OA16570A

OA16570A - Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators.

Info

Publication number: OA16570A
Application number: OA1201100224
Authority: OA
Inventors: Henricus Jacobus Maria Gijsen; Adriana Ingrid Velter; Gregor James Macdonald; François Paul BISCHOFF; Tongfei Wu; Sven Franciscus Anna Van Brandt; Michel Surkyn; Mirko Zaja; Serge Maria Aloysius Pieters; Didier Jean-Claude Berthelot; Michel Anna Jozef De Cleyn; Daniel Oehlrich
Original assignee: Ortho-Mcneil-Janssen Pharmaceuticals, Inc.
Priority date: 2009-02-06
Filing date: 2010-02-02
Publication date: 2015-11-20

Abstract

The present invention is concerned with substituted bicyclic heterocyclic compounds of formula (I)

Description

NOVEL SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS

GAMMA SECRETASE MODULATORS

Field of the Invention

The présent invention is concemed with novel substituted bicyclic heterocyclic compounds useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingrédient as well as the use of said compounds as a médicament.

Background of the invention

Alzhcimcr's Discase (AD) is a progressive ncurodegcncrativc disorder marked by loss of memory, cognition, and behavioral stability. AD afflicts 6-10 % ofthe population over age 65 and up to 50 % over age 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. There is currently no effective treatment for AD. The total net cost related to AD in the U.S. cxceeds $100 billion annually.

AD does not have a simple etiology, however, it has been associated with certain risk factors including (1) age, (2) family history and (3) head trauma; other factors include environmental toxins and low levels of éducation. Spécifie neuropathological lésions in the limbîc and cérébral cortices include intracellular neurofîbrillary tangles consisting of hyperphosphorylated tau protein and the extracellular déposition of fibrillar aggregates of amyloîd beta peptides (amyloid plaques). The major component of amyloîd plaques are the amyloid beta (A-beta, Abeta or AB) peptides of various lengths. A variant thereof, which is the AB 1-42peptide (Abcta-42), is believed to bc the major causativc agent for amyloid formation. Another variant is the AB 1-40-peptide (Abeta-40). Amyloid beta is the proteolytic product of a prccursor protein, beta amyloid precursor protein (beta-APP or APP).

Familial, early onset autosomal dominant forms of AD have been linked to missense mutations in the β-amyloid precursor protein (β-ΑΡΡ or APP) and in the presenilin proteins 1 and 2. ln some patients, late onset forms of AD have been correlated with a spécifie allele of the apolipoprotein E (ApoE) genc, and, more recently, the findîng of a mutation in alpha2-macroglobulin, which may be linked to at least 30 % of the AD population. Despite this heterogeneity, ail forms of AD exhibit similar pathological findings. Genetic analysis has provided the best clues for a logical

-2therapcutic approach to AD. Ail mutations found to date, affect the quantitative or qualitative production ofthe amyloidogcnic peptides known as Abeta-peptides (Αβ), specifically Αβ42, and hâve given strong support to the amyloid cascade hypothesis of AD (Tanzi and Bcrtram, 2005, Cell 120, 545). The likely link between Αβ peptide génération and AD pathology emphasizes the need for a better understanding ofthe mechanisms of Αβ production and strongly warrants a therapeutic approach at modulating Αβ levels.

The release of Αβ peptides is modulated by at least two protcolytic actîvîties referred to as β- and y-secretase clcavage at the N-tcrminus (Mct-Asp bond) and the C-tcrminus (residues 37-42) of the Αβ peptide, respectively. In the sccretory pathway, there is cvidence that β-secretase cleaves first, leading to the sécrétion ofs-ΑΡΡβ (sp) and the rétention of a 11 kDa membrane-bound carboxy terminal fragment (CTF). The latter is believed to give risc to Αβ peptides following clcavage by y-sccrctasc. The amount ofthe longer isoform, A342, is selectively increased in patients carrying certain mutations in a particular protein (presenilin), and these mutations hâve been correlated with early-onset familial Alzheimer's disease. Therefore, AB42 is believed by many researchers to be the main culprit of the pathogenesis of Alzheimcr's disease.

It has now bccomc clear that the γ-secretasc activity cannot bc ascribcd to a single protein, but is in fact associated with an assembly of different proteins.

The gamma (y)-secretasc activity résides within a multiprotein complex containing at least four components: the presenilin (PS) heterodimer, nicastrin, aph-1 and pen-2. The PS heterodimer consists ofthe amino- and carboxyterminal PS fragments generated by endoproteolysis ofthe precursor protein. The two aspartates of the catalytic site arc at the interface of this heterodimer. It has rcccntly been suggested thaï nicastrin serves as a gamma-secretase-substrate receptor. The fonctions of the other members of gamma-secretase are unknown, but they arc ail required for activity (Stciner, 2004. Curr. Alzheimer Rcscarch 1(3): 175-181).

Thus, although the molecular mechanism of the second cleavage-step has remained elusive until now, the y-secrctasc-complcx has become one of the prime targets in the search for compounds for the treatment of Alzheimer’s disease.

Various strategies bave been proposed for targeting gamma-secretase in

Alzheimer’s disease, ranging from targeting the catalytic site dircctly, dcvcloping substrate-specific inhibitors and modulators of gamma-secretase activity (Marjaux et al., 2004. Drug Discovery Today: Therapeutic Strategies, Volume 1, 1-6). Accordingly, a varicty of compounds were described that hâve secrctascs as targets (Lamcr, 2004,

-3Secrctases as thcrapeutics targets in Alzheimcr’s disease: patents 2000 - 2004. Expert Opîn. Ther. Patents 14, 1403-1420).

Indccd, this finding was rcccntly supported by biochemical studies in which an effect of certain NSAlDs on γ-sccrctasc was shown (Wcggen et al (2001) Nature 414, 6860, 212 and WO 01/78721 and US 2002/0128319; Morihara et al (2002) 1. Ncurochem. 83, 1009; Eriksen (2003) J. Clin. Invest. 112,440). Potcntial limitations for the use of NSAlDs to prevent or treat AD arc their inhibition activity of COX enzymes, which eau lead to unwanted side effects, and their low CNS pénétration (Perctto et al., 2005, J. Med. Chem. 48, 5705-5720).

WO-2008/137139 relates to heterocyclic dérivatives and their use as gamma sccretase modulators.

WO-2005/115990 discloses cinnamidc compounds that are useful for the treatment of neurodegencratîve diseases caused by amyloid β proteins such as Alzheimcr’s disease, senile dementia, Down’s syndrome and amyloidosis.

WO-2004/110350 relates to aryl compounds and their use in modulating amyloid β.

WO-2007/131991 discloses imidazopyrazinc compounds as MAPKAPK5 inhibitors useful for the treatment of degenerative and inflammatory discases.

WO-2004/017963 relates to benzimidazoles as coagulation factor Xa inhibitors for the treatment of thromboembolie illnesscs.

There is a strong need for novel compounds which modulate γ-secretase activity thereby opening new avenues for the treatment of Alzhcîmcr's disease. It is an object of the présent invention to ovcrcomc or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. It is accordingly an object of the présent invention to provide such novel compounds.

Summary of the invention

It has been found that the compounds of the présent invention are useful as gamma sccretase modulators. The compounds according to the invention and the pharmaceutically acceptable compositions thereof, may bc useful in the treatment or prévention of Alzhcîmcr's disease.

The présent invention concerne novel compounds of Formula (I):

(D

-4and stereoisomeric forms thereof, wherein

Het¹ is a 5-membercd or 6-membercd aromatic heterocycle, having formula (a-1), (a-2), (a-3), (a-4) or (a-5):

(a-l) (a-3) (a-5) (a-2) (a-4)

J

R° is H or Ci^alkyl;

R¹ is H, Cualkyl or CMalkyloxyCi^alkyl;

R² is Cj^alky 1 ;

X is O or S;

G¹ is CH or N;

G² is CH, N or C substituted with Ci ^alkyl;

provided that G¹ and G² arc not simultaneously N;

G’is CH or N;

R^,Oa and R^l0b each independently are hydrogen or Ci^alkyl;

A* is CR³ or N; wherein R³ is H, halo or Ci-.ialkyloxy;

A², A³ and A⁴ cach independently are CH, CF or N; provided that maximum two of A¹, A², A³ and A⁴ are N;

Hot² is a 9-membcrcd bicyclic aromatic heterocycle, having formula (b-1) or (b-2):

Z¹ is CH or N;

Z² is CR⁴ or N;

Z³ is CH or N; provided that maximum one of Z¹, Z² and Z³ is N; Y¹ is CH or N;

Y² is CR^4h or N;

-5Y³ is CH or N; provided that maximum one of Y¹, Y² and Y³ is N;

R‘^,a is H; halo; CMalkyloxy; cyano; cycloC^alkyl; CMalkylcarbonyl; CMalkyloxycarbonyl; or Cualkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and amino;

R⁴¹⁵ is H; halo; CMalkyloxy; cyano; cycloCwalkyl; or CMalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and amino;

R⁵ is H; halo; cyano; CMalkyloxy; C2^alkenyl; or Ci^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy and halo;

R^fia is Cî-fialkyl substituted with one or more halo substituents; C^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting of piperidinyl, Ar, CMalkyloxy, tctrahydropyranyl, cycloC^alkyloxy, and cycloCî.ialkyl; cycloC^alkyl; CMalkylcarbonyl; tetrahydropyranyl; Ar; R⁸R⁹Ncarbonyl; or CFh-O-Ar;

R^fil’is CZcalkyl substituted with onc or more halo substituents; Cj^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, Ci^alkyloxy, tctrahydropyranyl, cycloCj^alkyloxy, and cycloCî.îalkyl; cycloCj^alkyl; cycloCî-7alkyl substituted with onc or more phenyl substituents optionally substituted with onc or more halo substituents; piperidinyl; morpholinyl; pyrrolidinyl; NR⁸R⁹; tetrahydropyranyl; O-Ar; Ci-ûalkyloxy; Ci-calkylthio; Ar; Œh-O-Ar; S-Ar; NCHj-Ar; orNH-Ar;

wherein each piperidinyl, morpholinyl, and pyrrolidinyl may optionally be substituted with onc or more substituents each independently selected from the group consisting of CMûlkyl, Cî^alkcnyl, CMalkylcarbonyl, halo, and CMalkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, NR⁸R⁹, morpholinyl, Ci^alkyl, and CMalkyl substituted with onc or more halo substituents; pyridinyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, CMalkyl, and CMalkyi substituted with onc or more halo substituents; oxazolyl optionally substituted with one or more Cj^alkyl substituents; or thienyl optionally substituted with one or more halo substituents;

each R⁸ independently is H or Ci^alkyl;

each R⁹ independently is H or Ci^alkyl;

R⁷ is H, Ci^alkyl optionally substituted with one or more substituents each

-6independently selected from the group consisting of halo, phenyl, and C^alkyloxy; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

The présent invention also concerns methods for the préparation ofcompounds of Formula (I) and pharmaceutical compositions comprising them.

The présent compounds surprisingly were found to modulatc the γ-secretase activity in vitro and in vivo, and are therefore useful in the treatment or prévention of Alzheimcr's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), senilîty, dementia, dementia with Lewy bodies, cérébral amyloid angiopathy, multiinfarct dementia, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, preferably Alzlieimer's disease and other disorders with Beta-amyloid pathology (eg glaucoma).

In view of the aforcmentioncd pharmacology ofthe compounds ofFormula (l), it follows that they are suitable for use as a médicament.

More especially the compounds are suitable in the treatment or prévention of Alzheimer's disease, cérébral amylotd angiopathy, multi-infarct dementia, dementia pugilistica or Down syndrome.

The présent invention also concerns to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the manufacture of a médicament for the modulation ofγ-secretase activity.

Use of a compound of Formula (I) for the modulation ofγ-secretase activity resulting in a decreasc in the relative amount of AB42-pcptidcs produced are preferred.

One advantage of the compounds or a part of the compounds of the présent invention may lie in their enhanced CNS-pcnetratïon.

The présent invention will now bc further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may bc combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may bc combined with any other feature or features indicated as being preferred or advantageous.

-ΊDetailed description

When describing the compounds of the invention, the terms used arc to bc construcd in accordance with the following définitions, unless a context dictâtes otherwise.

When indicating the number of substituents, the term one or more means from one substituent to the highest possible number of substitution, i.e. replacement of onc hydrogen up to replacement of ail hydrogens by substituents each individually selected from the indicated groups, provided that the normal valcncy is not exceeded, and that the substitution results in a chcmically stable compound, i.e. a compound that is sufïîciently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. Thereby, onc, two, three or four substituents are preferred. In particular one, two or three subsitutents are preferred. More in particular one substituent is preferred.

The term “halo”, “Halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated.

The term Ci-ealkyl as a group or part of a group refers to a hydrocarbyl radical of Formula C_nH2_n+j wherein n is a number ranging from l to 6. Ci^alkyl groups comprise from l to 6 carbon atoms, in particular from l to 4 carbon atoms, more in particular from l to 3 carbon atoms, still more in particular l to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Cj-calkyl includes ail linear, or branched alkyl groups with between l and 6 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, r-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, üobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term C2-6alkyl as a group or part of a group refers to a hydrocarbyl radical of Formula C_nH2_n+i wherein n is a number ranging from 2 to 6. C2^alkyl groups comprise from 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms, more in particular from 2 to 3 carbon atoms. Alkyl groups may bc linear or branched and may bc substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Cî^alkyl includes ail linear, or branched alkyl groups with between 2 and 6 carbon atoms, and thus includes such as for example ethyl, n-propyl,

-8ι-propyl, 2-methyl-cthyl, butyl and its isomers (e.g. //-butyl, Λ’ο butyl and ze/ï-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term C]..ialkyl as a group or part of a group refers to a hydrocarbyl radical of Formula C_nH2_nu wherein n is a number ranging from 1 to 4. Ci_jalkyl groups comprise from 1 to 4 carbon atoms, in particular from 1 to 3 carbon atoms, more in particular I to 2 carbon atoms. Alkyl groups may bc linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Ci^alkyl includes ail linear, or branched alkyl groups with 10 between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. «-butyl, Zsobutyl and tertbutyl), and the like.

The term “Ci^alkyloxy” as a group or part of a group refers to a radical having the Formula OR^b wherein R^b is Ci^alkyl. Non-limitingexamplcs of suitable

C|.(,alkyloxy include methyloxy, cthyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, .sec-butyloxy, iert-butyloxy, pentyloxy, and hexyloxy.

The term “Ci_4alkyloxy” as a group or part of a group refers to a radical having the Formula OR^C wherein R^c is Ci^alkyl. Non-limiting cxamples of suitable Ci_4alkyloxy include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, 20 isobutyloxy, .reobutyloxy and re/7-butyloxy.

In the framework of this application, Cî^alkenyl is a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl, butcnyl, pcntenyl, l-propen-2-yl, hexenyl and the like.

The term “cycloCj^alkyl” alone or in combination, refers to a cyclic saturated 25 hydrocarbon radical having from 3 to 7 carbon atoms. Non-limiting examples of suitable cycloC3.7alkyl include cyclopropyl, cyclobuty), cyclopentyl, cyclohcxyl and cyclohcptyl.

The term “cycloC^alkyloxy” alone or in combination, refers to a radical having the Formula OR^d, wherein R^d is cycloCj-valkyl. Non-limiting examples of 30 suitable cycloC3.?alkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopcntyloxy, cyclohexyloxy and cyclohcptyloxy.

The chemical names of the compounds of the présent invention were generated according to the nomenclature raies agreed upon by the Chemical Abstracts Service.

-9In case of tautomeric forms, it should be clear that the other non-depicted tautomeric form is also included within the scope of the présent invention.

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

It will be appreciatcd that some of the compounds of Formula (I) and their pharmaceutically acceptable addition salts and stereoisomerïc forms may contain one or more centers of chirality and exist as stereoisomerïc forms.

The term “stereoisomerïc forms” as used hereinbefore defines ail the possible isomeric forms that the compounds of Formula (!) may possess. Unless otherwise mentioned or indicated, the chemical désignation of compounds dénotés the mixture of ail possible stereochemically isomeric forms More in particular, stereogcnic centers may hâve the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may hâve either the cîs- or trans-configuration. Compounds encompassing double bonds can hâve an E or Z-stcrcoclicmistry at said double bond. Stereoisomerïc forms of the compounds of Formula (I) arc cmbraccd within the scope of this invention.

When a spécifie stereoisomerïc 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 l % of the other isomcr(s).

When a spécifie 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 l % of the other isomer(s).

For therapeutic use, salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaccutically acceptable may also fïnd use, for examplc, in the préparation or purification of a pharmaceutically acceptable compound. Ail salts, whether pharmaceutically acceptable or not, arc included within the ambit of the présent invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hcretnabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition sait forms which the compounds of Formula (l) are able to form.

The pharmaceutically acceptable acid addition salts can conveniently bc obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for

- ιοcxampic, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacctic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), malcic, fumaric, malic, tartaric, citric, methanesulfonic, cthancsulfonic, benzencsulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Convcrscly said sait forms can bc converted by treatment with an appropriate base into the free base form.

The compounds of Formula (I) containing an acidic proton may also be converted into their non-toxic mêlai or amine addition sait forms by treatment with appropriate organic and inorganic bases. Appropriate base sait forms comprise, for example, the ammonium salts, the alkali and earth alkaline métal salts, e.g. the lithium, sodium, potassium, magnésium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as mcthylamînc, ethylamine, propylamine, isopropylamine, the four butylaminc isomers, dimethylamine, dîethylamine, diethano lamine, dipropylamine, diisopropylamine, di-»-butylamine, pyrrolidine, piperidinc, morpholinc, trimetliylamine, triethylamine, tripropylamine, quinuclidîne, pyridine, quinoline and isoquinoline; the benzathinc, A-mcthyl-D-glucamine, hydrabaminc salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the sait form can bc converted by treatment with acid into the free acid form.

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

The compounds of Formula (I) as prepared in the proccsscs described below may be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another following art-known résolution procedures. A manner of separating the cnantiomcric forms of the compounds of Formula (!) involvcs liquid chromatography using a chiral stationary phase. Said pure stercochemically isomcric forms may also be derived from the corresponding pure stercochemically isomeric forms of the appropriate starting materials, provided that the réaction occurs stereospccifically. Preferably if a spécifie stereoisomer is desired, said compound would be synthesized by stercospecific methods of préparation. These methods will advantageously employ enantiomerically pure starting materials.

In the framework of this application, a compound according to the invention is inherently intended to comprise ail isotopic combinations of its chemical cléments. In cV

the framework of this application, a chemical élément, in particular when mentioned in relation to a compound according to formula (I), comprises ail isotopes and isotopic mixtures of this element. For example, when hydrogen is mentioned, it is understood to refer to ’H, ²H, ³H and mixtures thereof.

A compound according to the invention therefore inhérently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, including a radioactive compound, also called radiolabcllcd compound, wherein one or more non-radioactive atoms has been replaced by one of its radioactive isotopes. By the term radiolabclled compound is meant any compound according to formula (I), or a pharmaceutically acceptable sait thereof, which contains at least one radioactive atom. For example, a compound can be labclled with positron or with gamma emitting radioactive isotopes. For radioligand-binding techniques, the ³H-atomor the ^l25I-atom is the atom of choicc to be replaced. For imaging, the most commonly used positron emitting (PET) radioactive isotopes are ^HC, ^l8F, ^ls0 and ^l3N, ail of which arc accelerator produced and hâve half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only fcasible to use them at institutions which hâve an accelerator on site for their production, thus limiting their use. The most widely used of these are ^l8F, ^99mTc, ^20lTl and ^l23l. The handling of these radioactive isotopes, their production, isolation and incorporation in a molécule 20 arc known to the ski lied perso n.

In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular, the radioactive isotope is selected from the group of ³H, ^l'C, ^l8F, ¹²²1, ^l231, ¹²⁵I, ^l311,⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.

As used in the spécification and the appended claims, the singular forms a, an, and the also include plural référents unless the context clearly dictâtes otherwLsc. By way of example, a compound means one compound or more than one compound.

The terms described above and others used in the spécification are well understood to those in the art.

Preferred features of the compounds of this invention are now sel forth.

The présent invention concerns novel compounds of Formula (I):

Het¹

A² M ^AYY ^^He‘²

A³ (O

and stereoisomeric forms thereof, wherein

Het¹ is a 5-membered or 6-membered aromatic heterocycle, having formula (a-1), (a-2), (a-3), (a-4) or (a-5):

R^ü is H or Ci^alkyl;

R¹ is H, Cj^alkyl or Ci^alkyloxyCi^alkyl;

R² is CMalkyl;

X is O or S;

G' is CH or N;

G² is CH, N or C substituted with CMalkyl;

provided that G¹ and G² are not simultaneously N;

G³ is CH or N;

R^10,1 and R¹⁰⁶ each independently are hydrogen or Ci^alkyl;

A¹ is CR³ or N; wherein R³ is H, halo or Cualkyloxy;

A², A³ and A¹¹ cach independently are CH, CF or N; provided that maximum two of A¹, A², A³ and A¹ are N;

Het² is a 9-membcred bicyclic aromatic heterocycle, having formula (b-1 ) or (b-2):

Z¹ is Ci l or N;

Z² is CR‘^,a or N;

Z³ is CH or N; provided that maximum one of Z¹, Z² and Z³ is N;

Y^! isCH or N;

Y² is CR⁴¹’ or N;

- 13Y³ is CH or N; provided that maximum one of Y¹, Y² and Y³ is N; R·¹” is H; halo; C^alkyloxy; cyano; cyeloC^alkyl; Cualkylcarbonyl; Cualkyloxycarbonyl; or Ci^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting ofhalo and amino;

R^4b is H; halo; Cj..ialkyloxy; cyano; cycloCj.ialkyl; or Cwalkyi optionally substituted with one or more substituents each independently selected from the group consisting of halo and amino;

R⁵ is H; halo; cyano; C₍^alkyloxy; Cjz.alkenyl; or C^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Cualkyloxy and halo;

R⁶’ is Cî-aaikyl substituted with one or more halo substituents; Ci^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, Ci-ealkyloxy, tctrahydropyranyl, cycloCî^alkyloxy, and cycloC^alkyl; cycloC^alkyl; Ci.^alkylcarbonyl; tetrahydropyranyl; Ar; R⁸R⁹Ncarbonyl; or CHî-O-Ar;

R^eh is C2-6alkyl substituted with onc or more halo substituents; Ci^alkyl optionally substituted with one or more substituents each independently selected from Lhe group consisting of piperidinyl, Ar, Ci^alkyloxy, tetrahydropyranyl, cycloCj^alkyloxy, and cycloCî^alkyl; cycloCî^alkyl; cycloCî^alkyl substituted with onc or more phenyl substituents optionally substituted with onc or more halo substituents; piperidinyl; morpholinyl; pyrrolidinyl; NR^SR⁹; tetrahydropyranyl; O-Ar; C^alkyloxy; Ci. ealkyIthio; Ar; CHî-O-Ar; S-Ar; NCHj-Ar; or NH-Ar;

wherein each piperidinyl, morpholinyl, and pyrrolidinyl may optionally bc substituted with one or more substituents each independently selected from the group consisting of Ci^alkyl, Cî^alkcnyl, CMalkyicarbonyl, halo, and C'i^alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting ofhalo, CMalkyloxy, cyano, NR^SR⁹, morpholinyl, Cj.^alkyl, and Ci^alkyl substituted with onc or more halo substituents; pyridinyl optionally substituted with onc or more substituents each independently selected from the group consisting ofhalo, CMalkyloxy, cyano, Ci^alkyl, and Cualkyl substituted with onc or more halo substituents; oxazolyl optionally substituted with one or more Cj.^alky 1 substituents; or thienyl optionally substituted with one or more halo substituents;

each R⁸ independently is H or C'ualkyt;

each R⁹ independent ly is H or Cnalkyl;

R⁷ is II, Ci-ealkyl optionally substituted with onc or more substituents each

independently selected from the group consisting of halo, phenyl, and Cualkyloxy; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentîoned in any of the other 5 embodiments, wherein one or more, preferably ail, of the following restrictions apply:

(a) A², A³ and A⁴ each independently are CH or N; provided that maximum two of A¹, A², A³ and A⁴ arc N;

(b) Z² is CR⁴'¹;

(c) R^4a is H; halo; cyano; cycloCj.7alkyl; CMalkylcarbonyl; Cualkyloxycarbonyl; or 10 CMalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and amino;

(d) R^s is H; halo; C Malkyloxy; Cj^alkcnyl; or Ci.fialkyl optionally substituted with one or more Cj^alkyloxy substituents;

(e) R^û“is Cj-calkyI optionally substituted with one or more substituents each independently selected from the group consisting of Ar, Ci^alkyloxy, and tetrahydropyranyl; cycloC^alkyl; CMalkylcarbonyl; tetrahydropyranyl; Ar; or R⁸R⁹Ncarbonyl;

(f) R^6b is C2.ûalkyl substituted with one or more halo substituents; Ci-ealkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, Ci^alkyloxy, tetrahydropyranyl, and cycloC₃.7alkyl; cycloCj.îalkyl; cycloCî.7alkyl substituted with one phenyl substituent optionally substituted with one or more halo substituents; unsubstituted pyrrolidinyl; NR^SR⁹; tetrahydropyranyl; Ar; or CHî-O-Ar;

(g) each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci^alkyloxy, CMalkyl, and Ci^alkyl substituted with one or more halo substituents; oxazolyl optionally substituted with one or more CMalkyl substituents; or thienyl optionally substituted with one or more halo substituents;

(h) each R⁸ independently is Ci^alkyl;

(i) each R⁹ independently is CMalkyl;

0) R⁷ is Ci-^alkyl optionally substituted with one or more Cualkyloxy substituents; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the invention relates to compounds of Formula (1) and stereoisomeric forms thereof, or any subgroup thereof as mentîoned in any of the other 35 embodiments, wherein one or more, preferably ail, of the following restrictions apply:

(a) R° is H or methyl;

(b) R¹ is H, methyl, isopropyl or methoxymcthyl;

(c) R² is methyl;

(d) G² is CH, N or C substituted with methyl; provided that G¹ and G² are not simultaneously N;

(e) R^IOa and R^10b each independently are hydrogen or methyl;

(f) A¹ is CR³ or N; wherein R³ is H, F or methoxy;

(g) A² is CH or N;

(h) A³ is CH;

(i) A⁴ is CH or N;

(j) Z² is CR⁴“;

(k) R‘^,a is H; Br; Cl; F; cyano; cyclopropyl; methylcarbonyl; methoxycarbonyl; or Cpialkyl optionally substituted with one or more substituents each independently selected from the group consisting of F and amino;

(l) R^4b is H; F; methoxy; cyano; cyclopropyl; or C^elky! optionally substituted with one or more substituents each independently selected from the group consisting of F and amino;

(m) R^s is H; I; methoxy; l-propen-2-yl; or Ci^alkyl optionally substituted with one or more methoxy substituents;

(n) R⁶ⁿis Ci^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting of Ar, cthoxy, and tetrahydropyranyl; cyclopropyl; methylcarbonyl; tetrahydropyranyl; Ar; or R⁸R⁹N-carbonyl;

(o) R⁶¹’ is C2z>alkyl substituted with onc or more F substituents; Cj-ealky! optionally substituted with one or more substituents each independently selected from the group consisting of Ar, isopropyloxy, tetrahydropyranyl, and cyclopropyl; cyclopropyl;

cyclopropyl substituted with onc phenyl substituent which is further substituted with onc or more Cl substituents; unsubstituted pyrrolidinyl; NR⁸R⁹; tetrahydropyranyl; Ar; or Cfh-O-Ar;

(p) wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of F, Cl,

Ci^alkyloxy, Ci.^alkyl, and Cualkyl substituted with one or more F substituents; oxazolyl optionally substituted with onc or more methyl substituents; or thienyl optionally substituted with one or more Cl substituents;

(q) each R⁸ is methyl;

(r) each R⁹ is methyl or 2-methyl-propyl;

(s) R⁷ is Ci .f,alkyl optionally substituted with one or more methoxy substituents;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

- loin an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, or any subgroup thereof as mentioncd in any of the other embodiments, wherein one or more, preferably ail, ofthe following restrictions apply:

(a) Hct‘ is a 5-membercd or 6-membered aromatic heterocycie, having formula (a-l) or (a-5); in particular (a-1);

(b) R^ü is H or C) ,ialkyI; in particular H or methyl;

(c) R' isH orC _Malkyl; in particular H or methyl;

(d) X is O ;

(e) R^lün and R^lüb each independently are hydrogen or C^alkyl; in particular R^IOa is H and R^,Ob is Ci^alkyl; more in particular R^lOfl is H and R^inb is methyl;

(f) A¹ is CR³ or N; wherein R³ is CMalkyloxy; iti particular R³ is methoxy;

(g) A², A³ and A*¹ arc CH;

(h) Hct² is a 9-mcmbcred bicyclic aromatic heterocycie, having formula (b-1) or (b-2); in particular (b-2);

(i) Z¹ and Z³ arc CH;

(j) Z² is CR⁴;

(k) R⁴¹’ is H or halo; in particular halo; more in particular fluoro;

(l) Y¹ and Y³ arc CH;

(ni) Y² is CR^4b;

(n) R^4b is H or CMalkyloxy; in particular H or methoxy;

(o) R⁵ is H or methyl; in particular H;

(p) R^fia is C^alkyl;

(q) R^fib is phenyl optionally substituted with one or more halo substituents; in particular phenyl substituted with one halo substituent; more in particular phenyl substituted with one F substituent; most in particular phenyl substituted with one F substituent in the para position.

(r) R⁷ is Ci^alky 1; in particular methyl or isopropyl;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the présent invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein

Het¹ is a 5-mcmbcred aromatic heterocycie, having formula (a-l), (a-2), (a-3) or (a-4)

- 17R° is H or Ci^alkyl;

R' is H or Cualkyl;

R²isC_Malkyl;

X is O or S;

G¹ is CH or N; G² is CH, N or C substituted with CMalkyl;

provided that G¹ and G² are not simultancously N;

G¹ is CH or N;

A¹ is CR³ or N; wherein R³ is H, halo or Cnalkyloxy;

A², A³ and A⁴ each independently are CH, CF or N; provided that maximum two of A¹, A², A³ and A⁴ are N;

Het² is a 9-membered bicyclic aromatîc hetcrocyclc, having formula (b-1) or (b-2):

Z¹ is CH or N; Z² is CR⁴; Z³ is CH;

Y¹ is CH or N; Y² is CR^4b; Y³ is CH;

R⁴ⁿ is H; halo; Cualkyloxy; cyano; or CM^Ikyl optionally substituted with onc or more halo substituents;

R⁴¹’ is H; halo; Cualkyloxy; cyano; or C|.<ialkyl optionally substituted with one or more halo substituents;

R⁵ is H; halo; cyano; or Ci-calkyl optionally substituted with one or more substituents each independently selected from the group consisting of C) ^alkyloxy and halo; R⁶ⁿ is C₂.₆alkyl substituted with one or more halo substituents; C^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting of piperidinyl, Ar, Ci-oalkyloxy, tetrahydropyranyl, cycloCî^alkyloxy, and cycloCj-valkyl; cycloC.v7alkyl; tetrahydropyranyl; Ar; or CH₂-O-Ar;

R^fib is C₂^alkyl substituted with one or more halo substituents; Ciz,alky! optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, Ci^alkyloxy, tetrahydropyranyl, cycloCj^alkyloxy, and cycloCj_7alkyl; cycloCî.7alkyl; piperidinyl; morpholinyl; pyrrolidinyl; NR R ;

tetrahydropyranyl; O-Ar; Ci^alkyloxy; Cbealkylthio; Ar; CH₂-O-Ar; S-Ar; NCHj-Ar or NH-Ar;

wherein each piperidinyl, morpholinyl, and pyrrolidinyl may optionally bc substituted with one or more substituents each independently selected from the group consisting of Cj^alkyl, C2^alkcnyl, Cualkylcarbonyl, halo, and Cj.«alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected front the group consisting of halo, Ci^alkyloxy, cyano, NR⁸R⁹, morpholinyl, Ci.«alkyl, and C|.«alkyl substituted with one or more halo substituents; or pyridinyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C|.«alkyloxy, cyano, Cj^alkyl, and Ci-«alkyl substituted with one or more halo substituents;

each R⁸ independently is H or Ci .«alkyl;

each R⁹ independently is H or CMalkyl;

R⁷ is H, Ci.salkyl optionally substituted with one or more substituents cach independently selected from the group consisting of halo, phenyl, and Cualkyloxy; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the présent invention concerns novel compounds of Formula (1):

A² β

Y Y ^^Het2

Ja⁴

Het¹ a³ (D and stereoisomeric forms thereof, wherein

Het¹ is a 5-mcmbcrcd aromatic hctcrocycle, having formula (a-1), (a-2), (a-3) or (a-4)

R° is H or CMalkyl;

R¹ is H or CMalkyl;

R² is Ci.«alkyl;

X is O or S;

G¹ is CH or N;

G² is CH, N or C substituted with Ci.«alkyl; provided that G¹ and G² arc not simultaneously N;

G³ is CH or N;

- 19A* is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A², A³ and A⁴ each independently are CH, CF or N; provided that no more than two of A¹, A², A³ and A⁴ are N;

Het² is a 9-mcmbercd bicyclic aromatic heterocycle, having formula (b-la) or (b-2a)

(b-1a) (b-2a) .

