s，3H)，2.81(d，J＝7.2Hz，2H)，3.81(s，3H)，6.72(s，1H)，6.86-6.91(m，3H)，7.03-7.09(m，1H)，7.16(d，J＝9.1Hz，1H)，7.19-7.24(m，2H)，7.62(d，J＝1.3Hz，1H).

Compound No. 25: (360MHz, DMSO-d₆)ppm 1.02(d，J＝7.0Hz，6H)，2.27-2.43(m，4H)，3.09(d，J＝7.3Hz，2H)，3.82(s，3H)，3.98(s，3H)，6.94(dd，J＝8.6，2.2Hz，1H)，7.08(d，J＝2.2Hz，1H)，7.39-7.55(m，4H)，7.66(s，1H)，9.31(d，J＝1.5Hz，1H)，9.53(br.s，1H).

Compound No. 37: (360MHz, CDCl)₃)δppm 1.68-1.80(m，2H)，1.81-1.93(m，2H)，1.98-2.10(m，2H)，2.12-2.22(m，2H)，2.30(s，3H)，3.33-3.43(m，J＝8.1，8.1，8.1，8.1Hz，1H)，3.81(s，3H)，6.70(s，1H)，6.85-6.90(m，3H)，7.01-7.07(m，1H)，7.14-7.22(m，3H)，7.63(d，J＝1.3Hz，1H).

Compound No. 38: (360MHz, CDCl)₃)δppm 1.32-1.51(m，3H)，1.73-1.87(m，3H)，1.88-2.04(m，4H)，2.30(s，3H)，2.86(tt，J＝11.8，3.4Hz，1H)，3.75(s，3H)，3.81(s，3H)，6.84-6.90(m，2H)，6.91-6.96(m，2H)，7.04(s，1H)，7.12-7.18(m，3H)，7.62(s，1H).

Compound No. 40: (360MHz, CDCl)₃)ppm 2.06-2.26(m，4H)，2.30(s，3H)，2.36(s，3H)，2.89-3.04(m，3H)，3.64(br.s，2H)，3.79(s，3H)，6.75(s，1H)，6.84-6.91(m，3H)，7.02-7.09(m，1H)，7.17(d，J＝8.8Hz，1H)，7.19-7.23(m，2H)，7.65(s，1H).

Compound No. 41: (360MHz, CDCl)₃)δppm 1.85-2.03(m，2H)，2.15(s，3H)，2.16-2.25(m，2H)，2.30(s，3H)，2.95(ddd，J＝13.7，11.1，3.1Hz，1H)，3.22(tt，J＝10.7，4.0Hz，1H)，3.30(ddd，J＝13.8，11.1，2.8Hz，1H)，3.82(s，3H)，3.92(dt，J＝13.8，4.2Hz，1H)，4.56(dt，J＝13.5，4.2Hz，1H)，6.74(s，1H)，6.86-6.91(m，3H)，7.02-7.08(m，1H)，7.17(d，J＝9.0Hz，1H)，7.20-7.25(m，2H)，7.63(d，J＝1.3Hz，1H).

Compound No. 42: (360MHz, CDCl)₃)δppm 1.48(s，9H)，1.84-1.97(m，2H)，2.08-2.18(m，2H)，2.30(s，3H)，2.99(t，J＝12.0Hz，2H)，3.13(tt，J＝11.0，3.9Hz，1H)，3.82(s，3H)，4.16(br.s，2H)，6.71(s，1H)，6.86-6.91(m，3H)，7.02-7.07(m，1H)，7.16-7.23(m，3H)，7.63(d，J＝1.3Hz，1H).

Compound No. 44: (600MHz, DMSO-d₆)δppm 1.15(d，J＝6.2Hz，6H)，2.14(d，J＝1.0Hz，3H)，2.61(dd，J＝12.3，10.4Hz，2H)，3.44(d，J＝12.0Hz，2H)，3.62(s，36H)，3.73(s，3H)，3.81-3.87(m，2H)，6.82(dd，J＝8.5，2.3Hz，1H)，6.96(dd，J＝6.5，2.4Hz，1H)，6.98(t，J＝1.2Hz，1H)，7.01-7.06(m，3H)，7.13(d，J＝8.5Hz，1H)，7.60(d，J＝1.3Hz，1H)，7.99(s，1H).

Compound No. 47: (360MHz, DMSO-d₆)δppm 2.14(s，3H)，3.74(s，3H)，3.85(s，3H)，3.85(s，3H)，6.92(dd，J＝8.5，2.3Hz，1H)，7.01(s，1H)，7.11-7.21(m，76H)，7.63(d，J＝1.3Hz，1H)，7.81(d，J＝8.6Hz，2H)，8.42(s，1H).

Compound No. 48: (360MHz, CDCl)₃)δppm 2.31(s，3H)，3.81(s，3H)，4.02(s，3H)，6.88(s，1H)，6.91-6.94(m，2H)，7.09-7.19(m，5H)，7.23-7.29(m，2H)，7.49-7.55(m，1H)，7.63(s，1H)，8.12(dd，J＝7.7，1.8Hz，1H).

Compound No. 54: (360MHz, DMSO-d₆)ppm 2.35(s，3H)3.15(s，3H)3.78(t，J＝4.76Hz，2H)3.83(s，3H)3.89(s，3H)4.62(t，J＝4.76Hz，2H)7.01(dd，J＝8.78，2.20Hz，1H)7.16(d，J＝2.20Hz，1H)7.30(dd，J＝8.05，1.83Hz，1H)7.41-7.57(m，5H)7.58-7.65(m，2H)7.66(s，1H)9.31(d，J＝1.46Hz，1H)9.44(br.s，1H)15.01(br.s，1H).

Compound No. 62: (360MHz, DMSO-d₆)δppm 2.14(s，3H)，3.75(s，3H)，6.93(dd，J＝8.5，2.3Hz，1H)，7.02(s，1H)，7.06-7.20(m，5H)，7.42(t，J＝8.7Hz，2H)，67.64(s，1H)，8.23(dd，J＝8.5，5.4Hz，2H)，8.38(s，1H)，12.93(s，1H).

Co.no. 63: (400MHz, CDCl)₃)ppm 3.81(s，3H)3.85(s，3H)6.92-7.01(m，3H)7.13-7.21(m，4H)7.21-7.30(m，4H)7.69-7.79(m，3H).

Compound No. 66: (360MHz, DMSO-d₆)δppm 2.14(s，3H)，3.70(d，J＝1.6Hz，3H)，3.74(s，3H)，6.93(dd，J＝8.5，2.3Hz，1H)，7.01(s，1H)，7.12(d，J＝2.2Hz，16H)，7.15-7.20(m，3H)，7.24(t，J＝7.7Hz，1H)，7.41-7.51(m，2H)，7.63(d，J＝1.3Hz，1H)，7.63-7.69(m，1H)，7.70-7.75(m，1H)，8.50(s，1H).

Compound No. 67: (400MHz, CDCl)₃)δppm 2.31(s，3H)，3.85(s，3H)，6.92(s，1H)，6.99-7.03(m，1H)，7.06(dd，J＝8.7，2.5Hz，1H)，7.15(s，1H)，7.18-7.30(m，6H)，7.65(s，1H)，7.74(dd，J＝8.5，5.3Hz，2H).

Compound No. 70: (400MHz, DMSO-d)₆)δppm 2.37(s，3H)，3.86(s，3H)，7.10(dd，J＝6.2，2.5Hz，1H)，7.19-7.26(m，2H)，7.42(t，J＝8.8Hz，2H)，7.67(d，J＝8.86Hz，1H)，7.81(dd，J＝8.8，2.8Hz，1H)，7.91(dd，J＝8.6，5.6Hz，2H)，8.41(d，J＝2.7Hz，1H)，8.74(s，1H)，9.06(s，1H).

Compound No. 71: (360MHz, DMSO-d₆)δppm 3.75(s，3H)，3.86(s，3H)，6.93(dd，J＝8.8，2.2Hz，1H)，7.13(d，J＝2.2Hz，1H)，7.16-7.25(m，4H)，7.44(t，J＝8.86Hz，2H)，7.50(d，J＝1.1Hz，1H)，7.78(d，J＝1.1Hz，1H)，7.92(dd，J＝8.5，5.5Hz，2H)，8.55(s，1H).

Compound No. 74: (360MHz, DMSO-d₆)δppm 1.67(d，J＝6.9Hz，6H)，2.35(s，3H)，4.67-4.80(m，J＝6.9，6.9，6.9，6.9Hz，1H)，7.13(dd，J＝8.7，2.5Hz，1H)，7.18 6(dd，J＝12.8，2.6Hz，1H)，7.42-7.52(m，2H)，7.55-7.62(m，3H)，7.75(d，J＝7.8Hz，1H)，7.91(dd，J＝8.5，5.3Hz，2H)，8.76(d，J＝2.0Hz，1H)，9.32(br.s，1H).

Compound No. 75: (360MHz, DMSO-d₆)ppm 1.69(d，J＝6.95Hz，6H)2.37(s，3H)3.84(s，3H)4.77(spt，J＝6.95Hz，1H)6.96(dd，J＝8.42，2.20Hz，1H)7.08(d，J＝2.20Hz，1H)7.47-7.55(m，3H)7.62(t，J＝8.78Hz，2H)7.67-7.73(m，1H)7.96(dd，J＝8.78，5.12Hz，2H)8.91(s，1H)9.40(br.s，1H).

Compound No. 79: (360MHz, CDCl)₃)δppm 2.31(s，3H)，3.82(s，3H)，5.41(s，2H)，6.80(d，J＝7.9Hz，1H)，6.88(s，1H)，6.94-6.99(m，2H)，7.09-7.20(m，7H)，7.25(d，J＝8.1Hz，1H)，7.30-7.38(m，3H)，7.61-7.68(m，3H).

Compound No. 80: (400MHz, DMSO-d)₆)δppm 2.15(d，J＝1.0Hz，3H)，3.76(s，3H)，6.90(dd，J＝8.5，2.3Hz，1H)，7.03(s，1H)，7.10(d，J＝2.3Hz，1H)，7.22(d，6J＝8.5Hz，1H)，7.25-7.34(m，3H)，7.47(t，J＝8.8Hz，2H)，7.65(d，J＝1.3Hz，1H)，8.25(dd，J＝8.8，5.4Hz，2H)，8.74(s，1H).

Compound No. 82: (360MHz, CDCl)₃)δppm 2.30(s，3H)，3.80(s，3H)，4.25(s，2H)，6.74(s，1H)，6.85-6.89(m，3H)，7.01-7.08(m，3H)，7.16(d，J＝9.0Hz，1H)，7.19-7.22(m，2H)，7.35(dd，J＝8.4，5.3Hz，2H)，7.62(d，J＝1.1Hz，1H).

Compound No. 86: (360MHz, CDCl)₃)δppm 2.31(d，J＝1.0Hz，3H)，3.84(s，3H)，6.87(s，1H)，6.88-6.91(m，1H)，6.93-6.97(m，2H)，7.16(dd，J＝7.4，1.5Hz，1H)，7.21(d，J＝9.0Hz，1H)，7.25-7.32(m，2H)，7.49(ddd，J＝8.0，4.9，0.9Hz，1H)，7.65(d，J＝1.3Hz，1H)，8.50(dt，J＝8.0，1.9Hz，1H)，8.77(dd，J＝4.9，1.7Hz，1H)，9.48(dd，J＝2.2，0.9Hz，1H).

Compound No. 92: (360MHz, DMSO-d₆)ppm 2.34(s，3H)3.85(s，3H)3.87(s，3H)7.20(d，J＝5.85Hz，1H)7.38-7.53(m，3H)7.92-8.00(m，3H)8.03(d，J＝5.85Hz，1H)8.06(d，J＝2.20Hz，1H)8.65(s，1H)9.34(s，1H).

Compound No. 104: (360MHz, DMSO-d₆)ppm 2.17(s，3H)3.72(s，3H)7.18(s，1H)7.24(d，J＝5.85Hz，1H)7.37(td，J＝8.60，2.20Hz，1H)7.46(t，J＝8.97Hz，1H)7.59(td，J＝9.15，2.20Hz，1H)7.78-7.89(m，2H)7.95(dd，J＝9.15，1.83Hz，1H)8.06(d，J＝5.85Hz，1H)8.39(dd，J＝14.27，2.20Hz，1H)9.69(s，1H).

Compound No. 106: (360MHz, CDCl)₃)ppm 1.63(d，J＝7.0Hz，6H)，2.30(s，3H)，4.10(s，3H)，4.70(spt，J＝7.0Hz，1H)，6.53(d，J＝8.1Hz，1H)，6.88(s，1H)，6.90(dd，J＝9.1，2.2Hz，1H)，7.26(t，J＝8.6Hz，2H)，7.43(d，J＝8.1Hz，1H)，7.55-7.68(m，3H)，7.96(s，1H)，8.12(dd，J＝12.8，2.2Hz，1H).

Compound No. 107: (360MHz, CHLOROFORM-d) ppm 1.42(d, J ═ 7.0Hz, 6H), 2.49(s, 3H), 3.12(spt, J ═ 7.0Hz, 1H), 3.82(s, 3H), 4.00(s, 3H), 6.74(s, 1H), 7.16(dd, J ═ 8.8, 1.8Hz, 1H), 7.22-7.31(m, 2H), 7.58(d, J ═ 8.8Hz, 1H), 7.74(dd, J ═ 8.1, 5.9Hz, 2H), 7.78(s, 1H), 8.51(s, 1H), 8.58(s, 1H).

Compound No. 108: (600MHz, CDCl)₃)ppm 2.31(d，J＝1.0Hz，3H)，2.65(s，3H)，3.81(s，3H)，6.77(d，J＝0.8Hz，1H)，6.92-6.95(m，1H)，7.24-7.30(m，3H)，7.44(dd，J＝8.7，2.4Hz，1H)，7.67(t，J＝1.4Hz，1H)，7.74(dd，J＝8.8，5.2Hz，2H)，7.80(s，1H)，8.35(dd，J＝13.5，2.4Hz，1H).