R⁴ is I I, halo, Ci^alkyloxy, cyano, or Cwalkyl optionally substituted with onc or more substituents selected from halo;

R^4b is H, halo, Cualkyloxy, cyano, or Ci^alkyl optionally substituted with one or more substituents selected from halo;

R⁵ is H; halo; cyano; or Cj^alkyl optionally substituted with onc or more substituents selected from Ci^alkyloxy and halo;

R⁶ is C2.6alkyl substituted with onc or more substituents selected from halo; Ci^alkyl optionally substituted with one or more substituents selected from piperidinyl, Ai^-, Cuealkyloxy, tetrahydropyranyl, cycloC3.7alkyloxy, and cycloCj.7alkyl; cycloC.^alkyl; tetrahydropyranyl; Ar; or CH2-O-Ar;

R^eh is C2^alkyl substituted with one or more substituents selected from halo; Ci^alkyl optionally substituted with onc or more substituents selected from piperidinyl, Ar, Cj^alkyloxy, tetrahydropyranyl, cycloC^alkyloxy, and cycloCî^alkyl; cycloCj.7alkyl; piperidinyl; morpholinyl; pyrrolidinyl; NR^SR⁹; tetrahydropyranyl; O-Ar; Cj.ûalkyloxy; CMalkylthio; Ar; CH2-O-Ar; S-Ar; NCFh-Ar or NH-Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl may optionally bc substituted with one or more substituents selected from Ci^alkyl, C2-ealkenyl, CMalkylcarbonyl, halo, and Ci^alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from halo, Cj^alkyloxy, cyano, NR R , morpholinyl, Cj^alkyl, and Cj^alkyl substituted with one or more substituents selected from halo; or pyridinyl optionally substituted with 1 or more substituents each independently selected from halo, CM^lkyloxy, cyano, Cualkyl, and Cualkyl substituted with one or more substituents selected from halo;

-20wherein R⁸ is H or Cwalkyl;

wherein R° is H or Cnalkyl;

R⁷ is H, Ci-^alkyl optionally substituted with one or more substituents selected from halo, phenyl and Cualkyloxy;

Z¹ isCHorN;

Y¹ isCH or N;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In another embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

Het¹ is a 5-mcmbcrcd aromatic heterocycle, having formula (a-1), (a-2), (a-3) or (a-4)

R° is H or Ci^alkyl;

R¹ is H or Cualkyl;

R² is Cnalkyl;

X is O or S;

G¹ is CH;

G² is CH, or C substituted with Cj^alkyl;

G³ is CH;

A¹ is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A², A³ and A⁴ each independently are CFI or N; provided that maximum two of A¹, A², A³ and A⁴ are N;

Het² is a 9-mcmbcred bicyclic aromatic heterocycle, having formula (b-1) or (b-2); wherein Z¹ is CH or N; Z² is CR⁴'¹; Z³ is CH; Y¹ is CH or N; Y² is CR^4b; Y³ is CI1;

R⁴⁰ is H; halo; cyano; or Ci^alkyl optionally substituted with one or more halo substituents;

R^4b is H; halo; cyano; or Ci^alkyl optionally substituted with one or more halo substituents;

R⁵ is H or Cnalkyl;

R⁶ is Ar; C2^>alkyl substituted with one or more halo substituents; or

Ci^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, Ci^alkyloxy, and cycloCj.îaLkyi;

R^fib is Ar; C2^alkyl substituted with one or more halo substituents;

-2l Ci^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, Ci^alkyloxy, and cycloCj.7alkyl; or CFh-O-Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, Cj^alkyloxy, Ci^alkyl, and Cualkyl substituted with onc or more halo substituents; R⁷ is Cj-oalkyl optionally substituted with onc or more substituents each independently selected from the group consisting of halo and Ci^alkyloxy;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

Het¹ is a 5-mcmbcrcd aromatic heterocycle, having formula (a-1 ), (a-2), (a-3) or (a-4); R° is H or Ci^alkyl;

R¹ is H or Cnalkyl;

R² is Cj^alkyl;

X is O or S;

G¹ is CH;

G² is CIi or C substituted with Ci^alkyl;

G³ is CH;

A¹ is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A² is CH or N;

A³ and A⁴ are CH;

Het² is a 9-membcred bicyclic aromatic heterocycle, having formula (b-1) or (b-2); wherein Z^J is CH or N; Z² is CR'¹⁰; Z³ is CH; Y¹ is CH or N; Y² is CR⁴¹’; Y³ is CH;

R⁴⁰ is H or halo;

R⁴¹¹ is H, halo or Ci^alkyI optionally substituted with one or more halo substituents;

R⁵ is H, or Ci.«alkyl;

R^û“ is Ar; or Ci-ûalkyI optionally substituted with one Ar;

R^6b is Ar; Cî-oalkyl substituted with onc or more halo substituents; Ci^alkyl optionally substituted with one or more Ar substituents; or CI b-O-Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo,

CMalkyloxy, Ci^alkyl, and Ci^alkyl substituted with onc or more halo substituents;

R⁷ is Ci^alkyl optionally substituted with onc or more Ct-«alkyloxy substituents;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

C/

-22In another embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

Het¹ is a 5-membered aromatic heterocycle, having formula (a-1), (a-2), (a-3)or(a-4); R° is H or methyl;

R¹ is H or methyl;

R² is methyl;

X is O or S;

G¹ is CH;

G² is CH, or C substituted with methyl;

G¹ is CH;

A¹ is CR³ or N; wherein R³ is H, F or methoxy;

A² and A³ are CH or N; provided that maximum two of A¹, A² and A³ are N;

A⁴ is CH;

Het² is a 9-membercd bicyclic aromatic heterocycle, having formula (b-1) or (b-2); wherein Z¹ is CH or N; Z² is CR⁴; Z³ is CH; Y^! is CH or N; Y² is CR⁴¹’; Y³ is CH;

R⁴ is H, Br, F, cyano or CFj;

R'^,b is H, F, cyano, CH} or CF₃;

R⁵ is H or CH₃;

R^ûa is Ar; ethyl; or methyl optionally substituted with one or more substituents cach independently selected from the group consisting of Ci-₃alkyloxy and Ar;

R^6bis Ar; 3,3,3-trifluoropropyl; cyclopropylmethyl; methyl optionally substituted with one or more Ar substituents; or CH₂-O-Ar;

wherein cach Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of F, Ci, CN, methyl, 2-propyl, methoxy, cthoxy, and trifluoromethyl;

R⁷ is methyl, 2-propyl, tert-butyl, or ethyl optionally substituted with one methoxy; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In another embodiment, the invention relates to compounds of Formula (1) and stereoisomeric forms thereof, wherein

Het¹ is a 5-mcmbered aromatic heterocycle, having formula (a-1), (a-2), (a-3) or (a-4); R° is H or methyl;

R¹ is H or methyl;

R² is methyl;

X is O or S;

G¹ is CH;

G² is CH, or C substituted with methyl;

-23G³ is CH;

A¹ is CR³ or N; wherein R³ is H, F or methoxy;

A² is CH or N

A³ and A⁴ are CH;

Het is a 9-mcmbcred bicyclic aromatic heterocycle, having formula (b-l) or (b-2); wherein Z¹ is CH or N; Z² is CR^4a; Z³ is CH; Y¹ is CH or N; Y² is CR^4t>; Y³ is CH;

R^4a is H or Br;

R⁴¹’ is H, F, CH₃ or CF,;

R⁵ is H, or CH₃;

R^fi“ is Ar; or methyl optionally substituted with one Ar;

R^6b is Ar; 3,3,3-trifluoropiOpyl; cyclopropylmethyl; methyl optionally substituted with one or more Ar substituents; or CHî-O-Ar;

wherein each Ar independently is phenyl optionally substituted with onc or more substituents each independently selected from the group consisting of F, Cl, methyl, 2-propyl, methoxy, cthoxy, and trifluoromethyl;

Het¹ îs a 5-membercd aromatic heterocycle, having formula (a-1);

R° is H or C_Malkyl;

R¹ is H or Cnalkyl;

Xis O;

A¹ is CR³ or N; wherein R³ is H, F or Ci^alkyloxy;

A², A³ and A⁴ arc CH;

Het² is a 9-membered bicyclic aromatic heterocycle, having formula (b-2); wherein Y¹is CH or N; Y² is CR⁴¹’; Y³ is CH;

R'^1b is H, F or CF₃;

R^ûb is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, methyl, and methoxy;

R⁷ is Ci^alkyl;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

Het¹ is a 5-membcrcd aromatic heterocycle, having formula (a-1);

R° is H or CMalkyl;

O<

-24R¹ is H or Cuaikyl;

X is O;

A¹ is CR³; wherein R³ is CMalkyloxy;

A², A³ and A*¹ are CH;

Het is a 9-membered bicyclic aromatic hcterocycle, having formula (b-2); wherein Y is CH; Y² is CH; Y³ is CH;

R^fi,’is phenyl optionally substituted with one or more halo substituents;

R⁷ îsCMalkyl;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

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

R⁶ is Cù^alkyl substituted with one or more halo substituents; Ci^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting of Ar, CMalkyloxy, cycloCj^alkyloxy, and cycloCî^alkyl; Ar; or Clh-O-Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, Ci^alkyl, and Ci^alkyl substituted with one or more halo substituents.

R^eb is Cî^alkyl substituted with one or more halo substituents; Cm,alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, C'Malkyloxy, cycloC3-7alkyloxy, and cycloC3-7alkyl; Ar; or CHî-O-Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected iforn the group consisting of halo, CMalkyloxy, cyano, Ci^alkyl, and Cualkyl substituted with onc or more halo substituents.

R^6,1 is isobutyl; cyclopropylmethyl; 3,3,3-trifluoropropyl; Cî^alky 1 substituted with methoxy; CH₂-O-Ar; or Ar;

Λ

-25CMalkyloxy, cyano, Cgalkyl, and C_Malkyl substituted with one or more halo substituents.

R^6b is isobutyl; cyclopropylmethyl; 3,3,3-trifluoropropyl; Cî^alkyl substituted with methoxy; CHî-O-Ar; or Ar;

wherein cach Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, Cgalkyl, and Ci^alkyl substituted with onc or more halo substituents.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R⁶* is Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting ofhalo, CMalkyloxy, cyano, Cgalkyl, and CMalkyl substituted with onc or more halo substituents.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R^fi“ is Cî^alkyl substituted with onc ore more halo substituents; or phenyl optionally substituted with one or more substituents cach independently selected from the group consisting of halo, CMalkyloxy, CMalkyl, and CMalkyl substituted with one or more halo substituents;

in particular phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, methoxy, methyl, and trifluoromcthyl.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R^6b is Ar;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, Cualkyloxy, cyano, CMalkyl, and Cualkyl substituted with one or more halo substituents.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R^6b is Ci^alkyl substituted with onc orc more halo substituents; or phenyl optionally substituted with one or more substituents cach independently selected from the group consisting of halo, CMalkyloxy, C|.^alkyl, and CMalkyl substituted with onc or more halo substituents;

-26in particular Cî^alkyl substituted with one ore more halo substituents; or phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, methoxy, methyl, and trifluoromethyl.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R⁴¹¹ is H, halo, Cualkyloxy, or methyl optionally substituted with one or more halo substituents; in particular H or halo; more in particular H or F.

In another embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein R^4a is H, halo, methyl, cyano or trifluoromethyl.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R^4b is H, halo, Ci^alkyloxy, or methyl optionally substituted with one or more halo substituents; in particular H, halo or Cualkyloxy; more in particular H, F or methoxy.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R^4b is H, halo, methyl, cyano or trifluoromethyl.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R⁷ is Ci^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and CMalkyloxy.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R⁷ is Cwalkyl.

In another embodiment, the invention relates to compounds according to any of the other embodiments, wherein R⁸ is II or Ci^alkyl; and wherein R⁹ is H or CijalkyL

Jn an embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein R^s is H or methyl;

R^6a is phenyl substituted in a meta position and optionally further substituted in other positions.

In an embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein

R⁵ is H or methyl;

R^ûa is phenyl substituted in an ortho position and optionally further substituted in other positions.

-27In an embodiment, the invention relates to compounds according to any of the other embodiments, wherein

R⁵ is H or methyl;

R⁶ is phenyl substituted in the para position and optionally further substituted in other positions.

In an embodiment, the invention relates to compounds according to any of the other embodiments, wherein

R⁵ is H or methyl;

R^6a is phenyl substituted with F in the para position and optionally further substituted in other positions.

R^J is H;

R^ûa is methyl substituted with phenyl, wherein phenyl is optionally substituted with onc or more substituents each independently selected from the group consisting of halo, Ci^alkyloxy, cyano, NR⁸R⁹, morpholînyl, Cj^alkyl, and CMalkyl substituted with onc or more halo substituents.

R^6b is phenyl substituted in a meta position and optionally further substituted in other positions.

RÛb is phenyl substituted in an ortho position and optionally further substituted in other positions.

R^6b is phenyl substituted in the para position and optionally further substituted in other positions.

R^ûb is phenyl substituted with F in the para position and optionally further substituted in other positions.

-28In an embodiment, the invention relates to compounds according to any of the other embodiments, wherein

R⁶¹’ is methyl substituted with phenyl, wherein phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, NR^SR⁹, morpholinyl, CMaiky), and CM^lkyl substituted with one or more halo substituents.

In an embodiment, the invention relates to compounds according to any of the other embodiments, wherein one of R° and R¹ is Ci^alkyl, and one of R° and R¹ îs H; in particular one of R° and R¹ is methyl, and one of R° and R¹ is H.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein X is O.

In a further embodiment, the invention relates to compounds according to any ofthe olher embodiments, wherein Het¹ is (a-l) and X is O.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein X is S.

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein Hct¹ is (a-l) and X is S.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein A¹ is CR³ or N; wherein R³ is H, F or methoxy.

In a next embodiment, the invention relates to compounds according to any of the other embodiments, wherein

A¹ is CR³ or N; wherein R³ is H, halo or CMalkyloxy; in particular R³ is H, F or C’i-ialkyloxy; more in particular R³ is H, F or methoxy; most in particular R³ is methoxy;

A² is CH, CF or N; in particular CH or N;

A³ and A⁴ are CH or N; provided that maximum two of A¹, A², A³ and A⁴ are N.

A¹ is CR³ or N; wherein R³ is H, halo or C|.<ialkyloxy;

A² is CH, CF or N; in particular CH or CF; more in particular CH;

A³ and A⁴ arc CH.

In a next embodiment, the invention relates to compounds according to any of the other embodiments, wherein A¹ is N and A² is CFI.

-29In a next embodiment, the invention relates to compounds according to any of the other embodiments, wherein A² is CH when A¹ is N.

In a next embodiment, the invention relates to compounds according to any of the other embodiments, wherein maximum onc of A¹, A², A³ and A⁴ is N.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Het¹ has formula (a-1).

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Het¹ has formula (a-2).

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Het¹ has formula (a-3).

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Het¹ has formula (a-4).

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein Het¹ has formula (a-5).

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Het² has formula (b-1 ).

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein Het² has formula (b-2).

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein Y¹ is CH.

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein Y¹ is N.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Z¹ is CH.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Z¹ is N.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Z² is CR^4a.

In a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein Z² is N,

In a further embodiment, the invention relates to compounds according to any ofthe other embodiments, wherein one of Z² and Z³ is N, or wherein one of Y² and Y³ is N.

ln a further embodiment, the invention relates to compounds according to any of the other embodiments, wherein C^alkyl is restricted to Cnalkyl.

In an embodiment the compound of Formula (I) is selected from the group comprising:

2-(4-fluorophcnyl)-7V-[3-methoxy-4-(5-oxazolyi)phenyl]-imidazo[l,2-ü]pyridin-8amine, /V-[4-(2,4-dimcthyl-5-oxazolyl)-3-mcthoxyphcnyl]-2-(4-fluorophcnyl)-imidazo[l,2«]pyridin-8-amine,

7V-[4-(2,4-dimethyl-5-oxazolyl)-3-methoxyphenyl]-3-methyl-2-phcnyl-imidazo[l,2«]pyridin-8-amîne,

2-(4-fluorophenyl)-A^r-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-imidazo[l,2a]pyridin-8-amine,

2-(4-fluorophcnyl)-jV-[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]-l-mcthyl-lA^rbenzimidazol-4-aminc,

2-(4-fluorophcnyl)-A'-[3-mcthoxy-4-(l-mcthyl-!//-pyrazol-4-yl)plicnyl]-l -methyll/7-benzimidazol-4-amine,

A^r-[4-(2,4-dimethyi-5-thiazolyl)-3-methoxyphenyl]-2-(3-methoxyphcnyl)-3-mcthylimidazof l ,2-fl]pyridin-8-amine, jV-[4-( l ,3-dimethyl-1 77-pyrazol-4-yl)-3-mcthoxyphenyl]-2-(3-mcthoxyphenyl)-3methyl-imidazo[ l ,2-a]pyridin-8-amine, ?/-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]-2-(3-methoxyphenyl)-3-methylimidazof 1,2-a]pyridin-8-aminc,

7V-[3-methoxy-4-(2-mcthyl-5-tlùazolyl)phcnyl]-2-(3-methoxyphenyl)-3-methylimidazo[l,2-a]pyridin-8-amine, /V-[4-(2,4-dimethyl-5-oxazolyl)-3-methoxyphenyl]-2-(4-fluorophenyl)-l-methyl-lHbenzimidazol-4-amine,

2-(4-fluorophenyl)-7V-[3-methoxy-4-( l -methyl- l//-pyrazol-5-yl)phcnyl]-1 -mcthyll /7-benzimidazo l-4-amine,

2-(4-fluoiOphcnyl)-/V-[3-methoxy-4-(3-mcthyl-l,2,4-oxadiazol-5-yl)phcnyl]-lmethyl- l/7-bcnzimidazol-4-amÎne,

2-(4-fluorophcnyl)-yV-[3-mcÎhoxy-4-(2-mcthyl-5-oxazolyl)pheny[]-l-methyl-\Hbenzimidazol-4-amine,

2-(4-fluorophcnyl)-l-mcthyl-A/-[5-(4-methyl-5-oxazolyl)-2-pyridinyl]-l/7benzimidazo l-4-amine,

JV-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-l-methyl-2-(3,3,3-trifhioropropyl)l /7-bcnzimidazo l-4-amine,

-317V-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-2-(3-methoxyphenyl)-l-niethyl-l/·/benzimidazol-4-amîne,

2-(3-chlorophenyl)-l-methyl-/V-[5-(4-mcthyl-5-oxazolyl)-2-pyridinyl]-l/7benzimidazo l-4-amine,

2-(4-chloro-3-methoxyphenyl)-l-mcthyl-/V-[5-(4-methyl-5-oxazolyl)-2-pyridinyl]l H-benzimidazol-4-aminc,

2-[4-cthoxy-2-methyl-5-(l-methylethyl)phenyl]-/V-[3-methoxy-4-(4-mcthyl-5oxazolyl)phcnyl]-l-methyl-1//-bcnzimidazo l-4-amine,

2-(4-fluorophenyl)-/V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2aJpyridin-8-amine,

2-(4-fluorophenyI)-A^r-[4-(2-methyl-5-oxazolyl)phenyl]-ii'nidazo[l,2-iï]pyrtdin-8amine,

1- (l,l-dimcthylethyi)-2-(4-fluorophenyl)-/V-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-

1//-bcnzimidazo l-4-aminc,

2- (4-fluorophenyl)-l-methyl-/V-[6-(4-mcthyl-5-oxazolyl)-3-pyridinyl]-l//bcnzimidazo l-4-aminc,

2-(4-fluorophcnyl)-l-(l-rnethylethyl)-/V-[4-(2-inethyl-5-oxazolyl)phenyl]-lHbcnzimidazo l-4-amine, /V-[4-(2-methyl-5-oxazolyl)phcnyl]-2-(2-mcthylphcnyl)-imidazo[l,2-a]pyridin-8amine,

2-(4-fluoro-2-methylphenyl)-/V-[6-(4-mcthyl-5-oxazolyl)-3-pyi‘idinyl]-imidazo[l,2iï]pyi‘idin-8-aminc,

2-(2-fluoro-4-mcthylphcnyl)-/V-[6-(4-niethyl-5-oxazolyl)-3-pyridinyl]-imidazo[l,2a]pyridin-8-aminc,

7V-[4-(2-methyl-5-oxazolyl)phcnyl]-2-[2-mcthyl-5-(trifluoromcthyl)phenyl]imidazo[ 1,2-û]pyridin-8-amine,

2-(2,4-difluorophcnyl)-/V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phenyl]-l-methyl-l//imidazo[4,5-c]pyridin-4-aminc,

1- (2-methoxyethyl)-/V-[3-methoxy-4-(2-inethyl-5-thiazolyl)phenyl]-2-methyl-l?7bcnzimidazo i-4-amine,

7/-[3-mcthoxy-4-(2-mcthyl-5-thiazolyr)phcnyl]-2-(2-mcthylphcnyl)-imidazo[l,2«]pyridin-8-amine,

2- (4-fluorophenyl)-l-methyl-?/-[4-(2-methyl-5-oxazolyl)phenyl]-l//-imidazo[4,5c]pyridin-4-amine,

2-(4-fluorophenyl)-A/-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-1 -( 1 mcthylethyl)-l//-benzimidazol-4-amine,

2-(4-fluorophenyl)-/V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phenyl]-l -methyl-\H16570

im idazo [4,5-c] pyr id in-4-amine,

2-(4-fluoro-2-mcthylphenyl)-A<-[4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2<ï]pyridin-8-amine,

2-(2-fluoiO-4-methylphcnyl)-/V-[4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2a]pyridin-8-amine,

2-(4-fluorophenyl)-1-methyl-Æ-[6-(2-methy l-5-oxazo lyl)-3-pyrid inyl] -1Hbenzimidazol-4-amine,

2-(2-chlorophenyl)-3-methyl-7V-[4-(2-mcthyl-5-oxazolyi)phenyl]-imidazo[l,2a]pyridin-8-aminc,

2-(5-methoxy-2-methylphenyl)-/'/-[4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2zï]pyridin-8-amine,

2-[(4-fluorophenyl)metliyl]-/V-[4-(2-methyl-5-oxazolyi)phenyl]-imidazo[l,2a]pyridin.-8-amine,

7V-[3-fluoro-4-(2-methyl-5-oxazoIyl)phenyl]-2-(4-fluorophenyl)-l-methyl- \Himidazo^.S-cJpyridin^-amine,

2-(5-fluoro-2-mcthylphcnyl)-/V-[3-nicthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]imidazo [ 1,2-a]pyridin-8-amine,

N-[6-(4-methyl-5-oxazolyl)-3-pyridÎnyl]-2-[2-rnethyl-5-(trifluoromethyl)phcnyl]imidazo[ 1,2-a]pyridin-8-aminc,

2-(3-mcthoxyphenyl)-J-(l-methylethyl)-jV-[4-(2-methyl-5-oxazolyl)phenyl]-l/ïbcnzimidazol-4-aminc,

2-(4-fluorophcnyl)-l-(l-mcthylcthyl)-Aⁱ-[5-(2-mcthyl-5-oxazolyl)-2-pyridinyl]-l//benzimidazol-4-amine,

2-(4-fluorophenyl)-7V-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-l-mcthyl-6(trifluoro methyl)-1 /7-benzimidazol-4-aminc,

2-(4-fluorophenyl)-l-(l-methylethyl)-ÏV-[4-(2-methyl-5-oxazolyl)phenyl]-l//irnidazo[4,5-c]pyridin-4-arnine,

2-(4-fluorophcny l)-7V-[3-methoxy-4-(2-mcthyl-5-oxazo ly l)phcnyl]-1-(1methylethyl)-lZY-imidazo[4,5-c]pyridin-4-amine,

N-[3-fluoro-4-(2-methyl-5-oxazolyl)phenyl]“2-(5-metlioxy-2-methylphcnyl)imidazo[l,2-û]pyridin-8-aminc, jV-[3-fluoro-4-(2-methyl-5-oxazolyl)phenyl]-2-(4-fluorophenyl)-1 -( 1 -methylethyl)1 //-benzimidazo 1-4-aminc,

2-(4-fluorophenyl)-l-(l-methylethyl)-jV-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]-l//benzimidazol-4-amiue,

2-(2,4-difluoiOphenyl)-1 -methyl-7/-[4-(2-methyl-5-oxazolyl)phenyl]-1HÎmidazo[4,5-c]pyridin-4-amine,

2-(2,4-difluorophenyl)-/V-[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-1 -methyl-1Himidazo[4,5-i.']pyridin-4-aminc, 2-(2,4-difluorophenyl)-N-[3-fluoro-4-(2-mcthyl-5-oxazolyl)phenyl]-l -methyl-\Himidazo[4,5-c]pyridin-4-amine, 6-fluoro-2-(3-methoxyphenyl)-l-methyl-/V-[4-(2-methyl-5-oxazolyl)phenyl]-l/7benzimidazol-4-amine, 2-(4-fluoro-2-methylphcnyl)-7V-[4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2a]pyrazin-8-amine, 2-(4-fluorophenyl)-l,6-dimethyl-!V-[4-(2-methyl-5-oxazolyl)phenyl]-l/7imidazo[4,5-c]pyridin-4-amme,

2-(4-fluorophenyl)-7V-[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phenyl]-l,6-dimcthyl-l//i m idazo [4,5 -c] pyr id i n -4 -am i ne, 6-bromo-2-(4-fluoro-2-mcthylphenyl)-/V-[4-(2-methyl-5-oxazolyl)phenyl]imidazo[ l ,2-û]pyrazin-8-amine,

1- methyl-7/-[6-(4-mcthyl-5-oxazolyl)-3-pyridinyl]-2-(phcnoxymethyl)-l/7bcnzimidazol-4-aminc,

2- (4-chloro-3-methoxyphenyl)-?/-[3-methoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-lmethyl-l/7-benzimidazol-4-amine, /V-[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-2-(3-mcthoxyphcnyl)-l-mcthyl-l/7benzimidazo l-4-amine, 2-(cyclopropylmcthyl)-l-ethyl-jV-[3-methoxy-4-(2-methyl-5-oxazolyl)phcnyl]-l/7bcnzimidazol-4-aminc, 7V-[3-fluoro-4-(4-methyl-5-oxazolyl)phcnyl]-2-(4-fluorophcnyl)-l-(l-methylcthyl)1 //-benzimidazo l-4-aminc, 2-(cyclopropylmcthyl)-/V-[3-fluoro-4-(2-methyl-5-oxazolyl)phcnyl]-l-mcthyl-l/7imidazo[4,5-c]pyridin-4-amine, 2-(4-fluorophcnyl)-7V-[3-methoxy-4-(2-methyl-5-thiazolyl)phenyl]-l-(lmcthylcthyl)-l//-bcnzimidazol-4-aminc, jV-[3-fluoiO-4-(2-methyl-5-oxazolyl)phcnyl]-2-(3-methoxyphcnyl)-l-mcthy!-l/7imidazo[4,5-c]pyridin-4-amine, 2-(2,4-difluorophcnyl)-jV-[3-mcthoxy-4-(2-mcthyl-5-thiazolyl)phcnyl]-l -methyl-1/7imidazo[4,5-c]pyridin-4-amine, jV-[3-fluoro-4-(2-methyl-5-oxazolyl)phenyl]-2-(4-fluorophenyl)-3-methyl-3/7imidazo[4,5-/)]pyridin-7-amine, jV-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-l-methyl-6-(trifhioromethyl)-2(3,3,3-trifluoropropyl)-l/7-benzimidazol-4-amine, 7V-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-2-methyl-6-(tri fluoromethy!)16570

-34imidazof l ,2-a]pyridin-8-amme, 2-(4-fluorophenyl)-(-methykV-[4-(l-methyl-l/7-pyrazol-4-yl)phenyl]-lHbcnzimidazol-4-amine,

8-[[3-fluoro-4-(2-methyi-5-oxazolyl)phenyl]amino]-JV,/V-dimethyl-6(trifluoromcthyl)-imidazo[ l ,2-a]pyridine-2-carboxamide, 6-fluoro-2-(3-methoxyphenyl)-l-mcthyl-jV-[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]l//-bcnzimidazol-4-aminc, ?/-[3-methoxy-4-(4-methyl-5-oxazolyl)phcnyl]-2,3-dimethyl-6-(trifluoromcthyl)imidazof l ,2-a]pyridin-8-amine, 7V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phenyl]-2-methyl-6-(trifluoromethyl)îmidazo[l,2-«]pyrazin-8-amine,

6-bromo-2-methyl-/V-[4-(2-methyl-5-oxazolyl)phenyl]-imidazo[l,2-fl]pyrazin-8aminc,

8-[[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2V,A/-dimethyl-6(trÎfluoiOmcthyI)-irnidazo[l,2-a]pyridine-2-carboxamidc, 2-(4-fluorophcnyl)-l-mcthyl-A^r-[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]-6(trifluoromethyl)-1 //-bcnzimîdazol-4-aniine,

1- methyl-2-[(l-mcthylethoxy)methyl]-/V-[4-(2-methyl-5-oxazolyl)phcnyl]-l Hbcnzimîdazol-4-amine,

2- (4-fluorophenyl)-1 -methyl-/V-[6-( l -methyl- l/Apyrazol-4-yl)-3-pyridiny!]-l//bcnzimidazol-4-amine, 2,3-dimcthyl-7V-[4-[2-(l-mcthylcthyl)-5-oxazolyl]phcnyl]-imidazo[l,2-a]pyridin-8amine, jV-[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-2,3-dimcthyl-imidazo[l,2-a]pyridin8-amine,

1- [8-[[3-methoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]amino]-6(trifluoromcthyl)imidazo[ l _}2-a]pyridin-2-yl]-cthanonc, 7V-[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-l-mcthyl-2-(3,3,3-trifluoropropyl)lA/-imidazo[4,5-c]pyridin-4-aminc,

2- (4-fluorophenyl)-/V-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]-l,6-dimcthyl-lHimidazo[4,5-c]pyridin-4-amine,

8-[[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2-mcthyl-imidazo[l,2ü]pyridine-6-carbonitrile,

A^r-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-2-mcthyl-6-(trifluoromethyl)imidazo[ l ,2-Z?]pyridazin-8-amine,

7/-[3-rncthoxy-4-(4-mcthyl-5-oxazolyl)phenyl]-2-methyl-6-(trifluoromcthyl)imidazo[l,2-à]pyridazin-8-amine,

6-fluoro-A/-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-l-methyl-2-(l-pyrrolidinyl)l //-benzimidazol-4-amine,

2-(4-fluorophenyl)-A/-[3-methoxy-4-( l-methyl-1 H-1,2,4-triazol-5-yl)phcnyl]-l methyl- i //-bcnzimidazol-4-amine,

6-flLioro-l-methyl-/V-[4-(2-methyl-5-oxazolyl)phenyl]-2-(l-pyrrolidinyl)-l//bcnzimidazol-4-amine,

6-fluoiO-2-(4-fluoro-2-methylphenyl)-/V-[3-rnethoxy-4-(4-mcthyl-5oxazolyl)phenyl]-imidazo[ l ,2-«]pyridin-8-amîne,

2-(4-fluoro-2-methylphcnyl)-8-[[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)pheiiyl]amino]imidazo[l,2-ùt]pyridine-6-carbonitrile,

2-(4-fluoiOphenyl)-/V-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-3-methyl-3/7imidazo[4,5-c]pyridin-7-amine,

2-(4-fluorophenyl)-/V-[3-methoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-3-methyl-3//imîdazo[4,5-c]pyridin-7-aniine,

7V-[3-methoxy-4-(2-mcthyl-5-oxazolyl)phenyl]-2-(3-methoxyphenyl)-l,6-dimcthyll//-imidazo[4,5-c]pyridin-4-aminc,

1- methyl-2-(4-methyl-5“Oxazolyl)-A-[4-(2-methyl-5-oxazolyl)phcnyl]-6- (tri fluoro methyl)-177-benzimidazol-4-amine,

2- (3-methoxyphenyl)-l₎6-dimcthyl-/V-[4-(2-mcthyl-5-oxazolyl)phcnyl]-lWimidazo[4,5-c']pyridin-4-amine,

2-(4-fluorophenyl)-l-rnethyl-/V-[5-(2-metliyl-5-oxazolyl)-2-pyrirnidiiiyl]-l//bcnzimidazo l-4-aminc, /V-[3-metlioxy-4-(4-methyl-5-oxazolyl)phenyl]-2-(3-methoxyphenyl)-l,6-dimethyll //-imidazo[4,5-c]pyridin-4-an]inc,

2-(3-mcthoxyphcnyl)-l-methyl-4-[[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]amino]-l//benzimidazole-6-carbonitrile, /V-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-2-methyl-imidazo[l,2-a]pyrazin-8amine,

6-fluoiO-A-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-2-(2-methylpropyl)imidazof l ,2-rz]pyridin-8-amine,

2-(4-fluorophcnyl)-7-[[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]amino]-3-mcthyl3//-imidazo[4,5-Z>]pyridine-5-carbonitrile,

1- methyl-7V-[4-(2-methyl-5-oxazolyl)phenyl]-2-(tetrahydro-2//-pyran-4-yl)-6- (trifluoromethyl)-1 //-bcnzimidazol-4-amine,

2- (4-fluorophenyl)- l-mcthyl-A/-[4-( l -methyl-1 H-pyrazol-5-yl)phenyl]- i Hbcnzimidazol-4-amine,

2-(4-fluorophenyl)-6-methoxy-A/-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-l-

M

-36methyl- lW-benzimidazol-4-amine,

A^f-[3-methoxy-4-(2-mcthyl-5-oxazolyl)phenyl]-l-(l-methylethyl)-2-(telrahydro-2//pyran-4-yl)-lJ7-benzimidazol-4-amine,

2-(4-fluorophenyI)-V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phenyl]-3,5-dimethyl-3J7imidazo[4,5-ô]pyridin-7-amine,

4-[[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2-(3-methoxyphenyl)-lmcthyl-l//-bcnzimidazole-6-carbonitrile,

2-(4-fluorophenyl)- l-methyl-/V-[5-( l -methyl-1 /f-pyrazol-5-yl)-2-pyridiny I]-\Hbenzimidazo l-4-amine,

2-(ethoxymethyl)-7V-[3-methoxy-4-(4-methyl-5-oxazo lyl)phenyl]-6(tri fluoro methyl)-lmidazo[ l ,2-ü]pyridÎn-8-aminc,

2-(4-fluoro-2-methylphenyl)-8-[[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)phenyl]amino]imidazof l ,2-iz]pyridine-6-methanamine, jV-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-l,6-dimcthyl-2-(tetrahydro-2//-pyran-

4- y !)-1 #~imidazo[4,5-c]pyridin-4-amine,

5- cyclopropyl-2-(4-fluorophcnyl)-A^r-[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-3rnethyt-3//-imÎdazo[4,5-i>]pyridin-7-amine,

2-(4-fluorophenyl)-3-(l-mcthylcthcnyl)-A/-[4-(2-methyl-5-oxazolyl)phenyl]imidazof l ,2-a]pyridin-8-amine,

6- cyclopropyl-2-(4“fluoiOphcnyl)-jV-[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-lmethyl-1 H-imidazo[4,5-c]pyridin-4-amine,

2-(4-fluorophcnyl)-3-(l-mcthylethyl)-A^r-[4-(2-mcthyl-5-oxazolyl)phcnyl]imidazo[ l ,2-iz]pyridin-8-amine,

2-(4-fluorophenyl)-4-[[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]amîno]-l-methyll/Y-bciizimidazole-6-carbonitrilc,

8-[[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2-(2-methylpropyl)imidazo[l,2-«]pyridinc-6-carbonitrile,

7V-[3-mcthoxy-4-(2-methyl-5-oxazolyl)phcnyl]-l,6-dimethyl-2-[3-(lrnethylethoxy)phcnyl]-l//-imidazo[4,5-c]pyrÎdm-4-amme, 6-fluoiO-/V-[4-(2-mcthyl-5-oxazolyl)phenyl]-2-(2-mcthylpropyl)-imidazo[l,2a]pyridin-8-aminc,

2-(4-fluorophenyl)-l-methyl-V-[6-(2-methyl-5-thiazolyl)-3-pyridÎnyl]-lHbenzimidazol-4-amine,

6-fluoro-2-(4-fluoro-2-methylphenyl)-7V-[4-(2-mcthyl-5-oxazolyl)phenyl]imidazo[ l ,2-a]pyridin-8-amine,

2-(4-fluoro-2-methylphenyl)-7\Z-[3-mcthoxy-4-(4-methyl-5-oxazolyl)phenyl]-6methyl-imidazo[l,2-û]pyridin-8-amine,

2-(4-fluorophenyl)-l-methyl-/V-[4-(4-mcthyl-5-oxazolyl)phenyl]-l//-benzimidazol-4amine,

2-(3-methoxyphenyl)-3-methyl-JV-[4-(4-methyl-5-oxazolyl)phenyl]-iniidazo[l,2a]pyridin-8-amine,

6-fluorO“M-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-7/²,l-dimethyl-/V²-(2methy I pro py l) -l //-benzi mid azo le-2,4-d iamine,

A/-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-2-(tetrahydro-2//-pyran-4-yl)imidazo[l,2-a]pyridin-8-amine,

2-(4-fluorophcnyl)-4-[[3-rnethoxy-4-(4-mcthyl-5-oxazo)yl)phcnyl]arnino]-l-rnethyll /7-benzimidazole-6-mcthanamme, /V-[6-(4-methyl-5-oxazolyl)-3-pyridLnyl]-2-(tetrahydiO-2ff-pyfan-4-yl)-ÎmÎdazo[l,2aJpyridin-8-amine,

2-(4-fluorophenyl)-l-methyl-4-[[6-(4-methyl-5-oxazolyl)-3-pyridinyl]amino]-l/A benzitnidazole-6-carbonilrile,

6-cyclopiOpyl-/V-[3-mcthoxy-4-(4-methyl-5-oxazolyl)phcnyl]-2-methyl-imidazo[l,2iz]pyrazin-8-amine,

2-(3-chlorophenyl)-l-(l-methylethyl)-N-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-l/7benzimidazol-4-amine,

2-(4-fluorophcnyl)-l-(l-methylethyl)-/V-[6-(4-mcthyl-5-oxazolyl)-3-pyridinyl]-l/7benzimidazo l-4-amîne,

2-(2-chlorophenyl)-6-fluoro-1 -methyl-?/-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-1Hbcnzimidazo l~4-aminc,

2-(2-ο1ιΙοΐΌρ1ιεηγ1)-Ι-πιοΙΙιγ1-Λ46-(4-ΠΊεΐΗγ1-5-οχ3ζο1γ1)-3-ργιϊάίηγ1]-1/7Îmidazo[4,5-c]pyridin-4-amine, jV-[4-(2,4-dimcthyl-5-oxazolyl)phenyl]-2-(4-fluoiOphcnyl)-l-methyl- \Hbenzimidazol-4-amine,

2-(4-fluorophenyl)-l-mcthyl-4-[[6-(2-methyl-5-oxazolyl)-3-pyridinyl]amino]-l?/benzimidazo lc-6-carbonitrilc,

6-fluoiO-2-(4-fluoro-2-methylphcnyl)-N-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]imidazo [ l ,2-a]pyridin-8-amine,

2-(2-chlorophcnyl)-l-methyl-yV-[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]-l//imidazo[4,5-c]pyridin-4-ainine,

2-(4-fluorophenyl)-A/-[3-methoxy-4-(2-methyl-5-oxazolyl)phcnyl]-3-methyl-5-(lmethylcthyl)-3//-imidazo[4,5-/j]pyridin-7-amine,

6-fluoro-2-(4“fluoiOphenyl)-i-metliyl-/V-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-lf7benzimidazo l-4-amine,

6-fluoro-2-(4-fluorophenyl)-l-methyl-N-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]-l77A

bcnzimidazol-4-aminc,

2-(2-chlorophcnyl)-6-f!uoro-l-methyl-N-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]-l//bcnzimidazol-4-amine,

6-chloro-N-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-2-(tetrahydro-27/-pyran-4yl)-imidazo[ l ,2-a]pyridin-8-amine,

2-(5-chloro-2-thienyl)-1 -( l -mcthylethyl)-JV-[6-(4-methyl-5-oxazolyl)-3-pyrid inyl]l 77-benzimidazo l-4-amine,

A/-[6-(2,4-dimethyl-5-oxazolyl)-3-pyridinyl]-2-(4-fluorophcnyl)-l-(l-mcthylethyl)l //-bcnzimidazo l-4-arninc,

2-(2-chlorophcnyl)-JV-[6-(2,4-dimethyl-5-oxazolyl)-3-pyridinyl]-6-fluoro- l-mcthyll//-bcnzimidazol-4-amine,

A/-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-3-(3-mctlioxypropyl)-2-[2(trifluoromcthyl)phenyl]-imidazo[l,2-iï]pyridin-8-aniine,

2-(4-iluorophcnyl)-3-methyl-A^r-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]-3Himidazo[4,5-c]pyrîdin-7-aminc,

2- (4-fluorophcnyl)-3-iodo-A/-[4-(2-mcthyl-5-oxazolyl)phcnyl]-imidazo[l,2-

a]pyridin-8-amine,

3- methyl-iV-[6-(2-mctbyl-5-oxazolyl)-3-pyridinyl]-2-[2-(trifluoromethyl)phenyl]imidazo[ l ,2-a]pyridin-8-aminc,

8-[[3-mcÉhoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2-(2-methylpropyl)imÎdazo[l,2-i/]pyridine-6-carboxylic acid methyl ester,

M[4-(2,4-dimcthyl-5-oxazolyl)-3-mcthoxyphenyl]-2-(4-fluorophcnyl)-l-(lmcthylcthyl)-1 JZ-benzîmidazol-4-amine, /V-[4-(2,4-dimethyl-5-oxazolyl)phenyl]-2-(4-fluorophenyl)-1 -( I -mcthylcthyl)-! Hbcnzimîdazol-4-amine,