Compound No. 110: (360MHz, CDCl)₃)ppm 1.34(d，J＝6.95Hz，6H)2.50(s，3H)3.10(spt，J＝6.95Hz，1H)3.91(s，3H)3.93(s，3H)6.98-7.08(m，3H)7.25(t，J＝8.42Hz，2H)7.33(s，1H)7.70(d，J＝8.05Hz，1H)7.78(dd，J＝8.42，5.31Hz，2H)8.54(s，1H).

Compound No. 111: (360MHz, CDCl)₃)ppm 1.39(d，J＝7.0Hz，6H)，2.31(s，3H)，3.17(spt，J＝6.9Hz，1H)，3.94(s，3H)，4.14(s，3H)，6.60(d，J＝8.1Hz，1H)，6.90(s，1H)，7.20-7.32(m，2H)，7.48(d，J＝8.1Hz，1H)，7.67(s，1H)，7.79(dd，J＝8.1，5.5Hz，2H)，8.05(s，1H)，8.21(s，1H).

Compound No. 112: (360MHz，DMSO-d₆)ppm 2.17(s，3H)，2.51(s，3H)，3.85(s，3H)，6.95(s，1H)，7.20(s，1H)，7.33(dd，J＝8.8，2.2Hz，1H)，7.37-7.47(m，3H)，7.52(t，J＝8.8Hz，1H)，7.84(s，1H)，7.96(dd，J＝8.8，5.5Hz，2H)，9.36(s，1H).

Compound No. 113: (360MHz, CDCl)₃)ppm 2.50(s，3H)2.60(s，3H)3.91(s，3H)3.92(s，3H)6.93(s，1H)6.97(d，J＝2.20Hz，1H)7.08(dd，J＝8.42，2.20Hz，1H)7.26(t，J＝8.60Hz，2H)7.35(s，1H)7.70(d，J＝8.42Hz，1H)7.78(dd，J＝8.78，5.49Hz，2H)8.55(s，1H).

Compound No. 114: (360MHz, DMSO-d₆)ppm 2.33(s，3H)，3.85(s，3H)，3.89(s，3H)，3.97(s，3H)，7.21(d，J＝5.9Hz，1H)，7.45(d，J＝8.8Hz，1H)，7.48(dd，J＝8.1，1.8Hz，1H)，7.62(d，J＝1.8Hz，1H)，7.67(d，J＝8.1Hz，1H)，7.99(dd，J＝8.8，2.2Hz，1H)，8.03(d，J＝5.9Hz，1H)，8.05(d，J＝2.2Hz，1H)，8.66(s，1H)，9.40(s，1H).

Compound No. 115: (360MHz, CDCl)₃)ppm 2.30(s，3H)，3.81(s，3H)，4.10(s，3H)，6.54(d，J＝8.1Hz，1H)，6.70(dd，J＝8.4，2.2Hz，1H)，6.89(s，1H)，7.21-7.32(m，2H)，7.44(d，J＝8.1Hz，1H)，7.65(s，1H)，7.74(dd，J＝8.2，5.3Hz，2H)，7.94(s，1H)，8.15(dd，J＝12.8，2.2Hz，1H).

Compound No. 116: (360MHz, CDCl)₃)ppm 1.67(d，J＝7.0Hz，6H)，2.30(s，3H)，4.06(s，3H)，4.73(spt，J＝7.0Hz，1H)，6.57(d，J＝8.1Hz，1H)，6.87(s，1H)，7.21-7.30(m，4H)，7.40(d，J＝8.1Hz，1H)，7.57-7.68(m，3H)，7.89(s，1H)，8.14(dd，J＝6.9，1.8Hz，1H).

Compound No. 118: (360MHz, DMSO-d₆)ppm 3.75(s，3H)3.86(s，3H)4.39(d，J＝5.49Hz，2H)4.91(t，J＝5.49Hz，1H)6.94(dd，J＝8.42，2.20Hz，1H)7.09-7.26(m，6H)7.44(t，J＝8.78Hz，2H)7.69(s，1H)7.92(dd，J＝8.78，5.49Hz，2H)8.47(s，1H).

Compound No. 131: (360MHz, DMSO-d₆)ppm 1.60(d，J＝6.95Hz，6H)2.14(s，3H)3.94(s，3H)3.96(s，3H)4.69(spt，J＝6.95Hz，1H)6.95(d，J＝8.42Hz，1H)7.07(t，J＝1.10Hz，1H)7.18-7.29(m，2H)7.38(d，J＝8.05Hz，1H)7.41(d，J＝1.83Hz，1H)7.60(d，J＝8.42Hz，1H)7.65(d，J＝8.05Hz，1H)7.70(d，J＝1.10Hz，1H)8.21(d，J＝8.05Hz，1H)9.17(s，1H).

Compound No. 132: (360MHz, DMSO-d₆)ppm 2.15(s，3H)3.94(s，3H)3.97(s，3H)6.97(d，J＝8.42Hz，1H)7.08(s，1H)7.24(d，J＝8.05Hz，1H)7.31(t，J＝7.87Hz，1H)7.62(d，J＝8.42Hz，1H)7.71(d，J＝1.10Hz，1H)7.94(dt，J＝8.42，1.83Hz，1H)8.09-8.17(m，2H)8.28(d，J＝8.05Hz，1H)9.24(s，1H).

Compound No. 133: (360MHz, DMSO-d₆)ppm 2.15(s，3H)3.88(s，3H)3.97(s，3H)6.96(d，J＝8.42Hz，1H)7.08(s，1H)7.20(d，J＝7.68Hz，1H)7.28(t，J＝8.05，7.68Hz，1H)7.56-7.67(m，2H)7.71(s，1H)7.96(ddd，J＝8.42，4.76，2.20Hz，1H)8.19-8.30(m，2H)9.20(s，1H).

Compound No. 135: (360MHz, CDCl)₃)ppm 2.49(s，3H)2.63(s，3H)3.83(s，3H)3.98(s，3H)4.02(s，3H)6.74(s，1H)7.14-7.24(m，2H)7.39(s，1H)7.54(d，J＝8.05Hz，1H)7.59(d，J＝8.78Hz，1H)7.73(s，1H)8.47(d，J＝1.46Hz，1H)8.51(s，1H).

Compound No. 136: (360MHz, CDCl)₃)ppm 2.31(s，3H)2.65(s，3H)3.83(s，3H)4.02(s，3H)6.76(s，1H)6.93(s，1H)7.20(dd，J＝8.23，1.65Hz，1H)7.26(t，J＝9.15，7.68Hz，1H)7.38(d，J＝1.83Hz，1H)7.46(dd，J＝8.78，2.20Hz，1H)7.54(d，J＝8.05Hz，1H)7.67(s，1H)7.79(s，1H)8.34(dd，J＝13.72，2.38Hz，1H).

Compound No. 142: (360MHz, CDCl)₃)ppm 2.31(s，3H)2.64(s，3H)3.05(s，6H)3.81(s，3H)6.76(s，1H)6.89(dd，J＝8.42，2.56Hz，1H)6.93(s，1H)6.96(d，J＝7.32Hz，1H)7.05(s，1H)7.25(t，J＝8.42Hz，1H)7.39(t，J＝7.87Hz，1H)7.46(dd，J＝8.78，1.83Hz，1H)7.66(s，1H)7.82(s，1H)8.34(dd，J＝13.90，2.20Hz，1H).

Compound No. 150: (360MHz, CDCl)₃)ppm 2.30(s，3H)2.65(s，3H)3.81(s，3H)3.95(s，3H)6.79(s，1H)6.90(s，1H)7.27(t，J＝8.42Hz，2H)7.55(d，J＝8.05Hz，1H)7.66(s，1H)7.76(dd，J＝8.42，5.12Hz，2H)8.27(s，1H)8.45(d，J＝8.42Hz，1H).

Compound No. 160: (360MHz, CDCl)₃)ppm 2.30(s，3H)3.80(s，3H)3.92(s，3H)4.09(s，3H)6.48(d，J＝1.46Hz，1H)6.57(d，J＝8.42Hz，1H)6.88(s，1H)7.24(t，J＝8.78Hz，2H)7.41(d，J＝8.42Hz，1H)7.64(s，1H)7.73(dd，J＝8.78，5.49Hz，2H)7.88(s，1H)7.96(d，J＝1.46Hz，1H).

Compound No. 161: (360MHz, DMSO-d₆)ppm 2.33(s，3H)3.86(s，3H)3.99(s，3H)6.96(d，J＝8.42Hz，1H)7.22(d，1H)7.27(t，J＝8.05Hz，1H)7.44(t，J＝8.78Hz，2H)7.77(d，J＝8.42Hz，1H)7.94(dd，J＝8.78，5.49Hz，2H)8.20(d，J＝7.68Hz，1H)8.68(s，1H)9.30(s，1H).

Compound No. 162: (360MHz, DMSO-d₆)ppm 1.60(d，J＝6.95Hz，6H)2.33(s，3H)3.99(s，3H)4.64(spt，J＝6.95Hz，1H)6.96(d，J＝8.42Hz，1H)7.23(t，J＝8.23Hz，1H)7.34-7.50(m，3H)7.67-7.80(m，3H)8.19(d，J＝7.68Hz，1H)8.68(s，1H)9.27(s，1H).

Compound No. 164: (360MHz, CDCl)₃)ppm 2.49(s，3H)2.63(s，3H)3.81(s，3H)3.98(s，3H)6.74(s，1H)7.20(dd，J＝8.78，2.20Hz，1H)7.26(t，J＝8.78Hz，2H)7.59(d，J＝8.42Hz，1H)7.69-7.79(m，3H)8.44(d，J＝2.20Hz，1H)8.51(s，1H).

Compound No. 165: (360MHz, DMSO-d₆)ppm 2.35(s，3H)3.97(s，3H)3.99(s，3H)7.00(d，J＝8.42Hz，1H)7.24-7.49(m，2H)7.53-7.77(m，4H)7.85(d，J＝8.78Hz，1H)8.32(dd，J＝6.95，2.20Hz，1H)9.33(d，J＝1.46Hz，1H)9.82(br.s，1H)14.91(br.s，1H).

Compound No. 167: (360MHz, DMSO-d₆)ppm 2.35(s，3H)4.00(s，6H)7.01(d，J＝8.42Hz，1H)7.47-7.57(m，2H)7.71(s，1H)7.89(d，J＝8.42Hz，1H)7.95(t，J＝7.68Hz，1H)8.10(d，J＝8.05Hz，1H)8.30(d，J＝8.05Hz，1H)8.36(s，1H)8.44(dd，J＝6.22，2.20Hz，1H)9.34(d，J＝1.46Hz，1H)10.18(br.s，1H)15.04(br.s，1H).

Compound No. 170: (360MHz, DMSO-d₆)ppm 2.35(s，3H)3.77(s，3H)3.98(s，3H)6.99(d，J＝8.42Hz，1H)7.23-7.38(m，1H)7.41-7.51(m，1H)7.60-8.01(m，6H)8.35(dd，J＝7.32，1.46Hz，1H)9.34(d，J＝1.46Hz，1H)9.97(br.s，1H)15.02(br.s，1H).

Compound No. 184: (360MHz, DMSO-d₆)ppm 2.36(s，3H)4.01(s，3H)4.02(s，3H)4.05(s，3H)7.04(d，J＝8.42Hz，1H)7.52-7.66(m，4H)7.72(s，1H)7.86(d，J＝8.05Hz，1H)7.92(d，J＝8.42Hz，1H)8.56(d，J＝6.22Hz，1H)9.36(d，J＝1.46Hz，1H)10.49(br.s，1H)15.13(br.s，1H).

Compound No. 186: (360MHz, DMSO-d₆)ppm 2.35(d，J＝0.73Hz，3H)3.89(s，6H)4.00(s，3H)4.04(s，3H)6.88(t，J＝1.83Hz，1H)7.03(d，J＝8.42Hz，1H)7.17(d，J＝1.83Hz，2H)7.56(br.s，2H)7.72(t，J＝0.73Hz，1H)7.91(d，J＝8.42Hz，1H)8.52(br.s，1H)9.35(d，J＝1.83Hz，1H)10.46(br.s，1H)15.01(br.s，1H).

Compound No. 201: (360MHz, CDCl)₃)ppm 2.31(s，3H)3.96(s，3H)4.11(s，3H)6.63(d，J＝8.05Hz，1H)6.90(t，J＝1.10Hz，1H)7.28(t，J＝8.60Hz，2H)7.50(d，J＝8.05Hz，1H)7.67(d，J＝1.10Hz，1H)7.81(dd，J＝8.96，5.31Hz，2H)8.10(s，1H)8.22(d，J＝5.85Hz，1H)8.32(d，J＝5.85Hz，1H).

Compound No. 202: (360MHz, CDCl)₃)ppm 2.30(s，3H)3.88(s，3H)4.02(s，3H)4.11(s，3H)6.61(d，J＝8.05Hz，1H)6.89(t，J＝1.10Hz，1H)7.25(t，J＝8.42Hz，2H)7.48(d，J＝8.05Hz，1H)7.63-7.69(m，2H)7.77(dd，J＝8.78，5.49Hz，2H)7.96(s，1H).

Compound No. 203: (360MHz, CDCl)₃)ppm 2.31(d，J＝0.73Hz，3H)2.67(s，3H)3.93(s，3H)4.12(s，3H)6.62(d，J＝8.05Hz，1H)6.90(t，J＝1.10Hz，1H)7.26(t，J＝8.78Hz，2H)7.49(d，J＝8.05Hz，1H)7.67(d，J＝1.10Hz，1H)7.79(dd，J＝8.78，5.12Hz，2H)8.02(s，1H)8.14(s，1H).

Compound No. 207: (360MHz, CDCl)₃)ppm 0.95-1.03(m，2H)1.06-1.12(m，2H)2.01-2.13(m，1H)2.32(s，3H)3.87(s，3H)6.94-6.98(m，2H)7.15(dd，J＝8.78，2.20Hz，1H)7.19-7.29(m，3H)7.30-7.38(m，2H)7.70(t，J＝1.46Hz，1H)7.77(dd，J＝8.78，5.12Hz，2H).