2-cyclopropyl-A^r-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-imidazo[l,2-«]pyridin-8amine,

2-cyclopropyl-A^r-[4-(2-mcthyl-5-oxazolyl)phcnyl]-imidazo[l,2-«]pyridin-8-aminc_>

6-fluoro-2-(4-fluorophenyl)-1 -( l -methylcthyl)-Æ-[6-(2-mcthyl-5-oxazolyl)-3pyridinyl]-l7/-benzimidazol-4-amine,

6-fluoro-N-[3-mcthoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]-2-(tctrahydro-2H-pyran-4y l)-imidazo[ 1,2-<a]pyridin-8-amine,

2-(4-fluorophenyl)-3-(mcthoxymethyl)-7V-[3-mcthoxy-4-(2-methyl-5oxazolyl)phenyl]-îmidazo[ l ,2-a]pyridin-8-amine,

2-[l-(4-chlorophcnyl)cyclopropyl]-l-methyl-/V-[6-(2-methyl-5-oxazolyI)-3pyr id iny l]-1 /7-benzimidazo l-4-amine, /V-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-2-[(tetrahydro-2H-pyran-4-yl)methyl]y

imidazo[ l ,2-a]pyridin-8-amine, 2-[i-(4-chlorophcnyl)ethyl]-l-methyl-7V-[6-(2-methyl-5-oxazolyl)-3-pyridinyl]-lf/benzî midazo l-4-amine,

2-(2-chlorophcnyl)-/V-[3-mcthoxy-4-(4-methyl-5-oxazolyl)phenyl]-l,6-dimcthyl-l//imidazo[4,5-c]pyridin-4-aminc,

2-(2-chloro phenyl)-1,6-dimethyl-A/-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-1Himidazo[4,5-c]pyridin-4-amine,

6-chloro-2-(5-fluoro-2-mcthylphenyl)-A-[6-(5-mcthyl-4-oxazolyl)-3-pyridinyl]imidazo[ I .Z-ijpyridazin-S-amine,

1- [8-[[3-mcthoxy-4-(4-methyl-5-oxazolyl)phenyl]amino]-2-(2- methylpropyl)imidazo[ 1,2-a]pyridin-6-yl]-ethanone,

2- (4-fluorophenyl)-3-(2-mcthoxycthyl)-)V-[3-mcthoxy-4-(2-mcthyl-5oxazolyl)phcnyl]-imidazo[ l ,2-a]pyridin-8-aminc,

2-(4-fluorophcnyl)-N-[4-[2-(methoxymethyl)-5-oxazolyl]phenyl]-l-(l-methylethyl)l H-benzimidazol-4-amine,

2-(2-chlorophcnyl)-3-mcthyl-A/-[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]-imidazo[l,2fl]pyridin-8-amine,

2-methyl-/V-[6-(2-methyl-5-oxazolyi)-3-pyridinyl]-imidazo|l,2-«]pyridin-8-amine, 2-(4-fluorophcnyl)-3-mcthyl-5-(l-mcthylcthyl)-A^r-[6-(2-mcthyl-5-oxazolyl)-3pyridinyl]-3//-imidazo[4,5-ô]pyridin-7-amiiie,

2-(4-fluorophenyl)-3-mcthoxy-/V-[6-(4-methyl-5-oxazolyl)-3-pyridinyl]-imidazo[l,2a]pyridin-8-aminc,

2-(5-fluotO-2-methylphenyl)-/V-[6-(4-mcthyl-5-oxazolyl)-3-pyridinyl]-iniidazo[l,2Z>]pyiïdazin-8-aminc,

2-(4-fluorophcnyl)-/V-[3-mcthoxy-4-( l -mcthyl-l/7-l ,2₁3-triazol-4-yl)phcnyi]-1 methyl-1 //-bcnzimidazoM-amine,

2-(4-fluorophenyl)-jV-[3-mcthoxy-4-(2-mcthyl-2//-l,2,3-triazol-4-yl)phenyl]-lmcthyl-1 //-bcnzimîdazo l-4-aminc,

2-(4-fluorophenyl)-?/-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-l -methyl- \Hbenzimidazol-4-aminc,

2-(4-fluorophcnyl)-/\Z-[3-mcthoxy-4-(2-mcthyl-4-pyridinyl)phenyl]-l,6-dimcthyl-//7imidazo[4,5-c]pyridin-4-amine,

2-(4-fluorophcnyl)-1 -methyl-N-[4-(2-mcthyi-4-pyridinyl)phenyl]- l//-benzimidazol4-amine,

2-(2-chlorophenyl)-A^r-[3-mcthoxy-4-(2-mcthyl-4-pyridinyl)phcnyl]-3-mcthylimidazo[ l ,2-a]pyrtdin-8-amine,

2-(4-fluorophenyl)-7V-[3-mcthoxy-4-(2-methyl-4-pyridinyl)phenyl]-l-(l16570

mcthylcthyl)-l/7-bcnzimidazol-4-amine,

2-(4-fluorophcnyl)-l,6-dimethyl-V-[4-(2-mcthyl-4-pyridinyl)phenyl]-l//imidazo[4,5-c]pyridin-4-amine,

2-(4-fluorophcnyl)-1 -( l -mcthylcthyl)-/V-[4-(2-mcthyl-4-pyridinyl)phenyl]-1Hbenzimidazol-4-amine,

2-(2-chlorophenyl)-3-mcthyl-jV-[4-(2-mcthyl-4-pyiïdinyl)phcnyl]-imidazo[l,2a]pyridin-8-aminc,

2-(4-fhiorophenyl)-/V-(2-methoxy-2'-methyl[3,4'-bipyridin]-6-yl)-1 -( l -methylethyl)l //-bcnzimidazol-4-amine,

2-(4-fluorophenyl)-yV-(2-mcthoxy-2’-methyl[3,4'-bipyridin]-6-yl)-l-mcthyl-//7benzimidazol-4-amine,

2-(2-chlorophenyl)-7V-(2-mcthoxy-2'-methyl[3,4'-bipyridin]-6-yl)-3-methylimidazo[l ^-tfjpyridin-g-arnme,

2-(4-fluorophcnyl)-/V-[6-melhoxy-5-(l-methyl-l/7-pyrazol-4-yl)-2-pyridinyl]-l-(lmcthylethyl)-l/7-benzimidazol-4-aminc,

2-(4-fluorophenyl)-/V-[6-mcthoxy-5-(l-methyl-l/7-pyrazol-4-yl)-2-pyridinyl]-lmethyl- l/f-benzimidazol-4-amine,

A/-[4-(2,6-dimethyl-4-pyridinyl)phenyl]-2-(4-fluorophenyl)-l-(l-mcthylcthyl)-lWbcnzimidazol-4-aminc, /V-[3-fluoro-4-(2-methyl-4-pyridinyl)pheny l]-2-(4-fluorop he tiy l )-1 -methyl-1 /7benzimidazol-4-aminc,

N-[3-fluoro-4-(2-mcthyl-4-pyridinyi)phcnyl]-2-(4-fluorophcnyl)-l-(l-mcthylcthyl)l //-benzim idazo I-4 -am ine,

2-(2-chlorophenyl)-7V-[3-fluoro-4-(2-mcthyl-4-pyridinyl)phcnyl]-3-mcthylimidazo[l,2-fl]pyridin-8-aminc,

M[3-iluoro-4-(2-mcthyl-4-pyridinyl)phenyl]-2-(4-fluorophenyl)-l,6-dimethyl-l/fi midazo [4,5-c] pyrid in-4-amine,

2-(4-fluorophenyl)-l-mcthyl-7V-[6-(2-mcthyl-4-pyridinyl)-3-pyridazinyl]-l/7bcnzimidazol-4-amine,

2-(4-fluorophenyl)-l,6-dimethyl-N-[6-(2-mcthyl-4-pyridinyl)-3-pyridazinyl]-l/7imidazo[4,5-c]pyridin-4-aminc, and

2-(4-fluorophenyl)-l-methyl-AL[4-(4-pyridinyl)phenyl]-l//-benzimidazol-4-amine, including any stereochemically isomeric form thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

In an embodiment preferably said compound of Formula (I) is 2-(4-fluorophenyl)-A([3-mcthoxy-4-(4-methyl-5-oxazolyl)phcnylJ-1 -methyl-177-bcnzimidazol-4-amine, of

-4l including any stereochemically isomeric forms thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

In an embodiment preferably said compound of Formula (!) is 2-(4-fluorophenyl)-/V[3-mcthoxy-4-(2-mcthyl-5-oxazolyl)phcnyl]-l-methyl-lff-bcnzimidazol-4-aminc, including any stereochemically isomeric forms thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

In an embodiment preferably said compound of Formula (l) is 2-(4-fluorophcnyl)-l(l-methylethyl)-W-[6-(2-mcthyI-5-oxazolyl)-3-pyridinyl]-lJf-beiizimidazol-4-amine, including any stereochemically isomeric forms thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

In an embodiment preferably said compound of Formula (!) is 2-(4-fluorophenyl)-l(l-methylcthyl)-7V-[6-(2-methyl-5-axazolyl)-3-pyridinyl]-l//-benzimidazol-4-amine.

In an embodiment the compound of Formula (I) is selected from the group consisting of: 2-(4-fluorophenyl)-l-(l-methylcthyl)-W-[6-(2-rnethyl-5-oxazolyl)-3-pyridinyl]-lJ7benzîmidazol-4-amine, 6-fluoro-7V-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-2-(2-methylpropyl)îmidazof l ,2-a]pyridin-8-amine .HCl, 2-(4-fluorophenyl)-6-methoxy-W-[3-methoxy-4-(2-mcthyl-5-oxazolyl)phenyl]-lmethyl-1 /7-bcnzimidazo l-4-amine, 2-(4-fluorophenyl)-/V-[3-methoxy-4-(4-methyl-5-oxazolyl)phenyl]-l-methyl-l/A benzimidazol-4-amine, 2-(4-fluorophenyl)-W-[3-mcthoxy-4-(2-methyl-4-pyridinyl)phenyl]-l-(l-methylethyl)l//-bcnzimidazol-4-aminc, including any stereochemically isomeric forms thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

In the passages above, the features of an embodiment can be combined with the features of another embodiment or combinations of embodiments.

The présent invention also encompasscs proccsscs for the préparation of compounds of Formula (I) and subgroups thereof. In the reactions described, it can bc necessary to protect reactive functional groups, for example hydroxy, amino, or carboxy groups, where these arc desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can bc used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in Protective Groups in

Organic Chemistry, John Wiley and Sons, 1999.

-42The compounds of Formula (I) and the subgroups thereof can be prepared by a succession of steps as described hercunder, They arc generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art. The compounds of the présent invention can be also prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry.

The general préparation of some typical cxamplcs is shown below:

Experimental procedure l ln general, compounds of formula (I), can be prepared as set out below in Scheme l wherein ail variables are defined as hereabove:

A¹^ Het^'_Ar^A‘	⁺ Halo---Het²
(H-a)	(ll!-a)	base, solvent	A¹ Het¹ A³ (D
/Halo YY Η,.Άί'* (ll-b)	+ H;N—Het² (lll-b)	catalyst, ligand

Scheme l

Compounds of formula (l) can bc prepared via a coupling reaction between intermediates of formula (ΙΙ-a) and (IH-a) or between intermediates of formula (Π-b) and (ΙΙΙ-b), wherein Halo is defined as Cl, Br or l and wherein ail other variables are as defined hereinbefore. This reaction may be performed in the presence of a suitable base such as, for examplc, CS2CO3 or sodium /err-butoxîdc. The réaction can bc performed in a rcaction-incrt solvent such as, for cxample, toluene, MA'-dimethylformamide (DMF), rerr-butanol or dioxanc. The reaction typically is performed in the presence of a catalyst System comprising of a suitable catalyst such as palladium(II) acetate (Pd(OAc)2) or tris(dibenzylidcneacetone)dîpalladium (Pdîfdbafr) and a ligand such as (QjQ-dimcthyl^/i-xanthcne^.S-diyObisfdiphenylphosphine] (Xantphos), [l,l^,-binaphthalcnc]-2,2’-diylbis[diphcnylphosphinc] (BINAP), or dicyclohexyl[2’,4',6'tris(l-mcthylcthyl)[l,l'-biphcnyl]-2-yl]-phosphine (X-phos). Preferably this reaction is carried out under an inert atmosphère, such as a nitrogen or an argon atmosphère. Reaction rate and yield may be enhanced by microwave assisted heating.

y

-43In an alternative procedure, that is only valid when Y¹, Y³, Z¹ or Z³ is N in the définition of Het², a compound of formula (I) wherein Y¹, Y³, Z¹ or Z³ is N, can bc prepared via an aromatic nucleophilic substitution between intermediates of formula (ΙΙ-a) and (111-a). This reaction may be performed in the presence of a suitable base such as, for example, K.2CO3 or diisopropylethylamine. The réaction can be performed in a reaction-inert solvent such as, for example, DMF or CH₃CN. This reaction may also be performed under acidic conditions, for example, in the presence of HCl or methancsulfonic acid. This reaction can be performed in a reaction-inert solvent such as, for example, 2-propanol. Reaction rate and yield may be enhanced by microwave assisted heating.

Experimental procedure 2

Compounds of formula (1), can also be prepared via a coupling reaction between an intermediate of formula (IV) and an intermediate of formula (V) according to Schcmc 2 wherein Halo is defined as Cl, Br or 1 and wherein ail other variables are as defined before.

Α’^γ^Ν'^Η _β'₂ xi Halo A3 (IV)	(V)	Δ2 ^H A N Α¹^γ 'Het² Het¹ A³ (l)
Scheme 2

In Scheme 2, intermediate of formula (V) may be commercially available or may bc prepared according to conventional reaction procedures generally know in the art. The coupling réaction is performed in the presence of a suitable base such as, for cxamplc, CS2CO3, Na₂CO,i or NaOH. The reaction can be performed in a reaction-inert solvent such as, for example, toluène, DMF or dioxane. The réaction typically is performed in the presence of a catalyst such as tetrakis(triphenylphosphinc)palladium (Pd(PPhj)i). Stirring, elevated températures (for cxample between 70-140 °C) and/or pressure may enhance the rate of the reaction. Preferably this reaction is carried out under an inert atmosphère, such as a nitrogen or argon atmosphère.

Alternatively, the boronic acid picanol ester dérivative of formula (V) can be replaced by the corresponding boronic acid dérivative.

-44Expcrimental procedure 3

Alternatively compounds of formula (I), can also be prepared via a coupling reaction between an intermediate of formula (Vl) and an intermediate of formula (Vil) according to Scheme 3 wherein Halo is defined as Cl, Br or I and wherein ail other variables are as defined before.

Het’

A² N

A³ (D

Schente 3

In Scheme 3 intermediates of formula (VII) may be commcrcially available or may be prepared according to conventional reaction procedures generally know in the art. The reaction conditions are analogous to the réaction conditions described in experimental procedure 2.

Experimental procedure 4

An intermediate of formula (Il-a) can be prepared by réduction ofan intermediate of formula (VIII) as is shown in Scheme 4, wherein ail variables arc as defined before.

(VIII) réduction

(ll-a)

Scheme 4

The réduction of (VIII) to (Π-a) can be conducted by conventional methods such as, for cxample, a reductivc hydrogénation or réduction with a métal or a métal sait and an acid [for example a métal such as iron or a mctal sait such as SnCb and acid such as an inorganic acid (hydrochloric acid, sulfuric acid or the like) or an organic acid (acetic acid or the like)], or other well-known methods for converting a nitro-group to the corresponding amine.

Experimental procedure 5

An intermediate of formula (VHI) wherein Hct¹ is restricted to oxazole substituted with R° in the 4-position, hcreby named intermediate of formula (XI), can be prepared by a condensation réaction of an intermediate of formula (X) with an intermediate of formula (IX) as is illustrated in Scheme 5. Intermediate (IX) may be commercially available or may be prepared according to conventional reaction procedures generally know in the art. This condensation reaction is performed in the presence of a suitable base such as, for example, K2CO3 or sodium ethoxîde (NaOEt). The reaction can bc performed in a protic solvent such as, for example, methanol (MeOH) or éthanol (EtOH). Stirring and/or elevated températures (for example between 70-110 °C) may enhance the rate of the réaction. In Scheme 5, ail variables are defined as mentioned hereabove.

(XI)

Scheme 5

Alternatively, the réaction described in Scheme 5 may also be performed with a benzaldéhyde dérivative of the intermediate of formula (IX) wherein NO2 is replaced by Cl, Br, 1, or NH-Het².

Experimental procedure 6

An intermediate of formula (11-a) can also be prepared by conversion of the Halosubstitutent in an intermediate of formula (Il-b) into an amino-group, or a masked or protected amino functionality which can subsequently be converted into an aminogroup, according to Scheme 6 by using reaction conditions well known to those skilled in the art. In Scheme 6, Halo is defined as Cl, Br or I, and ail other variables are defined 25 as mentioned hereabove.

Het¹

(ll-b)

(H-a)

Scheme 6

The intermediate of formula (Π-b), wherein Het¹ is limited to oxazole substituted with

R°, hereby named intermediate of formula (ΧΠ-b), can be prepared according to the synthesis protocol that was used for the synthesis of intermediate (XI), starting from an intermediate of formula (XII):

(Xll-b)

The intermediate of formula (XII) is commercially available or may be prepared according to conventional reaction procedures generally known in the art.

Experimental procedure 7

An intermediate of formula (VIH) wherein Het¹ is restricted to oxazole substituted with R¹ in the 2-postion and Clfi in the 4-position, hereby named an intermediate of formula (XIII), can be prepared by a condensation réaction of an intermediate of formula (XIV) with an intermediate of formula (IX) according to Scheme 7 wherein ail variables are defined as hereinbefore. Both intermediates may be commercially available or may be prepared according to conventional reaction procedures generally know in the art. This condensation réaction typically can be performed in a solvent such as pyridine. Stirring and/or elevated températures (for example between 70-110 °C) may enhance the rate of the reaction.

Experimental procedure 8

An intermediate of formula (IV) can bc prepared via a coupling reaction between an intermediate of formula (XV) and an intermediate of formula (ΙΠ-a), as is shown in Scheme 8 wherein Halo is defined as Cl, Br or I and wherein ail other variables are defined as hereinbefore. This reaction may be performed in analogy to the synthesis protocol described in Experimental procedure 1.

y

^A’ Ja« Halo as	A² n Base, solvenl A¹ Het² * H·¹» ^He'^! ------------ AJa- Halo a³
(XV)	(lll-a) (IV) Scheme 8

Experimental procedure 9

An intermediate of formula (VIII) wherein Het¹ is restricted as shown in Scheme 9, hereby named an intermediate of formula (XVIII), can bc prepared by condensation of an intermediate of formula (XVII) with an intermediate of formula (XVI) which is activated with iodobenzene diacetate in the presence oftrifluoiOmethanesulfonic acid. Stirring and/or elevated températures (for example between 70-100 °C) may enhance the rate of réaction. In Schcmc 9, R^la is defined as Cualkyl and ail other variables in are defined as hereinbefore.

R^1a-CN (XVII)

CF₃SO₃H

OAc

Ph-I

OAc

Scheme 9

An intermediate of formula (XVIII) wherein NO₂ is replaced by Cl or Br, can be prepared from an intermediate of formula (XVI) wherein NO₂ is replaced by the corresponding halogen (Cl or Br respectively).

Experimental procedure 10

An intermediate of formula (VIII) wherein Het¹ is restricted as shown in Scheme 10, hereby named an intermediate of formula (XXI), can be prepared via the condensation of an intermediate of formula (XIX) with an intermediate of formula (XX) as shown in Scheme 10 wherein ail variables are as defined before. Typically the réaction can be performed in acetic acid. Stirring and/or elevated températures (up to 90 °C) may enhance the rate of the reaction.

Experimental procedure 11

An intermediate of formula (XIX) can be prepared by the condensation of dimethylformamide dimethyl acetal (DMF-DMA) with an intermediate of formula (XVI) as depicted in Scheme 11. Stirring and/or elevated températures (for example between 70-l 10 °C) may enhance the rate of the reaction.

DMF-DMA

Scheme 11

Experimental procedure 12

An intermediate of formula (111-a) wherein Het² is restrictcd to resuit in an intermediate of formula (XXIV), can be prepared via a condensation réaction between an intermediate of formula (XXII) and an intermediate of formula (XXIII) as is illustrated in Scheme 12, wherein Halo is restrictcd to Br and Cl, and wherein ail other variables arc defined as hercabove. The reaction may be performed in a reaction-inert solvent such as, for example, EtOH or n-butanol, or by mixing the reagents without the presence of a solvent. The reaction may conveniently bc carried out at elevated températures ranging between 50 °C and the reflux température ofthe réaction mixture. Réaction rate and yield may be enhanced by microwave assisted heating.

Halo

O (XXIII)

(XXII) (XXIV)

Scheme 12

-49Experimental procedure 13

An intermediate of formula (Ill-a) wherein Het² is restricted to resuit in an intermediate of formula (XXVII) wherein R⁶¹’ is carbon-linkcd to the benzimidazole heterocycle, can bc prepared by an acylation of an intermediate of formula (XXV) with an intermediate of formula (XXVI) followed by a condensation reaction to yield (XXV11), according to Scheme 13 wherein Halo is restricted to Br, Cl and I and wherein ail other substituents arc as defined hcrcinbcforc. The acylation réaction can bc carried out in a solvent such as pyridine or a reaction inert solvent such as DMF in the presence of a base such as triethylamine (EtjN). The subséquent condensation reaction can be carried out by heating the crude acylatcd product in a solvent such as acctic acid.

Y'. -<;Y³Y²

H

N_x R6b

R⁷ ₊

(XXVI) (XXVII) (XXV)

Scheme J3

Experimental procedure 14

Alternatively, an intermediate of formula (XXV11) wherein R^6b is carbon-linkcd to the benzimidazole heterocycle can also be prepared by treatment of an intermediate (XXV) with an aldéhyde of formula (XXVIII). The reaction can bc performed in the presence of sodium metabisulfite in a réaction inert solvent such as /V,/V-dimethylacctamidc (DMA) according to Scheme 14 wherein Halo is restricted to Br, Cl and I and wherein ail other substituents arc as defined hereinbefore.

Y\ xiY³ o

Y² (XXVIII) (XXV)

Y² (XXVII)

Scheme 14

-50Experimental procedure 15

Alternatively, an intermediate of formula (XXVII) wherein R^ûh is carbon-linked to the benzimidazole heterocycie can also be prepared by treatment of an intermediate (XXIX) with an aldéhyde of formula (XXVIII) in the présence of sodiumdîthionitc in a reaction inert solvent such as EtOH according to Scheme 15 wherein Halo is restricted to Br, Cl and I and wherein ail other substituents are as defined hereinbefore.

(XXIX)

(XXVIII)

Y* (XXVII)

Scheme 15

7

For an intermediate of formula (XXVII) wherein R is H, an alternative R can be introduced via V-alkylation, lcading prcdominantly to an intermediate of formula (XXVII) wherein R⁷ is a substituent as defined before, cxcept hydrogen.

Experimental procedure 16

An intermediate of formula (XXV) can be prepared via réduction ofan intermediate (XXIX) as shown in Scheme 16 below, wherein Halo is restricted to Br, Cl and I and wherein ail other substituents arc as defined hereinbefore. The réduction of (XXIX) to (XXV) can be conducted by a conventional method such as, for example, a rcductive hydrogénation or réduction with a métal or a métal sait and an acid [for example a mctal such as iron, or a mctal sait such as SnCh and acid such as an înorganic acid (hydrochloric acid, sulfuric acid or the like) or an organic acid (acetic acid or the like)], or other well-known methods for converting a nitro-group to the corresponding amine.

réduction

Scheme 16

Experimental procedure 17

An intermediate of formula (XXIX) can be prepared via a substitution reaction of an intermediate of formula (XXX) with an intermediate of formula (XLV) as is shown in Scheme 17 below, wherein Halo is restricted to Br, Cl and l, Halo-b is defined as F, Cl, 5 or Br, and wherein ail other substituents arc as defined hcreinbefore. Intermediates of formula (XLV) are commercially available or may bc prepared according to conventional reaction procedures generally known in the art.

Halo-b

R⁷-NH₂ (XLV)

Y\ ^Y³

Y2 (XXIX) (XXX)

Scheme 17

Experimental procedure 18

An intermediate of formula (Vlll), can bc prepared via a coupling reaction between intermediates of formula (XXXI-a) and (XXXII-a) or between intermediates of formula (XXXI-b) and (XXXII-b), This réaction is shown in Scheme 18 wherein Halo is restricted to Br, Cl and 1 and wherein ail other variables arc defined as hcreinbefore. In Scheme 18, intermediates of formula (XXXI-a), (XXXI-b), (XXXII-a) and (XXXIl-b) may be commercially available or may be prepared according to conventional reaction procedures generally know in the art. The coupling réaction is performed in the presence of a suitable base such as, for example, CS2CO3, NaîCCh or NaOH. The reaction can bc performed in a reaction-inert solvent such as, for example, toluene, DMF or tetrahydrofuran (THF). The réaction typically is performed in the presence of a catalyst system comprising of a suitable catalyst such as palladium(II) acetate (Pd(OAc)2) and a ligand such as triphenylphosphine. Stirring, elevated températures (for cxamplc between 70-140 °C) and/or pressure may enhance the rate of the réaction. Preferably this reaction is carried out under an inert atmosphère, such as a nitrogen or argon atmosphère, lnstead of boronic acids (ΧΧΧΠ-a) or (XXXI-b), the corresponding boronate esters, such as pinacol esters can bc used.

Halo

A²

Tï >A«

A³

NO₂

-52OH

Het¹—B

OH (XXXi-a) (XXXII-a)

A²

Het¹

TT

A.^a‘ no₂

Het¹---Halo (XXXll-b)

Scheme !8 (VIII)

Experimental procedure 19

An intermediate of formula (XVI) can be prepared via a coupling reaction between an intermediate of formula (XXXI-a) and tributyl(l-ethoxyvinyl)tin according to Scheme 19 wherein Halo is defined as Br, Cl or I and wherein ail other variables are as defined before. In Scheme 19, an intermediate of formula (XXXl-a) may be commercially available or may be prepared according to conventional reaction procedures generally know in the art. The réaction can be performed in a reaction-incrt solvent such as, for example, toluene or DMF. The réaction typically is performed in the presence of a catalyst such as Pd(PPhî)4. Stirring, elevated températures (for cxample between 70140 °C) and/or pressure may enhance the ratcof the reaction. Preferably this reaction is carried out under an inert atmosphère, such as a nitrogen or an argon atmosphère. Subsequently, the obtained éthanol can be hydrolysed in acidic conditions such as, for example, by using hydrochloric acid, to yield the acetyl derivative of formula (XVI).

A² NO

Α^ι^γ ²

LJ I

HalcK ^3 (XXXi-a)

2) Acidic hydroiysis

A²

1) Tributyl(1-ethoxyvinyl)tin

Scheme 19

Experimental procedure 20

An intermediate of formula (XXXV) can be prepared via a condensation réaction between an intermediate of formula (XXXIV) and an intermediate of formula (XXX11I) as shown in Scheme 20 wherein R^ln is defined as Ci^alkyI and wherein ail other substituents are defined as hcreabove. The reaction can bc performed in a solvent such

as, for example, pyridine. Stirring, eievated températures (for example between 70 and 100 °C) may cnhance the rate of the réaction.

A2

° (XXXIV)

H N-OH

NH (XXXIII)

i (XXXV)

Scheme 20

Experimental procedure 21

An intermediate of formula (XXXIV) can be prepared via an activation réaction of an intermediate of formula (XXXVI) as is shown in Scheme 21 wherein ail variables are defined as hcrcabovc. The réaction can bc performed in a reaction-inert solvent such as, for example, chloroform, in the presence of DMF. The reaction typically is performed in the presence of an activating reagent such as, for cxamplc, SOCh- Stirring, eievated températures (for cxamplc between 50 and 80 °C) may cnhance the rate of the réaction.

A²

° (XXXVI)

NO₂ ⁰ (XXXIV)

Scheme 21

Experimental procedure 22

An intermediate of formula (XXXIX) can be prepared via a coupling réaction between an intermediate of formula (XXXVII) and an intermediate of formula (XXXVIII) according to Scheme 22 wherein Halo is defined as I or Br, and wherein ail other variables are defined as before. In Scheme 22, intermediates of formula (XXXVII) and (XXXVIII) may bc commercially available or may be prepared according to conventional reaction procedures generally know in the art. The coupling réaction is performed in the presence of a suitable base such as, for example, CS2CO3, or AgzCOj. The reaction can be performed in a reaction-inert solvent such as, for example, H2O, CFI3CN or DMF. The reaction typically is performed in the presence of a catalyst System comprising of a suitable catalyst such as palladium(II) acetate (PdfOAch) or 1. l-bis(diphcnylphosphinofcnOcencdichloropalladiumlI) (Pd(dppf)Cl2), and a ligand such as triphcnylphosphinc. Stirring, eievated températures (for cxample between 60 an 140 °C) may cnhance the rate of the reaction.

Experimental procedure 23

An intermediate of formula (XLl) can bc prepared via a décarboxylation réaction of a compound of formula (XL) as depicted in Scheme 23 wherein Halo is defined as Br, 1 or Cl, and wherein ail other variables are defined as hercinabove. The reaction can be performed in a solvent such as quinolinc or DMF in the presence of coppcr(II) oxide (CuO). The réaction typically requires high température (up to 150 °C).

Scheme 23

Experimental procedure 24

An intermediate of formula (XL) can be prepared via hydrolysis of the carboxylic ester function of a compound of formula (XLII) as depicted in Scheme 24 wherein Halo is defined as Br, 1 or Cl, and wherein ali other variables are defined as before. This réaction can be performed either in acidic conditions or in basic conditions. It will be preferably performed in basic conditions in the presence of a base such as NaOH or LiOH in a mixture of dioxane and water at room température.

Scheme 24

-55Experimental procedure 25

An intermediate of formula (XLll) can be prepared via a coupling reaction between an intermediate of formula (XLIIl) and an intermediate of formula (XLIV) as depicted in Scheme 25 wherein Halo is defined as Br, l or Cl, wherein Halo-c is defined as Br or I, and wherein ail other variables are defined as hereinbefore. Intermediates of formula (XLIIl) and (XLIV) may bc commercially available or may bc prepared according to conventional reaction procedures generally know in the art. The coupling reaction is performed in the presence of a suitable base such as, for example, CS2CO.1 or AgîCCh. The reaction can bc performed in a rcaction-inert solvent such as, for example, CHjCN, toluène or DMF. The reaction typically is performed in the presence of a catalyst systern comprising of a suitable catalyst such as palladium(Il) acetate (Pd(OAc)2) or [l,l ’-Bis(diphenylphosphino)fcrroccnc]dichloropalladium(I[) (Pd(dppf)Cl₂), and a ligand such as, for instance, triphenylphosphine or tri-o-toluylphosphine. Stirring, elevated températures (for example between 60 an 140 °C) may enhance the rate of the reaction.

(XLIIl)

Scheme 25

Where necessary or desired, any one or more of the following further steps in any order may bc performed:

Compounds of Formula (1), any subgroup thereof, addition salts, solvatés, and stereochemical isomeric forms thereof can be converted into further compounds according to the invention using procedures known in the art. In a particular case, a compound of formula (1), wherein R^4a or R^4b is defined as Cl, Br or I can be further derivatized to a compound of formula (I) wherein R⁴¹¹ or R⁴¹’ is H, under reductivc conditions well known by those skilled in the art.

It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to bc blocked by protecting groups. In case the functional groups of intermediate compounds were blocked by protecting groups, they can be deprotected after a reaction step.

- 56Pharmacology

It has been found that the compounds of the présent invention modulate the ysecretase activity. The compounds according to the invention and the pharmaceutically acceptable compositions thereof arc therefore useful in the treatment or prévention of Alzheimcr's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), senility, dementia, dementia with Lewy bodies, cérébral amyloid angîopathy, multiinfarct dementia, Down's syndrome, dementia associated with Parkinson’s disease and dementia associated with beta-amyloid, preferably Alzhcimer's disease.

As used herein, the term “modulation of γ-secretase activity’’ refers to an effect on the processing of APP by lhey-secretase-complex. Preferably it refers to an effect in which the overall rate of processing of APP romains essentially as without the application of said· compounds, but in which the relative quantities of the processed products are changed, more preferably in such a way that the amount ofthe AB42peptide produced is reduced. For cxample a different Abcta species can be produced (e.g. Abcta-38 or other Abeta peptide species of shorter amino acid sequence instead of Abeta-42) or the relative quantities of the products are different (e.g. the ratio of Abeta40 to Abeta-42 îs changed, preferably increased).

It has been previously shown that the γ-sccrctasc complex is also involved in the processing ofthe Notch-protein. Notch is a signaling protein which plays a crucial rôle in developmental processes (e.g. reviewcd in Schweisguth F (2004) Curr. Biol. 14, R129). With respect to the use of y-sccrctasc modulators in therapy, it sccms particularly advantageous not to interfère with the Notch-processing activity ofthe ysecretase activity in order to avoid putative undesired side-effects. While y-secretase inhibitors show side cffccts due to concomitant inhibition of Notch processing, ysccretase modulators may have the advantage of selectively decreasing the production of highly aggregatable and neurotoxic forms of Αβ, i.e. Αβ42, without decreasing the production of smaller, less aggregatable forms of Αβ, i.e. Αβ38 and without concomitant inhibition of Notch processing. Thus, compounds are preferred which do not show an effect on the Notch-processing activity of the y-secrctase-complex.

As used herein, the term treatment is intended to refer to ail processes, wherein there may bc a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total élimination ofall symptoms.

The invention relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatcs thereof, for use as a médicament.

ΙΟ

-5715

The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the treatment or prévention of discases or conditions selected from Alzhcimcr's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), senility, dementia, dementia with Lewy bodies, cérébral amyloid angiopathy, multi-infarct dementia, or Down's syndrome.

In an embodiment, said discase or condition is selected from Alzhcimcr's disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cérébral amyloid angiopathy, multi-infarct dementia, or Down's syndrome.

In an embodiment, said disease or condition is preferably Alzheimer's disease.

The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the treatment of said discases.

The invention also relates to a compound according to the general formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the treatment or prévention, in particular treatment, ofy-secretasc mediated diseases or conditions.

The invention also relates to the use ofa compound according to the general Formula (1), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the manufacture of a médicament.

The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the manufacture of a médicament for the modulation ofy-secrctase activity.

The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the manufacture of a médicament for the treatment or prévention of any one of the discase conditions mentioned hercinbefore.

The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof. for the manufacture of a médicament for the treatment of any one of the disease conditions mentioned hcreinbefore.

-58In the invention, particular preference is given to compounds of Formula (I), or any subgroup thereof with a IC50 value for the inhibition of the production of AB42peptide of less than 1000 nM, preferably less than 100 nM, more preferably less than 50 nM, even more preferably less than 20 nM as determined by a suitable assay, such as the assays used in the Examples below.

The compounds of the présent invention can bc administered to mammals, preferably humans for the treatment or prévention of any onc of the diseases mentioned hereinbefore.

In view ofthe utility ofthe compound of Formula (I), there is provided a method of treating warm-blooded animais, including humans, suffering from or a method of preventing warm-blooded animais, including humans, to suffer from any one of the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), a stereoisomeric form thereof and a pharmaceutically acceptable addition sait or solvaté thereof, to warm-blooded animais, including humans.

Those of skill in the treatment of such diseases could déterminé the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0,01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about l mg/kg, most preferably from about 0.05 mg/kg to about l mg/kg body weight. The amount of a compound according to the présent invention, also referred to here as the active ingrédient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the âge and condition of the récipient, and the particular disorder or disease being treated.

A method of treatment may also include admînistering the active ingrédient on a regîmen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations arc prepared by known procedures using well known and readily available ingrédients.

The compounds of the présent invention,that are suitable to treat or prevent

Alzheimer's disease or the symptoms thereof, may be administered alone or in

-59combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and cach additional therapeutic agents 5 in its own separate pharmaceutical dosage formulation. For example, a compound of

Formula (l) and a 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.

While it is possible for the active ingrédient to bc administered alone, it is préférable to présent it as a pharmaceutical composition.

Accordingly, the présent invention further provîdcs a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of a compound according to Formula (l).

The carrier or diluent must bc “acceptable” in the sense of being compatible with the other ingrédients of the composition and not dclctcrious to the récipients thereof.

For case of administration, the subject compounds may bc formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds according to Formula (I), a pharmaceutically acceptable acid or base addition sait thereof, a stereochcmically isomeric form thereof, or any subgroup or combination thereof may bc formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may bc cited ail compositions usually employed for systemically administering drugs.

To prépare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of préparation desired for administration. These pharmaceutical compositions are désirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parentéral 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, for cxample, water, glycols, oils, alcohols and the like in the case of oral liquid préparations such as suspensions, syrups, élixirs, émulsions and solutions; or solid carriers such as starchcs, sugars, kaolin, diluents, lubricants, binders,

-60disintcgrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers arc obviously employed. For parentéral compositions, the carrier will usually comprise stérile water, at least in large part, though other ingrédients, for cxample, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of Formula (I) may be formulated in an oil for prolongcd action. Appropriate oils for this purpose are, for example, peanut oil, scsame oil, cottonseed oil, com 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 arc solid form préparations that are intended to be convcrtcd, shortly before use, to liquid form préparations. In the compositions suitable for perculancous administration, the carrier optionally comprises a pénétration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introducc a significant dcleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may bc administered in various ways, e.g., as a transdcrmal patch, as a spot-on, as an oinlment. Acid or base addition salts of compounds of Formula (I) due to their increased water solubi lity over the corresponding base or acid form, are more suitable in the préparation of aqueous compositions.