Compound No. 209: (360MHz, CDCl)₃)ppm 2.48(s，3H)2.69(s，3H)2.89(s，6H)3.98(s，3H)7.04(s，1H)7.14(s，1H)7.21-7.34(m，5H)7.43(t，J＝8.60Hz，1H)7.71(dd，J＝8.42，5.12Hz，2H)9.04(s，1H)11.34(s，1H)

Compound No. 210: (360MHz, DMSO-d₆)ppm 2.35(s，3H)3.97(s，3H)3.98(s，3H)7.00(d，J＝8.78Hz，1H)7.50(br.s，2H)7.58(t，J＝8.78Hz，2H)7.71(s，1H)7.88(d，J＝8.42Hz，1H)8.05(dd，J＝8.23，5.67Hz，2H)8.40(br.s，1H)9.33(d，J＝1.46Hz，1H)10.19(br.s，1H)14.89(br.s，1H).

Compound No. 211: (360MHz, DMSO-d₆)ppm 2.38(s，3H)2.59(s，3H)3.89(s，3H)7.33(br.s，1H)7.49(t，J＝8.78Hz，2H)7.73(t.J＝8.42Hz，1H)7.80-7.90(m，2H)7.96(dd，J＝8，78，5.49Hz，2H)8.25(br.s，1H)9.49(s，1H)10.48(br.s，1H).

Pharmacology of

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

A1) Method 1

Selection was performed using SKNBE2 cells carrying APP 695-wild type, grown in Dulbecco's modified Eagle Medium/nutrient mixture F-12(DMEM/NUT-mix F-12) (HAM) supplied by Gibco (Cat. No. 31330-38) containing 5% serum/Fe supplemented with 1% non-essential amino acids. The cells were grown to juxtapose.

With Citron et al (1997) Nature Medicine 3: 67 for screening. Briefly, about 10 days before the addition of the compound⁵Cells/ml, cells were seeded in 96-well plates. The compounds were added to cells in Ultraculture (Lonza, BE12-725F) supplemented with 1% glutamine (Invitrogen, 25030-024) for 18 hours. A β 42 and a β total in the medium were determined by a double sandwich ELISA. The toxicity of the compounds was determined by WST-1 cell proliferation reagent (Roche, 1644807) according to the manufacturer's protocol.

To quantify the amount of a β 42 in the cell supernatants, a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Innotest) was usedBeta-amyloid protein_(1-42)Innogenetics n.v., Ghent, Belgium). A β 42ELISA was performed essentially according to the manufacturer's protocol. Briefly, a standard solution (synthetic A β 1-42 dilution) was prepared in polypropylene Eppendorf and the final concentration 8000 was reduced to 3.9pg/ml (1/2 dilution step). Samples, standards and blanks (100 μ l) were added to anti- Α β 42-coated plates (C-terminus of the capture antibody selectively recognizing the antigen) provided by the kit. The plate was incubated at 25 ℃ for 3h to allow antibody-amyloid complex formation. After completion of the incubation and subsequent washing steps, a selective anti- Α β -antibody conjugate (biotinylated 3D6) was added and incubated for at least 1 hour to allow antibody-amyloid-antibody-complex formation. After incubation and appropriate washing steps, pronged guanidine (Streptavidine) -peroxidase-conjugate was added, and after 30 minutes, a3, 3 ', 5, 5' -Tetramethylbenzidine (TMB)/peroxide mixture was added, resulting in conversion of the substrate to a colored product. The reaction is stopped by addition of sulfuric acid (0.9N), by photometry withColor intensity was measured with an ELISA-plate reader with a 450nm filter.

To quantify the amount of Α β total in the cell supernatant, the samples and the standard solution were added to the 6E10 coated plates. The plate was incubated at 4 ℃ overnight to allow antibody-amyloid complexes to form. After this incubation and the subsequent washing step, a selective anti- Α β -antibody conjugate (biotinylated 4G8) was added and incubated for at least 1 hour to allow antibody-amyloid-antibody-complex formation. After incubation and appropriate washing steps, pronguanidine (Streptavidine) -peroxidase-conjugate was added, and after 30 minutes, Quanta Blu fluorescent luminescent peroxidase substrate was added according to the manufacturer's instructions (Pierce corp.

To obtain the values reported in table 3a, sigmoidal dose-response curves were analyzed by computerized curve fitting and the percent inhibition was plotted against compound concentration. Determination of IC Using the 4 parameter equation in X1fit (model 205)₅₀. The top and bottom of the curve are fixed at 100 and 0, respectively, and the slope of the ramp is fixed at 1. IC (integrated circuit)₅₀Represents the concentration of compound required to inhibit the biological effect by 50% (in this context, it is the concentration at which the level of a β peptide is reduced by 50%).

IC₅₀The values are shown in table 3 a:

to obtain the values reported in table 3b, data were calculated as a percentage of the maximum amount of amyloid β 42 measured in the absence of test compound. Sigmoidal dose-response curves were analyzed by nonlinear regression analysis and plotted against the percent control versus the log concentration of compound. Determination of IC by 4-parameter equation₅₀. The values reported in Table 3b are the average IC₅₀The value is obtained.

IC₅₀The values are shown in table 3 b:

A2) method 2

Selection was performed using SKNBE2 cells harboring the APP 695-wild type, grown in Dulbecco's modified Eagle Medium/nutrient mixture F-12 (DMEM/NUT-mixture-F-12) (HAM) supplied by Invitrogen (Cat. No. 10371-029) containing 5% serum/Fe supplemented with 1% non-essential amino acids, 1-glutamine 2mM, Hepes 15mM, penicillin 50U/ml (units/ml) and streptomycin 50. mu.g/ml. The cells were allowed to grow until they were nearly confluent.

With a modified Citron et al (1997) Nature Medicine 3: 67 for screening. In short, press 10⁴Cells/well, cells were seeded in 384-well plates containing Ultrafiltration (Lonza, BE12-725F) supplemented with 1% glutamine (Invitrogen, 25030-. The cell/chemoattractant mixture was incubated at 37 ℃ with 5% CO₂The mixture was incubated overnight. The following day, the media were analyzed for a β 42 and a β total by two sandwich immunoassays.

The concentrations of Α β total and Α β 42 in the cell supernatants were quantified using the Aphalisa technique (Perkin Elmer). Alphalisa is a sandwich assay using biotinylated antibody linked to streptavidin-coated donor beads, and the antibody is conjugated to acceptor beads. The beads are brought into proximity with each other in the presence of the antigen. Excitation of the donor beads stimulates the release of singlet oxygen molecules, which trigger an energy transfer cascade in the acceptor beads, resulting in light emission. To quantify the amount of a β 42 in the cell supernatant, a monoclonal antibody specific for the C-terminus of a β 42 (JRF/cA β 42/26) was coupled to acceptor beads and biotinylated antibody specific for the N-terminus of a β (JRF/a β N/25) was reacted with donor beads. To quantify the amount of a β total in the cell supernatants, monoclonal antibodies specific for the N-terminus of a β (JRF/a β N/25) were coupled to acceptor beads, and biotinylated antibodies specific for the middle region of a β (biotinylated 4G8) were reacted with donor beads.

To obtain the values reported in table 3c, data were calculated as a percentage of the maximum amount of amyloid β 42 measured in the absence of test compound. Sigmoidal dose-response curves were analyzed by nonlinear regression analysis and plotted against the percent control versus the log concentration of compound. Determination of IC by 4-parameter equation₅₀。

IC₅₀The values are shown in table 3 c:

B) demonstration of in vivo efficacy

B1) Method 1

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

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

To determine whether a β 42-lowering drugs administered transiently reduced a β 42 levels in vivo, non-transgenic rodents, such as mice or rats, can be used. Alternatively, 2-3 month old Tg2576 mice expressing APP695 containing the "Swedish" variant, or a transgenic mouse model developed by Fred Van Leuven, doctor Belgium and colleagues, which neurons specifically express the clinically mutated human amyloid precursor protein [ V717I ] (Moechars et al 1999J. biol. chem.274, 6483) may be used. A β levels were high in the brain of the mouse transgenic but a β deposition could not be measured. At about 6-8 months of age, transgenic mice began to show spontaneous, progressive accumulation of β -amyloid (a β) in the brain, eventually leading to the formation of amyloid plaques in the brain's lower foot, hippocampus and cortex. Animals treated with a β 42-lowering drug are examined and brain levels of soluble a β 42 and total a β are quantified by standard techniques, such as ELISA, as compared to those animals that are untreated or treated with vehicle. The treatment period can be from hours (h) to days, and once the time course of onset is determined, the treatment period can be adjusted based on the results of a β 42 reduction.

A typical protocol for measuring a β 42 reduction in vivo is shown, but it is only one of a number of variants that can be used to optimize measurable a β levels. For example, at 20% CaptisolThe compound of reducing A beta 42 is prepared from (sulfobutyl ether of beta-cyclodextrin) aqueous solution or 20% hydroxypropyl beta cyclodextrin. The a β 42-lowering drug is administered to overnight fasted animals in a single oral dose or by any acceptable route of administration. After 4 hours, animals were sacrificed and analyzed for Α β 42 levels.

Blood is collected by cutting off the head, and the collected blood is put into a collection test tube processed by EDTA. Blood was centrifuged at 1900g for 10 minutes (min) at 4 ℃, plasma recovered, snap frozen for subsequent analysis. The brain was separated from the cranium and hindbrain. The cerebellum was removed and the left and right hemispheres were separated. The left hemisphere was stored at-18 ℃ for quantitative analysis of test compound levels. The right hemisphere was washed with Phosphate Buffered Saline (PBS) buffer, immediately frozen on dry ice, stored at-80 ℃ until homogenized for biochemical assays.

Mouse brains are resuspended in 10 volumes of 0.4% DEA (diethylamine)/50 mM NaCl pH 10 (for non-transgenic animals) or 0.1% Tris Buffered Saline (TBS) (for transgenic animals) 3- [ (3-chloroamidopropyl) -dimethyl-amino (amonio) ] -1-propanesulfonate (CHAPS) in 10 volumes with 10 volumes of 0.4% DEA per gram of tissue, e.g.in 0.158g of brain with 1.58ml of 0.4% DEA (diethylamine) added to 0.158g of brain. All samples were sonicated on ice for 30 seconds at 20% power output (pulse mode). The homogenate was centrifuged at 221.300x g for 50 minutes. The resulting high-speed supernatant is then transferred to a new tube, optionally for further purification before the next step. A portion of the supernatant was neutralized with 10% 0.5M Tris-HCl, and the solution was used to quantify A.beta.total.

The resulting supernatant was purified using a Water Oasis HLB reverse phase column (Waters corp., Milford, MA), and nonspecific immune active substances were removed from the brain lysate, followed by a β detection. Using a vacuum manifold, all solutions were passed through the column at a rate of about 1 ml/min, so the vacuum pressure was adjusted accordingly throughout the process. The column was pretreated with 1ml 100% MeOH, then with 1ml H₂And (4) balancing the oxygen. The unneutralized brain lysate was loaded on the column. The loaded sample was then washed twice, with the first wash being performed with 1ml of 5% MeOH and the second wash being performed with 1ml of 30% MeOH. Finally, with a 2% NH content₄OH in 90% MeOH eluted a β from the column into 100x30mm glass tubes. The eluate is then transferred to a 1.5ml tube and concentrated in a high temperature high speed evaporator (speed-vac concentrator) at 70 ℃ for about 1.5-2 h. The concentrated a β was then resuspended in ultracurture universal serum-free medium (Cambrex corp., walker, MD) and protease inhibitors were added.

To quantify the Abeta 4 of the soluble fraction of brain homogenates2, using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (e.g., Innotest)Beta-amyloid protein (1-42), innogenetics n.v., Ghent, Belgium). A β 42ELISA was performed using only the plates provided with the kit. Briefly, standard solutions (synthetic A.beta.1-42 dilutions) were prepared in 1.5ml Eppendorf tubes containing Ultrafiltration, at a final concentration of 25000-1.5 pg/ml. Samples, standards and blanks (60 μ l) were added to anti- Α β 42-coated plates (capture antibody selectively recognising the C-terminus of the antigen). The plate was incubated at 4 ℃ overnight to allow antibody-amyloid complexes to form. After incubation and subsequent washing steps, a selective anti- Α β -antibody conjugate (biotinylated detection antibody, e.g. biotinylated 4G8(Covance Research Products, Dedham, MA) is added, incubated for at least 1 hour, to allow antibody-amyloid-antibody-complex formation, after incubation and appropriate washing steps, streptavidin-peroxidase-conjugate is added, after 50 minutes, Quanta Blu fluorogenic peroxidase substrate (Pierce corp., Rockford, Il) is added, kinetic readings are taken every 5 minutes for 30 minutes (excitation wavelength 320 nm/emission wavelength 420nm) to quantify the amount of Α β total in the soluble fraction of the brain homogenate, samples and solution are added to a JRF/rA β/2 coated plate, the plate is incubated at 4 ℃ overnight to allow antibody-amyloid complex formation, then ELISA is performed, for A beta 42 detection.

In this model, a reduction in a β 42 of at least 20% compared to untreated animals would be advantageous.

The results are shown in table 4 a:

B2) method 2

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

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

To determine whether a β 42-lowering drugs administered transiently reduced a β 42 levels in vivo, non-transgenic rodents, such as mice or rats, can be used. Animals treated with a β 42-lowering drug are examined and brain levels of soluble a β 42 and total a β are quantified by standard techniques, such as ELISA, as compared to those animals that are untreated or treated with vehicle. The treatment period can be from hours (h) to days, and once the time course of onset is determined, the treatment period can be adjusted based on the results of a β 42 reduction.

A typical protocol for measuring a β 42 reduction in vivo is shown, but it is only one of a number of variants that can be used to optimize measurable a β levels. For example, at 20% CaptisolThe compound of reducing A beta 42 is prepared from (sulfobutyl ether of beta-cyclodextrin) aqueous solution or 20% hydroxypropyl beta cyclodextrin. The a β 42-lowering drug is administered to overnight fasted animals in a single oral dose or by any acceptable route of administration. After 4 hours, animals were sacrificed and analyzed for Α β 42 levels.