It is especially advantageous to formulate the aforcmentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrète units suitable as unilary dosages, each unit containing a predetermined quantity of active ingrédient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositorics, injectable solutions or suspensions and the like, and segregated multiples thereof

Since the compounds according to the invention are potent orally administrable compounds, pharmaceutical compositions comprising said compounds for administration orally arc especially advantageous.

-6l ·

In order to cnhance the solubility and/or the stability of the compounds of Formula (I) in pharmaceutical compositions, it can be advantageous to employ α-, β- or γ-cyclodextrins or their dérivatives, in particular hydroxyalkyi substituted cyclodextrins, e.g. 2-hydroxypropyl-p-cyclodextrin or sulfobutyl-P-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from O.l to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the compound of formula (I), and, from l 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, ail percentages being based on the total weight of the composition.

The following examples illustrate the présent invention.

Examples

Hereinafter, the term “DCM” means dichloromethane; “MeOH” means methanol; “LCMS” means Liquid Chromatography/Mass spcctrometry; “aq.” means aqueous; “sat.” means saturated; “sol.” means solution; “HPLC” means high-performance liquid chromatography; “r.t.” means room température; “AcOH” means acetic acid; “m.p.” means melting point; “Et20” means diethyl ether; “BDS” means base deactivated silica; “RP” means reversed phase; “min” means minute(s); “h” means hour(s); “I.D.” means internai diameter; “Pd(OAc)2” means palladium(Il) acetate; “LiHMDS” means lithium hexamethyldisilazane; “HBTU” means l-[bis(dimethylamino)methylene]-I//benzotriazol-l-ium 3-oxide hexafluorophosphate; “Xantphos” means (9,9-dimethyl9//-xanthcne-4,5-diyl)bis[diphcnylphosphine]; “X-Phos” means dicyclohexyl[2’,4',6'tris(l-methylethyl)[l,r-biphenyl]-2-yl]-phosphinc; “NH.jOAc” means ammonium acetate; “NMP” means l-methyl-2-pyrrolidinone; “SFC” means Supercritical Fluid Chromatography; “iPrNHî means isopropylamine; “DME” means 1,2dimethoxycthane; “EtOAc” means ethyl acetate; “BINAP” means [ 1,l'-binaphthalene]2,2'-diylbis[diphenylphosphine] (racemic); EtîN means triethylamine; “EtOH” means éthanol; “Pd(PPhj)4 means tetrakis(triphenylphosphine)palladium; “PPhj” means triphenylphosphine; “eq” means équivalent; “r.m.” means réaction mixture(s); “DIPE” means diisopropyl ether; “D1PEA” means diisopropylethylamine; “DMA” means N,Ndimethylacetamide; “THF” means tetrahydrofuran, “DMSO” means dimethyl sulfoxide; “DMF” means Λζ/V-dimethyl formamide; “DMF-DMA” means dimethylformamide dimethyl acetal; “PdC12(PPh?)2 means

-adichlorobis(triphenylphosphine)palladium; “KOzBu” means potassium tert-butoxide; “Ph(Phj)4” means tetrakis(triphenylphosphine)palladium and '‘Pd₂(dba).i” means tris[p[(l,2-p:4,5-q)-(lE,4E)-l,5-diphenyl-l,4-pentadien-3-one]]dipalladium.

A, Préparation of the intermediates

Examnle Al

a) Préparation of intermediate 1

K₂C0j (9.6 g, 69.5 mmol) and 1 -methyl-l-tosylmethylisocyanide (8 g, 38.2 mmol) were added to a sol. of 2-formyl-5-nitroanisole (6.29 g, 34.7 mmol) in MeOH (150 ml) and the r.m. was refluxed for 4 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO^), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: n-hcptanc/EtOAc from 100/0 to 50/50). The product fractions were collected and the solvent was evaporated. Yield: 6.24 gof intermediate 1 (77 %).

b) Préparation of intermediate 2

MeOH (150 ml) was added to Pd/C 10 % (1 g) under a N₂ atmosphère. Subsequently, a 0.4 % ihiophene sol. in DIPE (1 ml) and intermediate 1 (6.24 g, 26.6 mmol) were added. The r.m. was stirred at 25 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. Yield: 5.4 g of intermediate 2 (99 %).

Example A2

a) Préparation of intermediate 3

Iodobenzene diacetate (5.49 g, 18.44 mmol) and trifluoromcthanesulfonic acid (6.08 ml, 69.17 mmol) were stirred in CHjCN (100 ml) at r.t. for 1 h under N₂. 2’-Methoxy4’-nitiO-acetophcnone (3.0 g, 15.37 mmol) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h, then cooled to r.t. and carefully added to a stirred sat. aq.

-63sol. of Na₂COj (500 ml), The product was extracted with DCM and the organic phase was dried (MgSCL), filtered and the solvent was evaporated under reduced pressure. The resulting dark brown oil was purified by flash column chromatography over Silica gel (eluent: DCM/MeOH isocratic 95/5). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 3.0 g of intermediate 3 (75 %).

b) Préparation of intermediate 4

ÎO

MeOH (50 ml) was added to Pd/C 10 % (0.250 g) under a N₂ atmosphère. Subsequently, a 0.4 % thiophene sol. in DIPE (2 ml) and intermediate 3 (0.946 g, 4.04 mmol) were added. The r.m. was stirred at 25 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The product was triturated in DIPE, filtered off and dried under vacuum. Yield: 0.66 g of intermediate 4 (80 %).

Example A3

Préparation of intermediate 5

3-Bromo-2-pyridinamine (24.9 g, 144 mmol), 2-bromo-l-(3-methoxyphenyl)-lpropanone (42 g, 172.8 mmol) and 250 ml n-butanol were heated at reflux température for 3 nights. The mixture was separated between DCM and water. The organic layer was dried (MgSO«), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over Silica gel (eluent: DCM/MeOH(NHî) from 100/0 to 98/2. The purest fractions were concentrated under reduced pressure and the residue was crystallized from DIPE. Yield: 19 g of intermediate 5 (42 %). Example A4

Préparation of intermediate 6

CIIjO

Br

To a sol. of intermediate 5 (2 g, 6.3 mmol) and 4-bromo-3-mcthoxyaniline (1.40 g, 6.93 mmol) in DMF (40 ml) were added Cs₂CO? (4.1 g, 12.61 mmol), Pd₂(dba)₂ (0.144 g, 0.158 mmol) and BINAP (0.196 g, 0.315 mmol) and the mixture waspurged with N₂

for 5 min. The r.m. was heated at 120 °C for 2 h then cooled to r.t. To the r.m. H₂O (300 ml) and EtOAc (300 ml) were added and the mixture was stirred at r.t. for 15 min. The organic phase was separated, washed with H₂O and brine, dried (MgSO^), filtered and evaporated till dryness. The residue was crystallized from EtOH, filtered and dried. Yield: 1.8 g of intermediate 6 (65 %).

Example A5

Préparation of intermediate 7

Bis(pinacolato)diborane (0.191 g, 0.753 mmol), [l,r-Bis(diphenylphosphino) ferrocenejdichloropalladium (0.020 g, 0.025 mmol) and potassium acetate (0.049 g, 0.502 mmol) were added to a sol. of intermediate 6 (O.llO g, 0.251 mmol) in DMF (10 ml) and the mixture was purged with N₂ for 10 min. The r.m. was heated at 120 °C for 5 h. The r.m. was cooled to r.t. and lhe solvent was removed under reduced pressure. The residue was dissolved in DCM. The organic phase was washed with H₂O and brine, dried (MgSCL), filtered and evaporated till dryness. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.070 g of intermediate 7 (57 %).

Exemple A6

a) Préparation of intermediate 8

2-Methoxy-4-nitrobenzaldehyde (4.677 g, 25.817 mmol) and 2-acetamidoacrylic acid (5 g, 38.725 mmol) were added to pyridine (50 ml) and the r.m. was stirred at 120 °C overnight. After cooling the r.m. was poured into H₂O and the product was extracted with EtOAc. The organic phase was separated, dried (MgSOJ, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: «-hcptane/EtOAc from 100/0 to 75/25). The product fractions were collected and the solvent was evaporated. Yield: 0.9 g of intermediate 8 (14 %).

b) Préparation of intermediate 9

MeOH (50 ml) was added to Pd/C 10 % (0.2 g) under a N₂ atmosphère. Subsequently, a 0.4 % thiophene sol. in DIPE (0.5 ml) and intermediate 8 (0.9 g, 3.62 mmol) were added. The r.m. was stirred at 25 °C under a H₂ atmosphère until 3 cq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. Yield: 5.4 g of intermediate 9 (88 %).

Examplc A7

a) Préparation of intermediate 10

2¹-Methoxy-4’-nitro-acetophenonc (90564-14-0, 3.07 g, 15.73 mmol) in DMF-DMA was rcfluxcd for 6 h. The r.m. was cooled to r.t. and concentrated under reduced pressure. The residue was triturated in DIPE and the precipitate was filtered. Yield:

3.63 g of intermediate 10 (92 %).

b) Préparation of intermediates 11 and 12

Intermediate 10 (3.63 g, 14.505 mmol) was added to a sol. of methylhydrazinc (0.84 ml, 15.956 mmol) in AcOH (20 ml) and the resulting mixture was stirred at 90 °C for 3 h. The r.m. was cooled to r.t. and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/w-hcptane from 50/50 to 70/30). The product fractions were collected and the solvent was evaporated. Yield:

1.44 g of intermediate 11 (42 %) and 0.83 g of intermediate 12 (24 %).

c) Préparation of intermediate 13

MeOH (50 ml) was added to Pd/C 10 % (0.2 g) under a N₂ atmosphère. Subsequently, a

0.4 % thiophene sol. in DIPE (1 ml) and intermediate 12 (0.83 g, 3.57 mmol) were

added. The r.m. was stirred at 25 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. Yield: 0.72 g of intermediate 13 (98 %).

Example A8

a) Préparation of intermediate 14

N· ff—F'¹N

First K.2CO3 (14,84 g, 107.5 mmol) and then 1-methyl-l-tosylmethylisocyanide (13.5 g, 64.5 mmol) were added to a sol. of 6-bromopyridine-3-carbaldchyde (10.0 g, 53.76 mmol) in 200 ml MeOH. The r.m. was reftixed for 1 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H2O, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: nheptane/EtOAc from 100/0 to 50/50). The product fractions were collected and the solvent was evaporated. The residue was suspended in D1PE, the precipitate was filtered off and dried under vacuum at 50 °C. Yield: 6.8 g of intermediate 14 (53 %).

b) Préparation of intermediate 15

N—nh₂

N

2-Methyl-2-propanol, sodium sait (0.804 g, 8.36 mmol), B1NAP (0.521 g, 0.837 mmol), Pd₂(dba)₃ (0.383 g, 0.418 mmol) and benzophenone iminc (0.948 g, 5.23 mmol) were added to a sol. of intermediate 14 (1.0 g, 4.18 mmol) in toluene (20 ml). The r.m. was degassed and put under a N2 atmosphère. The r.m. was stirred at 100 °C for 2 h in the microwavc. After cooling most of the solvent was evaporated (almost dry) and a 1 N HC1:THF sol. (1/1, 100 ml) was added. The r.m. was stirred at r.t. for 1 h. The r.m. was treated with a 10 % Na₂CO3 sol. and the product was extracted with EtOAc. The organic phase was dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.29 g of intermediate 15 (39 %).

Example A9

Préparation of intermediate 16

Br

-67A mixture of 3-bromo-2-pyridinamine (50 g, 289 mmol) and 2-bromo-l-(4fluorophenyl)ethanone (75.3 g, 346.8 mmol) in EtOH (300 ml) was heated at 75 °C for 17 h. The r.m. was cooled to r.t. The formed precipitate was filtered off, washed with EtOH (50 ml) and dried in vacuo, yielding fraction l. The corresponding filtrate was concentrated to a volume of 100 ml. EtOH (20 ml) and DIPE (100 ml) were added to the concentrate resulting in précipitation of the product. The solids were filtered off, washed with a mixture of DIPE (50 ml) and EtOH (10 ml), and dried in vacuo, yielding fraction 2. Fractions l and 2 were combined and stirred for 30 min in a sat. aq. NaHCOi sol. (500 ml). This mixture was extracted with DCM (500 ml). The separated organic layer was dried (NaîSO^), filtered and the solvent was evaporated in vacuo. The residue was recrystallizcd from EtOAc. The solid was filtered off and dried in vacuo. Yield; 46.5 g of intermediate 16 (55 %).

Example A10

a) Préparation of intermediate 17

An 8 M methylamine sol. in éthanol (100 ml, 0.8 mol) was added to 1-biomo-3-fluoro2-nitro-bcnzene (19.8 g, 90 mmol). The mixture was cooled on a water bath and was stirred overnight at r.t. Then, the solvent was evaporated and the residue was partitioned between water and DCM, The combined organic layers were dried (MgSO^), filtered and concentrated in vacuo. Yield: 20 g of intermediate 17 (96%), which was used as such in the next step.

b) Préparation of intermediate 18

Intermediate 17 (20 g, 86.6 mmol) and iron powder (15 g, 269 mmol) were added to acetic acid (150 ml), and the resulting suspension was stirred and heated at 60 °C for 1 h. The r.m. was concentrated in vacuo and the residue was partitioned between DCM and a sat. aq. NaHCO? sol. The organic layer was dried (MgSCL), filtered and concentrated in vacuo. Yield: 14 g of intermediate 18 (80 %), which was used as such in the next step.

EtyN (8.1 g, 80 mmol) was added to a sol. of intermediate 18 (10 g, 39.8 mmol) in DCM (250 ml). Subsequently, 4-fluoro-benzoylchloride (5.5 g, 34.7 mmol) was added dropwise at r.t., and the r.m. was stirred at r.t. overnight. The r.m. was washed with water, and the organic layers was dried (MgSOi), filtered and concentrated in vacuo.

The residue was dissolved in AcOH (100 ml), and a concentrated aq. HCl sol. (3 ml) was added. The r.m. was stirred at 100 °C for 2 h. The r.m. was concentrated in vacuo and the residue was dissolved in DCM and washed with a sat. aq. NaHCCh sol. and water. The organic layer was dried (MgSOq), filtered and concentrated in vacuo. Yield: 12 g of intermediate 19, which was used as such in the next step.

Examp le AI I

Préparation of intermediate 20

4,4,4-TrifluotObutyraldehyde (1.891 g, 15 mmol) was dropwise added at r.t. to a sol. of intermediate 18 (3.015 g, 15 mmol) and sodium metabisulfite (3.707 g, 19.5 mmol) in DMA (80 ml). The reaction was prefonned in the microwawe at 220 °C for 45 min. The r.m. was diluted in EtOAc and the organic layer was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by RP préparative HPLC [RP Shandon Hyperprep® C18 BDS (8 pm, 250 g, I.D. 5 cm); mobile phase: a gradient of (0.25 % NH.1HCO3 sol. in water)/MeOH], The product fractions were collected and worked up. Yield: 0.670 g of intermediate 20 (14.5 %). Example Al 2

Préparation of intermediate 21

A mixture of3-bromo-2-pyridinamine (1 g, 5.78 mmol) and 2-bromo-1-phenyl-1propanone (1.48 g, 6.94 mmol) in EtOH (20 ml) was stirred and heated at 100 °C for 2 days. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (eluent; DCM/MeOH (NH₃) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was purified by

-69RP préparative HPLC [RP Shandon Hypcrprcp® Cl 8 BDS (8 pm, 250 g, I.D, 5 cm); mobile phase: a gradient of (0.25 % NH«HCOj sol. in water)/MeOH]. The product fractions were collected and worked up. Yield: 0.850 g of intermediate 21 (51 %). Examplc A13

a) Préparation of intermediate 22

Br

MeOH (100 ml) was added to Pt/C 5 % (1 g) under N₂ atmosphère. Subsequently, a 0.4 % thiophene sol. in DIPE (2 ml) and 4-amino-2-bromo-3-nitro-pyridine (3.5 g, 16 mmol) were added. The r.m. was stirred at 25 °C under H₂ atmosphère until 3 eq of H₂was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was concentrated in vacuo. Yield: 1.8 g of intermediate 22 (63 %), which was used as such in the next step.

A mixture of intermediate 22 (1.8 g, 9.57 mmol) and 4-fluoro-benzoic acid (1.34 g, 9.57 mmol) in polyphosphoric acid (25 g) was stirred and heated at 180 °C for Ih. The r.m. was cooled to r.t, and water was added. The resulting sol. was neutralized with K₂CO.i, and the resulting precipitate was filtered off and washed with water. Yield: 1 g of crude intermediate 23, which was used as such in the next step.

Intermediate 23 (825 mg, 2.8 mmol), CH.J (400 mg, 2.8 mmol), and K₂CCh (830 mg, 6 mmol) were added to DMF (25 ml). The resulting mixture was stirred at 50 °C for 1 h.

The r.m. was cooled to r.t., and concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried (MgSO«), filtered and concentrated in vacuo. The residue was purified by RP préparative HPLC [RP Shandon

Hypcrprcp® Cl8 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: a gradient of (0.25 %

NH4HCO1 sol. in water)/MeOH], The product fractions were collected and worked up.

Yield: 180 mg of intermediate 24 (21 %).

cf

-70Examplc A14

a) Préparation of intermediate 25

HjCO

l-Methyl-4-pyrazoyl boronic acid (0.63 g, 4.99 mmol) and Cs₂COj (3.257 g, 9.99 mmol) were added to a sol. of2-bromo-5-nitroanisole (1.16 g, 4.99 mmol), palladium(ll)acetate (0.112 g, 0.5 mmol) and triphenylphosphine (0.262 g, l mmol) in THF (20 ml). After stirring for 10 min, a 3 N NaOH sol. (1.6 ml) was added and the mixture was purged with N₂ for 2 min. The r.m. was stined at r.t. overnight and the product was extracted with EtOAc. The organic layer was washed with H₂O dried (MgSOi), filtered and evaporated off. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 96/4). The product fractions were collected and the solvent was evaporated. Yield: 0.630 g of intermediate 25 (54 %).

b) Préparation of intermediate 26

MeOH (l 00 ml) was added to Pd/C 10 % (0.2 g) under a N₂ atmosphère. Subsequently, a 0.4 % thiophene sol. in DIPE (0.5 ml) and intermediate 25 (0.926 g, 3.97 mmol) were added. The r.m. was stirred at 50 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was diluted in DCM and the organic layer was washed with H₂O, dried (MgSCXi), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.82 g of intermediate 26 (100 %).

Example Al5

a) Préparation of intermediate 27

N·

First K₂COj (36 g, 262 mmol) and then l-methyl-l-tosylmcthylisocyanidc (35 g, 167 mmol) were added to a sol. of 5-nitropyridine-2-carboxaldehyde (I3l mmol) in MeOH (500 ml) and the r.m. was refluxed for 4 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with

- 7l H₂O, dried (Na₂SO.i), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: pcLrolcum ether/EtOAc 4/l). The product fractions were collected and the solvent was evaporated. Yield: 15 gof intermediate 27 (56 %).

b) Préparation of intermediate 28 νΑ sol. of intermediate 27 (10 g, 48.7 mmol) in THF (300 ml) was added to a sol. of ammonium chloride (2.6 g, 48.7 mmol) in H₂O (100 ml). Iron (l 6.3 g, 292 mmol) was then added and the r.m. was refluxed for 4 h. The precipitate was removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with H₂O, dried (Na₂SO.i), filtered and the solvent was evaporated in vacuo. The residue was dissolved in a 2 N HCl sol. and the aq. phase was washed with DCM, made basic by adition of a 2 N NaOH sol. and the product was extracted by EtOAc. The organic layer was washed, dried (Na₂SO.i), filtered and the solvent was evaporated in vacuo to yield 6 gof intermediate 28 (71 %).

Example Al 6

a) Préparation of intermediate 29

Q,

A mixture of 5-bromo-2-nitropyridinc (5 g, 24.63 mmol), tributyl(l-cthoxyvinyl)tin (9.785 g, 27.1 mmol) and Ph(PPh.i)4 (0.284 g, 0.246 mmol) in DMF (100 ml) were stirred at 120 °C for 3 h. After cooling, a l N HCl sol. was added and the r.m. was stirred at r.t. for 18 h. The r.m. was neutralized with a sat. aq. NalICCh sol. and the product was extracted with DCM. The organic phase was dried (Na₂SO<i), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: DCM/McOH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 3.44 gofintermediate 29 (83 %).

b) Préparation of intermediate 30 no₂

N lodobenzcne diacetatc (2.327 g, 7.2 mmol) and trifluoromethanesulfonic acid (2.397 ml, 27.1 mmol) were stirred in CHjCN (50 ml) at r.t. for 20 min under N₂. Intermediate 29 (1 g, 6.0 mmol) in CH3CN (10 ml) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h. After cooling the excess of CH3CN was removed under reduced pressure and the crude product was extracted with DCM. The organic layer was washed with a sat. aq. sol. of Na₂CO₂, dried (MgSOi), filtered and the solvent was

-72evaporated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/McOH from J00/0 to 99/1). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 0.73 gof intermediate 30 (47 %).

c) Préparation of intermediate 31

MeOH (150 ml) was added to Pd/C 10 % (0.5 g) under a N₂ atmosphère. Subsequently, a 0.4 % thiophcnc sol. in DIPE (2 ml) and intermediate 30 (2.2 g, 10.7 mmol) were added. The r.m. was stirred at 50 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaccous earth and the filtrate was evaporated. Yield: l.6 gofintermediate31 (68%).

Example Al 7

a) Préparation of intermediate 32

lsopropylamine (12.9 g, 218 mmol) was added to a sol. of l-bromo-3-f!uoro-2-nitrobcnzcnc (8.0 g, 36 mmol) in EtOH (40 mL). The r.m. was stirred at r.t. overnight. Then, the solvent was evaporated and the residue was partitioned between water and DCM. The combined organic layers were dried (MgSO.i), filtered and concentrated in vacuo. Yield: 8.3 g of intermediate 32 (88 %), which was used as such in the next step.

b) Préparation of intermediate 33

Intermediate 32 (8.3 g, 32 mmol) and iron powder (8.95 g, 160 mmol) were added to acetic acid (50 ml), and the resulting suspension was stirred and heated at 60 °C for lh. The r.m. was concentrated in vacuo and the residue was partitioned between DCM and a sat. aq. NaHCOi sol. The organic layer was dried (MgSO<i), filtered and concentrated in vacuo. Yield: 7.5 g of intermediate 33 (100 %), which was used as such in the next step.

c) Préparation of intermediate 34

-734-Fluoro-benzaldehydc (2,28 g, 18,3 mmol) and NajSzOs (3.73 g, 19.6 mmol) were added to a sol. of intermediate 33 (3 g, I3.l mmol) in DMA (50 ml). The r.m. was stirred at r.t. overnight. Then, the r.m. was poured into water, resulting in the précipitation of a solid. The solid was filtered off, washed with water, and suspcndcd in DIPE. The resulting solid was filtered off, washed with DIPE, and dried. Yield: 2.3 g of intermediate 34 (53 %).

Example Al8

a) Préparation of intermediate 35 ch₃o

2-Iodo-5-nitroanisole (0.675 g, 2.42 mmol), Ag^COj (l.l l g, 4.0 mmol), [l,l Bis(diphcnylphosphino)ferrocene]dichloropalladium(Il) (0.073 g, 0.10I mmol) and PPhj (0.053 g, 0.20 mmol) wcrc thoroughly mixed. 2-Mcthythiazole (0.2 g, 2.02 mmol) was added followed by CHjCN (10 ml) and the mixture was purged with N2 for 2 min. The r.m. was stirred at 60 °C overnight. After cooling DCM (20 ml) and acetone (IO ml) were added and the suspension was filtered over diatomaccous earth and extensively washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography over Silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 0.257 g of intermediate 35 (51 %).

b) Préparation of intermediate 36

Intermediate 35 (0.25 g, l mmol) and iron (0.278 g, 5 mmol) were shaken in AcOH (6 ml) for 1.5 h. The solvent was evaporated. The residue was taken up in DCM and the organic layer was washed with a l N NaOH sol., dried (MgSCb), filtered and concentrated under reduced pressure. Yield: 0.220 g of intermediate 36 (IOO %). Example Al9

a) Préparation of intermediate 37

A suspension of 2-methoxy-4-nitro-benzoic acid (4.0 g, 20.3 mmol), SOCI2 (4,72 ml,

64,9 mmol), CIICI3 (20 ml) and a drop of DMF was refluxed for 6 h. After cooling, the solvents were removed under reduced pressure and the crude residual oil was used in the next step without purification. Yield: 4.4 g of intermediate 37 (100 %).

b) Préparation of intermediate 38 ch₃o

A sol. of intermediate 37 (4.374 g, 20.3 mmol) and acetamide oxime (1.653 g, 22.32 mmol) in pyridine (50 ml) was refluxed overnight. After cooling the solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with H₂O, dried (MgSOq), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 3.8 g of intermediate 38 (79 %).

c) Préparation of intermediate 39

Intermediate 38 (0.2 g, 0.85 mmol) and tin(II) chloride dihydrate (0.959 g, 4.25 mmol) in EtOH (5 ml) were stirred at 60 °C for 1.5 h. After cooling the r.m. was poured into a mixture of a sat. Na₂CO₃ sol. (15 ml) and DCM (8 ml). The 2 phases were separated and the aq. phase was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. Yield: 0.153 g of intermediate 39 (87 %).

Example A 20

a) Préparation of intermediate 40

A 2 M sol. of mcthylamine in THF (0.80 g, 25.9 mmol) was added at 0 °C to a mixture of 2,4-dichlotO-3-nitropyridine (5.0 g, 25.9 mmol) and Et₃N (4 ml, 28.9 mmol) in DMF (15 ml). The r.m. was stirred at r.t. for 1 h, then poured into ice water and the resulting solid was filtered, washed with H₂O and dried under vacuum.

Yield: 3.0 g of intermediate 40 (62 %).

b) Préparation of intermediate 41

Cl

-754-Fluorobenzaldchyde (l .74 g, 14.08 mmol) and NaîSîO^ (8.3 g, 47.7 mmol) were added to a sol. of intermediate 40 (2.5 g, 13.32 mmol) in EtOH (60 ml). The r.m. was heated under microwave conditions at 150 °C for 45 min. The r.m. was cooled to r.t. and filtered through diatomaceous earth. The filtrate was evaporated and the residue was purified by flash column chromatography over Silica gel (eluent: DCM/ ΜεΟΗ(ΝΗί) 99/1). The product fractions were collected and the solvent was evaporated. Yield: 0.44 g of intermediate 41 (13 %).

Example A2l

a) Préparation of intermediate 42

Trifluoromethanesulfonic acid (2.39 ml, 27.0 mmol) was added to a sol. of iodobenzene diacetate (2.32 g, 7.21 mmol) in CH3CN (60 ml) and the r.m. was stirred at r.t. for 20 min under N2. A sol. of 2’-fluoro-4’-nitro-acetophenone ( l. I g, 6.0 mmol) in CH3CN (10 ml) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h and subsequently cooled to r.t. CHjCN was evaporated and the residue was extracted with DCM. The organic phase was washed with a sat. aq. NaHCCh sol., dried (MgSO.i)> filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography over Silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 0.75 g of intermediate 42 (53 %).

b) Préparation of intermediate 43

MeOH (50 ml) was added to Pd/C 10 % (0.2 g) under a N2 atmosphère. Subsequently, a 0.4 % thiophenc sol. in DIPE (l ml) and intermediate 42 (0.7 g, 3.15 mmol) were added. The r.m. was stirred at 25 °C under a H2 atmosphère until 3 eq of H2 was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. Yield: 0.6 g of intermediate 43 (77 %).

Example A22

a) Préparation of intermediate 44

Br

-76A sol. of2-iodo-5-bromopyridine (13.7 g, 48.2 mmol), 2-mcthyl-4-oxazolc carboxylic acid methyl ester (3.4 g, 24.1 mmol), palladium(n)acetatc (0.54 g, 2.41 mmol), tri-otoluylphosphine (1.47 g, 4.81 mmol) and CS2CO3 (15.7 g, 48.2 mmol) in toluène (75 ml) was flushcd with N2, sealed and stirred at 110 °C overnight. The catalyst was filtered over diatomaceous earth and the filtrate was evaporated. The crude product was purified by flash column chromatography over Silica gel (eluent: DCM/MeOHfNHî) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 5.64 g of intermediate 44 (13 %).

b) Préparation of intermediate 45

Br

Intermediate 44 (5.64 g, 15.4 mmol) and LiOH (0.91 g, 38 mmol) were dissolved in a mixture of dioxanc (40 ml) and H2O (10 ml). The r.m. was stirred at r.t. for 5 h, then treated with a 1 M HCl soi. until pH = 2. The obtained precipitate was filtered and dried under vacuum. The filtrate was extracted with CHCb and the organic layer was dried (MgSCh), filtered and the solvent was removed under rcduccd pressure to afford a solid. The two solid fractions were combined. Yield: 4.75 g of intermediate 45 (97 %).

c) Préparation of intermediate 46

Br

Copper(II) oxide (1.33 g, 16.8 mmol) was added to a sol. of intermediate 45 (4.75 g, 16.8 mmol) in DMF (75 ml). The r.m. was heated at 150 °C for 15 h. After cooling, the catalyst was filtered over diatomaceous earth and the filtrate was evaporated. The residue was triturated in DIPE/CH3CN and the resulting solid was filtered off. The filtrate was evaporated and the residue was used as such in the next step. Yield: 1 g of intermediate 46 (14,5 %).

d) Préparation of intermediate 47

Intermediate 46 (0.53 g, 2.23 mmol), Pdîfdbab (0.204 g, 0.223 mmol), dicyclohexyl[2',4',6'-tris( i -methylethyl)[ 1, l'-biphenyl]-2-yl]phosphine (0.212 g, 0.446 mmol) and CS2CO3 (2.18 g, 6.69 mmol) wcrc added to a sol. N-bcnzylaminc (0.239 g, 2.23 mmol) in 2-rncthyl-2-propanol (20 ml), and the r.m. was heated at 110 °C overnight. After cooling, H2O was added and the product was extracted with DCM. The organic phase was dried (MgSO4) filtered and concentrated under rcduccd pressure. The residue was purified by flash chromatography over Silica gel (eluent; DCM/ MeOH(NHj) from 100/0 to 98/2) and the product fractions were collectcd and the solvent was evaporated. Yield: 0.15 g of intermediate 47 (21 %).

e) Préparation of intermediate 48

N=\

MeOH (50 ml) was added to Pd/C 10 % (0.05 g) under a N₂ atmosphère. Subsequently, intermediate 47 (0.15 g, 0.565 mmol) was added. The r.m. was stitred at 50 °C under a H₂ atmosphère until l eq of H₂ was absorbed. The catalyst was filtered off over diatomaccous earth and the filtrate was evaporated. Yield: 0.105 g of intermediate 48 (95 %).

Example A23

a) Préparation of intermediate 49

HO

A l M sol. of LiHMDS in THF (47 ml, 47 mmol) was added dropwise at 0 °C under a N₂ atmosphère to a sol. of 5-(4-nitrophenyl)-oxazole (6.0 g, 31.6 mmol) in THF (100 ml). The r.m. was stirred at 0 °C for 30 min, and then DMF (3.67 ml, 47 mmol) was added and the mixture was allowed to warm to r.t. The r.m. was stirred at r.t. for 1 h and then MeOH (100 ml) and NaBH₄ (1.55 g, 41 mmol) were added. The r.m. was stirred at r.t. for 16 h, and then the solvents were partially removed in vacuo. H₂O was added, and the mixure was neutralized by adding AcOH. The mixture was extracted with DCM. The organic phase was separated, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was triturated with D1PE. Yield: 4.6 g of intermediate 49 (61 %).

b) Préparation of intermediate 50

A suspension of 60 % NaH in minerai oil (600 mg, 15 mmol) was added under a N₂atmosphère to a sol. of intermediate 49 (1.79 g, 7.5 mmol) in THF (61 ml). The r.m. was stirred at r.t. for 30 min, and thon CH3I (1.87 ml, 30 mmol) was added. The r.m. was stirred at 60 °C for 4 h, and then brine was added. The organic phase was separated, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column cliromatography over silica gel (eluent: DCM/MeOH(NH₃) 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 790 mg of intermediate 50 (41 %).

c) Préparation of intermediate 51 ''XdC¹··™¹

MeOH (100 ml) was added to Pd/C 10 % (0.2 g) under a N₂ atmosphère. Subséquently, a 0.4 % thiophene sol. in DIPE (0.5 ml) and intermediate 50 (0.79 g, 3.1 mmol) were added. The r.m. was stirred at 25 °C under a H₂ atmosphère until 3 eq of H₂ was absorbed. The catalyst was filtered off over diatomaccous earth and the filtrate was evaporated. Yield: 0.65 g of intermediate 51 (quantitative).

Example A24

a) Préparation of intermediate 52

A mixture of7V-(5-bromo-l,6-dihydro-6-oxo-2-pyridinyl)-acetamide (8.6 g, 37.2 mmol), CHjI (13.2 g, 93 mmol), and Ag₂CÛ3 (10.2 g, 3.2 mmol) in toluene (275 mi) was stirred at 60 °C for 48 h. The r.m. was cooled to r.t., and the solvent was removed in vacuo. The residue was partitioncd between DCM and I1₂O. The organic phase was separated, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was triturated with DIPE. Yield: 5.7 g of intermediate 52 (62 %).

b) Préparation of intermediate 53

l-Methyl-4-pyrazoyl boronîc acid pinacol ester (1.96 g, 9.4 mmol) and Pd(PPhî)< (0.835 g, 0.72 mmol) were added to a solution of intermediate 52 (1.77 g, 7.2 mmol) in DMF (15 ml), H₂O (5 ml) and K₂CO3 (2.0 g, 14.4 mmol). The r.m. was degassed, put under N₂, stirred and heated for 30 min at 140° C under microwave irradiation. The r.m. was cooled to r.t. and partitioncd between I1₂O and DCM. The organic phase was separated, dried (MgSO«), filtered and the solvent was evaporated in vacuo. The residue was triturated with CH3CN. Yield: 1.35 g of intermediate 53 (76 %).

c) Préparation of intermediate 54

An aq. 10 % NaOH sol. (50 ml) was added to a solution of intermediate 53 (1.3 g, 5.28 mmol) in MeOH (100 ml), and the r.m. was stirred at 80 °C for 18 h. The organic solvent was removed in vacuo and DCM and H₂O were added. The organic phase was

scparated, dried (MgSO«), filtered and the solvent was evaporated in vacuo. The residue was trituratcd with DIPE. Yield: 0.95 g of intermediate 54 (88 %). Examplc A25

a) Préparation of intermediate 55

och₃

2-Methylpyridinc-4-boronic acid pinacol ester (3178 mg, 14.5 mmol) and Pd(PPhj)« (l .22 g, 1.06 mmol) were added to a solution of2-bromo-5-nitroanisole (3.06 g, 13.2 mmol) in DME (40 ml), water ( 16 ml) and Cs₂COj (l .33 g, 40.9 mmol). The resulting mixture was stirred and heated at reflux température for 16 h. The r.m. was cooled to r.t. and partitioned between H₂O and DCM. The organic phase was separated, dried (MgSOO, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 2.04 gof intermediate 55 (63 %).

b) Préparation of intermediate 56

OCH₃

Intermediate 55 (2.04g, 9.50 mmol) was added to a stirring mixture of 10 % Pd/C (500 mg) and a 4 % thiophene solution in MeOH (l ml). The r.m. was heated at 50 °C under a H₂ atmosphère. Aflcr 3 eq. of H₂ were absorbed, the catalyst was removed by filtration over dîatomaccous earth. The filtrate was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: McOH/DCM 10/90). The product fractions were combined and evaporated to yield a light-brown solid. Yield: 1700 mg of intermediate 56 (95 %).

Example A26

Préparation of intermediate 57

X^-0 /=N

Il /—4 f—ci

Trifluoromethancsulfonic acid (7.63 ml, 86 mmol) was added to a sol. of iodobenzene diacetate (7.41 g, 23 mmol) in CThCN (50 ml) and the r.m. was stirred at r.t. for 20 min under N₂. A sol. of l-(2-chloro-5-pyrimidinyl)-cthanonc (3 g, 19.2 mmol) in CHjCN ( 10 ml) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h and subsequently cooled to r.t. CH3CN was evaporated and the residue was extracted with

Z

-80DCM. The organic phase was washed with a sat. aq. NaHCOj sol., dried (MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography over Silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 1.6 gofintermediate 57 (43 %).

Examplc A27

a) Préparation of intermediate 58

HiCO.

HN

A mixture of l-ethynyl-2-mcthoxy-4-nitro-bcnzene (785 mg, 4.43 mmol) and trimcthylsilyi azide (1.75 ml, 13.3 mmol) was devidcd over 6 microwave vials and heated at at 150 °C for 2 h under microwave irradiation. The r.m. was cooled to r.t. and filtered over diatomaccous earth using DCM. The filtrate was washed with H₂O. The organic phase was separated, dried (MgSCM), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/McOH from 100/0 to 96/4). The product fractions were collected and concentrated in vacuo, yielding 344 mg of intermediate 58 (35 %).

b) Préparation of intermediate 59 and intermediate 60

HjCO

Intermediate 59

Intermediate 60

K₂CO₃ (580 mg, 4.2 mmol) was added to a sol. of intermediate 58 (462 mg, 2.1 mmol) in THF (10 ml). The mixture was cooled to 0-5 °C, and CHU (0.131 ml, 2.1 mmol) was added. The r.m. was stirred at r.t. for 3 h. The r.m. was filtered over diatomaceous earth using DCM. The filtrate was washed with water. The organic phase was separated, dried (MgSO^), filtered and the solvent was evaporated in vacuo. The residue was purified by Préparative SFC (Chiralpak Diacel AD 20 x 250 mm; Mobile phase CO₂, MeOH with 0.2 % iPrNH₂). The product fractions were collected and concentrated in vacuo. Yield: 214 mg of intermediate 59 (43 %); 70 mgof intermediate 60 (14 %).

c) Préparation of intermediate 61

HjCO

MeOH (40 ml) was added to Pd/C 10 % (0.05 g) under a N₂ atmosphère. Subsequently, a 0.4 % thîophcne sol. in DIPE (0.1 ml) and intermediate 59 (0.214 g, 0.91 mmol) were

-8I added. The r.m. was stirred at 25 °C under a H2 atmosphère until 3 eq of H2 was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The redsidue was partitioned between DCM and H₂O. The organic phase was separated, dried (MgSO,»), filtered and the solvent was evaporated in vacuo. Yield: 0.198 g of intermediate 61 (98 %).

d) Préparation of intermediate 62

MeOH (40 ml) was added to Pd/C 10 % (0.05 g) under a N2 atmosphère. Subsequently, a 0.4 % thiophenc sol. in DIPE (0.1 ml) and intermediate 60 (0.070 g, 0.3 mmol) were added. The r.m. was stirred at 25 °C under a H2 atmosphère until 3 cq of H2 was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The redsidue was partitioned between DCM and water. The organic phase was separated, dried (MgSCL), filtered and the solvent was evaporated in vacuo. Yield: 0.073 g of intermediate 62 (quantitative).

Example A28

Préparation of intermediate 63

A stainless steel autoclave was loaded with intermediate 19 (370 mg, 1.21 mmol), coppcr(l)oxide (10 mg), and a 0.5 M sol. of NHj in dioxane (30ml, 15 mmol). The autoclave was closed and the r.m. was heated at 150 °C for 18 h. Then, the r.m. was cooled, a sat. aq. NH.1OH sol. (5 ml) was added, and the r.m. was heated at 150 °C for another 18 h. The r.m. was cooled, and the r.m. was concentrated in vacuo. The residue was partitioned between DCM and a saturated aq. NHjCI sol. The organic layer was dried (MgSO<i), filtered and concentrated in vacuo. Yield: 240 mg of intermediate 63 (82 %), which was used as such in the next reaction step.

Example A29

a) Préparation of intermediate 64

Br

NaiSaOs (1.64 g, 8.62 mmol) and 4-fluoro-bcnzaldchyde (891 mg, 7.18 mmol) were added to a soi. of 3-bromo-5-trifluoromcthyl-l,2-diaminobenzcne (1.65 g, 6.47 mmol)

in DMA (40 ml). The r.m. was stirred overnight at 70 °C. Then, the r.m. was cooled to

r.t. and poured into water. The solid was filtered off, washed with water, and suspended in DIPE and some drops of 2-propanol. The resulting solid was filtered off, washed with DIPE, and dried. Yield: 1.95 g of intermediate 64 (84 %).

A l M sol. of LiHMDS in THF (9.2 ml, 9.2 mmol) was added dropwise at r.t. under a Nî atmosphère to a sol. of intermediate 64 (1.65 g, 4.6 mmol) in THF (50 ml). The r.m. was stirred at r.t. for 30 min, and then CII3I (3.26 g, 23 mmol) was added. The r.m. was stirred at r.t. for l h and then washed with a sat. aq. NaHCO, sol. and brine. The organic phase was separated, dried (MgSCL), filtered and the solvent was evaporated in vacuo. The residue was purified by RP préparative HPLC [RP Shandon Ilyperprep® Cl8 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: a gradient of (0.25 % NH4HCO3 sol. in water)/McOH/CH₃CN], The product fractions were collected and worked up. Yield: 720 mg of intermediate 65 (42 %).

Example A30

Na2S20s (5.56 g, 29.2 mmol) and 4-fluoro-benzaldehyde (2.91 g, 23.4 mmol) were added to a sol. of3-bromo-5-fluoro-l,2-diaminobenzenc (4.0 g, 19.5 mmol) in DMA (80 ml). The r.m. was stirred overnight at 70 °C. Then, the r.m, was cooled to r.t. and poured into water. The solid was filtered off, washed with water, and dried. Yield: 6 g of intermediate 66, used as such in the next reaction step.

b) Préparation of intermediate 67

A suspension of 60 % NaH in minerai oil (233 mg, 5.82 mmol) was added under a N2 atmosphère to a cooled (5°C) sol. of intermediate 66 (900 mg, 2.91 mmol) in THF (5 ml). The r.m. was stirred at 5°C for 30 min, and then isopropyliodide (l .98 g, 11.6

mmol) was added. The r.m. was stirred at !30°C for 2 h under microwave irradiation.

-83The r.m. was cooled, extra THF was added and the mixture was washed with brine. The organic phase was separated, dried (MgSO.|), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: heptanc/DCM 50/50 to 0/100), The product fractions were collected and the solvent was evaporated. Yield: 350 mg of intermediate 67 (34 %).

Example A31

a) Préparation of intermediate 68

/V-lodosuccinimide (26.7 g, 119 mmol) and TFA (2.5 mL, 32.4 mmol) were added to a suspension of 2,4-dich!oro-pyridin-3-ylamine (17.6 g, 108 mmol) in CH₃CN (150 ml). The réaction mixture was stirred at r.t, for 16 h., and then heated to 4Û °C for 6 h. The

r.m. was diluted with EtOAc and washed with a sat. aq. Na₂S₂O₃ sol. The aq. phase was extracted with EtOAc, and the combined organic layers were dried (MgSOj), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated. Yield: 22 g of intermediate 68 (7I %).

b) Préparation of intermediate 69 and intermediate 70

inlemiediale 69

intermixlialc 70

A sol. of methylamine in THF (2 M, 25 ml, 50 mmol) was added to a sol. of intermediate 68 (4.8 g, 16.6 mmol) in EtOH (20 ml). The r.m. was stirred at 160°C under microwave irradiation for 8 h. Then, the solvent was evaporated and the residue was partitioned between aq. NaHCO₃ sol. and DCM. The combined organic layers were dried (Na₂SO.i), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: heptane/DCM 100/0 to 0/100). The product fractions were collected and the solvent was evaporated. Yield: 950 mg of intermediate 69 (20 %) and 2900 mg of intermediate 70 (62 %).

c) Préparation of intermediate 71

EtiN (3.61 ml, 26.5 mmol) and 4-fluoro*benzoylchloridc (1.68 g, 10.6 mmol) were added to a sol. of intermediate 70 (2.5 g, 8.8 mmol) in DCM (100 ml), and the r.m. was stirred at r.t. for 4 h. The r.m. was concentrated in vacuo. Yield: 2.7 g of crude intermediate 71 (75 %), which was used as such in the next step.

Phosphoroxychloridc (907 mg, 5.9 mmol) was added to a sol. of intermediate 71 (2.0 g,

4.93 mmol) in dichloroethane (15 ml), and the resulting mixture was stirred and heated at 150 °C for 0.25 h under microwavc irradiation. The r.m. was concentrated in vacuo, and the residue was purified by flash column chromatography over silica gel (eluent: DCM/McOH(NH₃) from 100/0 to 97/3). The product fractions were collected and the 10 solvent was evaporated. Yield: 1.56 g of intermediate 72 (81 %).

c) Préparation of intermediate 73

Cl

Isopropenylboronic acid pinacol ester (867 mg, 5.16 mmol) and Pd(PPh₃)₄ (298 mg, 0.258 mmol) was added to a sol. of intermediate 72 (2.0 g, 5.16 mmol) in dioxane (8 ml) and an aq. NaHCO₃ sol. (4 ml), and the resultingmixture was stirred and heated at 160 °C for 10 min. under microwavc irradiation. The r.m. was cooled to r.t. and filtered over diatomaceous earth using EtOAc, and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM/McOH(NH₃) from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 1.25 g of intermediate 73 (80 %).

-85MeOH (40 ml) was added to Pt/C 5 % (100 mg) under N₂ atmosphère. Subsequently, intermediate 73 (l .25 g, 4.14 mmol) was added. The r.m. was stirred at 25 °C under H₂atmosphère until l eq of 1-I₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. Yield: 0.9 g of crude intermediate 74 (71 %), which was used as such in the next reaction step.

Methylboronic acid (93 mg, 1.55 mmol) and Pd(PPh₃)4 (71 mg, 0.062 mmol) was added to a sol. of intermediate 72 (600 mg, 0.31 mmol) in dioxane (10 ml) and anaq. NaHCOî sol. (5 ml), The resulting mixture was stirred and heated at 150 °C for 20 min. under microwave irradiation. The r.m. was cooled to r.t. and partitioncd between water and DCM. The organic phase was separated, dried (MgSCL), filtered and the solvent was evaporated in vacuo. Yield: 180 mg oferude intermediate 75 which was used as such in the next réaction step.

Zn(CN)₂ (36 mg, 0.31 mmol) and Pd(PPh₃)4 (30 mg, 0.026 mmol) were added to a solution of intermediate 72 (200 mg, 0.52 mmol) in DMF (5 IL). The resulting mixture was stirred and heated at 160 °C for 10 min. under microwavc irradiation. The r.m. was cooled to r.t. and filtered through diatomaceous earth. The filtrate was conc. in vacuo and the residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NH₂) 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.14 g of intermediate 76 (95 %).

Examnle A32

a) Préparation of intermediate 77

4-Fluorobenzaldehyde (1.11 g, 8.93 mmol) and Na₂S₂O4 (3.89 g, 22.3 mmol) were added to a sol. of 2-chloro-/V-6-dimcthyl-3-nitro-pyridin-4-aminc (1.5 g, 7.44 mmol) in

EtOH (15 ml). The r.m. was heated under microwave conditions for 1 h at 160 °C. The

r.m. was cooled to r.t. and filtered through diatomaceous earth using EtOAc, This was repcatcd 3 x. The combined filtrâtes were evaporated and the residue was purified by

RP préparative HPLC [RP Vydec Denali Cl 8 (10 μιη, 250 g, I.D. 5 cm); mobile phase:

a gradient of (0.25 % NH4HCO3 sol. in waterj/CHjCN]. The product fractions were collected and worked up. Yield: l .95 g of intermediate 77 (32 %).

Example A3 3

a) Préparation of intermediate 78

EtjN (l .87 ml, 13.8 mmol) and 4-fluoro-benzoylchloridc (873 mg, 5.5 mmol) were added to a sol. of intermediate 69 (l.3 g, 4.6 mmol) in DCM (80 ml), and the r.m. was stirred at r.t. for 4 h. The r.m. was concentrated in vacuo. Yield: l .5 g of crude intermediate 78 (81 %), which was used as such in the next reaction step.

b) Préparation of intermediate 79

Phosphoroxychloridc (I2l mg, 0.79 mmol) was added to a sol. of intermediate 78 (267 mg, 0.66 mmol) in dichlorocthane (2 ml), and the mixture was stirred and heated at 150 °C for 0.25 h under microwave irradiation. The r.m. was concentrated in vacuo, and the residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NHj) from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 2I5 mg of intermediate 79 (84 %).

c) Préparation of intermediate 80

Cl

Isopropcnylboronic acid pinacol ester (434 mg, 2.58 mmol) and Pd(PPIij)4 ( 149 mg, 0.129 mmol) was added to a sol. of intermediate 79 (l .0 g, 2.58 mmol) in dioxane (8 ml) and an aq. NaHCOj sol. (4 ml), and the resulting mixture was stirred and heated at 160 °C for 10 min. under microwavc irradiation. The r.m. was cooled to r.t. and filtered over diatomaceous earth using EtOAc, and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM/McOII(NHj)

- 87from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.72 g of intermediate 80 (92 %).

d) Préparation of intermediate 81

MeOH (40 ml) was added to Pt/C 5 % (100 mg) under N₂ atmosphère. Subsequently, intermediate 80 (0.75 g, 2.49 mmol) was added. The r.m. was stirred at 25 °C under H₂atmosphère until l eq of H₂ was absorbed. The catalyst was fdtered off over diatomaceous earth and the filtrate was evaporated. Yield: 0.55 g of crude intermediate 81 (73 %), which was used as such in the next reaction step.

e) Préparation of intermediate 82

Cyclopropylboronic acid (86 mg, 1.0 mmol) and Pd(PPhî)4 (78 mg, 0.067 mmol) was added to a sol. of intermediate 79 (260 mg, 0.67 mmol) in dioxane (6 ml) and an aq. NaliCOi sol, (3 ml). The mixture was stirred and heated at 160 °C for 10 min. under microwavc irradiation. The r.m. was cooled to r.t. and filtered over diatomaceous earth using EtOAc, and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NH₂) from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.15 g of intermediate 82 (74 %).

Example A34

a) Préparation of intermediate 83

Phosphoroxychloride (1.25 ml, 13.7 mmol) was added to DMF (3.5 ml) at 0 °C and the mixture was stirred for 0.5 h at this température. Intermediate 16(1 g, 3.44 mmol) was added at 0 °C, and the r.m. was stirred at r.t. and DMF (5 ml) was added. The r.m. was stirred at r.t. overnight. The r.m. was poured into on ice and the mixture was neutralized by adding NaHCOj. The mixture was extracted with DCM. The organic layer was dried (MgSO^), filtered and the solvent was evaporated in vacuo. The residue

was triturated with DIPE. The solid was collected and dried. Yield: 0.625 g of intermediate 83 (57 %).

b~) Préparation of intermediate 84

NaBKi (28 mg, 0.75 mmol) was added to a solution of intermediate 83 (200 mg, 0.63 mmol) in MeOH (5 ml) and THF (2 ml). The r.m. was stirred at r.t for 15 min, then the solvents were removed in vacuo. The residue was partitioned between DCM and water. The organic layer was dried (MgSOi), filtered and the solvent was evaporated in vacuo. Yield: 90 mg of intermediate 84 (45 %).

c) Préparation of intermediate 85

Thionylchlorîde (33 mg, 0.28 mmol) was added to intermediate 84 (90 mg, 0,28 mmol) in DCM (2 ml). The r.m. was stirred at r.t for 30 min and an aq.sat. NaHCOj sol. was added. The organic layer was separated, filtered over diatomaceous earth and the filtrate was concentrated. Yield: 90 mg of intermediate 85 (95 %).

d) Préparation of intermediate 86

A 0.5 M NaOMe solution in MeOH (0.64 ml, 0.32 mmol) was added to a sol. of intermediate 85 (90 mg, 0.265 mmol) in MeOH (2 ml). The r.m. was stirred at r.t for 30 min, then the solvents were removed in vacuo. The residue was partitioned between

DCM and H2O. The organic layer was filtered over diatomaceous earth and the filtrate was concentrated. The residue was triturated with DIPE and dried in vacuo. Yield: 60 mg of intermediate 86 (67 %).

e) Préparation of intermediate 87

-89A solution of KOrBu (0.87 g, 7.74 mmol) in THF (7 ml) was added to a suspension of mcthoxymethylenctriphcnylphosphonium chloride (l .53 g, 4.47 mmol) in THF (3 ml) at -15 °C. The r.m. was stirred for 30 min. Subsequently, a solution of intermediate 83 (0.95 g, 3 mmol) in THF (3 ml) was added at 5 °C, and the r.m. was stirred for l h at r.t. The r.m. was partitioned between DCM and H2O. The organic layer was dried (MgSO-i), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over silicagel (eluent: DCM/MeOH 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 700 mg of intermediate 87 as an E/Z mixture (68 %).

Examplc A35

a) Préparation of intermediate 88

l-Iodo-2,5-pynOlidinedione (5.54 g, 24.6 mmol) was added to 8-bromo-2-(2trifluoromethyl-phenyl)-imidazo[l,2-a]pyridine (prepared from 3-bromo-2pyridinamine and 2-bromo-l-(2-trifluoromethyl-phenyl)ethanone, according to examplc A9; 5.6 g, 16.4 mmol) in DCM (50 ml). The r.m. was stirred at r.t. for 24 h, diluted with extra DCM, then washed with a 15 % aq. NaOH solution, followed by a sat. aq. NaHSOj solution. The organic layer was dried (MgSO.|), filtered, concentrated in vacuo. Yield: 7.2 g of intermediate 88 (94 %).

b) Préparation of intermediate 89

OCH3

A mixture of intermediate 88 (350 mg, 0.75 mmol), 3-mcthoxy-propyne (58 mg, 0.82 mmol), PdCI₂(PPhj)2 (20 mg, 0.028 mmol), Cul (5 mg, 0.027 mmol) in EtjN (3 ml) was stirred at 50 °C for 20 h under a N2 atmosphère. The mixture was partitioned between DCM and H₂O. The organic layer was dried (MgSCb), filtered, and concentrated in vacuo. The residue was purified by column chromatography over silicagel (eluent: DCM/McOH 99/l). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 100 mg of intermediate 89 (33 %).

c) Préparation of intermediate 90

Intermediate 4 (50 mg, 0.24 mmol), Pd2(dba)j (22 mg, 0.024 mmol), X-phos (23 mg, 0.049 mmol) and CS2CO3 (240 mg, 0.73 mmol) were added to a solution of intermediate 89 (100 mg, 0.24 mmol) in 2-mcthyl-2-propanol (10 ml) under a N2 atmosphère. The r.m. was heated at 100 °C for 20 h. Then, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO«), filtered and the solvent was evaporated. The residue was purified by flash chromatography over silicagel (eluent: DCM/MeOHfNHî) fiom 100/0 to 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 30 mg of intermediate 90 (23 %).

Example A36

a) Préparation of intermediate 91

A mixture of 3-bromo-5-fluoro-l,2-diaminobcnzcnc (10.5 g, 51 mmol) and urca (3.84 g, 64 mmol) in xylene (100 ml) was stirred at reflux overnight. Subsequently, the r.m. was cooled to r.t., and the resulting precipitate was filtered off. The solid was suspended in an aq. 1 N HCl sol., and filtered off again, then dried. The resulting solid was triturated with D1PE, Yield: 9.5 g of intermediate 91 (80 %).

b) Préparation of intermediate 92

Br

Phosphoroxychloridc (30 ml) was added slowly to intermediate 91 (3.0 g, 13 mmol), followed by an aq. conc. HCl sol. (1 ml). The r.m. was heated at reflux for 2 days. The r.m. was concentrated in vacuo. The residue was partitioned between DCM and an aq. NaHCOj sol. The organic layer was dricd(MgSO«), filtered and evaporated. Yield: 3.0 g (93%) of crude intermediate 92.

c) Préparation of intermediate 93

A suspension of 60 % NaH in minerai oil (721 mg, I8 mmol) was added under a N2 atmosphère to a cooled (5°C) sol. of intermediate 92 (3.0 g, 12 mmol) in DMF (40 ml). The r.m. was stirred at 5°C for 30 min, and then CHjI (8.53 g, 60 mmol) was added.

The r.m. was stirred at r.t. for 3 h, and then partitioned between water and EtOAc.. The organic phase was separated, dried (MgSCU), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: heptanc/EtOAc 80/20 to 50/50). The product fractions were collected and the solvent was evaporated. Yield: 850 mg of intermediate 93 (27 %).

A mixture of intermediate 93 (760 mg, 2.88 mmol), and pyrrolidinc ( 1.03 g, 14.4 mmol) in NMP (l 5 ml) was heated at 180 °C under microwave irradiation for 10 min. The r.m. was cooled to r.t., and poured into H2O (100 ml). The resulting precipitate was filtered off, and washed with H2O. The solid was dried and triturated with DIPE.

Yield: 675 mg (78 %) of intermediate 94.

Example A37

a) Préparation of intermediate 95

2-Chloro-aetaldehyde (6 Μ, l .0 ml, 6.0 mmol) and NaîSîOs ( l. 14 g, 6.0 mmol) were added to a sol. of intermediate 18 (800 mg, 3.98 mmol) in DMA (ÎO ml). The r.m. was stirred at r.t. for 2 h. The r.m. was poured into H2O. The solid was filtered off, washed with H2O and suspended in DIPE. The solid was filtered off, washed with DIPE, and dried. Yield: 0.15 g of intermediate 95 (l 5 %).

b) Préparation of intermediate 96

-92Α suspension of 60 % NaH in minerai oil (193 mg, 4.82 mmol) was added under a N₂atmosphère to a sol. of 2-propanol (232 mg, 3.85 mmol) in DMF (10 ml). The r.m. was stirred at r.t. for 30 min, and then intermediate 95 (0.5 g, 1.93 mmol) was added. The r.m. was stirred at r.t. for 2 h, and then partitioncd between H2O and EtOAc. The organic phase was separated, dried (MgSCL), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NHj) 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. Yield: 120 mg of intermediate 96 (l5 %).

Example A38

a) Préparation of intermediate 97 i

Ethyl 8-iodo-6-(trifluoromcthyl)imÎdazo[i,2-a]pyridine-2-carboxylate (0.60 g l .56 mmol) and LiOH (38 mg, l .6 mmol) were dissolved in a mixture of THF/H₂O (10 ml/10 ml) and the mixture was stirred for 20 Ii at r.t. The mixture was acidified with an aq. I N HCl solution until the product prccîpitated. The precipitate was filtered ofT, and dried m vacuo. Yield: 0.5 g of intermediate 97 (90 %).

b) Préparation of intermediate 98

A 2 M sol. ofdimcthylamine in THF (0.58 ml, 1.16 mmol) in THF (10 ml) was added to a mixture of intermediate 97 (500 mg, l .4 mmol) and HBTLJ (533 mg, 1.4 mmol) in DMF (10 ml). Then DIPEA (0.98 ml, 5.62 mmol) was added, and the r.m. was stirred for 18 h at r.t. The mixture was diluted with DCM, and washed with an aq. 0.5 N NaOH sol. and H₂O. The organic layer was dried (MgSO<i), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silicagel (eluent: DCM/MeOH (NHj) 99/1 ). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 490 mg of intermediate 98 (90 %).

Example A39

a) Préparation of intermediate 99

-93BF₃ etherate (0.154 ml, l .32 mmol) was added to a mixture of 4-fluorophenylglyoxal hydrate (4.5 g, 26.5 mmol) and 2-amino-3-bromopyridine (4.72 g, 26.5 mmol) in DCM (100 ml). The r.m. was stirred at r.t. for 6 h. The resulting precipitate was filtered off and dried in vacuo. Yield: 4 g of intermediate 99 (49 %).

b) Préparation of intermediate 100

NaH (60 % in minerai oil, 414 mg, 10.3 mmol) was added to an ice-cooled solution of intermediate 99 ( l.06 g, 3.45 mmol) in DMF (50 ml). The r.m. was stirred at 0°C for 15 min, then CH^l (0.258 ml, 4.14 mmol) was added and the resulting r.m. was stirred at r.t. overnight. The r.m. was quenched with water, and then concentrated in vacuo. The residue was partitioned between DCM and H₂O. The organic layer was dried (MgSO.4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silicagel (eluent: n-heptane/EtOAc 100/0 to 50/50). The product fractions were collected and the solvent was evaporated in vacuo. The residue was suspended in DIPE and dried in vacuo. Yield: 445 mg of intermediate 100 (40 %). Example A40

Préparation of intermediate 101

Cl

3,5-Dibromo-pyrazin-2-ylaminc (5 g, 19.8 mmol), 2-chloro-acctone (18.3 g, 198 mmol) and dioxane (40 ml) were heated at reflux température for 16 h. The r.m was concentrated under reduced pressure, and the residue was triturated with DIPE. Yield: 3.6 g of intermediate 101 (55 %).

Example A41

a)

Préparation of intermediate 102

Bromine (3.15 ml, 61.3 mmol) was added dropwisc at 15 °C to a solution of 4-amino3-nitro-benzonitrilc (10 g, 61.3 mmol) in AcOH (80 ml). The r.m was stirred at r.t overnight, and extra bromine (1.58 ml, 30.7 mmol) was added. After another 6 h at r.t,, again bromine (0.79 ml, 15.3 mmol) was added, and stirring continucd at r.t. over weekend. The r.m. was concentrated under reduced pressure, and the residue was triturated with water. The residue was purified by flash column chromatography over

-94silicagel (eluent: DCM/MeOH 98/2). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 6.24 g of intermediate 102 (35 %).

b) Préparation ofintermediate 103

4-Fluorobenzaldehyde (0.96 ml, 9.1 mmol) and Na₂S₂0i (5.04 g, 28.9 mmol) were added to a sol. of intermediate 102 (2 g, 6.86 mmol) in EtOH (10 ml). The r.m. was heated under microwave conditions at 150 °C for 45 min. The r.m. was cooled to r.t. and filtered through diatomaceous earth. The filtrate was evaporated and the residue was dissolved in DMF. H2O was added. The resulting prccipitate was filtered off and washed with H₂O. The residue was suspended in toluene, and the solvent was removed under reduced pressure. Yield: 1.6 g of intermediate 103 (70 %).

A suspension of 60 % NaH in minerai oil (569 mg, 14.2 mmol) was added under a N₂atmosphère to a sol. of intermediate 103 (3 g, 9 mmol) in DMF (20 ml) at 5 °C. The r.m. was stirred at 5 °C for 15 min, and then CHiI (1.48 ml, 23.7 mmol) was added. The r.m. was stirred at r.t. for 30 min, and partitioncd between EtOAc and H₂O. The organic phase was separated, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH 100/0 to 99/1). The product fractions were collected and the solvent was evaporated. The residue was purified further by preparative HPLC [RP Shandon Hyperprep Cl8 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: (0.25 % NH₄CO₃ sol. in water, CHjCN/MeOH)]. The product fractions were collected and concentrated under reduced pressure. Yield: 1.1g of intermediate 104 (37 %). Example A42

a) Préparation of intermediate 105	Br
f	zAy-NH₂
J HjCcr

MeOH (150 ml) was added to Pt/C 5 % (1 g) under N₂ atmosphère. Subsequently, a

0.4 % thiophene sol. in DI PE (2 ml) and 2-bromo-4-methoxy-6-nitroanilinc (5 g,

20.2 mmol) were added. The r.m. was stirred at 25 °C under H₂ atmosphère until 3 eq

X

-95of H₂ was absorbed. The catalyst was filtered off over diatomaceous earLh and the filtrate was concentrated in vacuo. Yield: 4.33 g of intermediate 105 (99 %), which was used as such in the next step.

4-Fluoro-benzaldehyde (1.17 ml, 11,1 mmol) and Na₂S₂O5 (2.63 g, 13.8 mmol) were added to a sol. of intermediate 105 (2 g, 9.2 mmol) in DMA (40 ml). The r.m. was stirred at 90 °C overnight. Then, the r.m. was poured into water, resulting in the précipitation of a solid. The solid was filtered off, washed with water, and suspendcd in DIPE. The resulting solid was filtered off, washed with DIPE, and dried. Yield: 2.9 g of intermediate 106 (98 %).

A suspension of 60% NaH in minerai oil (486 mg, 12.1 mmol) was added under a N₂atmosphère to a sol. of intermediate 106 (2.6 g, 8.1 mmol) in DMF (15 ml) at 5 °C. The r.m. was stirred at 5 °C for 30 min, and then methyliodide (1.26 ml, 20.2 mmol) was added. The r.m. was stirred at r.t. for 3 h., and partitioned between EtOAc and water. The organic phase was separated, dried (MgSOj), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/McOH 100/0 to 99/1). The product fractions were collected and the solvent was evaporated. Yield: 1.25 g of intermediate 107 (46 %).

Example A4 3

a) Préparation of intermediate 108

Br

Conc. HNOs (12.5 ml) was added to a sol. of 3,5-dibromo-pyridine /V-oxide (4.5 g, 17.8 mmol) in conc. H2SO4 (16 ml). The r.m. was refluxed for 4 h., then cooled and poured onto ice-water. The resulting precipitate was collected by filtration and dried. Yield: 3.1 g of intermediate 108 (58 %), which was used as such in the next step.

-96b) Préparation of intermediate 109

A 2 M sol. of methylamine in THF (7.15 ml, ] 4.3 mmol) was added to a mixture of intermediate 108 (2.66 g, 8.9 mmol) in THF (100 ml). The r.m. was stirred at 60 °C for 2 days, then conc. in vacuo. The residue was partitioncd between DCM and an aq. NaHCOj sol. The organic phase was separated, dried (Na₂SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: hcptane/DCM/MeOH(NHj) 100/0/0 to 0/l 00/0 to 0/70/30). The product fractions were collected and the solvent was evaporated. Yield: 1.2 gof intermediate 109 (54 %).

c) Préparation of intermediate 110

4-Fluorobenzaldehyde (252 mg, 2.0 mmol) and Na₂S₂O.| (1.18 g, 6.8 mmol) were added to a sol. of intermediate 109 (420 mg, 1.7 mmol) in EtOH (6 ml). The r.m. was heated under microwave conditions at 160 °C for 45 min. The r.m. was cooled to r.t.

and diluted with EtOAc. The mixture was washed with an aq. NaHCO3 sol. and brine. The organic phase was separated, dried (MgSO.:), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NH₃) 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 0.35 g of intermediate i 10 (68 %). Example A44

A mixture of 6-amino-5-biOrno-nicotinonitrile (4 g, 20.2 mmol) and l-bromo-4-methyl2-pcntanone (5.43 g, 30.3 mmol) in NMP (40 ml) was heated at 150 °C for 2 h. The r.m. was cooled to r.t. and poured into an aq. 10% NaHCOj sol. The mixture was extracted with toluene. l he organic layer was dried (MgSO^), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: zi-hcptane/EtOAc 100/0 to 50/50). The product fractions were

-97collected and the solvent was evaporated. The residue was triturated with DIPE. Yield: 2.9 g of intermediate 111 (52%).

B, Préparation of the compounds

Example B1

Préparation of compound 1

CS2CO3 (0.56 g, 1.72 mmol), Pd2(dba)î (0.039 g, 0.043 mmol) and B1NAP (0.053 g, 0.086 mmol) were added to a sol. of intermediate 16 (0.25 g, 0.859 mmol) and intermediate 2 (0.184 g, 0.902 mmol) in DMF (80 ml). The r.m. was purged with N₂ for 5 min. and was then heated at ! 00 °C for 18 h. The r.m. was concentrated under reduced pressure, The residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by préparative HPLC [RP Shandon Hypcrprcp® C18 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: (0.25 % NI-L1CO3 sol. in water, MeOH + CH3CN). The product fractions were collected and concentrated under reduced pressure. The residue was suspended in DIPE and the precipitate was collected by filtration and dried under vacuum at 60 °C. Yield: 0.068 g of compound 1 (19 %). Example B2

Préparation of compound 2

CS2CO3 (0.616 g, 1.892 mmol), Pd₂(dba)j (0.043 g, 0.047 mmol) and ΒΓΝΑΡ (0.058 g, 0.094 mmol) were added to a sol. of intermediate 5 (0.3 g, 0.95 mmol) and intermediate 2 (0.203 g, 0.993 mmol) in DMF (20 ml). The mixture was purged with N₂ for 5 min. and was then heated at 100 °C for 18 h. The r.m. was concentrated under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by préparative HPLC [RP Shandon Hyperprep® Cl8 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: (0.25 % NH4CO3 sol. in water, MeOH + CH3CN). The

product fractions were collected and concentrated under reduced pressure. The solid product was dried under vacuum at 60 °C. Yield: 0.129 g of compound 2 (30 %). Example B3

Préparation of compound 3

Intermediate 16 (0.230 g, 0.793 mmol), Pd₂(dba)3 (0.060 g, 0.066 mmol), dicyclohexyl[2',4',6'-tris(l-methylethyl)[l,r-biphenyl]-2-yl]phosphine (0.069 g, 0.145 mmol) and Cs₂COî (0.646 g, l .98 mmol) were added to a sol. of intermediate 4 (0.135 g, 0.661 mmol) in 2-methyl-2-propanol (IO ml), and the r.m. was heated at l IO °C overnight. After cooling, H₂O was added and the product was extracted with DCM.

IO The organic phase was dried (MgSO4) filtered and concentrated under rcduccd pressure. The residue was purified by Flash column chromatography over Silica gel (eluent: DCM/MeOH from Ί 00/0 to 98/2) and the product fractions were collected and worked up. The residue was crystallizcd from DIPE, filtered and dried under vacuum at 80 °C. Yield: 0.032 gof compound 3 (11.7 %).

Example B4

d) Préparation of compound 4

A sol. of intermediate 7 (0.070 g, 0.14 mmol), 5-bromo-2-methylthiazole (0.051 g, 0.29 mmol), CS2CO3 (0.047 g, 0.14 mmol), Pd(PPh3)i (0.033 g, 0. 29 mmol) and a 3 N NaOH aq. sol, (0.024 ml, 0.07 mmol) in 1,4-dioxane (10 ml) was purged withN2 for 2 min. The r.m. was stirred at 80 °C overnight. After cooling, H2O was added and the product was extracted with DCM. The organic phase was washed with brine, dried (Na₂SO4) filtered and concentrated under reduced pressure. The residue was purified by préparative HPLC [RP Shandon Hyperprcp® Cl8 BDS (8 pm, 250 g, LD. 5 cm);

mobile phase: (0.25 % NH4CO3 sol. in water, MeOH + CH3CN)]. The product fractions 25 were collected and concentrated under reduced pressure. Yield: 0.0J3 g of compound (19.7%).

-99Example B5

Préparation of compound 5

A sol. of intermediate 6 (0.220 g, 0.50 mmol), 2,4-diinetliyl-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-l,3-thîazole (859833-13-9, 0.240 g, l.O mmol), Pd(PPhs)₄(0.116 g, 0. I mmol),Cs2CO.i (0.163 g, 0.50 mmol) and a 3N NaOH aq. sol. (0.084 ml, 0.251 mmol) in 1,4-dioxane (20 ml) was purged with N2 for 2 min. The r.m. was stirred at 80 °C overnight. After cooling, the r.m. was concentrated, H₂O was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified by préparative HPLC [RP Shandon Hypcrprcp® C18 BDS (8 pm, 250 g, I.D. 5 cm); mobile phase: (0.5 % NH₄OAc sol. in water + 10% CH3CN, CH3CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.078 gof compound 5 (33 %).

Example B6

Préparation of compound 6

A sol. of intermediate 6 (0.220 g, 0.502 mmol), Pd(PPh3)₄ (0.116 g, 0. 1 mmol) in 1,4dioxane (20 ml) was purged with N2 for 2 min, and the r.m. was stirred at r.t. for 10 min. l//-Pyrazole-l,3-dimethyl-4-(4,4,5,5-tetramcthyl-l,3,2-dioxaborolan-2-yl) (0.223 g, 1.0 mmol), and CS2CO3 (0.327 g, 1.0 mmol), were added into the r.m. After stirring for 10 min at r.t. a 3 N NaOH aq. sol. (0.084 ml, 0.251 mmol) was added. The r.m. was stirred at 80 °C overnight. After cooling, the r.m. was concentrated, H2O was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na₂SO4) filtered and concentrated under reduced pressure. The residue was purified by préparative HPLC [RP Shandon Hyperprep® Cl8 BDS (8 pm, 250 g, l.D. 5 cm); mobile phase: (0.25 % NHjCO.i sol. in water, CH3CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.055 g of compound 6 (24 %).

Example B7

Préparation of compound 7

- ΙΟΟ -

Cs₂CO₃ (1.137 g, 3.491 mmol), Pd₂(dba)₃ (0.080 g, 0.087 mmol) and B1NAP (0.109 g, 0.175 mmol) were added to a sol. of intermediate 16 (0.508 g, 1.75 mmol) and intermediate 9 (0.400 g, 1.83 mmol) in DMF (30 ml). The mixture was purged with N₂for 5 min. The r.m. was then heated at 100 °C for 18 h and subsequently concentrated under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by prcparatîve HPLC [RP Shandon Hyperprep® Cl 8 BDS (8 tint, 250 g, l.D. 5 cm); mobile phase: (0.25 % NH4CO3 sol. in water, MeOH + CHjCN)]. The product fractions were collected and evaporated off. The residue was re-purified by flash chromatography over Silica gel (eluent: DCM /MeOH from 100/0 to 95/5). The product fractions wcrc collected and the solvent was evaporated. The residue was crystallized from «-hcptanc/DlPE, and the precipitatc was filtered and dried under vacuum at 50 °C. Yield: 0.099 g of compound 7 (13.2 %).

Example B8

Préparation of compound 8

Cs₂CO₃ (0.261 g, 0.80 mmol), Pd₂(dba)₃ (0.018 g, 0.02 mmol) and BINAP (0.025 g, 0.04 mmol) were added to a sol. of intermediate 21 (0.115 g, 0.4 mmol) and intermediate 9 (0.091 g, 0.42 mmol) in DMF (20 ml) and the mixture was purged with N₂ for 5 min. The r.m. was heated at 100 °C for 18 h and then concentrated under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by préparative HPLC [RP Shandon Hyperprep® C18 BDS (8 μηι, 250 g, l.D. 5 cm); mobile phase: (0.25 % NH_flCO₃ sol. in water, MeOH + CH₃CN)J. The product fractions were collected and concentrated under reduced pressure. The solid residue was dried under vacuum at 60 °C. Yield: 0.043 g of compound 8 (25.3 %).