Blood is collected by cutting off the head, and the collected blood is put into a collection test tube processed by EDTA. Blood was centrifuged at 1900g for 10 minutes (min) at 4 ℃, plasma recovered, snap frozen for subsequent analysis. The brain was separated from the cranium and hindbrain. The cerebellum was removed and the left and right hemispheres were separated. The left hemisphere was stored at-18 ℃ for quantitative analysis of test compound levels. The right hemisphere was washed with Phosphate Buffered Saline (PBS) buffer, immediately frozen on dry ice, stored at-80 ℃ until homogenized for biochemical assays.

The mouse brains from non-transgenic animals are resuspended in 8 volumes of 0.4% DEA (diethylamine)/50 mM NaCl and contain protease inhibitors (Roche-11873580001 or 04693159001) per gram of tissue, e.g. for 0.158g brain, 1.264ml of 0.4% DEA is added. All samples were homogenized at 6m/s for 20 seconds in a FastPrep-24 system (MP Biomedicals) using lysis medium D (MPBio # 6913-. The homogenate was centrifuged at 221.300Xg for 50 minutes. The resulting high-speed supernatant was then transferred to a new microcentrifuge tube. 9 parts of the supernatant were neutralized with 1 part of 0.5M Tris-HCl pH 6.8 and used to quantify A β total and A β 42.

To quantify the amount of a β total and a β 42 in the brain homogenate soluble fraction, an enzyme-linked immunosorbent assay was used. Briefly, standard solutions (dilutions of synthetic A β 1-40 and A β 1-42, Bachem) were prepared in serum-free medium in 1.5ml microcentrifuge tubes to final concentrations ranging between 10000 and 0.3 pg/ml. Samples and standards were incubated with HRPO-labeled N-terminal antibody for A β 42 detection and biotinylated mid-region antibody 4G8 for A β total 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 for A.beta.42 detection, antibody JRF/cA. beta. 42/26 and the N-terminus of A.beta.for A.beta.total detection, antibody JRF/r A. beta./2). The plates were incubated overnight at 4 ℃ to allow formation of antibody-amyloid complexes. After this incubation and subsequent washing step, the ELISA for Α β 42 quantification was performed by adding Quanta Blu fluorescent peroxidase substrate according to the manufacturer's instructions (Pierce corp., Rockford, ii). The reading is carried out after 10-15 minutes (excitation wavelength 320 nm/emission wavelength 420 nm).

For Α β total detection, pronged guanidine-peroxidase-conjugate was added, after 60 minutes through an additional washing step and Quanta Blu fluorescent peroxidase substrate was added according to the manufacturer's instructions (Pierce corp., Rockford, ii). The reading is carried out after 10-15 minutes (excitation wavelength 320 nm/emission wavelength 420 nm).

In this model, a reduction in a β 42 of at least 20% compared to untreated animals would be advantageous.

The results are shown in table 4 b:

C) to pairγInfluence of the Notch-processing Activity of the secretase Complex

Notch cell-free assay

The Notch transmembrane domain was dissociated by gamma secretase to release the Notch intracellular C-terminal domain (NICD). Notch is a signaling protein that plays a key role in development, and therefore, compounds that do not show an effect on the Notch-processing activity of the γ -secretase complex are preferable.

To monitor the effect of compounds on NICD production, recombinant Notch substrates were prepared (N99). A Notch substrate consisting of a mouse Notch fragment (V1711-E1809), N-terminal methionine and C-terminal FLAG sequence (dydddk) was expressed in escherichia coli (e.coli) and purified on a column containing anti-FLAG M2 affinity matrix.

A typical Notch cell-free assay consists of 0.3-0.5. mu.M Notch substrate, γ -secretase-rich preparation, and 1. mu.M test compound (compounds 8, 15, 92, 108, 114, and 130 of the invention). The control comprises a gamma-secretase inhibitor (GSI), e.g. (2S) -N- [2- (3, 5-difluorophenyl) acetyl]-L-alanyl-2-phenyl-glycine 1, 1-dimethylethyl ester (DAPT) or (2S) -2-hydroxy-3-methyl-N- [ (1S) -1-methyl-2-oxo-2- [ [ (1S) -2, 3, 4, 5-tetrahydro-3-methyl-2-oxo-1H-3-benzazepine-1-yl]Amino group]Ethyl radical]-butyramide (Semagacestat) and DMSO at a final concentration of 1%. Recombinant Notch substrate was treated with 17. mu.M DTT (1, 4)Dithiothreitol) and 0.02% SDS (sodium dodecyl sulfate) and heated at 65 ℃ for 10 minutes. The substrate, gamma-secretase and compound/DMSO mixture was incubated at 37 ℃ for 6-22 hours (h). Incubation for 6 hours was sufficient to obtain the maximum amount of NICD, and the dissociated product was kept stable for another 16 h. The reaction product was treated for SDS PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and Western blotting. The blot was probed with anti-Flag M2 antibody, LI-COR infrared secondary antibody, in sequence, and imaged with the Odyssey infrared imaging System (LI-COR)Biosciences).

None of the test compounds (compounds 8, 15, 92, 108, 114 and 130) inhibited C99 dissociation by gamma-secretase in the cell-free Notch assay, whereas production of NICD was blocked by control GSI (DAPT or semagastatt). Thus, it was demonstrated that compounds 8, 15, 92, 108, 114 and 130 showed no effect on the Notch-processing activity of the γ -secretase-complex (production of NICD).

Notch cell-based assay

The Notch cell-based assay is based on the interaction of Notch with its ligand in a co-culture system and monitoring of NICD production using the Dual-Glo luciferase assay System (Promega). Two stable cell lines, N2-CHO and DL-CHO, were created to express full-length mouse Notch2 and delta, respectively. Mouse Notch-expressing cells were also transfected with two plasmids, pTP1-Luc and pCMV-Rluc, to express firefly and Renilla luciferase. Firefly luciferase is expressed under the control of the TP1 promoter in response to NICD activation. The CMV promoter that drives expression of Renilla luciferase does not respond to NICD activation and is therefore used as a control for transfection efficiency and compound toxicity.

One day before transfection, at 1X10⁵N2-CHO cells were seeded in 24-well plates per well. The following day, cells were double transfected with 3. mu.g/well pTP1-Luc (expressing firefly luciferase) and 0.3 ng/well pCMV-RLuc (expressing Renilla luciferase). After 6h incubation, the transfected N2-CHO cells were washed and DL-CHO cells were added (2x10⁵Cells/well).

The compounds were premixed with the DL-CHO cell suspension in the 5-point curve. Typically, compounds (3. mu.M-0.3 nM) were treated in duplicate, in DMSO, in serial 1: 10 dilutions. The final concentration of DMSO in a given culture was 1%. Controls included untransfected cells and transfected cells treated with GSI or DMSO alone. Luciferase assays were performed after 16h co-culture and compound treatment.

Luciferase assays were performed as per the manufacturer's instructions. Briefly, cells were washed with PBS (phosphate buffered saline), lysed with Passive lysis buffer (Promega), and incubated for 20 minutes at room temperature. The lysate was mixed with the Dual-Glo luciferase reagent and the firefly luciferase activity was measured by reading the luminescence signal in an EnVision 2101 Multilabel plate reader. Dual-Glo Stop & Glo reagents were then added to each well and Renilla luciferase signal was measured.