Examplc Β9

Préparation of compound 9

- ΙΟΙ -

Intermediate 19 (0.305 g, l mmol), Pd₂(dba)3 (0.091 g, 0.0.98 mmol), dicycIohexyl[2',4',6'-tris(l-methylcthyl)[l,r-biphenyl]-2-yl]phosphinc (0.095 g, 0.2 mmol) and Cs₂COî (0.978 g, 3.0 mmol) were added to a sol. of intermediate 13 (0.172 g, 0.983 mmol) in 2-methyl-2-propanol (20 ml), and the r.m. was heated at 110 °C ovemight. The r.m. was then concentrated under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with H₂O, dried (MgSO-O filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/McOH(NH3) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 0.160 g of compound 9 (37.4 %).

Example BIP

Préparation of compound 10

N·

Intermediate 19 (0.300 g, 0.983 mmol), Pd₂(dba)j (0.090 g, 0.098 mmol), dicyclohcxyl[2^,,4',6'-tris(l-mcthylcthyl)[!,l'-biphenyl]-2-yl]phosphtnc (0.103 g, 0.216 mmol) and Cs₂CO3 (0.961 g, 2.95 mmol) were added to a sol. of intermediate 15 (0.172 g, l mmol) in 2-methyl-2-propanol ( 10 ml), and the r.m. was heated at 110 °C ovemight. After cooling, H₂O was added and the mixture was stirred for 10 min prior to being diluted with DCM and filtered through diatomaceous earth. The filtrate was washed with H₂O and the organic phase was dried (MgSOi) and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.169 g of compound 10 (43 %).

Examnlc B11

Préparation of compound 11

- 102 h₃co

Intermediate 20 (0.210 g, 0.684 mmol), Pd₂(dba)₃ (0.062 g, 0.068 mmol), dicyclohcxyl[2',4',6'-tris(l-methylethyl)[l,r-biphcnyl]-2-yl]pliosphinc (0.071 g, 0.15 mmol) and Cs₂CO₃ (0.688 g, 2.05 mmol) were added to a sol. of intermediate 2 (0.139 g, 0.684 mmol) in 2-mcthyl-2-propanol (10 ml), and the r.m. was heated at 110 °C for 6

h. After cooling, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by préparative HPLC [RP Shandon Hyperprcp® Cl8 BDS (8 pm, 250 g, I.D. 5 cm); mobile phase: (0.25 % NH.₍CO₃ sol. in water, CH₃CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.197 gof compound (67 %).

Example B12

Préparation of compound 12

HiCO

NIntermediate 19 (0.660 g, 2.16 mmol), Pd₂(dba)₃ (0.198 g, 0.216 mmol), dicyc!ohexyl[2',4',6'-tris(l-methylethyl)[l,r-biphcnyl]-2-yl]phosphinc (0.226 g, 0.476 mmol) and Cs₂CO₃ (2.115 g, 6.49 mmol) were added to a sol. of intermediate 2 (0,441 g, 2.16 mmol) in 2-mcthyI-2-propanol (30 ml), and the r.m. was heated at 90 °C for 72 hours. After cooling, the solvent was evaporated. H₂O was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSCb) and concentrated under rcduccd pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH(NH₃) from 100/0 to 99/1). The product fractions were collected and the solvent was evaporated. The product was crystallized from DIPE, filtered off and dried under vacuum. Yield: 0.465 g of compound 12 (50 %).

Examplc B13

Préparation of compound 13

- 103 HjCO

Intermediate 19 (0.304 g, 0.99 mmol), Pd₂(dba)j (0.091 g, 0.099 mmol), dicyclohcxyltZ’.d'.ô’-trisil-mcthylethylXU'-biphcnyl^-yllphosphinc (0.104 g, 0.22 mmol) and Cs₂CO₂ (0.976 g, 3.0 mmol) were added to a sol. of intermediate 26 (0.203 g, 1.0 mmol) in 2-methyl-2-propanol (8 ml), and the r.m. was heated at 110 °C for 16 hours. After cooling, H₂O was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO.1) and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM isocratic). The product fractions were collected and the solvent was evaporated. The product was crystallizcd from DIPE, filtered off and dried under vacuum. Yield: 0.065 g of compound 13 ( 15.2 %).

Examplc B14

Préparation of compound 14

Intermediate 24 (0.298 g, 1.14 mmol), Pd₂(dba)₃ (0.104 g, 0.114 mmol), dicyclohcxyl[2',4',6’-tris(l-mcthylcthyl)[l,r-biphcnyl]-2-yl]phosphine (0.108 g, 0.228 mmol) and Cs₂CO₃ (1.108 g, 3.42 mmol) were added to a sol. of intermediate 4 (0.233 g, 1.14 mmol) in 2-methyl-2-propanol (15 ml), and the r.m. was heated at 110 °C overnight. After cooling, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO4) filtered and concentrated under reduced pressure. The residue was crystallizcd in D1PE/CN₃CN and the precipitate was filtered and dried in vacuum. Yield: 0.246 g of compound 14 (50 %).

Examplg B15

Préparation of compound 15

- 104 -

Intermediate 34 (0.320 g, 0.96 mmol), Pd₂(dba)j (0.088 g, 0.096 mmol), dicyclohcxyl^'^'.ô'-tristl-mcthylethylXlJ'-biphenylJ^-yllphosphinc (0.091 g, 0.192 mmol) and Cs₂COj (0.939 g, 2.881 mmol) were added to a sol. of intermediate 31 (0.320 g, 0.96 mmol) in 2-methyl-2-propanol (15 ml), and the r.m. was heated at 100 °C ovemight. After cooling, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO«) filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/McOH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 0.216 g of compound 15 (51.5 %).

Example B16

Préparation of compound 16

Intermediate 19 (0.336 g, 1.10 mmol), Pd₂(dba)j (0.101 g, 0.11 mmol), dicyclohcxyl[2^,,4',6'-tris(l-mcthylcthyl)[l,l'-biphenyl]-2-yl]phosphine(0.115 g, 0.242 mmol) and Cs₂CÜ3 (1.077 g, 3.31 mmol) were added to a sol. of intermediate 4 (0.225 g, 1.10 mmol) in 2-mcthyl-2-propanol (15 ml), and the r.m. was heated at 90 °C for 72 h. After cooling, the solvent was evaporated, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH from 100/0 to 99/1) and the product fractions were collected and the solvent was evaporated. The residue was crystallizcd from DIPE, filtered and dried under vacuum at 80 °C. Yield: 0.220 g of compound 16 (46.6%).

- 105Example Bl7

Préparation of compound 17

Intermediate 41 (0.22 g, 0.84 mmol), Pd₂(dba)₃ (0.077 g, 0.084 mmol), dicyclohcxyl[2',4',6'-tris(l-mcthylcthyl)[l,l'-biphcnyl]-2-yl]phosphinc (0.080 g, 0.168 mmol) and Cs₂CO₃ (0.822 g, 2.52 mmol) were added to a sol. of intermediate 43 (Ο.361 g, 0.841 mmol) in 2-methyl-2-propanol (15 ml), and the r.m. was heated at 100 °C for 20 h. After cooling, the solvent was evaporated, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO4) filtered and the solvent was evaporated. The residue was purified by flash chromatography over Silica gel (eluent: DCM/MeOH(NH₃) 99/l) and the product fractions were collected and the solvent was evapoarted. Yield: 0.20 g of compound 17 (57 %).

Example BIS

Préparation of compound 18

Intermediate 34 (0.190 g, 0,57 mmol), Pd₂(dba)₃ (0.052 g, 0.057 mmol), dicyclohcxyl^'^'.ô'-trisiI-rnethylcthylXljr-biphenyl^-yqphosphine (0.054 g, 0.114 mmol) and Cs₂CO₃ (0.558 g, 1.71 mmol) were added to a sol. of intermediate 48 (0.100 g, 0.571 mmol) in 2-methyl-2-propanol (10 ml), and the r.m. was heated at 110 °C for 14 h. After cooling, H₂O was added and the product was extracted with DCM. The organic phase was dried (MgSO.i) filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (eluent; DCM/ McOH(NH₃) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 0.093 g of compound 18 (38 %).

-106Example B19

Préparation of compound 169

A mixture of intermediate 90 (30 mg, 0.056 mmol), and Raney nickel (20 mg), in THF (30 ml) was stirred at r.t. under H2 (atmospheric pressure). After uptake of Hj (2 eq), the catalyst was filtered off over diatomaceous earth. The solvent was evaporated and the residue was partitioned between DCM and Η₂Ο. The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by preparative HPLC [RP Vydac Denali C18 (10 gm, 250 g, I.D. 5 cm); mobile phase: (0.25 % NH4CO3 sol. in water, CHjCN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 1.1 mg of compound 169 (4 %).

Example B20

Préparation of compound 188

Intermediate 57 (0.224 g, 1.15 mmol), Pd(OAc)₂ (0.034 g, 0.15 mmol), Xantphos (0.133 g, 0.23 mmol) and CS2CO3 (0.498 g, 1.53 mmol) were added to a sol. of intermediate 63 (0.185 g, 0.76 mmol) in dioxanc (3 ml), and the r.m. was heated at 160 °C for 1 h under microwavc irradiation. After cooling, H₂O was added and the product was extracted with DCM, The organic phase was dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by preparative IIPLC [RP Shandon Hypcrprcp® Cl8 BDS (8 gm, 250 g, I.D. 5 cm); mobile phase: (0.25 % NH4CO3 sol. in water, MeOH)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.040 g of compound 188 (13 %).

Example B21

Intermediate 34 (0.405 g, I.l7 mmol), PdîfdbaL (0.107 g, 0.12 mmol), X-Phos (0.122 g, 0.26 mmol) and CsîCOj ( l. 14 g, 3.5 mmol) were added to a sol. of intermediate 56 (0.250 g, 1.17 mmol) in 2-mcthyl-2-propanol ( 10 ml), and the r.m. was heated at 100 °C for 4 h. After cooling, H2O was added and the product was extracted with DCM. The organic phase was dried (MgSCL) filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/ McOH(NHj) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was triturated with DlPE/2-propanol. Yield: 0.284 g of compound 128 (52 %).

Example B22

Préparation of compound 165

A solution of compound 143 (prepared form intermediate 98 and intermediate 2, according to example B3, 150 mg, 0.33 mmol) in THF (5 ml) was added slowly to a 1 M solution of CHjLi in THF (1 ml, 1 mmol) at 0 °C . The mixture was stirred at r.t.

for 2 h, and then an additional 1 M sol. of CH3L1 in THF (1 ml, 1 mmol) was added and stirring was continucd at r.t. for lh. An aq. 10 % HCl solution was added and the mixture was extracted with DCM. The organic phase was dried (MgSO^) filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over Silica gel (eluent: DCM/ MeOH(NHj) from 100/0 to 99/1). The product fractions were collected and the solvent was evaporated. Yield; 21 mg of compound 165 (15 %).

Example B23

Préparation of compound 120

A mixture of compound 123 (prepared form intermediate 104 and intermediate 2, according to example B18,40 mg, 0.088 mmol), and Raney nickel (20 mg), in

McOH(NHj) (40 ml) was stirred at r.t. under H2 (atmospheric pressure). After uptakc

- 108 of H₂ (2 eq), the catalyst was filtered off over diatomaceous carth. The solvent was evaporated and the residue was purified by flash chromatography over siiica gel (eluent: DCM/McOH(NH₂) 90/10). The product fractions were collectcd and the solvent was evaporated. Yield: 7 mg of compound 120 (17 %).

Example B24

Préparation of compound 197

A. 1:1 mixture ofTHF and MeOH (100 ml) was added to Pd/C (10%, 500 mg) under a N₂ atmosphère. Subsequently, a 0.4 % thiophene solution in DIPE (0.5 ml), compound 198 (prepared according to example B3, 49 mg, 0.11 mmol), and KOAc (13 mg, 0.13 mmol) were added, and the r.m. was stirred at 25 °C under a H₂ atmosphère until 1 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth. The filtrate was evaporated and the residue was partitioned between DCM and a sat. aq. NaHCOj sol. The organic layer was dried (MgSO«), filtered and the solvent was evaporated. The residue was purified by flash chromatography over siiica gel (eluent: DCM/ MeOH(NHj) from 100/0 to 96/4). The product fractions were collectcd and the solvent was evaporated. Yield: 9.5 mg of compound 197 (21 %).

Example B25

Préparation of compound 179

Br

A mixture of 4-(2-methyl-oxazol-5-yl)-phenylamine (615 mg, 3.53 mmol), intermediate 101 (933 mg, 3.21 mmol), and D1PEA (1.24 g, 9.62 mmol) in CHjCN (10 ml) were heated at 200 °C under microwave irradiation for 1.5 h. The volatiles were evaporated under reduced pressure and the residue was partitioned between DCM and H₂O. The organic layer was dried (MgSOJ, filtered and the solvent was evaporated. The residue was purified by flash chromatography over siiica gel (eluent: DCM/ MeOH(NHj) 95/5). The fractions containing product were collectcd and the solvent was evaporated. The residue was purified further by préparative HPLC [RP Shandon Hyperprep® Cl8 BDS (8 μηι, 250 g, I.D. 5 cm); mobile phase: (0.25 % NH«CO₂ sol. in water, MeOH)]. The product fractions were collectcd and concentrated under reduced pressure. Yield: 0.031 g of compound 179 (3 %).

- 109Example B26

a) Préparation of compound 185

l-Iodo-2,5-pyrrolidinedione (837 mg, 3.72 mmol) was added to compound 42 (1.3 g, 3.38 mmol) in DCM (50 ml) and AcOH (5 ml). The r.m. was stirred at r.t. for 5 min., then washed with an aq. NaHCCh sol. The organic layer was dried (MgSCM), filtered, concentrated in vacuo. The residue was purified by flash chromatography over silica gel (eluent: DCM/ MeOH(NHî) from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 500 mg of compound 185 (29 %).

b) Préparation of compound 177

Isopropenylboronic acid pinacol ester (151 mg, 0.9 mmol) and Pd(PPhj)4 (52 mg, 0.045 mmol) was added to a sol. of compound 185 (230 mg, 0.45 mmol) in dioxane (2 ml) and an aq. NaHCOj sol. (2 ml), and the mixture was stirred and heated at 150 °C for 10 min. under microwave irradiation. The r.m, was cooled to r.t. and filtered over diatomaceous earth using EtOAc, and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM/McOH(NHî) from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. Yield: 14 mg of compound 177 (7 %).

c) Préparation of compound 175

MeOH (40 ml) was added to Pt/C 5 % (50 mg) under N₂ atmosphère. Subsequently, compound 177 (150 mg, 0,35 mmol) was added. The r.m. was stirred at 25 °C under H₂atmosphère until 1 eq of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was triturated with DIPE. Yield: 70 mg of crude compound 175 (46 %).

- lioExample B27

a) Préparation of compound 156

A 3 M CHjMgBr sol. in Et₂O was added to a sol. of compound I5l (prepared from intermediate 2 and intermediate 111 according to example B3, 105 mg, 0.26 mmol) in THF (20 ml) at 0 °C. Th r.m. was stirred at r.t. ovemight, and then quenched with a sat. aq. NH4CI sol. Water was added, and the mixture was extracted with DCM. The organic layer was dried (MgSO₄), filtered, concentrated in vacuo. The residue was purified by flash chromatography over silica gel (eluent: DCM/ MeOH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. The residue was dissolved in DIPE/CH3CN, and a 6 N HCl sol. in 2-propanol was added. The resulting precipitate was collected by filtration and dried. Yield: 3.2 mg of compound 156 as HCl sait (3 %).

b) Préparation of compound 162

A solut ion of NaOH (2 g, 50 mmol) in H₂O (40 ml) was added to a sol. of compound 151 (0.4 g, 1 mmol) in dioxane (40 ml). The r.m. was stirred at reflux for 3 h, and was then cooled to r.t. and ncutralized to pH 7 with aq. conc. HCl. The resulting precipitate was collected by filtration and dried. Part of the residue (213 mg, 0.51 mmol) was dissolved in DCM (13 ml), and oxalylchloride (0.13 ml, 1.52 mmol) and DMF (0.2 ml, 2.58 mmol) were subsequently added. The r.m. was stirred at r.t. ovemight, then poured into MeOH (20 ml) and stirred at r.t. for 1 h. The mixture was partitioned between DCM and an aq. sat. NaHCOj sol. The organic layer was dried (MgSO^), filtered, concentrated /« vacuo. The residue was purified by flash chromatography over silica gel (eluent: DCM/ MeOH from 100/0 to 95/5). The product fractions were collected

and the solvent was evaporated. The residue was triturated with DIPE. Yield: 58 mg of compound 162 (20 % yield over the 2 steps).

Compounds l to 202 in tables l, 2, 3, 4 and 5 list the compounds that were prepared by analogy to onc of the above Examples. In case no sait form is indicated, the compound 5 was obtained as a free base. ‘Pr.’ refers to the Example number according to which protocol the compound was synthesized. ‘Co. No.’ means compound number. ‘Bx’ refers to the general Experimental Procedure l wherein sodium re/7-butoxide, toluene, BINAP and Pd(OAc)₂ were used.

In order to obtain the IICI sait forms of the compounds, typical procedures known to 10 those skilled in the art can be used. In a typical procedure, for example, the crude residue (free base) was dissolved in DIPE or Et₂O and subscquently, a 6 N HCl solution in 2-propanol or a l N HCl solution in Et₂O was added dropwise. The mixture was stirred for IO minutes and the product was filtered off. The HCl sait was dried in vacuo.

Table l a'-a²

Co. No.	Pr.	Het‘	Λ¹	A²	Y¹	R^4b	R⁶¹’	r’	sait form
13	B13	X>-	COCHj	CH	CH	H	0	CH₃
9	B9	L?.....	COCH,	CH	CH	H	0	CHj
19	B3	.....	CH	CH	CH	H	0	CH(CHj)₂	.2 HCl
11	BU	Q-	COCHj	CH	CH	H	f	CHj

Co. No.	Pr.	Het¹	A¹	A²	Y^J	R^4h	R«b	R⁷	sait form
20	Bx	0-	COCHj	CH	CH	H	0-och₃	CHj
2I	B3		CH	CH	CH	H	0-OC».,	CH(CHj)₂
22	B3	Q-	COCHj	CH	CH	II	-Y	CHj
23	B3		CH	CH	N	H	0'	CH₃
15	B15		CH	N	CH	H	0	CH(CHj)₂
12	B12	Q.....	COCHj	CH	CH	H	0	CHj
16	B16	.....	COCHj	CH	CH	H	0	CHj
24	B3	Ύ0-	COCHj	CH	CH	H	0	CHj
14	B14	Ύ>-	COCHj	CH	N	H	0	CHj
25	B3		COCHj	CH	CH	H	0'	CH(CHj)₂	.2 HCl

Co. No.	Pr.	Ilet'	A*	A¹	Y*	R^Jb	R⁶	R’	sait form
26	B3	Ί0-	CH	CH	N	H	0	CH(CHj)₂
27	B3	.....	COCI-h	CH	N	H	0	CH(CH₃)₂
18	Bl8	Ύ>-	N	CH	CH	H	0	CH(CH₃)₂
28	B3	Ύ>·	CF	CH	CH	H	F 0 f	CH(CHj)₂
17	Bl7	Ύ>·	CF	CH	N	H	F 0	CH₃
29	B3	ΊΟ.....	N	CH	CH	H	0	ch₃
10	BIO	Q--	CH	N	CH	H	0	ch₃
30	B3	ΊΟ-·	COCHj	CH	CH	cf₃	0	ch₃
31	B3	ΊΟ.....	COCHj	CH	N	H	F 0 F	CHj
32	Bx	iQ.....	CH	N	CH	H	/	CH₃
33	Bx	Q-	CH	N	CH	H		ch₃

Co. No.	Pr.	Het'	Α¹	A²	Y*	_R4b	R⁶”	R⁷	sait form
34	B3	Q-	Ν	CH	CH	H	0	C(CH₃)₃
35	B3	%	Ν	CH	CH	II	0'	ch₃
36	B3		COCHj	CH	CH	H	/“Q~^f	CHj
37	B3	Ύ>-	COCHj	CH	CH	H	ch₃
53	B3	Ύ>-	CH	CH	N	H	0 F	CHj
54	B3	jQ-	COCHj	CH	N	f-I	0	CHj
55	B3	Ύ>·	CF	CH	N	H	A	CHj
56	B3	Ύ>-	CH	CH	CH	F	Q-™	CHj
58	B3	Ύ>-	CH	CH	N	CHj	0	CHj
59	B3	Ύ>-	COCHj	CH	N	ch₃	0	CHj

-115-

Co. No.	Pr.	Het'	A¹	A²	Y¹	R^4b	_R60	R⁷	sait form
61	B3	Q.....	N	CH	CH	H	,P	CH₃
62	B3	ï>-	COCHj	Cil	CH	H	fjH-CCH.	CH-,
63	B3		COCHj	CH	CH	H		CI1₃
64	B3	Ÿü	COCH,	CH	CH	H	.·—*x]	c₂h₅
65	B3	Q-	CF	CH	CH	H	F ό y	y_	.HCl
66	B3	Ύ>-	CF	CH	N	H		ch₃
67	Bl8	X>~	CH	CH	CH	H	F 0	ch.
68	Bl8	jo-	COCHj	N	CH	H	0 y	ch₃
69	Bl8	X>-·	COCH,	N	CH	H	0	V
70	Bl8		N	CH	CH	H	0 /	CHî	.2HCI

Co. No.	Pr.	Het¹	A¹	A¹	Y¹	R^Jb	_R6b	R⁷	sait form
71	Bl8	V.....	CH	N	CH	H	0	CH,
72	Bl8	! N'\ Q.....	CH	CH	CH	H		CH₃
73	Bl8		COCHj	CH	CH	H	0	ch₃
74	BIS	J>-	COCHj	CH	CH	H	0	ch₃
75	B18	IL >.....	COCH₃	CH	CH	H	0	ch₃
76	Bl8	Y>-	N	CH	CH	H	F ό /	ch₃
77	Bl8	ï>-	COCH₃	CH	CH	H	0	\_
		Ύ>-					x	ch₃
78	Bl7		COCH3	CH	N	II	0-
79	Bl8		N	CH	CH	F	A	CH₃
80	B3	.....	COCH3	CH	CH	H	d		.HCl

Co. No.	Pr.	Het'	A¹	A²	Y	_RJb	_Rib	R⁷	sait form
81	B18		CH	CH	CH	H	0	V
82	BI8		N	CH	CH	H	0	V
83	B18		CH	CH	CH	H	0	ch₃
84	BIS	.....	CH	CH	CH	H	r 0	V
85	B17	Ύ>-	N	CH	N	H	R	ch₃
86	B18	Ό-	N	CH	CH	CN	F 0	CH₃
87	B18	Ύ>·~	N	CH	CH	H		CHj
88	B18	Ύ>-	N	CH	CH	H	5“Ο^α	ch₃	.2HCI ,H₂O
89	B18	Ύ>.....	N	CH	CH	F	F 0	V	.1.7HC1 ,1.6H₂O.
90	B18	Ύ>-	CH	CH	CH	F	P	CH,

Co. No.	Pr.	Het¹	Α¹	A²	ytl	R^Jb	_R6b	R⁷	sait form
91	Bl7	D.....	COCHj	CH	N	H	Λ	CHj
92	Bl7	D.....	COCHj	CH	N	CHj	P	CHj
93	Bl8		COCHj	CH	CH	H	P y	y
94	B17	Ύ>-	COCHj	CH	N	>	ό	CHj
95	B18	Ό-	COCHj	CH	CH	OCHj	0	CHj
96	B18	Ί>-	CH	CH	CH	H	/—0	CHj
97	B17	ϊ>.....	COCHj	CH	N	CHj	^~~y~ ocM,	CHj
98	B17	1}.....	CH	CH	N	CHj	ocn,	CHj
99	B18	Ύ>.....	CH	CH	CH	CFj	H	CHj
I00	B18	Ύ>.....	CH	CH	CH	CF,	P	CHj

Co. No.	Pr.	Het¹	A¹	A²	Y¹	_R4b	_R«b	R⁷	sait form
ΙΟΙ	B18		N	CH	CH	cfj	0	CHj
102	B17		COCHj	CH	N	ch₃	Çp~	CHj
103	B18		N	CH	CH	CN	Q-och, y	CHj
104	B18	.....	COCHj	CH	CH	F	P	CHj
105	B18		N	CH	CH	F		CHj
106	B18	Ύ>-	N	CH	CH	F	0	CHj
107	B18	Ύ>·	N	CH	CH	F	A	CHj
108	B18	ΊΟ™	COCHj	CH	CH	F	p-	CHj	.2HC1 .HjO
109	B17	Ύ>·	CF	CH	N	H		CHj
110	B18	Q-·	N	CH	CH	CN	0	CHj
111	B17	Q-	N	CH	N	ch₃	CP	CHj

Co. No.	Pr.	Het¹	A¹	A¹	Y¹	R^4b	R^6b	R⁷	sait form
112	B18	Q.....	N	CH	CH	H	Q-a		.1.5HC1 .2HjO
113	B17	Q.....	COCHj	CH	N	CHj	A.	CHj
114	B18	Q-	N	CH	CH	F	A	CH,
115	B18	Q-	N	en	CH	H	pr
116	BIS	Q.....	N	CH	CH	H	pr	y_	.2HC1
117	B17	Q.....	N	CH	N	H	R	CHj
118	B18	Q.....	N	CH	CH	H	0	y_	.2HC1
119	B18	Q-	N	CH	CH	F	0	CHj
120	B23	Q-	COCHj	CH	CH	CH₂NHî	0	CHj
121	B17	A	COCHj	CH	N	CH,	OCHj	CH,
122	Bl 8	Q-	COCHj	CH	CH	CN	^y-ocib	CHj
123	B18	Q.....	COCHj	CH	CH	CN	F ό y	CH₃

Co. No.	Pr.	Het'	A¹	A²	Y¹	_RJb	_R6b	R⁷	sait form
124	Bl8	Q-	CH	CH	CH	H	d	CHj
		Q.....					F
125	Bl7	COCHj	CII	N	CHj	d	CHj
126	Bl8	Q-	COCH,	CH	CH	CFj		CHj
127	B2l	b-	COCHj	CH	N	CHj	0	CHj
128	B2l	b.....	COCHj	CH	CH	H	0
129	B2l	b.....	COCHj	N	CH	H	b	CHj
130	B2I	b-	COCHj	N	CII	H	0	v
I3l	B2I	b-	CH	CH	CH	H	0	\_
132	B2l	b.....	CH	CH	N	CH,	0	CHj
I33	B2l	b-·	CF	CH	CH	H	0	CHj

Co. No.	Pr.	Het¹	A¹	A¹	Y¹	_R4b		R⁷	sait form
134	BÏ7	b-	N	N	N	CH₃	d	CH₃
		y					F
135	Bi8	b.....	N	N	CH	H	0	CHj
		y					F
136	B2l	b-	CF	CH	N	CHj	0	CHj
137	B2l		CF	CH	CH	H	0	y /
138	B2l	b- y	CH	CH	CH	H	0 F	CHj
139	B2l	b-	COCHj	CH	CH	H	0	CHj
							F	y
140	B2l	p--	CH	CH	CH	H	0
184	B2l	o-	CH	CH	CH	H	0	CH,

-123Table 2

Co. no.	Pr.	Het¹	A'	Z¹	R⁴	R^s	R«.	sait form
6	B6	.....	coci-i.	CH	H	CHj
38	Al	0.....	COCHj	CH	H	H	d
39	B3	ï>-	CH	CH	H	H	P	.2 HCl
2	B2	Q-	COCHj	CH	H	CHj	OCH,
40	B3	ï>.....	CH	CH	H	H
41	B3		CF	CH	H	H	-^^-OCH,
42	B3	Ύ>-	CH	CH	H	H	d
3	B3	Ύ>·	COCHj	CH	H	H	F d
1	B1	nQ.....	COCHj	CH	H	H	F 0
43	B3	Ύ>	CH	CH	H	H	/~O“^f

Co. no.	Pr.	Het'	Α¹	Z¹		R⁵	R^e	sait form
44	B3	Q-	Ν	CH	H	H	-0
45	B3	Q.....	Ν	CH	H	H
46	B3		CH	CH	H	H	F -0
47	B3		CH	CH	H	H
48	B3	γμ	COCHj	CH	H	H	-Ch y	.HCl
49	Bx	Ύ>.....	CH	CH	H	CH₃	a-Q i
50	B3		CH	CH	H	H	-Çy_a,
51	B3		Ν	CH	H	H	CA /
8	B8		COCHj	CH	H	CH₃	P
7	B7	η·.....	COCHj	CH	H	H	0
4	B4	Ύ>-	COCH₃	CH	H	CIlj	00—OCllj

- 125 -

Co. no.	Pr,	Het'	A'	Z^l	R⁴’	R^s	R⁶*	sait form
57	B24		CH	N	H	H	0’
60	B25	ï>-	CH	N	Br	H	-0
52	B3	Yy...	COCHj	CH	H	H	P
5	B5	0--	COCHj	CH	H	CHj
141	B3	0-	COCHj	CH	CFj	H	CHj	.2 HCI
142	B3	Q-	COCHj	CH	CFj	CHj	CH₃
143	B3	0-	COCHj	CH	CFj	H	(C=O)N(CH₃)₂
144	B3	jQ-	COCHj	CH	H	CHj	CH,
145	B3	«Q-	COCHj	CH	CN	H	CHj
146	B3	0-	COCHj	CH	CN	H	-0
147	B3	Q.....	COCHj	CH	F	H	-0	.HCl .H₂0
148	B3	0-	COCHj	CH	CFj	H	o f

Co. no.	Pr.	Het‘	A'	Z¹	_r4.	R^s	_r6»	sait form
149	B23	Q-	coch₃	CH	CHj	II	-d	.HCl
150	B23	jQ.....	COCHj	CH	CHjNI-h	H	55
151	B3	Q.....	COCHj	CH	CN	H	/H
202	B3	Q-	COCHj	CH	CN	H	λΧ	.2 HCl
152	B3	Q.....	CH	CH	H	CHj
153	B3	Q.....	COCHj	N	> X	H	CHj
154	B3	Q-	N	CH	H	H	P
155	B3	Q.....	COCHj	CH	H	H	P X	.2HCI
156	B27a	Q-	COCHj	CH	y J	H	H	.HCl
157	B3	Q.....	COCHj	CH	F	H	/“(	.HCl
158	B3	Q-	COCHj	N	H	H	CHj
159	B3	Q-	COCHj	CH	Cl	H	P	.2HC1

Co. no.	Pr.	Het¹	A'	Z¹	R⁴*	R⁵	_r6.	sait form
160	B3	Q--	N	CH	H	H	> f
I6l	B3	Y	N	CH	H	och₃	d /
162	B27b	Q-	COCHj	CH	H,CO >0	H	H
163	B3	Q-	COCHj	CH	F	H	p
164	B3	0.....	N	CH	H	H	/-O	.HCl .0.45H₂O
165	B22	Q-	COCHj	CH	cf₃	H	(C=O)CH₃
166	B3	vy.	CH	CH	H	H	> / /
767	B3	Ύ>·	N	CH	H	CH₃	9..
168	B3	.....	COCHj	CH	H	CH₂OCHj	d f
169	B19		COCH,	CH	H	(CH₂)₃OCH₃	Q ·' Vf,
170	B3	vy-	COCIIj	N	CF₃	H	ci-i₃
171	B3	ΊΟ···	N	CH	F	H	-d y	1.2HCI

Co. no.	Pr.	Het'	A¹	Z¹	R⁴’	R*	R⁶*	sait form
172	B3	ÏV-	N	CH	H	H	ch₃
173	B3		N	CH	H	CH₃	Q Cl
174	B19		COCHj	CH	H	(CH₂)₂OCH₃	0
175	B26c		CH	CH	H	V y	0
176	B3	YY··	CH	CH	F	H	F Y
177	B26b	ï>-	CH	CH	H		1' 0
178	B3	Ύ>-	CH	CH	F	H	A..........	.2 I-ICi
179	B25	.....	CH	N	Br	H	CHj
180	B3	Λο.....	CH	CH	H	CHj	CHj
I8l	B3	vy-	CF	CH	CF₃	H	(C=O)N(CHj)₂
182	B21	.....	CF	CH	H	CHj	R
183	B21	b-	CH	CH	H	CH,	R.
185	B26a	Ύ>-	CH	CH	H	I	0

- 129-

Co. no.	Pr.	Het¹	A¹	Z¹	R⁴	R^s	rC	sait form
201	B2l	b-	COCHj	CH	H	CHj	Q Cl

Table 3

Co. No.	Pr.	Het'	A¹	A²	A⁴	R⁴¹’	y’	R⁶	R⁷
187	B17	.....	CF	CH	CH	H	N	0	CHj
188	B20	D.....	CH	N	N	H	CH	d /	CHj
189	B18		COCHj	CH	CH	CN	N	d	CHj
190	B26c	.....	COCHj	CH	CH	V r	N	0	CHj
191	B17		N	CH	CH	Y	N	0	CHj
192	B17		COCHj	CH	CH	> J t	N	0 Z	CHj
193	B17	.....	COCHj	CH	CH	CHj	N	F 0	CHj

Table 4

Table 5

Co. No.	Pr.	Het¹	A¹	A¹	_R6b	r’
199	Bl8	Q.....	COCHj	CH	d	CHj
200	Bl8	.....	N	CH	0	ch₃

4»«

- I3l -

Co. No.	Pr.	Het'	A'	A¹	_R6b	R¹
186	Bl8	T>.....	COCHj	CH	d	CHj

Analytical Part

LCMS

General procedure A

The LC measurement was performed using an Acquity UPLC (Waters) system comprising a bînary pump, a sample organizer, a column heater (set at 55 °C), a diodearray detcctor (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spcctromcter. The MS detector was configured with an elcctrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwcll time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source température was maintained at 140 °C. Nitrogen was used as the ncbulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

General procedure B

The IIPLC measurement was performed using an Agiient 1100 sériés liquid chromatography system comprising a bînary pump with degasser, an autosamplcr, a column oven, a UV detcctor and a column as specified in the respective methods below. Flow from the column was split to a MS spcctromcter. The MS detector was configured with an elcctrospray ionization source. The capillary voltage was 3 kV, the quadrupolc température was maintained at 100 °C and the desolvation température was 300 °C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an Agiient Chemstation data system.

General procedure C

The HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosamplcr, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spcctromcter. The MS detcctor was configured with an elcctrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in l second using a dwell time of O.l second. The capillary needle voltage was 3 kV and the source température

- 132 was maintained at 140 °C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

LCMS Method 1 ln addition to general procedure A: Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsîloxane/silica hybrid (BEH) Cl8 column (1.7 gm, 2.1 x 50 mm; Waters Acquity) with a flow rate of0.8 ml/min. Two mobile phases (25 mM NH^OAc in H2O/CH3CN 95/5; mobile phase B: CH3CN) were used lo run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes (min) and hold for 0,3 min. An injection volume of 0.5 μΙ was used. Cône voltage was 10 V for positive ionization mode and 20 V for négative ionization mode.

LCMS Method 2 ln addition to general procedure A: Reversed phase UPLC was carried out on a BEH C18 column ( 1.7 gm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1 % formic acid in H2O/MCOH 95/5; mobile phase B: MeOH) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 min and hold for 0.2 min. An injection volume of 0.5 gl was used. Cône voltage was 10 V for positive and 20 V for négative ionization mode.

LCMS Method 3 ln addition to general procedure B: Reversed phase HPLC was carried out on a YMCPack ODS-AQ Cl 8 column (4,6 x 50 mm) with a flow rate of 2.6 ml/min. A gradient run was used from 95 % water and 5 % CHjCN to 95 % CHjCN in 4.80 min and was hold for 1,20 min. Mass spectra were acquired by scanning from 100 to 1400. Injection volume was 10 gl. Column température was 35 °C.

LCMS Method 4

In addition to general procedure C: Column heater was set at 60 °C. Reversed phase HPLC was carried out on an Xtcrra MS C18 column (3.5 gm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A; 95 % 25 mM NH4OAC + 5 % CHjCN; mobile phase B: CHjCN; mobile phase C: MeOH) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 min and hold these conditions for 1 min and rccquilibrate with 100 % A for 1.5 minutes. An injection volume of 10 gl was used. Cône voltage was 10 V for positive ionization mode and 20 V for négative ionization mode.

LCMS Method 5

In addition to general procedure C: Column heater was set at 45 °C. Reversed phase

HPLC was carried out on an Atlantis Cl8 column (3.5 gm, 4.6 x 100 mm) with a flow

- 133rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70 % MeOH + 30 % H2O; mobile phase B: 0.1 % formic acid in H₂O/MeOH 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 9 min and hold these conditions for 3 min. An injection volume of 10 pl was used. Cône voltage was ΙΟ V for positive ionization mode and 20 V for négative ionization mode.

LCMS Method 6

In addition to general procedure C: Revcrsed phase HPLC was carried out on an Xtcrra MS Cl8 column (3.5 pm, 4.6 x 100 mm) with a flow rate of l .6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM NH₄OAc + 5 % CH3CN; mobile phase B: CH3CN; mobile phase C: MeOH) were employed to run a gradient condition from 100 % A to l % A, 49 % B and 50 % C in 6.5 min, to l % A and 99 % B in l min and hold these conditions for l min and reequilibrate with 100 % A for l .5 min. An injection volume of 10 pl was used. Cône voltage was ΙΟ V for positive and 20 V for négative ionization mode.

LCMS Method 7

In addition to general procedure A: Reversed phase UPLC was carried out on a bridged BEH Cl8 column (1.7 pm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (25 mM NH₄OAc in H2O/CH3CN 95/5; mobile phase B: CHjCN) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 min and hold for 0.3 min. An injection volume of 0.5 μΐ was used.

Cône voltage was 30 V for positive and 30 V for négative ionization mode.