The results of the Notch cell-based assay are consistent with those of the cell-free NICD assay. Average IC of DAPT and Semagacestat from Notch cell-based assays based on luciferase assay readout₅₀Values were 45nM and 40nM, respectively, whereas no inhibition was found with compounds 15, 92, 108, 114 and 130 of the invention.

D. Composition examples

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

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

1. tablet formulation

2. Suspension

An aqueous suspension for oral administration is prepared containing 1-5mg of active ingredient, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol per ml, and water to 1 ml.

3. Injection preparation

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

4. Ointment formulation

In this example, the active ingredient may be replaced by the same amount of any compound of 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. It is therefore evident that the described invention may be modified in a number of ways by those skilled in the art.

Claims (15)

1. A compound of formula (I) or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof:

wherein:

R¹is hydrogen, cyano, CF₃Halogen or C optionally substituted with one or more substituents_1-4Alkyl radicals, said substitutionEach radical is independently selected from hydroxy and C_1-4An alkoxy group;

R²is hydrogen, C_1-4Alkyl or halo;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, morpholinyl, pyrrolidinyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from halogen, cyano, phenyl and C_3-7Cycloalkyl and C_1-4An alkoxy group.

2. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH or N;

provided that Y is¹、Y²And Y³Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen or C_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

3. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is hydrogen, C_1-4Alkyl, cyano, CF₃Or a halo group;

R²is hydrogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or halo;

A¹is CR⁶Or N;

R⁶is hydrogen, halo or C_1-4An alkoxy group;

A²、A³and A⁴Each independently CH, CF or N;

with the proviso that A¹、A²、A³And A⁴No more than two of which are N;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH;

R⁴is hydrogen, halo, C_1-4Alkoxy, cyano, or C optionally substituted with one or more halo substituents_1-4An alkyl group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl, C_3-7Cycloalkyloxy and C_3-7A cycloalkyl group; c_3-7Cycloalkyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, O-Ar, NR⁷R⁸、C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar、S-Ar、NCH₃-Ar or NH-Ar;

wherein piperidinyl, morpholinyl and pyrrolidinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each one ofAr is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸Morpholinyl radical, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group; or is selected from pyridyl, pyrimidyl, or,Azolyl, furyl, thienyl, pyrazolyl, iso-Oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,5-or 6-membered heteroaryl of oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, C_1-4Alkyl and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁷Independently selected from hydrogen or C_1-4An alkyl group;

each R⁸Independently selected from hydrogen or C_1-4An alkyl group;

z is O or NR⁹；

R⁹Is hydrogen or C optionally substituted with one or more substituents_1-6Alkyl, each of said substituents being independently selected from halo, phenyl and C_1-4An alkoxy group.

4. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is hydrogen, cyano, halo or C optionally substituted with one or more hydroxy groups_1-4An alkyl group;

R⁵is hydrogen;

Y¹is CH or N;

Y²is CR⁴Or N;

Y³is CH;

provided that Y is¹And Y²Only one of which may represent N;

R⁴is hydrogen, halo, C_1-4Alkoxy radical, C_3-7Cycloalkyl radical, C_2-4Alkenyl or C optionally substituted with one or more substituents_1-4Alkyl, each of said substituents being independently selected from halo and C_1-4An alkoxy group;

R³is C substituted with one or more halo substituents_2-6An alkyl group; c optionally substituted with one or more substituents_1-6Alkyl, the substituents are respectively and independently selected from piperidyl, Ar and C_1-6Alkoxy, tetrahydropyranyl and C_3-7A cycloalkyl group; c substituted with one or more phenyl substituents_3-7Cycloalkyl, said phenyl substituent being optionally substituted with one or more halo substituents; c_3-7Cycloalkyl, piperidinyl, morpholinyl, tetrahydropyranyl, O-Ar, C_1-6Alkoxy radical, C_1-6Alkylthio, Ar, CH₂-O-Ar, NH-Ar or 1, 6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein piperidinyl and morpholinyl may each be substituted with one or more substituents each independently selected from C_1-4Alkyl radical, C_1-4Alkylcarbonyl, halo and C_1-4An alkoxycarbonyl group;

wherein each Ar is independently phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, cyano, NR⁷R⁸、C_1-4Alkyl, C substituted with one or more halo substituents_1-4Alkoxy and C substituted with one or more halo substituents_1-4An alkyl group; or a 5-or 6-membered heteroaryl selected from pyridyl and thienyl; wherein the 5-or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halo and C substituted with one or more halo substituents_1-4An alkyl group;

each R⁸Is independently selected fromC_1-4Alkyl or C_1-4An alkylcarbonyl group.

5. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is methyl;

R²is hydrogen.

6. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is C_1-4An alkyl group;

R²is hydrogen;

x is CH or N;

A¹is CR⁶；

R⁶Is hydrogen, methoxy or halo;

A²is CH or N;

A³and A⁴Is CH;

Y¹is CH or N; y is²Is CR⁴；Y³Is CH;

R⁴is hydrogen, halo or C_1-4An alkyl group;

R³is phenyl optionally substituted with one or more substituents each independently selected from halo, C_1-4Alkoxy, NR⁷R⁸And C substituted with one or more halo substituents_1-4An alkyl group;

R⁷is hydrogen;

R⁸is C_1-4An alkylcarbonyl group;

z is NR⁹；

R⁹Is C_1-6An alkyl group.

7. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is C_1-4An alkyl group;

R²is hydrogen;

x is CH;

A¹is CR⁶；

R⁶Is F or methoxy;

A²is N or CH;

A³and A⁴Is CH;

Y¹is CH or N;

Y²is CR⁴；

Y³Is CH;

R⁴is hydrogen or methyl;

R³is phenyl optionally substituted with one or more substituents each independently selected from halo and methoxy;

z is NR⁹；

R⁹Is C_1-6An alkyl group.

8. A compound according to claim 1, or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof, wherein:

R¹is C_1-4An alkyl group;

R²is hydrogen;

x is CH;

A¹is COCH₃；A²Is N; a. the³Is CH; a. the⁴Is CH;

Y¹、Y²and Y³Is CH;

R³is phenyl optionally substituted with one or more halo substituents;

z is NR⁹；

R⁹Is C_1-6An alkyl group.

9. The compound of claim 1, wherein the compound is:

1) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine,

2) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine, bis-methanesulfonate,

3) n- [ 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) phenyl ] -2- (4-fluorophenyl) -1, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine dihydrochloride,

4)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

5)2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride,

6)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine dihydrochloride monohydrate,

7)2- (2, 3-difluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

8)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzoimidazol-4-amine dihydrochloride monohydrate,

9)2- (4-fluoro-3-methoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine,

10)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridinyl ] -1-methyl-1H-benzimidazol-4-amine dihydrochloride monohydrate, or

11)2- (3, 5-dimethoxyphenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

including any stereochemically isomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof.

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

2- (4-fluorophenyl) -N- [ 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -2-pyridyl ] -1-methyl-1H-benzimidazol-4-amine,

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, senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, 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 as defined in any one of claims 1 to 10 in the manufacture of a medicament for modulating the activity of gamma-secretase.