Mcltinu Points

For a number of compounds, melting points (m.p.) were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a température gradient of 30 °C/minute. Maximum température was 400 °C. Values are peak values.

The results of the analytical measurements are shown in table 6.

Table 6: Rétention time (R_t) in min., [M+H]* peak (protonated molécule), LCMS method and m.p. (melting point in °C). (n.d. means not determined)

Co. No.	Rt	[M+Hf	LCMS Method	m.p. (°C)
I	1.15	415	1	163.2
2	I.l8	441	1	n.d.
3	l.4l	415	2	219.1

Co. No.	Rt	[M+Hf	LCMS Method	— m.p. (°C)
4	8.42	457	5	n.d.
5	I.26	471	l	n.d.
6	I.l6	454	l	n.d.

Co. No.	Rt	[M+H\|^f	LCMS Method	m.p. (°C)
7	6.09	429	4	n.d.
8	1.32	425	2	n.d.
9	1.33	428	2	n.d.
10	5.72	400	4	195.4
11	1.08	431	1	n.d.
12	1.13	429	1	n.d.
13	1.27	428	2	157.6
14	7.02	430	5	204.9
15	1.23	428	1	n.d.
16	1.15	429	1	189.0
17	1.13	418	1	n.d.
18	1.12	428	1	133.4
19	1.54	427	2	n.d.
20	3.11	441	3	n.d.
21	n.d.	n.d.		n.d.
22	1.53	511	2	n.d.
23	1.06	400	1	184.8
24	6.00	443	4	174.1
25	1.27	457	1	n.d.
26	1.22	428	1	n.d.
27	1.24	458	1	n.d.
28	1.46	445	2	n.d.
29	1.00	400	1	n.d.
30	1.31	497	1	201.9
31	1.12	448	1	210.1
32	2.95	416	3	n.d.
33	2.90	446	3	n.d.
34	1.22	442	1	n.d.
35	1.07	400	1	n.d.
36	1.1	430	1	n.d.
37	1.01	409	1	n.d.
38	1.16	401	1	n.d.
39	1.23	381	1	n.d.
40	1.20	411	1	n.d.

Co. No.	Rt	IM+Hf	LCMS Method	m.p. (°C)
41	n.d.	n.d.	-	n.d.
42	1.42	385	2	181.8
43	1.15	399	1	n.d.
44	1.15	400	1	n.d.
45	1.21	400	1	n,d.
46	8.45	399	5	135.3
47	9.55	399	5	n.d.
48	1.35	429	2	n.d.
49	6.78	415	4	213.0
50	9.61	449	5	125.5
51	1.28	450	1	n.d.
52	1.27	427	1	n.d.
53	1.09	418	1	171.4
54	1.08	448	1	156.8
55	1.14	436	1	204.8
56	n.d.	n.d.	-	n.d.
57	1.43	400	2	n.d.
58	1.15	414	1	230.2
59	1.18	444	1	250.8
60	1.53	478	2	n.d.
61	1.07	412	1	145.1
62	3.73	475	3	n.d.
63	3.26	441	3	n.d.
64	2.64	403	3	n.d.
65	6.63	445	6	n.d.
66	1.01	378	7	172.5
67	1.09	398	7	195.9
68	1.15	429	7	168.9
69	6.69	457	6	192.8
70	0.96	399	7	n.d.
71	1.06	399	7	113.5
72	1.13	398	7	146.3
73	6.27	429	6	184.1
74	5.87	429	6	153.3

Co. No.	Rt	[M+Hf	LCMS Method	m.p. (°C)
75	0.99	429	7	224.7
76	1.07	416	7	147.3
77	l.3l	473	7	n.d.
78	l .15	464	7	122.5
79	1.15	448	7	n.d.
80	1.25	471	7	n.d.
8I	1.28	441	7	n.d.
82	1.20	442	7	n.d.
83	1.17	413	7	n.d.
84	6.45	457	6	172.5
85	0.97	417	7	n.d.
86	0.97	425	7	253.6
87	1.14	444	7	n.d.
88	1.16	456	7	n.d.
89	1.15	446	7	n.d.
90	1.12	392	7	n.d.
91	1.04	432	7	190.7
92	0.99	434	7	n.d.
93	1.11	447	7	191.6
94	1.27	470	7	n.d.
95	1.37	459	2	n.d.
96	1.07	377	7	n.d.
97	1.19	456	7	183.0
98	1.17	426	7	158.8
99	1.15	454	7	190.1
100	1.12	457	7	204.6
ΙΟΙ	1.13	468	7	173.6
I02	1.30	484	7	n.d.
103	1.27	437	2	n.d.
104	1.14	422	7	n.d.
105	1.05	430	7	n.d.
106	1.03	418	7	190.2
107	1.06	434	7	118.3
108	6.83	438	6	n.d.

Co. No.	Rt	[M+Hf	LCMS Method	in.p. (°O
109	1.14	430	7	190.4
110	1.03	425	7	230.6
111	1.13	431	7	220.2
112	1.25	444	7	n.d.
113	1.19	460	7	139.5
114	1.12	434	7	n.d.
115	1.54	450	2	n.d.
116	9.50	450	5	n.d.
117	1.03	417	7	189.2
118	1.17	428	7	n.d.
119	1.39	418	2	179.6
120	0.79	458	7	n.d.
121	1.18	456	7	176.2
122	1.10	466	7	n.d.
123	1.37	454	2	208.9
124	1.15	399	7	n.d.
125	1.16	444	7	211.0
126	1.20	499	7	180.2
127	1.30	454	7	201.1
128	1.38	467	7	n.d.
129	1.37	440	7	n.d.
130	1.45	468	7	n.d.
131	1.13	437	2	n.d.
132	0.90	424	2	240.0
133	1.20	427	7	n.d.
134	n.d.	n.d.	n.d.	258.8
135	0.99	411	7	220.0
136	1.24	442	7	230.5
137	1.31	455	7	n.d.
138	6.58	409	6	168.9
139	1.17	439	7	163.2
140	1.31	451	7	n.d.
141	6.20	403	6	n.d.
142	1.17	417	7	n.d.

y

Co. No.	Rt	[M+Hf	LCMS Method	m.p. (°C)
143	n.d.	n.d.		201.8
144	0.99	349	7	122.0
I45	0.93	360	Ί	186.6
146	1.21	454	7	195,2
147	1.27	447	7	n.d.
148	0.91	202	2	n.d.
149	6.68	443	6	n.d.
150	0.93	458	7	n.d.
151	6.27	402	6	n.d.
152	1.21	411	7	123.7
153	1.44	376	2	n.d.
154	5.20	376	6	n.d.
155	5.63	405	6	201.2
156	6.09	419	6	n.d.
157	6.45	395	6	n.d.
158	0.92	336	7	263.0
159	1.09	439	7	n.d.
160	0.82	332	2	n.d.
161	n.d.	n.d.	n.d.	176.9
162	n.d.	n.d.	n.d.	157.1
163	1.01	423	7	155.2
164	5.41	390	6	n.d.
165	n.d.	n.d.		183.6
166	0.96	331	2	n.d.
167	n.d.	n.d.	n.d.	n.d.
168	1.22	459	7	170.8
169	1.27	537	7	n.d.
170	1.42	404	2	239.8
171	1.12	418	7	n.d.
172	0.77	306	7	n.d.

Co. No.	Rt	[M+Hf	LCMS Method	in.p. (°C)
173	6.17	415	6	n.d.
174	1.24	473	7	163.5
175	1.33	427	7	157.2
176	1.28	417	7	n.d.
177	1.36	425	7	n.d.
178	6.64	365	6	n.d.
179	1.39	385	2	200.1
180	1.15	347	7	n.d.
181	1.02	448	7	n.d.
182	1.30	443	7	166.2
183	1.43	425	7	210.8
184	1.14	395	7	230.5
185	1.38	511	7	n.d.
186	0.93	430	7	254.2
187	1.05	418	7	179.4
188	1.23	401	2	n.d.
189	1.14	455	7	276.3
190	1.28	472	7	191.7
191	1.13	443	7	n.d.
192	1.28	470	7	n.d.
193	1.34	444	2	n.d.
194	1.44	456	7	175.2
195	1.16	404	7	168.9
196	1.12	404	7	171.5
197	1.14	401	7	n.d.
198	1.30	436	Ί	230.1
199	0.91	430	7	n.d.
200	0.82	401	7	217.5
201	6.92	455	6	n.d.
202	6.26	402	6	n.d.

- 137NMR

For a number of compounds, ’H NMR spectra were recorded on a Bruker DPX-360, on a Bruker DPX-400, or on a Bruker Avance 600 spectrometer with standard puise sequences, operating at 360, 400 and 600 MHz respectively, using CHLOROFORM-7 or DMSO-r/ô as solvents. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internai standard.

Compound I : ’H NMR (360 MHz, DMSO-î/₆) δ ppm 2.11 (s, 3 H), 3.80 (s, 3 H), 6.81 (t, 7=7.1 Hz, 1 H), 7.03 - 7.13 (m, 2 H), 7.18 (d, 7=2.0 Hz, 1 H), 7.28 (d, 7=8.4 Hz, 1 H), 7.30 (t, 7=8.7 Hz, 2 H), 8.02 -8.11 (m, 3 H), 8.27 (s, 1 H), 8.39 (s, 1 H), 8.52 (s, 1 H).

Compound 2: 'H NMR (360 MHz, DMSO-</₆) δ ppm 2.11 (s, 3 H), 2.65 (s, 3 H), 3.80 (s, 3 H), 3.83 (s, 3 H), 6.88 (t, 7=7.1 Hz, 1 H), 6.94 (dt, 7=5.9, 2.9 Hz, 1 H), 7.05 - 7.11 (m, 2 H), 7.17 (d, 7=2.0 Hz, 1 H), 7.27 (d, 7=8.3 Hz, 1 H), 7.37 - 7.43 (m, 3 H), 7.90 (d, 7=6.8 Hz, 1 H), 8.26 (s, 1 H), 8.53 (s, 1 H).

Compound 3: ‘11 NMR (360 MHz, DMSO-7₆) δ ppm 2.46 (s, 3 H), 3.92 (s, 3 H), 6.82 (t, 7=7.1 Hz, 1 H), 7.06 (d, 7=7.5 Hz, 1 H), 7.09 (dd, 7=8.5, 2.0 Hz, 1 H), 7.19 (d, 7=2.0 Hz, 1 H), 7.24 (s, 1 H), 7.30 (t, 7=8.8 Hz, 2 H), 7.56 (d, 7=8.4 Hz, 1 H), 8.04 - 8.09 (m, 3 H), 8.39 (s, 1 II), 8.48 (s, 1 H).

Compound 4: 'H NMR (400 MHz, DMSO-7₆) δ ppm 2.64 (s, 3 H), 2.65 (s, 3 H), 3.83 (s, 3 H), 3.89 (s, 3 H), 6.87 (1,7=7.1 Hz, 1 H), 6.94 (dt, 7=6.4, 2.8 Hz, 1 H), 7.04 - 7.09 (m, 2 H), 7.18 (d, 7=2.2 Hz, 1 H), 7.36 - 7.44 (m, 3 H), 7.60 (d, 7=8.4 Hz, 1 H), 7.88 (d, 7=6.7 Hz, 1 H), 7.97 (s, 1 H), 8.45 (s, 1 H).

Compound 5: ’H NMR (360 MHz, DMSO-</<,) δ ppm 2.22 (s, 3 H), 2.60 (s, 3 H), 2.65 (s, 3 H), 3.77 (s, 3 H), 3.83 (s, 3 H), 6.87 (t, 7=7.1 Hz, 1 H), 6.94 (dt, 7=5.9, 3.0 Hz, 1 H), 7.03 - 7.10 (m, 2 H), 7.16 (d, 7=2.0 Hz, 1 H), 7.20 (d, 7=8.3 Hz, 1 H), 7.37 - 7.43 (m, 3 H), 7.88 (d, 7=6.8 Hz, 1 II), 8.46 (s, 1 H).

Compound 6: ^!H NMR (360 MHz, DMSO-r/e) δ ppm 2.14 (s, 3 II), 2.64 (s, 3 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 3.83 (s, 3 H), 6.85 (t, 7=7.1 Hz, 1 H), 6.94 (dt, 7=6.0, 2.9 Hz, 1 H), 7.00 (d, 7=7.5 Hz, 1 H), 7.00-7.04 (m, 1 H), 7.12 (d, 7=2.1 Hz, 1 H), 7.16 (d, 7=8.2 Hz, 1 H), 7.38 - 7.42 (m, 3 H), 7.65 (s, 1 H), 7.83 (d, 7=6.7 Hz, 1 H), 8.25 (s, 1 H).

Compound 7; ^]H NMR (360 MHz, DMSO-r/₆) δ ppm 2.04 (s, 3 H) 2.38 (s, 3 H) 3.80 (s, 3 H) 6.81 (1,7=7.32 Hz, 1 H) 6.99 - 7.11 (m, 2 H) 7.16 (d, 7=1.83 Hz, 1 H) 7.24 (d, J=8.42 Hz, 1 H) 7.30 (t, 7=8.78 Hz, 2 H) 7.99 - 8.15 (m, 3 H) 8.39 (s, 1 H) 8.48 (s, 1 H).

Compound 8: 'H NMR (360 MHz, DMSO-r4) δ ppm 2.04 (s, 3 H), 2.38 (s, 3 II), 2.65 (s, 3 H), 3.79 (s, 3 H), 6.88 (t, 7=7.1 Hz, 1 H), 7.04 - 7.11 (m, 2 H), 7.16 (d, 7=2.0 Hz, 1

- 138H), 7.24 (d, 7=8.3 Hz, l H), 7.36 (t, 7=7.4 Hz, l H), 7.49 (t, 7=7.5 Hz, 2 H), 7.86 (d, 7=7.7 Hz, 2 H), 7.89 (d, 7=6.7 Hz, l H), 8.48 (s, l H).

Compound 9: IH NMR (360 MHz, CHLOROFORM-7) 5 ppm 3.76 (s, 3 H), 3.81 (s, 3 H), 3.85 (s, 3 H), 6.24 (d, 7=1.9 Hz, 1 H), 6.92 (d,7=2.1 Hz, 1 H), 6.94-7.01 (m, 2 H), 7.14 (s, I H), 7.17 (d, J=8.2 Hz, 1 H), 7.22-7.32 (m, 4 H), 7.52 (d, 7=1.9 Hz, 1 H), 7.75 (dd, 7=8.5, 5.4 Hz, 2 H).

Compound 10; ¹H NMR (360 MHz, DMSO-7_fl) δ ppm 2.35 (s, 3 H), 3.86 (s, 3 H), 7.21 (dd, 7=8.1, 1.4 Hz, 1 H), 7.25 (1,7=7.8 Hz, 1 H), 7.39 (d, 7=8.8 Hz, 1 H), 7.44 ((,7=8.8 Hz, 2 H), 7.81 (dd, 7=8.8, 2.5 Hz, I H), 7.94 (dd, 7=8.6,5.6 Hz, 2 H), 8.28 (dd, 7=7.5, 1.3 Hz, 1 H), 8.32 (s, 1 H), 8.47 (d, 7=2.5 Hz, 1 H), 9.22 (s, 1 H).

Compound 111 ^J H NMR (360 MHz, CHLOROFORM-J) δ ppm 2.24 (s, 3 H), 2.76 2.90 (m, 2 H), 3.10 - 3.16 (m, 2 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 6.87 - 6.91 (m, 2 H), 6.97 (dd, 7=8.3, 2.1 Hz, 1 H), 6.96 (s, 1 H), 7.20 (1,7=7.7 Hz, 1 H), 7.24 (dd, 7=7.9, 1.5 Hz, 1 H), 7.85 (s, 1 H).

Compound 12: ¹ II NMR (360 MHz, DMSO-7₆) δ ppm 2.10 (s, 3 H), 3.75 (s, 3 H), 3.86 (s, 3 H), 6.95 (dd, 7=8.4, 2.0 Hz, 1 H), 7.06 (d, 7=2.0 Hz, 1 H), 7.15 - 7.26 (m, 4 H),

7.43 (t, 7=8.7 Hz, 2 H), 7.92 (dd, 7=8.4, 5.4 Hz, 2 H), 8.23 (s, 1 H), 8.53 (s, 1 H).

Compound 13: *H NMR (360 MHz, CHLOROFORM-J) δ ppm 3.84 (s, 3 H), 3.89 (s, 3 H), 3.94 (s, 3 H), 6.89 - 6.93 (m, 2 H), 6.97 (dd, 7=8.2, 2.1 Hz, 1 H), 7.07 (s, 1 H), 7.21

- 7.28 (m, 4 H), 7.45 (d, 7=8.2 Hz, 1 H), 7.75 (dd, 7=8.6, 5.3 Hz, 2 H), 7.79 (s, 1 H), 7.83 (s, 1 H).

Compound 14: 'H NMR (360 MHz, DMSO-Æ) δ ppm 2.46 (s, 3 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 7.18 (d, 7=5.8 Hz, 1 H), 7.23 (s, 1 H), 7.46 (t, 7=8.8 Hz, 2 H), 7.53 (d, 7=9.0 Hz, 1 H), 7.93 - 7.99 (m, 4 H), 8.03 (d, 7=5.8 Hz, 1 H), 9.26 (s, 1 H).

Compound 15: ¹H NMR (360 MHz, DMSO-7₆) δ ppm 1.59 (d, 7=6.9 Hz, 6 H), 2.47 (s, 3 II), 4.58 - 4.69 (m, 1 H), 7.20 (t, 7=8.1 Hz, 1 H), 7.35 (d, 7=8.8 Hz, 1 H), 7.38 (d, .7=7.9 Hz, 1 H), 7.39 (s, 1 H), 7.43 (t, 7=8.8 Hz, 2 H), 7.74 (dd, 7=8.6, 5.5 Hz, 2 H), 7.83 (dd, 7=8.8, 2.5 Hz, 1 H), 8.24 (d, 7=8.0 Hz, 1 H), 8.52 (d, 7=2.4 Hz, 1 H), 9,14 (s, I H).

Compound 16: ¹H NMR (360 MHz, DMSO-7₆) δ ppm 2.45 (s, 3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 6.97 (dd, 7=8.5, 2.0 Hz, 1 H), 7.07 (d, 7=2.0 Hz, 1 H), 7.14 - 7.25 (m, 4 H),

7.43 (t, 7=8.8 Hz, 2 H), 7.49 (d, 7=8.5 Hz, 1 H), 7.92 (dd, 7=8.6, 5.5 Hz, 2 H), 8.50 (s, 1 H).

Compound 18:¹H NMR (360 MHz. CHLOROFORM-7) δ ppm 1.66 (d, 7=6.95 Hz, 6 H) 2.56 (s, 3 H) 4.73 (spt, 7=6.92, 6.77 Hz, 1 II) 7.13 (s, 1 H) 7.15 - 7.22 (m, 3 H) 7.22

- 7.28 (m, 2 H) 7.40 (s, 1 H) 7.54 (d, 7=8.78 Hz, 1 II) 7.62 (dd, 7=8.60, 5.31 Hz, 2 H) 7.69 (dd, 7=8.60, 2.74 Hz, 1 H) 8.61 (d, 7=2.56 Hz, 1 H).

Compound 25: *H NMR (360 MHz, DMSO-îZ₆) δ ppm l .68 (d,>6.95 Hz, 6 H) 2.47 (s, 3 H) 3.90 (s, 3 H) 4.71 - 4.82 (m, l H) 6.93 (dd, >8.42, 1.83 Hz, l H) 6.98 (s, l H)

7.44 - 7.52 (m, 2 H) 7.57 (d, >8.42 Hz, l H) 7.61 (t, >8.96 Hz, 2 H) 7.67 (t, 1 H) 7.95 (dd, >8.60, 5.31 Hz, 2 H) 9.17 (br. s., 1 H).

Compound 38:¹H NMR (360 MHz, DMSO-î/₆) δ ppm 3.93 (s, 3 H) 6.82 (t,>7.32 Hz,

H) 7.08 (d,>7.68 Hz, 1 H) 7.11 (dd, >8.42, 2.20 Hz, 1 H) 7.21 (d,>2.20 Hz, 1 H) 7.30 (t, >8.78 Hz, 2 H) 7.40 (s, 1 H) 7.63 (d, >8.42 Hz, 1 H) 8.01 - 8.09 (m, 3 H) 8.36 (s, 1 H) 8.40 (s, 1 H) 8.54 (s, 1 H).

Compound 40: 'H NMR (360 MHz, CHLOROFORM-îZ) δ ppm 2.49 (s, 3 H) 2.53 (s, 3 10 H) 3.88 (s, 3 H) 6.72 (dd,>7.32, 6.95 Hz, 1 H) 6.85 (dd,>8.42,2.93 Hz, 1 H) 6.94 (d, >6.95 Hz, 1 H) 7.14 (s, 1 H) 7.20 (d, >8.42 Hz, I H) 7.33 - 7.39 (m, 3 H) 7.51 (d, >2.56 Hz, 1 H) 7.60 (m, 2 H) 7.69 (s, 1 H) 7.71 (dd, >6.59, 0.73 Hz, 1 H).

Compound 57: ’H NMR (600 MHz, CHLOROFORM-îZ) δ ppm 2.53 (s, 3 H), 2.53 (s, 3 H), 7.00 - 7.04 (m, 2 H), 7.15 (s, 1 H), 7.50 (d, >4.6 Hz, 1 H), 7.60 (d,>4,6 Hz, 1 H), 15 7.62 (d, .7=8.7 Hz, 2 H), 7.62 (s, 1 H), 7.77 (dd, >8.1,6.0 Hz, 1 H), 7.94 (d, >8.7 Hz,

H), 8.20 (s, 1 H).

Compound 60: ^]H NMR (600 MHz, CHLOROFORM-îZ) δ ppm 2.52 (s, 3 H), 2.53 (s, 3 H), 6.99 - 7.05 (m, 2 H), 7.16 (s, 1 H), 7.59 (s, 1 H), 7.64 (d, >8.5 Hz, 2 H), 7.74 (d, >7.2 Hz, 1 H), 7.76 (s, 1 H), 7.93 (d, >8.6 Hz, 2 H), 8.24 (s, 1 H).

Compound 89: ¹H NMR (360 MHz, DMSO-îZ_fl) δ ppm 1.64 (d, >6.95 Hz, 6 H) 2.52 (s,

H) 4.72 (spt, 1 H) 7.18 (dd, >11.89, 1.65 Hz, 1 H) 7.52 - 7.64 (m, 4 H) 7.73 (d, >8.78 Hz, 1 H) 7.87 - 7.94 (m, 3 H) 8.60 (d, >2.56 Hz, 1 H) 9.74 (br. s., 1 H).

Compound 95: ¹H NMR (360 MHz, CHLOROFORM-îZ) δ ppm 2.52 (s, 3 H) 3.80 (s, 3 , H) 3.89 (s, 3 H) 3.94 (s, 3 H) 6.39 (d, >1.83 Hz, I H) 6.87 - 6.93 (m, 2 II) 7.00 (dd, >8.42, 2.20 Hz, 1 H) 7.10 (s, 1 H) 7.19 - 7.28 (m, 2 H) 7.29 (s, 1 H) 7.66 (d, >8.42

Hz, 1 H) 7.72 (dd, >8.60, 5.31 Hz, 2 H).

Compound 97: ¹H NMR (360 MHz, DMSO-îZ₆) δ ppm 2.46 (s, 3 H) 2.54 (s, 3 II) 3.83 (s, 3 H) 3.86 (s, 3 H) 3.94 (s, 3 H) 7.02 (s, 1 H) 7.11 - 7.17 (m, 1 H) 7.22 (s, 1 H) 7.40 7.46 (m, 2 H) 7.46 - 7.54 (m, 2 H) 7.77 (dd,>8.78, 1.83 Hz, 1 H) 8.32 (d, >1.83 Hz, 30 1 H) 9.24 (s, l H).

Compound 99: 'H NMR (600 MHz, CHLOROFORM-îZ) δ ppm 2.53 (s, 3 H), 2.66 (s, 3 H), 4.03 (s, 3 H), 7.12 (br. s., 1 H), 7.15 (s, 1 H), 7.19 (s, 1 H), 7.36 (d, >8.5 Hz, 2 H),

7.36 (s, 1 H), 7,62 (d, >8.5 Hz, 2 H), 8.00 (s, 1 II).

Compound 101 : 'H NMR (360 MHz, CHLOROFORM-îZ) δ ppm 2.57 (s, 3 H) 3.91 (s,

3 H) 7.22 (s, 1 H) 7.24 - 7.33 (m, 2 H) 7.36 (s, 1 H) 7.45 (s, 1 H) 7.61 (d, >8.78 Hz, 1

H) 7.71 (dd, >8.78, 2.93 Hz, 1 H) 7.77 (dd, .7=8.78, 5.12 Hz, 2 H) 8.64 (d, >2.56 Hz, IH).

- 140 Compound 106: ’H NMR (360 MHz, CHLOROFORMA 5 ppm 2.57 (s, 3 H) 3.81 (s, 3 H) 6.65 (dd,7=8.78, l.83Hz, I H) 6.90 (dd, 7=12.08,2.20 Hz, l H)7.l9(s, l H) 7.25 (t, 7=8.23 Hz, 2 H) 7.44 (s, l H) 7.58 (d, 7=8.78 Hz, l H) 7.71 - 7.78 (m, 3 H) 8.60 (d, 7=2.56 Hz, l H).

Compound 127: 'H NMR (400 MHz, DMSOA) δ ppm 2.49 (s, 3 H) 2.54 (s, 3 H) 3.81 (s, 3 H) 3.84 (s, 3 H) 7.00 (s, l H)7.3l (d, 7=8.48 Hz, l H) 7.34 (dd,7=5.05, l.4l Hz, l H) 7.40 (s, l H) 7.43 (t, 7=8.88 Hz, 2 H) 7.79 (dd, 7=8.48, 2.02 Hz, l H) 7.94 (dd, 7=8.88, 5.65 Hz, 2 H) 8.29 (d, 7=2.02 Hz, l H) 8.39 (d, 7=5.25 Hz, l H) 9.19 (s, l H). Compound 129: 'H NMR (360 MHz, CHLOROFORMA δ ppm 2.60 (s, 3 H) 3.85 (s, 3 H) 4.10 (s, 3 H) 6.65 (d, 7=8.05 Hz, l H) 7.02 (d, 7=8.05 Hz, l H) 7.22 - 7.30 (m, 2 H) 7.30 - 7.37 (m, 2 H) 7.39 (s, I H) 7.62 (d, 7=8.42 Hz, I H) 7.76 (dd, 7=8.60, 5.31 Hz, 2 H) 7.91 (s, l H) 8.25 (d, 7=7.68 Hz, l H) 8.48 (d, 7=5.12 Hz, I H).

Compound 139: ïl NMR (360 MHz, DMSOA) δ ppm 2.48 (s, 3 H) 3.76 (s, 3 H) 3.86 (s, 3 H) 6.98 (dd, 7=8.42, 2.20 Hz, 1 H) 7.08 (d, 7=2.20 Hz, 1 H) 7.12 - 7.34 (m, 5 H) 7.37 (s, 1 H) 7.44 (t, 7=8.78 Hz, 2 H) 7.93 (dd, 7=8.78,5.49 Hz, 2 H) 8.38 (d,7=5.12 Hz, 1 H) 8.50 (s, 1 H).

Compound 157: ¹H NMR (360 MHz, DMSOA) δ ppm 0.96 (d, 7=6.59 Hz, 6 H) 2.12 (s, 3 FI) 2.13 - 2.22 (m, 1 H) 2.73 (d, 7=6.95 Hz, 2 H) 3.81 (s, 3 H) 7.05 (dd, 7=8.42, 1.83 Hz, 1 H) 7.09 (d, 7=1.83 Hz, 1 H) 7.38 (d, 7=8.42 Hz, 1 H) 7.55 (d, 7=10.98 Hz, 1 H) 8.06 (s, 1 H) 8.30 (s, 1 H) 8.56 (br. s., 1 H) 9.73 (br. s„ 1 H).

Compound 167: 'H NMR (360 MHz, DMSOA) δ ppm 2.30 (s, 3 H) 2.49 (s, 3 H) 6.91 (t, 7=6.95 Hz, 1 H) 7.03 (d, 7=7.32 Hz, I H) 7.46 (s, 1 H) 7.54 (d, 7=7.32 Hz, 1 H) 7.60 (d, 7=8.78 Hz, 1 H) 7.68 (t, 7=7.68 Hz, 1 H) 7.76 (t, 7=7.68 Hz, 1 H) 7.81 (dd, 7=8.78, 2.56 Hz, 1 H) 7.85 - 7.93 (m, 2 H) 8.65 (d, 7=2.56 Hz, 1 H) 8.77 (s, 1 H).

Compound 173: ’H NMR (360 MHz, CHLOROFORMA δ ppm 2.44 (s, 3 H) 2.57 (s, 3 H) 6.82 (1,7=7.14 Hz, 1 H) 6.95 (d, 7=6.95 Hz, 1 H) 7.31 - 7.42 (m, 3 H) 7.44 (s, 1 H) 7.48 - 7.62 (m, 4 H) 7.69 (dd, 7=8.42, 2.56 Hz, 1 H) 8.64 (d, 7=2.56 Hz, 1 H).

Compound 186: ¹H NMR (360 MHz, CHLOROFORMA δ ppm 2.52 (s, 3 H) 3.94 (s, 3 H) 3.95 (s, 3 H) 6.90 (s, 1 H) 6.92 (d, 7=2.20 Hz, 1 H) 6.98 (dd, 7=8.42, 2.20 Hz, 1 H) 7.27 - 7.33 (m, 3 H) 7.68 (d, 7=8.42 Hz, 1 H) 7.79 (dd,7=8.23, 5.31 Hz, 2 H) 8.45 (s, 1 H) 8.61 (s, 1 H).

Compound 187: '11 NMR (400 MHz, DMSOA) δ ppm 2.49 (s, 3 H), 3.88 (s, 3 H), 7.10 (d, 7=5.6 Hz, 1 H), 7.26 (d, 7=3.5 Hz, 1 H), 7.33 - 7.38 (m, 2 H), 7.44 (t, 7=8.8 Hz, 2 H), 7.66 (t, 7=8.5 Hz, 1 H), 7,98 (dd, 7=8.7, 5.5 Hz, 2 H), 8.15 (d, 7=5.5 Hz, 1 H), 9.48 (s, 1 H).

Compound 190: 'H NMR (360 MHz, CHLOROFORMA δ ppm 1.35 (d, 7=6.95 Hz, 6 H) 2.53 (s, 3 H) 3.10 (spt, 7=6.95 Hz, 1 H) 3.93 (s, 3 H) 3.96 (s, 3 H) 6.96 (d, 7=1.83

- I4l Hz, l H) 7.00 (dd, ./=8.05, 1.83 Hz, l H) 7,04 (s, l H) 7.25 (t, .7=8.60 Hz, 2 H) 7.32 (s,

H) 7.35 (s, 1 H) 7.73 (d, 7=8.05 Hz, 1 H) 7.78 (dd, 7=8.60, 5.31 Hz, 2 H). Compound 191 : 'H NMR (360 MHz, CHLOROFORM-7) δ ppm 1.34 (d, 7=6.95 Hz, 6 H) 2.58 (s, 3 H) 3.09 (spt, 7=6.95 Hz, 1 H) 3.93 (s, 3 H) 6.93 (s, 1 H) 7.25 (t, 7=8.42 Hz, 2 H) 7.31 (s, 1 H) 7.48 (s, 1 H) 7.63 (d, 7=8.42 Hz, 1 H) 7.70 (dd, 7=8.42,2.56 Hz, 1 H) 7.78 (dd, 7=8.42, 5.85 Hz, 2 H) 8.70 (d, 7=2.56 Hz, 1 H).

Compound 194; 'H NMR (360 MHz, CHLOROFORM-7) δ ppm 2.44 (s, 3 H) 2.60 (s, 3 H) 4,11 (s, 3 H) 6.61 (d, 7=8.05 Hz, I H) 6.90 (t, 7=7.14 Hz, 1 H) 7.32 - 7.43 (m, 4 H) 7.50 - 7.61 (m, 3 H) 7.63 (d, 7=8.05 Hz, 1 H) 8.07 (s, 1 H) 8.23 (d, 7=6.95 Hz, 1 H) 8,49 (d, 7=5.49 Hz, 1 H).

Compound 195: ’H NMR (360 MHz, DMSO-7₆) δ ppm2.47 (s, 3 H), 2.49 (s, 3 H), 3.95 (s, 3 H), 6.79 (s, 1 H), 7.15 (dd, 7=8.3, 2.0 Hz, 1 H), 7.24 (d, 7=2.0 Hz, 1 H), 7.33 (s, 1 H), 7.71 (d, 7=8.4 Hz, 1 H), 7.97 (s, 1 H), 10.02 (s, 1 H).

Pharmacology

A) Screening of the compounds of the invention for γ-sccretase-modulating activity

Al) Method 1

Screening was carried out using SKNBE2 cells carrying the APP 695 wild type, grown in Dulbecco's Modifîed Eagle's Mcdium/Nutrient mixture F-12 (DMEM/NUT-mix F-l 2) (HAM) provided by Gibco (cat no. 31330-38) containing 5 % Scrum/Fc supplémented with 1 % non-csscntial amino acids. Cells were grown to near confluency.

The screening was performed using the assay as described in Citron et al (1997) Nature Medicine 3: 67. Briefly, cells were plated in a 96-well plate at about 10^scells/ml one day prior to addition of compounds. Compounds were added to the cells in Ultraculture (Lonza, BE12-725F) supplemented with 1 % glutamine (Invitrogen, 25030-024) for 18 hours, The media were assayed by two sandwich ELISAs, for AB42 and ABtotal. Toxicity of the compounds was assayed by WST-1 cell prolifération rcagent (Roche, 1 644 807) according to the manufacturées protocol.

To quantify the amount of Αβ42 in the cell supernatant, commercially available Enzyme-Linked-Immunosorbcnt-Assay (EL1SA) kits were used (lnnotest® βAmyloid₍M2), lnnogcnctics N.V., Ghcnt, Bclgium). The Αβ42 ELIS A was performed essentially according to the manufacturer^ protocol. Briefly, the standards (dilutions of synthetic Αβ1-42) were prepared in polypropylene Eppendorf with final concentrations of 8000 down to 3.9 pg/ml (1/2 dilution step). Samples, standards and blanks (100 μΙ)

- 142were added to the anti-Ap42-coated plate supplied with the kit (the capture antibody selectively recognizes the C-terminal end of the antigen). The plate was allowed to încubate 3 h at 25 °C in order to allow formation of the antibody-amyloid complex. Following this incubation and subséquent wash steps a sélective anti-AP-antibody conjugale (biotinylated 3D6) was added and incubated for a minimum of l hour in order to allow formation ofthe antibody-Amyloid-antibody-complex. After incubation and appropriate wash steps, a Strcptavidine-Peroxidase-Conjugate was added, followed 30 minutes later by an addition of ST'^.S'-tetramethylbenzidine (TMB)/pcroxidc mixture, resulting in the conversion ofthe substrate into a eoloured product. This réaction was stopped by the addition of sulfuric acid (0.9 N) and the colour intensity was measured by means of photometry with an ELISA-readcr with a 450 nm filter.

To quantify the amount of A R tôt al in the cell supematant, samples and standards were added to a 6ElO-coatcd plate. The plate was allowed to incubatc overnight at 4 °C in order to allow formation of the antibody-amyloid complex. Following this incubation and subséquent wash steps a sélective antî-AB-antibody conjugate (biotinylated 4G8) was added and incubated for a minimum of l hour in order to allow formation of the antibody-Amyloid-antibody-complex. After incubation and appropriate wash steps, a Strcptavidine-Peroxidase-Conjugate was added, followed 30 minutes later by an addition of Quanta Blu fluorogenic peroxidasc subslratc according to the manufacturées instructions (Pîercc Corp., Rockford, II).

To obtain the values reported in Table 7a, the sigmoidal dose response curves were analyscd by computeriscd curve-fïtting, with percent of inhibition plotted against compound concentration. A 4-parameter équation (model 205) in XL/it was used to détermine the ICso- The top and the bottom of the curvc were fixed to 100 and 0, respectively, and the hill slope was fixed to l. The IC₅₀ represents the concentration of a compound that is required for inhibiting a biological effect by 50 % (Here, it is the concentration where AB peptide level is reduced by 50 %).

The IC50 values are shown in Table 7a:

Co. No.	ic₅₀ Αβ42 (μΜ)	IC_5I) Αβ total (μΜ)
I	0.203	>5
2	0.022	>3
3	0.196	>Ι0
4	0.067	>3

Co. No.	ICjn Αβ42 (μΜ)	IC_5O Aptotal (μΜ)
5	0.063	>3
6	0.077	>3
7	0.334	>10
8	0.275	>5

Co. No.	IC_fn Αβ42 (μΜ)	ÏC₅o Αβ total (μΜ)
9	0.399	>3
10	0.358	n.d.
ll	0.072	n.d.
12	0.023	>1

Co. No.	ic₅₀ Αβ42 (μΜ)	IC_5OΑβ total (μΜ)
13	0.065	>3
14	0.109	>3
16	0.011	>3
19	0.049	>3
20	0.0 i 3	>]
22	0,123	>3
23	0.417	>3
24	0.056	>3
25	0.024	>3
29	0.029	>3

Co. No.	ic_i0 Αβ42 (μΜ)	ic_5tt Αβ total (μΜ)
31	0.076	>3
32	0.235	>10
33	0.102	>10
34	0.0I6	>3
35	0.090	>3
36	0.328	>3
38	0.562	>10
39	0.053	>3
40	O.Oll	>3
42	0.096	>3

Co. No.	IC50 Αβ42 (μΜ)	ic₅₀ Αβ total (μΜ)
44	0.140	>10
45	0.848	>30
47	0.486	>3
49	0.021	>3
50	0.038	>3

To obtain the values reported in Table 7b, the data were calculated as percentage of the maximum amount of amyloid Beta 42 measured in the absence of the test compound. The sigmoidal dose response curves were analyzed using non-linear régression analysis with percentage of the control plottcd against the log concentration of the compound. A 4-parameter équation was used to déterminé the IC50. The values reported in Table 7b are averaged IC50 values.

The IC₅₀ values are shown in Table 7b (n.d. means not determined):

Co. No.	IC_SO Αβ42 (μΜ)	ic₅₀ Aptotal (μΜ)
66	>3	n.d.
179	>3	>3
180	>3	>3
181	>3	>3
55	3.02	>10
190	0.005	>3
105	0.007	>3
16	0.009	>3
21	0.009	>3
62	0.009	>3
173	0.009	>3

Co. No.	ic₅₀ Αβ42 (μΜ)	IC_Sfl Αβ total (μΜ)
17	>10	>3
106	0.010	>1
174	0.010	>3
63	0.011	>3
40	0.012	>3
192	0.013	>3
20	0.017	>1
107	0.018	>3
86	0.019	>3
193	0.019	>3
2	0.020	>3

Co. No.	ÏC₅o Αβ42 (μΜ)	ICjo Αβ total (μΜ)
49	0,020	>3
50	0.020	>3
121	0.020	>3
I7l	0.020	>3
12	0.021	>3
97	0.021	>3
167	0.021	>3
25	0,023	>3
95	0.023	>3
152	0.023	>3
102	0.024	>3

Co. No.	IC50 Αβ42 (μΜ)	IC_ÎO Ahtotal (μΜ)
119	0.025	>3
162	0.025	>10
123	0.026	>1
19	0.028	>3
29	0.028	>3
79	0.028	>3
U2	0.028	>1
56	0.030	>3
125	0.033	n.d.
175	0.033	>3
18	0.035	>3
30	0.035	>10
103	0.036	>3
82	0.037	>3
122	0.038	>3
176	0.041	>3
77	0.043	>3
169	0.045	>3
349	0.047	>3
39	0.051	>3
124	0.051	>3
24	0.055	>3
83	0.059	>3
4	0.063	>3
13	0.063	>3
67	0.065	>3
85	0.066	>3
88	0.066	>10
64	0.068	>3
11	0.071	n.d.
98	0.071	>3
51	0.072	>3
59	0.072	>3

Co. No.	IC_i0 Αβ42 (μΜ)	ICso Afttotal (μΜ)
114	0.072	>3
70	0.076	>3
5	0.078	>3
31	0.078	>3
157	0.081	>10
65	0.083	>3
94	0.083	>3
110	0.083	>3
118	0.083	>3
147	0.085	n.d.
178	0.085	>3
35	0.089	n.d.
15	0.100	>3
6	0.102	>3
14	0.105	>3
177	0.105	>3
28	0.110	>3
34	0.110	>3
46	0.110	>3
22	0.115	>3
42	0.123	>3
41	0.126	>3
48	0.132	>10
108	0.132	>10
202	0.135	>3
44	0.138	>10
160	0.138	>3
33	0.141	>10
109	0.145	2.82
186	0.162	>10
52	0,166	>3
145	0.166	n.d.
3	0.178	>10

Co. No.	IC50 Αβ42 (μΜ)	ICso ΑβίοΙηΙ (μΜ)
43	0.182	>10
76	0.182	>3
195	0.195	>10
1	0.200	>5
36	0.204	>3
126	0.214	n.d.
9	0.240	>3
58	0.240	>10
199	0.240	>30
163	0.245	>10
87	0.251	>10
141	0.251	>10
148	0.251	>10
78	0.275	>3
8	0.282	>5
32	0.282	>10
165	0.288	>30
200	0.295	>3
7	0.302	>10
120	0.324	>3
111	0.339	>10
10	0.355	n.d.
146	0.355	>30
37	0.380	>3
155	0.389	14.79
23	0.398	>3
150	0.437	8.13
47	0.447	>3
142	0.468	>10
144	0.468	13.80
54	0.490	>10
38	0.550	>10
27	0.676	>3

T

Co. No.	ic_sû Αβ42 (PM)	1C_5O Αβ total (PM)
196	0.676	>3
117	0.724	>10
166	0.741	>3
45	0.813	>30
26	0.871	>30
72	0.955	>3
61	1.071	>3
57	1.072	>10

Co. No.	IC50 Αβ42 (pM)	lC_5a Afitotal (PM)
90	1.096	>3
75	1.148	>3
153	1.318	>3
164	1.413	9.33
91	1.445	66.07
93	1.862	n.d.
53	1.905	>10
71	1.950	>3

Co. No.	IC_;0 Αβ42 (μΜ)	IC_SO ABtotal (PM)
154	2.042	>3
172	2.089	>3
99	2.188	n.d.
100	2.239	25.12
92	2.570	>3
60	3.020	>3
170	3.548	n.d.
143	9.772	>30

A 2) Method 2

Screening was carried out using SKNBE2 cells carrying the APP 695 wild type, grown in Dulbecco's Modificd Eagle's Mcdium/Nutrient mixture F-12 (DMEM/NUT-mix F-12) (HAM) provided by Invitrogen (cat no. 10371-029) containing 5 % Scrum/Fe suppiemented with I % non-essential amino acids, Iglutamine 2 mM, Hepes 15 mM, penicillin 50 U/ml (units/ml) en strcptomycin 50 pg/ml. Cells were grown to near conflucncy.

The screening was performed using a modification of the assay as described 10 in Citron et al (1997) Nature Medicine 3: 67. Briefly, cells were platcd in a 384-well plate at 10⁴ cells/wcll in Ultraculturc (Lonza, BE12-725F) suppiemented with 1 % glutamine (Invitrogen, 25030-024), 1 % non-essential amino acid (NEAA), penicillin 50 U/ml cn streptomycin 50 pg/ml in the presence of test compound at different test concentrations. The ccll/compound mixture was incubated ovemight at 37 °C, 5 % CO,. 15 The next day the media were assayed by two sandwich immuno-assays, for AB42 and Afltotal.

ABtotal and AB42 concentrations were quantified in the cell supernatant using the Aphalisa tcchnology (Perkin Elmcr). Alphalisa is a sandwich assay using biotinylated antibody attached to streptavidin coated donorbeads and antibody 20 conjugatcd to accepter beads. In the presence of antigen, the beads corne into close proximity. The excitation ofthe donor beads provokes the release ofsinglet oxygen molécules that trigger a cascade of energy transfer in the acceptor beads, resulting in light émission. To quantify the amount of Αβ42 in the cell supernatant, monoclonal antibody spécifie to the C-terminus of AB42 (JRF/cAB42/26) was coupled to the

receptor beads and biotinylated antibody spécifie to the ΛΓ-terminus of AB (JRF/ABN/25) was used to react with the donor beads. To quantify the amount of Aptotal in the cell supernatant, monoclonal antibody specifc to the //-terminus of AB (JRF/ABN/25) was coupled to the receptor beads and biotinylated antibody spécifie to 5 the mid région of AB (biotinylated 4G8) was used to react with the donor beads.

To obtain the values reported in Table 7c, the data were calculated as percentage of the maximum amount of amyloid Beta 42 measured in the absence of the test compound. The sigmoidal dose response curves were analyzed using non-lincar régression analysis with percentage of the control plottcd against the log concentration of the compound. A 4-paramctcr équation was used to détermine the IC50.

The IC50 values are shown in Table 7c:

Co. No.	1C_5O Αβ42 (μΜ)	IC_SO Aptotal (μΜ)
ÎO	1.738	>10
11	0.363	>10
12	0.035	7.76
16	0.016	8.71
17	0.166	>10
18	0.020	6.46
26	0.19I	>10
35	0.214	>10
49	0.040	>10
50	0.072	>10
65	0.U7	>10
66	>10	>10
68	0.018	>10
69	0.022	>10
73	0.141	5.62
74	7.413	4.47
79	0.076	>10
80	0.049	>10
SI	0.095	>10
82	0.049	>10
84	0.112	>10

Co. No.	IC₅₀ Αβ42 (μΜ)	IC_5O A β total (μΜ)
85	0.363	>10
86	0.052	>10
87	0.288	9.12
88	0.058	8.91
89	0.019	9.77
93	2.754	>10
96	0.245	>10
99	7.943	>10
101	0.046	>10
104	0.501	>10
105	0.014	>10
106	0.024	>10
107	0.025	>10
Il 1	0.204	>10
113	0.066	4.90
116	0.072	>10
119	0.043	>10
125	0.195	>10
126	0.741	n.d.
127	0.044	3.63
128	0.039	9.12

Co. No.	ic₅₀ Αβ42 (μΜ)	IC_Stt Aptotal (μΜ)
129	0.017	5.25
130	0.030	>10
131	0.028	>10
132	0.123	6.31
133	0.191	>10
135	0.347	>10
136	0.112	>10
137	0.117	>10
138	0.049	7.08
139	0.060	6.61
140	0,759	>10
145	1.047	6.31
147	0.468	n.d.
156	0.042	8.91
158	1,862	>10
159	0.269	>10
161	0.155	>10
162	0.032	>10
163	0.158	>10
164	1.318	6.76
167	0.018	>10

- 147 -

Co. No.	lCso Αβ42 (μΜ)	IC_SO A β total (μΜ)
168	0.051	>10
170	7.413	>10
I7l	0.038	>10
172	0.661	>10
173	0.007	>10
174	0.022	>10
182	0.162	7.76

Co. No.	IC50 Αβ42 (μΜ)	IC_SO Αβ total (μΜ)
183	0.083	8.71
186	0.041	>10
187	0.062	>10
188	>10	>10
189	2.399	>10
190	0.010	>10
191	0.012	>10

Co. No.	ic₅₀ Αβ42 (μΜ)	IC₅₀ Aptotal (μΜ)
194	0.017	-6.76
195	0.282	>10
197	0.550	>10
198	1.175	6.76
201	0.045	>10
202	0.245	8.51

B) Démonstration of in vivo efficacy

Αβ42 lowering agents of the invention can be used to treat AD in mammals such as humans or altematively demonstrating efficacy in animal modeis such as, but not limited to, the mouse, rat, or guinca pig. The mammal may not be diagnosed with AD, or may not hâve a genetic prédisposition for AD, but may be transgenic such that it overproduces and evcntually deposits Αβ in a manner similar to that seen in humans afflicted with AD.

Αβ42 lowering agents can be administered in any standard form using any standard method. For example, but not limited to, Αβ42 lowering agents can bc in the form of liquid, tablets or capsules that are taken orally or by injection. Αβ42 lowering agents can be administered at any dose that is sufficient to significantly reduce levels of Αβ42 in the blood, blood plasma, sérum, ccrebrospinal fluid (CSF), or brain.

To détermine whether acute administration of an Αβ42 lowering agent would reduce Αβ42 levels in vivo, non-transgenic rodents, e.g. mice or rats were used. Altematively, two to three month old Tg2576 mice expressing APP695 containing the “Swcdish” variant can bc used or a transgenic mouse model developed by Dr. Frcd Van Leuven (K.U.Leuven, Belgium) and co-workcrs, with neuron-specific expression of a clinical mutant of the human amyloîd prccursor protein [V7171] (Mocchars et al., 1999 J, Biol. Chem. 274, 6483). Young transgenic mice hâve high levels of Αβ in the brain but no détectable Αβ déposition. At approximately 6-8 months ofage, the transgenic mice start to display spontaneous, progressive accumulation of β-amyloîd (Αβ) in the brain, eventually resulting in amyloîd plaques within the subiculum, hippocampus and cortex. Animais treated with the Αβ42 lowering agent were cxamîned and compared to those untreated or treated with vehicle and brain levels of soluble Αβ42 and total Αβ

- 148 would be quantîtated by standard techniques, for example, using ELIS A. Treatment periods varied from hours to days and were adjusted based on the results of the Αβ42 lowering once a time course of onset of effect could be estabiished.

A typical protocol for measuring Αβ42 lowering in vivo is shown but it is only one of many variations that could be used to optimize the levels of détectable Αβ, For example, Αβ42 lowering compounds were formulated in 20 % of Captisol® (a sulfobutyl ether of β-cyclodcxtrin) in water or 20 % hydroxypropyl β cyclodcxtrin. The Αβ42 lowering agents were administered as a single oral dose or by any acceptable route of administration to overnight fasted animais. After four hours, the animais were sacrificed and Αβ42 levels were analysed.

Blood was collected by décapitation and exsanguinations in EDTA-treated collection tubes. Blood was centrifuged at 1900 g for 10 min at 4 °C and the plasma recovered and flash frozen for later analysis. The brain was removed from the cranium and hindbrain. The cercbellum was removed and the left and right hemisphere were separated. The left hemisphere was stored at -18 °C for quantitative analysis of test compound levels. The right hemisphere was rinsed withphosphate-buffered saline (PBS) buffer and immcdiatcly frozen on dry ice and stored at -80 °C until homogenization for biochemical assays.

Mouse brains were resuspended in 10 volumes of 0.4 % DEA (diethylamine) /50 mM NaCl pH 10 (for non-transgcnic animais) or 0.1 % 3-[(3cholamidopropyl)-dimcthyl-ammonio]-l-propancsulfonatc (CHAPS) in tris buffered saline (TBS) (for transgenic animais) containing protease inhibitors (Roche11873580001 or 04693159001) per gram of tissue, e.g. for 0.158 g brain, add 1.58 ml of 0.4 % DEA. Ail samples were sonicatcd for 30 sec on ice at 20 % power output (puise mode). Homogenates were centrifuged at 221.300 x g for 50 min. The resulting high speed supernatants were then transferred to fresh tubes and were optionally further purified before the ncxt step. A portion of the supernatant was neutralized with 10 % 0.5 M Tris-HCI and this was used to quantify ABtotal.

The obtained supernatants were purified with Water Oasis HLB reverse phase columns (Waters Corp., Milford, MA) to remove non-specific immunoreactive material from the brain lysâtes prior subséquent Αβ détection. Using a vacuum manifold, ail solutions were passed through the columns at a rate of approximately 1 ml per minute, so the vacuum pressure was adjusted accordingly throughout the procedure.

Columns were preconditioncd with 1 ml of 100 % MeOH, before équilibration with 1 ml of H₂O. Non-neutralized brain lysâtes were loaded onto the columns. The loaded

- 149 samples were then washed twice with the first wash performed with l ml of 5 % MeOH, and the second wash with l ml of 30 % MeOH. Final)y, the Αβ was eluted from the columns and into 100 x 30 mm glass tubes, with a solution of 90 % MeOH with 2 % NH₄OH. The eluate was then transfcrrcd into J.5 ml tubes and concentrated in a speed-vac concentrator on high heat for about l .5-2 h at 70°C. The concentrated Αβ was then resuspended in UltraCULTURE General Purpose Serum-Free Medium (Cambrex Corp., Walkcrsville, MD) plus Protease Inhibitors added according to the manufacturera recommendation.

To quantify the amount of Αβ42 in the soluble fraction of the brain homogenates, commercially available Enzymc-Linkcd-Immunosorbcnt-Assay (ELISA) kits were used (e.g, Innotest® p-Amyloid(M2), Innogenctics N.V., Ghent, Belgium).

The Αβ42 ELISA was performed using the plate provided with the kit only. Briefly, the standards (a dilution of synthetic ΑβΙ-42) were prepared in 1.5 ml Eppcndorf tube in Ultraculture, with final concentrations ranging from 25000 to 1.5 pg/ml. Samples, standards and blanks (60 μΐ) were added to the anti-Ap42-coated plate (the capture antibody selectively rccognizcs the C-terminal end of the antigen). The plate was allowed to incubate overnight at 4 ^DC in order to allow formation of the antibodyamyloid complex. Following this incubation and subséquent wash steps a sélective anti-Ap-antibody conjugate (biotinylated détection antibody, e.g., biotinylated 4G8 (Covancc Rcsearch Products, Dedham, MA) was added and incubated for a minimum of l h in order to allow formation of the antibody-Amyloid-antibody-complex. After incubation and appropriate wash steps, a Streptavîdinc-Peroxidase-Conjugatc was added, followed 50 min later by an addition of Quanta Blu fhiorogenic peroxidasc substrate according to the manufacturer’s instructions (Piercc Corp., Rockford, II). A kinetic reading was performed every 5 minutes for 30 min (excitation 320 / émission 420). To quantify the amount of ABtotal in the soluble fraction of the brain homogenates, samples and standards were added to JRF/rAB/2-coated plate. The plate was allowed to incubate overnight at 4 °C in order to allow formation of the antibodyamyloid complex. The ELISA was then performed as for AB42 détection.

In this model at least 20 % AB42 lowering compared to untreated animais would bc advantageous.

The results arc shown in Table 8:

Co. No.	Αβ42 (%Ctrl) Mean	Afttotal (%Ctrl) Mean
195	89	99
2	95	104
104	110	97
186	52	82
97	71	102
157	77	100
95	47	88
• 10	106	109
11	91	99
12	56	101

Co. No.	Αβ42 (%Ctrl) Mean	Αβ total (%Ctrl) Mean
13	87	105
14	78	91
16	58	95
17	106	109
18	54	94
25	76	96
30	96	92
31	91	102
40	77	102
41	93	87

Co. No.	Αβ42 (%Ctrl) Mean	Aptotal (%Ctrl) Mean
101	77	92
170	99	99
105	104	96
181	104	105
141	87	89
63	56	90
59	97	95
58	89	105
54	101	104

C) Effect on the Notch-proccssing activity of the y-secretase-complex

Notch cell-free assay

The Notch transmembrane domain is cleaved by gamma secretasc to release

Notch Intracellular C-terminal Domain (NICD). Notch is a signaling protein which plays a crucial rôle in dcvelopmental processes, and thus compounds arc preferred which do not show an effect on the Notch-processing activity of the γ-sccrctasecomplex.

To monitor the effect of compounds on NICD production, a recombinant Notch substratc (N99) was prepared. The Notch substrate, comprîsed of mouse Notch fragment (VI7I l-El 809), an N-terminal méthionine and a C-terminal FL AG sequence (DYDDDDK), was expressed in E. coli and purified on a column containing an antiFLAG M2 affinity matrix.

A typical Notch cell-ffcc assay consisted of 0.3 - 0.5 μΜ Notch substrate, an cnrichcd préparation of gamma sccretase and l μΜ of a test compound (compounds 16, 18 and 106 of the présent invention). Contrôle included a gamma sccretase inhibitor (GSI), such as (28)-7/-(2-(3,5-difluorophenyl)acetyl]-L-alanyl-2-phcnyl-glycine 1,1dimethylethyl ester (DAPT) or(2S)-2-hydiOxy-3-mcthyl-7/-[(lS)-l-mcthyl-2-oxo-220 ([(lS)-2,3,4,5-tetraliydro-3-methyl-2-oxo-lj^c/-3-bcnzazepin-l-yl]amino]cthyl]butanamide (Semagacestat), and DMSO, the final concentration of DMSO being 1%. Recombinant Notch substrate was pre-treated with 17 μΜ DTT (1,4-dithiothreitol) and

0.02 % SDS (Sodium Dodecyl Sulfate) and heated at 65 °C for 10 min. The mixture of substrate, gamma secretase and compound/DMSO was incubated at 37 °C for 6 to 22 hours (h). Six-hour incubation was sufficient to producc the maximal amount of NICD and the clcaved product remaincd stable for an additional 16 h. Reaction products were processed for SDS PAGE (Sodium Dodecyl Sulfate - Poly Acrylamide Gel Electrophoresis) and western blotting. Blots were probed with an anti-Flag M2 antibody, followcd by LI-COR infrared secondary antibody, and analyzcd with the Odyssey Infrared Imaging System (LI-COR® Bioscicnces).

In the cell-free Notch assay, no test compounds (compounds 16,18 and 106 of the présent invention) inhibited the clcavagc of C99 by gamma secretase, whcrcas the production of NICD was blocked by the control GSI (DAPT or Semagaccstat), Thus it was demonstrated that compounds 16,18 and 106 ofthe présent invention did not show an effect on the Notch-proccssing activity ofthe γ-sccrctasc-complcx (production of NICD).

Notch cell-based assay

The Notch cell-based assay was based on the interaction of Notch and its ligand in a co-culture system and utilized the Dual-Glo Luciferase Assay System (Promega) to monitor NICD production. Two stable cell lines, N2-CHO and DL-CHO, were established to express full-length mouse Notch2 and Delta respectively. Cells that expressed mouse Notch were also transfected with two plasmids, pTPl-Luc and pCMV-RLuc, to express firefly and ReniUa luciferase. Expression of firefly luciferase was under the control of TPI promoter that responded to NICD activation. The CMV promoter that drove the expression of ReniUa luciferase did not respond to NICD activation and therefore was used to control for transfection efficiency and compound toxicity.

N2-CHO cells were sccded at lxl0⁵/well in 24-well plates the day before transfection. On the second day, cells wcrc double transfected with 3 pg/well pTPl-Luc (expressing firefly luciferase) and 0.3 ng/well pCMV-RLuc (expressing ReniUa luciferase). After 6 h incubation, transfected N2-CHO cells were washed and DL-CHO 30 cells (2 x 10⁵ cclls/wcll) wcrc added.

Compounds were pre-mixed with DL-CHO cell suspension in a five- point curve. Typically, compound treatment was performed in duplicate with a serial l : 10 dilution (3 μΜ - 0.3 nM) in DMSO. The final concentration of DMSO in a given culture was l%. Controls included non-transfected cells and transfected cells treated

- 152-

with a GSI or DMSO only, Luciferase assays were performed after 16 h co-culture and compound treatment,

The luciferase assay was carried out according to manufacture’s instructions. Briefly, cells were washed with PBS (Phosphate Buffcrcd Saline), lysed with Passive Lysis Buffer (Promega), and incubatcd at room température for 20 min. Lysâtes were mixed with Dual-GIo Luciferase Reagent and the firefly luciferase activity was measured by rcading the luminescence signal in the EnVision 2101 Multilabcl reader. Dual-GIo Stop & Glo Reagent was then added to each well and the Renilla luciferase signal was measured.

The results of the Notch cell-based assay were in agrccment with those in the cell-frce NICD assay. On the basis of luciferase assay rcadouts, the average IC50 values of DAPT and Semagacestat from the Notch cell-based assay were 45 nM and 40 nM respectively, whereas compound 18 of the présent invention was found to bc noninhibitory.

D. Composition cxamplcs “Active ingrédient” (a.i.) as used throughout these cxamplcs relates to a compound of formula (I), including any stereochemically isomeric form thereof, a pharmaceutically acceptable sait thereof or a solvaté thereof; in particular to any one of the excmplified compounds.

Typical examples of recipes for the formulation of the invention are as follows:

/. Tablets

Active ingrédient Di-calcium phosphate Lactose Talcum Magnésium stéarate Potato starch

5 to 50 mg 20 mg 30 mg 10 mg 5 mg ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that each millilitcr contains l to 5 mg of active ingrédient, 50 mg of sodium carboxymethyl cellulose, l mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

A parentéral composition is prepared by stirring 1.5 % (weight/volumc) of active ingrédient in 0.9 % NaC! solution or in 10 % by volume propylcnc glycol in water.

o(

4. Ointment

Active ingrédient

Stearyl alcoliol

Lanoline

White petroleum to 1000 mg

3g

5g g

Water ad 100 g

In this Example, active ingrédient can bc replaced with the same amount of any of the compounds according to the présent invention, in particular by the same amount ofany 10 o f the exemp lifiedeompounds.

Rcasonable variations are not to bc regardcd as a departure from the scopc of the invention. It will bc obvious that the thus described invention may bc varied in many __ ways by those skilled in the art.

Claims

Ciaims

1. A compound of formula (])

Het¹

A2 R ^ΑΓΥ ^^Het2

A³ (D or a stereoisomeric form thereof, wherein

Het‘ is a 5-membered or 6-membered aromatic heterocycle, having formula (a-1), (a-2), (a-3), (a-4) or (a-5):

R° is H or C_Malkyl;

R¹ is H, Ci-qalkyl or CMalkyloxyCMalkyl;

R² isCwalkyl;

X is O or S;

G¹ isCHorN;

G² is CH, N or C substituted with Ci^alkyl;

provided that G¹ and G² are not simultaneously N;

G³ is CH or N;

R^|fln and R^tnb each independently arc hydrogen or Cwalkyl;

A¹ is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A², A³ and A⁴ each independently are CH, CF or N; provided that maximum two of A¹, A², A³ and A⁴ arc N;

Het² is a 9-membercd bicyclic aromatic heterocycle, having formula (b-1) or (b-2):

(b-1)

- I55Z' isCH or N;

Z² is CR‘¹ⁿ or N;

Z³ is CH or N; provided that maximum one of Z¹, Z² and Z³ is N;

Y¹ is CH or N;

Y² is CR^4b or N;

Y' is CH or N; provided that maximum onc of Y¹, Y² and Y³ is N;

R⁴ is H; halo; Cmalkyloxy; cyano; cycloCj.7alkyl; Cmalkylcarbony 1; C|.₄alkyloxycarbonyl; or Cmalkyl optionally substituted with one or more substituents each independently selected from the group consisting ofhalo and amino; R^4h is H; halo; Cmalkyloxy; cyano; cycloCî^alkyl; or Cmalkyl optionally substituted with one or more substituents cach independently selected from the group consisting of halo and amino;

R⁵ is H; halo; cyano; Cmalkyloxy; C₂^alkenyl; or Cmalkyl optionally substituted with one or more substituents each independently selected from the group consisting of Cmalkyloxy and halo;

R⁶ⁿ is Cmalkyl substituted with onc or more halo substituents; Cmalkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, Cmalkyloxy, tetrahydropyranyl, cycloCî.7alkyloxy, and cycloCî^alkyl; cycloC’î^alkyl; Cmalkylcarbonyl; tetrahydropyranyl; Ar; R⁸Rⁱ⁾N-carbonyl; or CH₂-O-Ar;

R^6bis C2.ealkyl substituted with one or more halo substituents; Cmalkyl optionally substituted with onc or more substituents cach independently selected from the group consisting of piperidinyl, Ar, Cmalkyloxy, tetrahydropyranyl, cycloC^alkyloxy, and cycloCî^alkyl; cycloCî-îalkyl; cycloCj^alkyl substituted with onc or more phenyl substituents optionally substituted with onc or more halo substituents; piperidinyl; morpholinyl; pyrrolidinyl; NR⁸R⁹; tetrahydropyranyl; O-Ar; Cmalkyloxy; Cmalkylthio; Ar; CH2-O-Ar; S-Ar; NCIL-Ar; orNH-Ar;

wherein cach piperidinyl, morpholinyl, and pyrrolidinyl may optionally be substituted with one or more substituents each independently selected from the group consisting of Cmalkyl, C2^alkenyl, Cmalkylcarbonyl, halo, and Cmalkyloxycarbonyl;

wherein cach Ar independently is phenyl optionally substituted with onc or more substituents each independently selected from the group consisting ofhalo,

Cmalkyloxy, cyano, NR⁸R⁹, morpholinyl, Cmalkyl, and Cmalkyl substituted with onc or more halo substituents; pyridiny 1 optionally substituted with one or more substituents each independently selected from the group consistingofhalo,

Cmalkyloxy, cyano, Cmalkyl, and Cmalkyl substituted with one or more halo substituents; oxazolyl optionally substituted with one or more Cmalkyl substituents; or

- 156thicnyl optionally substituted with onc or more halo substituents;

each R⁸ independently is H or C_Malkyl;

each R⁹ independently is H or Ci-^alkyl;

R⁷ is H, Ci^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting ofhalo, phenyl, and Cwalkyloxy; or a pharmaceutically acceptable addition sait or a solvaté thereof.
2. The compound according to claim l or a stereoisomeric form thereof, wherein Het¹ is a 5-membered aromatic heterocycle, having formula (a-1 ), (a-2), (a-3) or (a-4); R° is H or Cj^alkyl;

R¹ is H orCMalkyl;

R² is Ci^alkyl;

X is Ô or S;

G¹ is CH or N; G² is CH, N or C substituted with Ci-ialkyl; provided that G¹ and G² are not simultaneously N;

G³ is CH or N;

A¹ is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A², A³ and A⁴ each independently are CH, CF or N; provided that maximum two of A¹, A², A³ and A⁴ arc N;

Het² is a 9-membered bicyclic aromatic heterocycle, having formula (b-1) or (b-2):

Z¹ is CH or N; Z² is CR‘^,a; Z³ is CH;

Y¹ is CH or N; Y² is CR^4b; Y³ is CH;

R⁴ is H; halo; Cualkyloxy; cyano; or C_Malky 1 optionally substituted with one or more halo substituents;

R^4b is H; halo; Ci.<alkyloxy; cyano; or C^alkyl optionally substituted with one or more halo substituents;

R³ is H; halo; cyano; or Ci^alky 1 optionally substituted with one or more substituents each independently selected from the group consisting of Ci^alkyloxy and halo;

R⁶ⁿ is C₂^alkyl substituted with onc or more halo substituents; C^alkyl optionally

-157substituted with one or more substituents each independently selected from the group consisting of pîperidinyl, Ar, Ci-ealkyloxy, tetrahydropyranyl, cycloC₃.₇alkyloxy, and cycloCî-valkyl; cycloC3.₇alkyl; tetrahydropyranyl; Ar; or CH₂-O-Ar;

R^ûb is C2^alkyl substituted with one or more halo substituents; Ci-salkyl optionally substituted with one or more substituents each independently selected from the group consisting of pîperidinyl, Ar, Ci-salkyloxy, tetrahydropyranyl, cycloCj^alkyloxy, and cycloCj.7alkyl; cycloC3.7alkyl; pîperidinyl; morpholinyl; pyrrolidinyl; NR^SR⁹; tetrahydropyranyl; O-Ar; Ci^alkyloxy; Cj^alkylthio; Ar; CH2-O-Ar; S-Ar; NCHi-Ar or NH-Ar;

wherein each pîperidinyl, morpholinyl, and pyrrolidinyl may optionally bc substituted with one or more substituents each independently selected from the group consisting of C^aUcyl, C2^alkenyl, CMalkylcarbonyl, halo, and CMalkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, cyano, NR⁸R⁹, morpholinyl, Cj^alkyl, and Ci_₄alkyl substituted with one or more halo substituents; or pyridinyl optionally substituted with onc or more substituents cach independently selected from the group consisting of halo, C|.₄alkyloxy, cyano, Ci^alkyl, and Ci^alkyl substituted with one or more halo substituents;

each R⁸ independently is H or Cwalkyl;

each R⁹ independently is H or Ci^alkyl;

R⁷ is H, Ci^alkyl optionally substituted with onc or more substituents each independently selected from the group consisting of halo, phenyl, and C^alkyloxy; or a pharmaceutically acceptable addition sait or a solvatc thereof.
3. The compound according to claim l or a stereoisomeric form thereof, wherein A¹ is CR³ or N; wherein R³ is H, halo or Ci^alkyloxy;

A², A³ and A⁴ cach independently arc CH or N; provided that maximum two of A¹, A², A³ and A⁴ arc N;

Z² is CR⁴;

R⁴ⁿ is H; halo; cyano; cycloCi.₇alkyl; CMalkylcarbonyl; CMalkyloxycarbonyl; or Cj.

₄alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and amino;

R⁵ is H; halo; CMalkyloxy; C2.6alkenyl; or Ci-ealkyl optionally substituted with one or more Ci^alkyloxy substituents;

R⁶ⁿ is Ci-ealkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, CMalkyloxy, and tetrahydropyranyl;

-158cycloC^alkyl; CMalkylcarbonyl; tctrahydropyranyl; Ar; or R⁸R⁹N-carbonyl;

R^ûbis C2-ealkyl substituted with one or more halo substituents; Ci-ealkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, Ci^alkyloxy, tetrahydropyranyl, and cycloC3_7alkyl; cycloCj^alkyl; cycloCî^alkyl substituted with one phenyl optionally substituted with one or more halo substituents; unsubstituted pyrrolidinyl; NR^SR⁹; tetrahydropyranyl; Ar; or CHi-O-Ar; each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, CMalkyloxy, Ci .4alky 1, and C]uialkyl substituted with one or more halo substituents; oxazolyl optionally substituted with one or more Cualkyl substituents; or thienyl optionally substituted with one or more halo substituents; each R⁸ independently is Ci_4alkyl;

each R⁹ independently is Cnalkyl;

R⁷ is Ci«alkyl optionally substituted with one or more CMalkyloxy substituents; or a pharmaceutically acceptable addition sait or a solvaté thereof.
4. The compound according to claim 1 or a stereoisomeric form thereof, wherein Het¹ is a 5-membered aromatic heterocycle, having formula (a-1), (a-2), (a-3) or (a-4); R° is H or Ci^alkyl; R¹ is H or Ci^alkyl;

R² is Ci^alkyl;

X is O or S;

G¹ is CH;

G² is CH or C substituted with Ci^alkyl;

G³ is CH;

A¹ is CR³ or N; wherein R³ is H, halo or C|.₄alkyloxy;

A² is CI I or N;

A³ and A⁴ arc CH;

Het² is a 9-membcrcd bicyclic aromatic heterocycle, having formula (b-1) or (b-2); wherein Z¹ is CH or N; Z² is CR⁹; Z³ is CH; Y¹ is CI-I or N; Y² is CR⁴¹¹; Y³ is CH; R⁴ is H or halo;

R^4b is H, halo or Ci_₄alkyl optionally substituted with onc or more halo substituents; R⁵ is H, or Cj^alkyl;

R^û“ is Ar; or Ci^alky 1 optionally substituted with one Ar;

R^Gb is Ar; Cï-ealkyl substituted with one or more halo substituents; Ci.«alkyl optionally substituted with one or more Ar substituents; or Clh-O-Ar;

wherein each Ar independently is phenyl optionally substituted with one or more

- 159 substituents each independently selected from the group consisting of halo, Oalkyloxy, Ci-^alkyl, and C_Malkyl substituted with one or more halo substituents; R⁷ is C|.₆alkyl optionally substituted with one or more Oalkyloxy substituents; or a pharmaceutically acceptable addition sait or a solvaté thereof.
5. The compound according to claim l or a stereoisomeric form thereof, wherein Het' is a 5-mcmbered or 6-membered aromatic heterocycle, having formula (a-l) or (a-5);

R^u is H or Ciealkyl;

10 R¹ is H or C_Malkyl;

XisO;

R^IOa and R^l0b each independently arc hydrogen orCi^alkyl;

A¹ is CR'¹ or N; wherein R³ is Ci^alkyloxy;

A², A³ and A⁴ are CH;

15 Het² is a 9-membered bicyclic aromatic heterocycle, having formula (b-1 ) or (b-2); Z¹ and Z¹ are CH;

Z² is CR^4a; R^4a is H or halo; in particular halo; more in particular fluoro;

Y¹ and Y³ are CH;

Y² is CR⁴¹’; R⁴¹’ is H or Ci^alkyloxy; in particular H or methoxy;

20 R⁵ is H or methyl;

R⁶ⁿ isC^alkyl;

R^rth is phenyl optionally substituted with onc or more halo substituents;

R⁷ is Cj^alkyl;

or a pharmaceutically acceptable addition sait or a solvaté thereof..
6. The compound according to claim 5 wherein Het¹ has formula (a-1).
7. The compound according to claim 5 wherein Het² has formula (b-2).

30
8. The compound according to claim 1, wherein the compound is

2-(4-fluorophcnyl)-1-( 1 -mcthylcthyl)-Æ-[6-(2-mcthyl-5-oxazolyl)-3-pyridinyl]-1Hbenzimidazol-4-amine,

6-fluoro-?/-[3-methoxy-4-(4-mcthyl-5-oxazolyl)phcnyl]-2-(2-methylpropyl)imidazo[ 1,2-<3]pyridin-8-amine .HCl,

35 2-(4-fluorophenyl)-6-mcthoxy-/V-[3-methoxy-4-(2-methyl-5-oxazolyl)phenyl]-lmethyl-1 ZZ-benzimidazo 1-4-amine,

2-(4-fluorophenyl)-Af-[3-methoxy-4-(4-methyl-5-oxazoly!)phenyl]-l-methyl-l/716570 bcnzimidazol-4-aminc, or

2-(4“fluoiOphcnyl)-A''-[3-mc:thoxy-4-(2-mcth.y l-4-pyridinyl)phenyIJ-1 -( l -niethylethyl)l/f-bcnzimidazol-4-amine, including any stcrcochemically isomeric form thereof or a pharmaceutically acceptable 5 add it io n sa lt o r a so lvat e t hcreo f.
9. The compound according to claim l, wherein the compound is 2-(4-fluorophenyl)-l-(l-methylctliyl)-A^f-[6-(2-mcthyl-5-oxazo lyl)-3-pyridinyl]-l//benzimidazol-4-amine.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of a compound as defined in any onc of claims 1 to 9.

15
11. A compound as defined in any one of claims 1 to 9 for use as a médicament.
12. A compound as defined in any one of claims 1 to 9 for the treatment or prévention of a disease or condition selected from Alzhcimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia, dementia with Lcwy bodies, cérébral amyloid

20 angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with

Parkinson's disease and dementia associated with beta-amyloid.
13. The compound according to claim 12 wherein the disease is Alzheimer's disease.

25 14. Use of a compound as defined in any of claims 1 to 9 for the manufacture of a médicament for the modulation ofgamma-sccretasc activity.